SULFONE DERIVATIVES

Abstract

The present invention provides compounds of Formula I (see Formula) (I) wherein X1, X2, X3, X4, R1, R1a, R1b, R2', R2", R3', R3", R6, and R7 are as described herein, as well as their pharmaceutically acceptable salts. Furthermore, the present invention relates to the manufacture of compounds of Formula I, pharmaceutical compositions comprising them, and their use as medicaments.

Description

The present invention provides compounds that are inhibitors of human methionine adenosyltransferase 2A (Mat2A), for use in the treatment, prevention and / or delay of the progression of cancer. In particular, the present invention relates to compounds of Formula I CCfrQ Ln / Zznz / E / YIAI where X1is N or C X2es N or CR4 X3es N or CR5 X4 is N or CH provided that no more than two of X1, X2 and X3 represent N; the dashed lines represent a single or double bond, to enable six-membered rings to be aromatic with the proviso that when X1 is N and X2 is C=O then the bond between X1 and X2, the bond between X2 and single bonds and the bond between X3y CR7y b are double bonds; and with the condition that when X1 is N and X2 is not C=O then the link between X1 and R1es -SO2R1ao-SOR1b; R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Ca-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Cs), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Cs) , hydroxy-alkyl (Ci-Ce), alkoxy (Ci-Ce)alkyl (Oí-Ce), NR1aR1b, oxetanyl, furanyl and pyranyl, where at least one of R1a and R1 is alkyl (Ci-Ce) and the other is H or alkyl (Oí-Ce); either R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (CrCe), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R2” is hydrogen, halogen, -NH2, alkyl (Ci-Cs), alkoxy (Oí-Ce), halo-alkyl (Ci-Cs) or halo-alkoxy (Ci-C6); R3' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (CrCe), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3” is hydrogen, halogen, -NH2, alkyl (Ci-Cs), alkoxy (Oí-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R4is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, alkyl (Ci-Cs), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), alkoxy (Ci- CeJ-alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, -SO(NR4h) R4a or -SO2(NR4i)R4¡; R4a, R4b and R4c are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (C3-C6), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4d, R4e and R4f are independently selected from hydrogen, alkyl (Ct-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4h and R4g are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4i and R4¡ are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R5 is hydrogen, halogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); R6is halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxetanyl or thiophenyl or -SO2R6a ; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7aR7b, where one of R7a and R7bes hydrogen and the another is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce), alkyl (Ci-Ce)- O-alkyl (Ci-Ce)-NH2, alkyl (Ci-Ce)-NHCO-alkyl (Ci-C6) or alkyl (Ci-Ce)-NH2; and its pharmaceutically acceptable salts. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as customarily given to them by a person of the intermediate level trade to which this invention belongs. Although methods and materials similar or equivalent to those described herein may be used in the practice or evaluation of the invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The nomenclature used in this application is based on the IUPAC systematic nomenclature, unless otherwise indicated. Any open valence appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures described herein indicates the presence of a hydrogen atom, unless otherwise indicated. “halo” or “halogen” denotes fluorine, chlorine, bromine or iodine, particularly chlorine or fluorine. CCfrQ Ln / Zznz / E / YIAI “hydroxy” refers to an -OH group. “alkyl (Ci-Cs)” refers to a linear or branched hydrocarbon chain of one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t -butyl, pentyl and hexyl. “alkoxy (Ci-Ce)” denotes a Formula -ORa moiety, where Ra is an alkyl moiety (Ci-Ce) as defined herein. Example alkoxy moieties (Ci-Ce) include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. The term “cycloalkyl (Cs-Ce)” indicates a saturated monocyclic monovalent hydrocarbon group of the 3 to 6 carbon atoms of the ring. Examples of monocyclic cycloalkyl (Cs-Ce) are cyclopropyl, cyclobutanyl, cyclopentyl or cyclohexyl. A particular example of cycloalkyl (Cs-Ce) is cyclopropyl. “cycloalkyl (Ca-Cej-alkyl (Ci-Ce)” refers to an alkyl (Ci-Ce), as defined above, substituted with one or more cycloalkyl groups (Ca-Ce), particularly with a cycloalkyl group (Ca -EC). CCfrQ Ln / Zznz / E / YIAI More particularly "cycloalkyl (Cs-Cej-alkyl (Ci-Ce) refers to or The term perhalo-alkyl (C1-C3) denotes an alkyl group (C1-C3) as defined above, where all hydrogen atoms have been replaced with halogen atoms. More particularly "perhalo(C1-C3)alkyl" is perfluoro(C1-C3)alkyl, most preferably trifluoromethyl. “Halo-alkyl (Oí-Ce)” refers to an alkyl (Ci-Ce), as defined above, substituted with one or more halogen atoms, particularly with one to three halogen atoms. More particularly halo-alkyl (Oí-Ce) is chloro- and fluoro-alkyl (Ci-Ce). In some particular embodiments halo-alkyl (Ci-Ce) refers to perhalo-alkyl (C1-C3) as defined herein. More particularly halo-alkyl (Ci-Ce) is trifluoromethyl, difluoromethyl or fluoromethyl. “Halo-alkoxy (Ci-Ce)” refers to an alkoxy (Ci-Ce), as defined above, substituted with one or more halogen atoms, particularly with one to three halogen atoms. More particularly halo-alkoxy (Ci-Ce) is chloro- and fluoro-alkoxy (Ci-Ce). In some particular embodiments halo-alkoxy (Ci-Ce) refers to perhalo-alkoxy (C1-C3), such as trifluoromethoxy or difluoromethoxy. “Hydroxy-alkyl (Ci-Ce)” refers to an alkyl (O-Ce), as defined above, substituted with one or more hydroxy groups, particularly with a hydroxy group. More particularly hydroxy-alkyl (Ci-Ce) refers to methyl hydroxide or ethyl hydroxide. “alkoxy (Ci-Cs)-alkyl (Oí-Ce)” refers to an alkyl (Ci-Ce), as defined above, substituted with one or more alkoxy groups (Ci-Ce) as defined herein, particularly with an alkoxy group (Ci-Ce). More particularly alkoxy (Ci-Cej-alkyl (Ci-Ce) refers to -CH2-O-CH3 or -CH2CH2-O-CH3. "halo-alkoxy (Ci-Ce)" refers to an alkoxy, as defined above, substituted with one or more halogen atoms, particularly with one to three halogen atoms. More particularly haloalkoxy (Ci-Ce) are chloro- and fluoro-alkoxy (Ci-Ce). “Heteroaryl” denotes a monovalent monocyclic or bicyclic portion of the 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), the remaining atoms of the ring are C, it being understood that the attachment point of the heteroaryl moiety will be in 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, benzofuranzyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzoisoxazolyl or benzothienyl, imidazo[1,2-a]-pyridyl, imidazo[2,1-b]thiazolyl, and Their derivatives. "N-heteroaryl" in particular refers to heteroaryl as previously defined containing at least one nitrogen atom. The point of attachment of the N-heteroaryl portion of the molecule can be through the nitrogen or a carbon ring atom. Examples of N-heteroaryl are pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl. The term “heterocycloalkyl” or “heterocyclic” indicates a monovalent saturated or partially unsaturated mono- or bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. , where the remaining ring atoms are carbon. Examples of heterocycloalkyl are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolane, 1,1-dioxothiomorpholin-4-yl, azepanyl, diaze panyl, homopiperazinyl or oxazepanil. More particularly heterocycloalkyl refers to dihydrofuryl, 1,3-dioxolyl, dihydropyrryl, dihydrothiophil, dihydropyrazolyl, dihydroisoxazolyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 3,4-dihydro-2H-1,4oxazinyl, 3,4-dihydro-2H- 1,4-thiazil, 1,2,3,4-tetrahydropyrazil. The term “therapeutically effective amount” indicates an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition, or disorder, (i) attenuates, relieves or eliminates one or more symptoms of the particular disease, condition or disorder, or (iii) prevents or delays the occurrence of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease being treated, the severity of the disease being treated, the age and relative health of the subject, the route and manner of administration, the judgment of the clinician or veterinarian, and others. factors. The term “optional” or “optionally” denotes that a subsequently described event or circumstance may but must not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, aryl group optionally substituted with an alkyl group denotes that alkyl may be present, but is not necessary, and the CCfrQ Ln / Zznz / E / YIAI description includes situations where the aryl group is substituted with an alkyl group and situations where the aryl group is not substituted with the 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., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). ). In some embodiments, the individual or subject is a human being. The terms "compound(s) of this invention" and "compound(s) of the present invention" refer to compounds as described herein and their stereoisomers, tautomers, solvates and salts (e.g., commercially acceptable salts). from a pharmaceutical point of view). Where the compounds of the invention are solids, those skilled in the art will understand that these compounds, and their solvates and salts, may exist in different solid forms, particularly different crystalline forms, all of which are intended to be within the scope of the present invention and specified formulas. The term “pharmaceutically acceptable salts” indicates salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acidic and basic addition salts. The term “pharmaceutically acceptable acid addition salt” indicates those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and acids. organics selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, acid maleic, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. The term “pharmaceutically acceptable basic addition salt” indicates those pharmaceutically acceptable salts formed with 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 organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine resins, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, Usine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N- ethylpiperidine and polyamine. The term “active pharmaceutical ingredient” (or “API”) denotes the compound or molecule in a pharmaceutical composition that has a particular biological activity. CCfrQ Ln / Zznz / E / YIAI The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients for administration to a mammal, for example, a human who needs it. The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” may be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition. that has no therapeutic activity and is not toxic to the subject to whom it is administered, such as disintegrants, binders, filling agents, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in the formulation of pharmaceutical products. The terms “treat” or “treatment” of a disease include inhibiting the disease, that is, stopping the development of the disease or its clinical symptoms, or alleviating the disease, that is, causing a temporary or permanent regression of the disease or its symptoms. clinical symptoms. Compounds that have the same molecular formula but differ in the nature or sequence of the bonds of their atoms or the arrangement of their atoms in space are called “isomers.” Isomers that differ in the arrangement of their atoms in space are called “stereoisomers.” 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 bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S- priority rules of Cahn, Ingold and Prelog, or according to the way in which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomer, respectively). A chiral compound can exist as an individual enantiomer or as their mixtures. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.” Compounds of Formula I may have one or more asymmetric centers or axes. Unless otherwise indicated, the description or name of a particular compound in the specification and claims is intended to include both individual enantiomers, atropisomers and their mixtures, racemic or otherwise, as well as individual epimers, atropisomers and their mixtures. The method for determination of stoichiometry and separation of stereoisomers are well known in the art (see discussion in Chapter 4 of Advanced Organic Chemistry, 4th edition J. March, John Wiley and Sons, New York, 1992). Certain compounds can exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototrophic tautomers form from the migration between two atoms of a covalently bonded hydrogen atom. Tautomers generally exist in equilibrium and usually when attempting to isolate an individual tautomer there is a CCfrQ Ln / Zznz / E / YIAI mixture whose chemical and physical properties are consistent with those of a mixture of compounds. The equilibrium position depends on intrinsic chemical characteristics of 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 prototrophic tautomers include keto / enol (-C(=O)-CH- θ -C(-OH)=CH-), amide / imidic acid tautomers (-C(=O)-NH- θ -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. The present compounds of Formula I were recently found to be inhibitors of Mat2A and as such may be of therapeutic use for the treatment of cancer-related disorders including lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme and mesothelioma. These compounds are potent inhibitors of human methionine adenosyltransferase II alpha (MAT2A). MAT2A and MAT1A (methionine adenosyltransferase I alpha) are two genes that encode methionine adenosyltransferase activity that thus produce S-adenosylmethionine (SAM), the main donor of the methyl group in cells. MAT1A is a liver-specific SAM-producing enzyme, while MAT2A is ubiquitously expressed 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, when bound to MAT2B, is more active under conditions of low methionine concentrations, but is inhibited under conditions of high methionine concentrations. Loss-of-function mutations in tumor suppressor genes are critical in the pathogenesis of cancer, however, targeting tumor suppressor genes successfully has been difficult to achieve mainly because the mutated proteins cannot be directly inhibited. to achieve therapeutic benefit, and restoration of mutated function (such as restoration of function of p53 mutation) has not been possible so far. The recent clinical success of inhibiting PARP in BRCA1 / 2-deficient patients showed that targeting conditional synthetic lethality (CSL) arising from loss-of-function mutations in tumor suppressors is a valid clinical approach for the treatment of cancers. The CSL relationship is not only valid for tumor suppressors but can also be extended to genes that reside in the same genetic region as tumor suppressor genes and are lost when that region is deleted. Methylthioadenosine phosphorylase (MTAP) is one such gene that is located in the vicinity of the tumor suppressor CDKN2A, and is deleted in ~15% of all cancers. MTAP is deleted in, but not limited to, ~53% glioblastoma multiforme (GBM), ~25% pancreatic adenocarcinoma (PDAC), ~25% melanoma, ~23% lung squamous cell carcinoma, ~20% of head and neck squamous cell carcinoma, and ~15% of lung adenocarcinoma. In fact, this deletion occurs for multiple conditions, many of which are areas in great need for medical solutions with CCfrQ Ln / Zznz / E / YIAI limited effective therapies. In glioblastoma, where the median survival is 14 months, the approval of newer therapies has not significantly increased overall survival (OS) time and the standard of care (SoC) has remained for more than one of each. The same is true for most PDAC patients where OS is less than 1 year. MTAP deletion is a stem event that occurs in early stages of tumor development and could be carried during all tumor evolution processes including metastasis. Therefore, its loss represents an alteration that is not affected due to tumor heterogeneity, genetic background, or resistance to any agent approved in clinical science. A CSL relationship that is identified for MTAP deficiency could represent a true Achilles' heel for multiple tumor-related conditions. MTAP is located very close to the tumor suppressor CDKN2A on chromosome 9. When CDKN2A is deleted, it is frequently deleted along with MTAP. Its loss is thought to be a neighborhood effect and phenotypically neutral. MTAP is the cornerstone of the adenine and methionine salvage pathways in cells. The methionine salvage pathway feeds the SAM production pathway and SAM levels are essential regulators of cancer cell growth that need to be strictly regulated since large changes in SAM concentrations, whether increases or decreases, lead to to cell cycle arrest. The importance of SAM levels in cancer growth lies in its central role in the methylation of proteins, DNA, and RNA, as it acts as a checkpoint for the health of the cell, and can be interpreted as hypomethylation when SAM decreases. or hypermethylation when SAM increases. Cells lacking MTAP accumulate methylthioadenosine (MTA) and decarboxylated SAM (dcSAM) without negatively affecting the levels of any metabolites / salvage products including SAM. This accumulation creates a new stress in the cell where MTA acts as a competitive inhibitor of SAM-dependent reactions, due to their structural similarity. Loss of MTAP forces the cell to adapt to a new MTA / SAM paradigm without loss of viability, which an MTAP-competent cell would not have to face, and this adaptation creates a robust dependence on methionine adenosyltransferase II alpha 2 (MAT2A). ), one of the enzymes that produces SAM, in MTAP-deficient cells. This synthetic conditional lethal (CSL) relationship of 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 inhibition by a small molecule could provide benefits to a genetically defined patient population, representing many areas in great need for medical solutions. The objects of the present invention are compounds of Formula I and the use of such compounds for the preparation of medicaments for the treatment, prevention and / or delay of the progression of cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, cell carcinoma. squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, carcinoma of the esophagus, glioblastoma multiforme, and mesothelioma, more particularly for the treatment of cancer CCfrQ Ln / Zznz / E / YIAI including lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme, and squamous cell carcinoma of the head and neck, their manufacture and medicaments based on compounds of Formula I according to the invention. Other objects of the present invention are all forms of optically pure enantiomers, racemates of diastereomeric mixtures or compounds of Formula I. In particular, the present invention relates to compounds of Formula CCfrQ Ln / Zznz / E / YIAI (the) where X1is N or C; X3is N or CR5the dotted line represents a double bond to enable the six-membered ring to be aromatic with the proviso that when R1es -S02R1ao-SOR1b; R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Ca-Ce), cycloalkyl (Ca-Cej-alkyl (Ci-Cb), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Cb), hydroxy-alkyl (C-i-Cb), alkoxy (Ci-Cb)alkyl (Ci-Cb), NR1aR1b, oxetanyl, furanyl and pyranyl, where at least one of R1a and R1bes alkyl (Ci-Cb) and the other is H or alkyl (Ci-Cb); or R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Cb), halo-alkyl (Ci-Cb) or halo-alkoxy (Ci-Ce); R2” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3' is hydrogen, halogen, -NH2, alkyl (O-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Cb) or halo-alkoxy (Ci-C6); R3” is hydrogen, halogen, -NH2, alkyl (Ci-Cb), alkoxy (CrCe), halo-alkyl (CrCe) or halo-alkoxy (Ci-C6); R4is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), alkoxy (Ci- C6)-alkyl (Ci-Cb), cycloalkyl (Cs-Ce), cycloalkyl (Ca-Cej-alkyl (Ci-C6), -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, -SO(NR4h) R4s or -SO2(NR4i)R4i; R4a, R4b and R4c are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4d, R4e and R4' are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4h and R4a are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4i and R4¡ are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R5 is hydrogen, halogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); R6is halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxetanyl or thiophenyl or -SO2R6a ; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7aR7b, where one of R7a and R7bes hydrogen and the another is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce), alkyl (Ci-C6)- O-alkyl (Ci-Ce)-NH2, alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce) or alkyl (Ci-C6)-NH2; and its pharmaceutically acceptable salts. In particular, the present invention relates to compounds of Formula Ib CCfrQ Ln / Zznz / E / YIAI (Ib) where X3es N or CR5 R1es -S02R1ao-SOR1b; R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) , hydroxy-alkyl (Ci-Ce), alkoxy (Ci-Ce)alkyl (Ci-Ce), NR1aR1b, oxetanyl, furanyl and pyranyl, where at least one of R1a and R1 is alkyl (Ci-Ce) and the other is H or alkyl (Ci-Ce); either R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (CrCe), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R2” is hydrogen, halogen, -NH2, alkyl (Ci-Cs), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (C1-C6); R3” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Cs) or halo-alkoxy (Ci-C6); R4is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Cs), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), alkoxy (Ci- CeJ-alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-CeJ-alkyl (Ci-Ce), -CO2R4a, -CONR4bR4c, -SO2R4b, -SOR4e, -SR4f, -SO(NR4h)R49 or -SO2(NR4i)R4i; R4a, R4b and R4c are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4d, R4e and R4f are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4h and R49 are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4i and R4¡ are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R5 is hydrogen, halogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); R6is halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxetanyl or thiophenyl or -SO2R6a ; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7aR7b, where one of R7a and R7bes hydrogen and the another is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce), alkyl (Ci-C6)- O-alkyl (Ci-Ce)-NH2, alkyl (Ci-CeJ-NHCO-alkyl (Ci-Ce) or alkyl (Ci-Ce)-NH2; and its pharmaceutically acceptable salts. In another embodiment, the present invention relates to compounds of Formula le CCfrQ Ln / Zznz / E / YIAI CCfrQ Ln / Zznz / E / YIAI (le) where R1es -S02R1ao-SOR1b; R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (C-i-Ce) , hydroxy-alkyl (Ci-Ce), alkoxy (Ci-Ce)alkyl (Ci-Ce), NR1aR1b, oxetanyl, furanyl and pyranyl, where at least one of R1a and R1bes alkyl (Ci-Ce) and the other is H or alkyl (Ci-Ce); either R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R2 is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Cs) or halo-alkoxy (Ci-C6); R3 is hydrogen, halogen, -NH2, alkyl (Oí-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R5 is hydrogen, halogen, alkyl (Ci-Ce), cycloalkyl (Ca-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); R6is halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxetanyl or thiophenyl or -SO2R6a ; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7aR7b, where one of R7a and R7bes hydrogen and the another is hydrogen, alkyl (Oí-Ce), alkoxy (Ci-Ce), alkyl (Ci-CeJ-O-alkyl (Ci-CeJ-NHCO-alkyl (Ci-Ce), alkyl (Ci-Cej-O-alkyl (Ci-C6)-NH2, alkyl (Ci-C6)-NHCO-alkyl (Ci-Ce) or alkyl (Ci-Ce)-NH2; and their pharmaceutically acceptable salts. In another embodiment, the present invention provides a compound of Formula Id: CCfrQ Ln / Zznz / E / YIAI (Id) where R1es -S02R1ao-SOR1b; R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Ca-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (C-i-Ce) , hydroxy-alkyl (Ci-Ce), alkoxy (Ci-Ce)alkyl (Ci-Ce), NR1aR1b, oxetanyl, furanyl and pyranyl, where at least one of R1a and R1bes alkyl (Ci-Ce) and the other is H or alkyl (Ci-Ce); either R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R2 is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Cs) or halo-alkoxy (Ci-C6); R3 is hydrogen, halogen, -NH2, alkyl (Oí-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R4is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), alkoxy (O- CeJ-alkyl (Ci-Ce), cycloalkyl (Ca-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), -CO2R4a, -CONR4bR4c, -SOaR4d, -SOR4e, -SR4f, -SO(NR4h) R49 or -SO2(NR4i)R4¡; R4a, R4b and R4c are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Ca-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4d, R4e and R4' are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Ca-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4h and R4a are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Ca-Ce), cycloalkyl (Cs-CeJ-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4i and R4¡ are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Ca-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R5 is hydrogen, halogen, alkyl (Ci-Ce), cycloalkyl (Ca-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); R6es are halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxetanyl or thiophenyl or -SÜ2R6a ; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7aR7b, where one of R7a and R7bes hydrogen and the another is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce), alkyl (Ci-Ce)- O-alkyl (Ci-Ce)-NH2, alkyl (Ci-C6)-NHCO-alkyl (Ci-Ce) or alkyl (Ci-Ce)-NH2; and its pharmaceutically acceptable salts. In another embodiment, the present invention relates to a compound of Formula le CCfrQ Ln / Zznz / E / YIAI R1 (him) where R1es -S02R1ao-SOR1b; R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce). Ce), hydroxy-alkyl (Ci-Ce), alkoxy (Ci-Ce)alkyl (Ci-Ce), NR1aR1b, oxetanyl, furanyl and pyranyl, where at least one of R1a and R1 is alkyl (Ci-Ce) and the other is H or alkyl (Ci-Ce); either R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R2” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3 is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R4is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), alkoxy (Ci- Ce)-alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce)-alkyl (Ci-C6), -CO2R4a, -CONR4bR4c, -SO2R4d, -SR4f, -SO(NR4h) R4a or -SO2(NR4i)R4i; R4a, R4b and R4c are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4d, R4e and R4' are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4h and R4a are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R4i and R4¡ are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl; R6is halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxetanyl or thiophenyl or -SO2R6a ; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7aR7b, where one of R7a and R7bes hydrogen and the another is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce), alkyl (Ci-Ce)- O-alkyl (Ci-Ce)-NH2, alkyl (Ci-CeJ-NHCO-alkyl (Ci-Ce) or alkyl (Ci-Ce)-NH2; and their pharmaceutically acceptable salts. Furthermore, it should be understood that any embodiment that refers to a X1, X2, X3, , R4e, R4f, R4h, R49, R4i, R4¡, R5, R6, R6a, R7, R7a and R7b as described herein, can be combined with any other embodiment that refers to another X1, X2, X3, R1, R1a , R1b, R1a, R1'jib, R2', R2”, R3', R3”, R4, R4a, R4b, R4c, R4d, R4e, R4f, R4h, R4a, R4', R4¡, R5, R6, R6a ; R7, R7a and R7b as described herein. A particular embodiment of the present invention relates to a compound of Formula I, wherein X4 is N. A particular 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 particular embodiment of the present invention relates to a compound of Formula I, wherein X1 is C. A particular embodiment of the present invention relates to a compound of Formula I, wherein X2 is CR4. A particular embodiment of the present invention relates to a compound of Formula I, wherein X3 is N. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, le, Id or le wherein R1 is -SO2R1a. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, le, Id or le wherein R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3- Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), hydroxy-alkyl (Ci-Ce), alkoxy (Ci-Ce)-alkyl (Ci-Ce) , NR1aR1b, oxetanyl, furanyl and pyranyl, where at least one of R1a and R1bes is alkyl (Ci-Ce) and the other is H or alkyl (Ci-Ce), particularly where R1ase selects from alkyl CCfrQ Ln / Zznz / E / YIAI (C1-C3), cycloalkyl (C3-C4), cycloalkyl (C3-C4)-alkyl (C1-C3), halo-alkyl (C1-C3), hydroxy-alkyl (C1- C3), alkoxy (Ci-C3)-alkyl (C1-C3), NR1'aR1b and oxetanyl, where at least one of R1a and R1bes alkyl (C1-C3) and the other is H or alkyl (C1-C3), more particularly where R1ase selects from methyl, CCfrQ Ln / Zznz / E / YIAI ethyl, propyl, i-propyl, i-butyl, cyclopropyl, , ., fluoromethyl, difluoromethyl, fluoro-ethanyl, difluoro-ethanyl, 1,2-difluoroethanenyl, 1,1,2-trifluoroethanenyl, 1,2,2-trifluoroethanenyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methylaminyl (-NHCH3), dimethylaminyl (-N(CH3)2) and oxetanyl, even more particularly wherein R1ase selects from ethyl, propyl, i-propyl, i-butyl, cyclopropyl, fluoromethyl, difluoromethyl, fluoro-ethanyl, difluoro-ethanyl, 1,2-difluoroethanyl, 1,1,2-trifluoroethanyl and 1,2,2-trifluoroethanyl, with the greatest particularity where R1ase selects from methyl, ethyl, cyclopropyl and difluoromethyl. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, le, Id or le wherein R1bes alkyl (Ci-Cs), more particularly is alkyl (C1-C3), with the greatest particularity methyl . A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, le, Id or le if R2' is other than hydrogen as defined herein, then R3' is hydrogen, R2" is hydrogen and R3” is as defined herein and vice versa 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, la, Ib, le, Id or le wherein one of R2 and R2" is hydrogen, halogen, -NH2, alkyl (C1-C2), alkoxy (C1 -C2) or haloalkyl (C1-C2), while the other is hydrogen, particularly where R2' is hydrogen, halogen, -NH2, methyl, ethyl, methoxy fluoromethyl, difluoromethyl, fluoro-ethanyl, difluoro-ethanyl or 1, 2 difluoroethanyl, and R2 is hydrogen, R2' is methyl, ethyl, fluoromethyl, difluoromethyl, fluoro-ethanyl, difluoro-ethanyl, 1,2 difluoroethanyl, and R2' is hydrogen, more particularly R2' is methyl or difluoromethyl and R2" is hydrogen. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, le, Id or le wherein one of R3' and R3" is hydrogen, halogen, -NH2, alkyl (C1-C3), alkoxy ( Ci-C3) or haloalkyl (C1-C3), while the other is hydrogen, more particularly R3" is hydrogen, halogen or alkyl (C1-C3) and R3' is hydrogen, even more particularly R3 is hydrogen or fluorine and R3' is hydrogen, with the greatest particularity both R3' and R3” are hydrogen. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, Id or le wherein R4 is cyano, oxo, hydroxy, alkyl (C1-C3), alkoxy (C1-C3), halo-alkyl ( C1-C3), halo-alkoxy (Ci-C6), alkoxy (Ci-C3)-alkyl (C1-C3), cycloalkyl (C3-C4), -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, -SO(NR4h)R49 or -SO2(NR4i)R4¡, particularly where R4 is cyano, oxo, hydroxy, alkoxy (C1-C2), haloalkyl (C1-C2), halo-alkoxy (C1-C2), alkoxy ( Ci-C2)-alkyl (C1-C2), cyclopropyl, -CO2H, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, or -SO(NH)CH3 particularly where R4 is cyano, oxo, hydroxy, methoxy, -CF3 , -OCF3, -methyl-methoxy, cyclopropyl, -CO2H, -CONR4bR4c, -SO2R4d, -SOR4e 0-SR4f, with the greatest particularity R4is cyano, oxo, -CONHR4co -SO2R4d. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, Id or le wherein R4a, R4b and R4c, are independently selected from hydrogen, alkyl (C1-C3), cycloalkyl (C3-C4), and oxetanyl, particularly wherein R4a, R4b and R4c are independently selected from hydrogen, (C1-C3) alkyl, cyclopropyl, and oxetanyl, more particularly R4a, R4b and R4c are independently selected from hydrogen, (C1-C3) alkyl and cyclopropyl, with the greatest particularity R4a and R4b are hydrogen, R4ces hydrogen or methyl. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, Id or le wherein R4d, R4e and R4f are independently selected from (C1-C3)alkyl, (C3-C4)cycloalkyl, and oxetanyl, particularly wherein R4d, R4e and R4f are independently selected from (C1-C3) alkyl, cyclopropyl, and oxetanyl, more particularly R4d, R4e and R4f are independently selected from (C1-C3) alkyl and cyclopropyl, most particularly R4des methyl or cyclopropyl. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, Id or le wherein R4h and R49 are independently selected from hydrogen and alkyl (Ci-Ce), particularly hydrogen and alkyl (C1-C3), more particularly where R4hes hydrogen and R4ges alkyl (C1-C3), with the greatest particularity where R4hes hydrogen and R4ges methyl. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, Id or le wherein R4i and R4¡ are independently selected from hydrogen and alkyl (Ci-Ce), particularly hydrogen and alkyl (C1-C3) , more particularly where R4 is hydrogen and R4' is (C1-C3) alkyl, with the greatest particularity where R4 is hydrogen and R49 is methyl. A particular embodiment of the present invention relates to a compound of formula I, la, Ib, le or Id where R5 is hydrogen, halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce) or cycloalkyl (Cs-Ce) , particularly R5 is hydrogen, halogen, (C1-C2) alkyl, (C1-C2) alkoxy or (C3-C4) cycloalkyl, more particularly R5 is hydrogen, fluorine, chlorine, cyclopropyl, methyl or methoxy, with most particularity R5 is hydrogen. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, le, Id or le wherein R6 is halogen, alkyl (Ci-Ce), alkoxy (Ci-Cb), cyano, halo-alkyl ( Ci-Ce), halo-alkoxy (Oí-Ce), cycloalkyl (Cs-Ce), thiophenyl, oxetanyl or -SOsR63, where R6a is alkyl (Ci-Ce), particularly R6 is bromo, alkyl (C1-C3), alkoxy (C1-C3), cyano, halo-alkyl (C1-C3), halo-alkoxy (C1-C3), cycloalkyl (C3-C4), thiophenyl, oxetanyl or -SOsR63, where R6a is alkyl (Ci-Ce), particularly R6 is halo-alkyl (C1-C3), halo-alkoxy (C1-C3) or cycloalkyl (C3-C4), more particularly R6 is trifluoromethyl, trifluoromethoxy, difluoromethoxy or cyclopropyl. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, le, Id or le wherein R6a is alkyl (Ci-Ce), more particularly R6a is methyl. A particular embodiment of the present invention relates to a compound of Formula I, la, Ib, le, Id or le wherein R7 is hydrogen, halogen, hydroxy or alkyl (Ci-Ce), particularly 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, la, Ib, le, Id or le wherein one of R7a and R7bes hydrogen and the other is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce ), CCfrQ Ln / Zznz / E / YIAI alkyl (Ci-C3)-O-alkyl (Ci-C3)-NHCO-alkyl (C1-C3), alkyl (Ci-C3)O-alkyl (Ci-CsJ-NHs, alkyl (C1-C3)NHCO-alkyl (C1-C3) or alkyl (Ci-CsJ-NHs, in particular where one of R7a and R7 is hydrogen and the other is hydrogen, alkyl (Ci-Ce), or alkoxy (Ci- Ce), more particularly wherein one of R7a and R7bes hydrogen and the other is hydrogen, alkyl (C1-C3), or alkoxy (C1-C3). The particular compounds of Formula I of the present invention are those selected from the group consisting of: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methoxy-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(methylsulfonyl)phenyl)-3-cyclopropyl-1 H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(4-(methylsuifonyl)-3-(trifluoromethyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 4-(3-cyclopropyl-1 H-pyrazolo[4,3-c]pyridin-4-yl)-N,N,2-trimethylbenzenesulfonamide; 3-cyclopropyl-5-methoxy-4-(4-methylsulfonylphenyl)-1 H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(4-(cyclopropylsulfonyl)-3-methylphenyl)-1 H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(cyclopropylsulfonyl)phenyl)-3-cyclopropyl-1 H-pyrazolo[4,3-c]pyridine; 2-chloro-4-(3-cyclopropyl-1 H-pyrazolo[4,3-c]pyr¡din-4-¡l)-N,N-dimethylbenzenesulfonamide; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazolo[3,4-b]pyridine; 4-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-1 H-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-(methylsulfon¡l)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrrolo[3,2-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 5-(3-cyclopropyl-1 H-prázolo[4,3-c]pyridín-4-íl)-2-(methylsulfoníl)aníline; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1 H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(1,1-difluoroethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methylsuifoni l)phenyl)-1 H-pyrazolo[4,3-c]pyridine-3-carbonitrile; 3-(difluoromethyl)-4-(3-methyl-4-methylsulfonylphenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-isopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1 H-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)-1 H-pyrazolo[4,3-c]pyridine hydrochloride; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxylic acid 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1 H-indazole-5-carbonitrile; 3-cyclopropyl-4-(3-methyl-4-methylsulfinyl-phenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridin-7-ol CCfrQ Ln / Zznz / E / YIAI 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1 H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-5-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine; 3-ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1 H-pyrazolo[4,3-c]pyridine; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1 H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(4-ethylsulfonyl-3-methyl-phenyl)-1 H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-methylsulfoníl-pheníl)-3-(oxetan-3-íl)-1 H-pyrazolo[4,3-c]pyrádine; 4-[4-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-3-(difluoromethoxy)-1 H-pyrazolo[4,3-c]pyr dna; 3-(difluoromethoxy)-4-(3-methyl-4-propylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-1 H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(4-isopropylsulfonyl-3-methyl-phenyl)-1 H-pyrazolo[4,3-c]pyridine; 4-[3-(difluoromethox¡)-1 H-prázolo[4,3-c]pyr¡din-4-¡l]-N,2-dimethyl-benzenesulfonamide; 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-indazol-5-carbonitrile; 3-(difluoromethoxy¡)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-indazole-5-carbonitrile; 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[3-methyl-4-(oxetan-3-lsulfonyl)phenyl]-1H-pyrazolo[4,3-c]pyridine; 2-[4-[3-(difluoromethoxy¡)-1 H-pyrazolo[4,3-c]pyri¡din-4-¡l]-2-methyl-phen¡l]sulfon¡lethanol acid 3-Cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1Hpyrazolo[4,3-c]pyridine 2,2,2-trifluoroacetic acid; 3-(difluoromethoxy)-4-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1 H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1 H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-d]pyridazine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1 H-indazole; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfinyl)-1 H-indazole; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1 H-indazole; 3-(difluoromethoxy¡)-4-[4-(methoxymethylsulfon¡l)-3-methyl-phen¡l]-1 H-pyrazolo[4,3c]pyridine formic acid; 5-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazolo[3,4-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridine; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-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)-1 H-pyrazolo[4,3-b]pyridin-5-one; 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pindine; 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; CCfrQ Ln / Zznz / E / YIAI 3-cyclopropyl-5-(methoxymethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5carboxamide ; 3,5-dicyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1 H-pyrazolo[3,4-c]pyridine; N,3-dicyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-indazole-5-carbonitrile; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-1 H-pyrazolo[3,4-c]pyridina-5-carbonítrilo; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1 H-indazole 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1 H-indole-5-carbonitrile; 3-c¡c¡cloprop¡l-4-(4-c¡cloprop¡lsulfon¡l-3-methyl-phenyl)-N-methyl-1 H-pyrazolo[3,4-c]p¡r dina-5-carboxamide; 3-cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-indazole-5-carboxamide; 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-indazole-5-carboxamide; 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1 #H l-indazole-5-carbonitrile; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carbonitrate; 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(tnfluoromethoxy)-1 H-pyrazolo[4,3-b]pyridín-5-one; 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrrolo[3,2-b]pyridin-5-one; 4-[3-(difluoromethoxy¡)-1 H-pyrazolo[4,3-c]pyridin-4-¡l]-2-(difluoromethyl)-N,N-dimethylbenzenesulfonamide; 3-(difluoromethoxy¡)-4-(3-methyl¡l-4-(methylsulfon¡l)phen¡l)-5-(methylsulfonyl)-1 H-indazole; 3-cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1 H-pyrazolo[3,4-c]pyridine-5-carbonitrilo; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1 H-indazole; 3-cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1 H-pyrazolo[3,4-c]pyridine-5carboxamide; 3-(difluoromethoxy¡)-4-(3-methyl¡l-4-methylsulfon¡l-phen¡l)-1 H-pyrazolo[3,4-c]pyrid¡ne-5-carbon¡ trilo; 3-(difluoromethoxy)-4-[5-(difluoromethyl)-2-methyl-4-methylsulfinyl-phenyl]-1 H-plrazolo[3,4-c]pindine-5carbonitrile; 4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-5-methoxy-3-(trifluoromethyl)-1 H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfon 11)-1 H-indazole; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1 H-pyrazolo[3,4-c]pyridine-5carboxamide; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-5-methylsulfonyl-1 H-indazole; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-N-nnethyl-1 H-pyrazolo[3,4-c]pyridine-5carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1 H-pyrazolo[3,4-c]pyridine-5CCfrQ Ln / Zznz / E / YIAI carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfoníl)-3-methyl-phenyl]-N-(oxetan-3-íl)-1 H-pyrazolo[3,4c] pyridine-5-carboxymide; 3-(difluoromethoxy)-4-[4-(difluoromethylsuIfonyl)-3-methyl-phenyl]-N-methyl-1 H-pyrazolo[3,4-c]pyridine-5carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(2-methoxyethyl)-1 H-pyrazolo[3,4c]pyridine-5-carboxamide; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1 H-indazole; [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1 H-indazol-5-yl]-amino-methyl-oxo-sulfane; [3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-indazol-5-yl]-methyl-methylimino-oxo-A6-sulfane; 3-cyclopropyl-N, N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-indazole-5-sulfonamide; 3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-indazole-5-sulfonamide; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-5-(methylsulfonyl)-1 H-indazole; 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-indazole; 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1 H-indazole; either 4-(4-cyclopropylsulfoníl-3-methyl-pheníl)-3-(difluoromethoxy)-N-methyl-1 H-pyrazolo[3,4-c]pyridine-5carboxamide and its commercially acceptable salts pharmaceutical view. The particular compounds of Formula I of the present invention are those selected from the group consisting of: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-indazole-5-carbonitrile; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carbon trilo; 4-(3-methyl-4-(methylsulfoníl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1 H-indazole; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1 H-indazole; 3-cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methyl l-phenyl]-1 H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methylsulfonyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1 H-indazole; 3-cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1 H-pyrazolo[3,4-c]pyridine-5carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; either 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1 H-pyrazolo[3,4-c]pyridine-5carboxamide and its pharmaceutically acceptable salts. CCfrQ Ln / Zznz / E / YIAI In another embodiment, the present invention provides a compound according to formula I, la, Ib, le, Id or le as described herein for use as a therapeutically active substance. In yet another embodiment, the present invention provides a compound according to formula I, la, Ib, le, Id or le as described herein for the treatment, prevention and / or delay of the progression of, 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, squamous cell lung, glioblastoma multiforme and squamous cell carcinoma of the head and neck. In yet another embodiment, the present invention provides a compound according to formula I, la, Ib, le, Id or le as described herein for the preparation of a medicament for the treatment, prevention and / or delay of progression of, 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, adenocarcinoma of lung, squamous cell carcinoma of the lung, glioblastoma multiforme and squamous cell carcinoma of the head and neck. In one aspect, the application provides a method of treating a Mat2A disorder in a subject having Mat2A-related disorders, said method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds. previous. In another embodiment, the present invention provides a method for the treatment, prevention and / or delay of the progression of, more particularly treatment of cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma. , squamous cell carcinoma of the lung, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly adenocarcinoma of the lung, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme, and squamous cell carcinoma of the head and neck, comprising administering an effective amount of a compound according to formula I, la, Ib, le, Id or le as described herein. In a particular embodiment, the present invention provides a method for the treatment, prevention and / or delay of the progression of, more particularly treatment 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 adenocarcinoma of the lung, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme, and squamous cell carcinoma of the head and neck, comprising administering an effective amount of a compound according to formula I, la, Ib, le, Id or le as described herein. CCfrQ Ln / Zznz / E / YIAI In particular, Mat2A-dependent disorders or Mat2A-related diseases are 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 carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and squamous cell carcinoma of the head and neck. In one aspect, the application provides a pharmaceutical composition comprising the compound of any of the above embodiments, mixed with at least one pharmaceutically acceptable carrier, such as an excipient or diluent. In another embodiment, the present invention provides a use of a compound of Formula I, la, Ib, le, Id or le in the preparation of a medicament for the treatment, prevention and / or delay of the progression of, more particularly for the treatment of, diseases associated with Mat2A. In yet another embodiment, the present invention also provides medicaments containing a compound of Formula I, la, Ib, le, Id or le as defined herein or a pharmaceutically acceptable salt thereof and a therapeutically acceptable carrier. inert, are also an object of the present invention, as is a process for their production, which comprises associating one or more compounds of Formula I, la, Ib, le, Id or le and / or acid addition salts acceptable from from the pharmaceutical point of view and, if desired, one or more other therapeutically valuable substances in a galenic administration form together with one or more therapeutically inert carriers. Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or pharmaceutically acceptable excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. The compositions are formulated, dosed and administered in accordance with good medical practices. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of administration of the agent, the method of administration, the schedule of administration, and others. factors known to health professionals. For example, such an amount may be less than the amount that is toxic to normal cells, or to the mammal as a whole. The compounds of the invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired, for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention can be administered in any convenient administration form, for example, tablets, coated tablets, dragees, powders, capsules (hard or soft gelatin capsules), solutions (i.e., solutions for injection), dispersions, suspensions , syrups, sprays, suppositories, gels, emulsions, patches, drops CCfrQ Ln / Zznz / E / YIAI for eyes, ear drops, etc. Such compositions may contain conventional components 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 and a pharmaceutically acceptable carrier or excipient. Suitable carriers and excipients are widely known to those of the mid-level craft and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosaqe Forms and Druq Delivery Systems. Philadelphia: Lippincott, Williams, and Wilkins, 2004; Gennaro, Alfonso R., et al Reminqton: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams, and Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Pharmaceutically acceptable carriers can be solid or liquid. Preparations in solid form include powders, tablets, pills, capsules, wafers, 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 finely divided solid that is a mixture with the finely divided active component. In tablets, the active component is usually mixed with the carrier which in suitable proportions has the necessary binding capacity and compacted into the desired shape and sizes. The powders and tablets preferably contain from about (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 dose at which the compound of the present invention can be administered can vary within wide limits and will undoubtedly be adjusted to the individual needs of 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, la, Ib, le, Id or le should be appropriate, although the above upper limit may also be exceeded when necessary. An example of a suitable oral dosage form is a tablet containing about 10 to 500 mg of the compound of the invention together 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. First, the powdered ingredients are mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed into a tablet using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example, 10 to 100 mg of the invention in a suitable buffer solution, for example, a phosphate buffer, adding a tonicity modifier, for example, a salt such as chloride CCfrQ Ln / Zznz / E / YIAI sodium, if desired. The solution can be filtered, for example, using a 0.2 pm filter, to remove impurities and contaminants. One embodiment, therefore, includes a pharmaceutical composition comprising a compound according to the invention described herein, or a stereoisomer thereof. In a further embodiment, it includes a pharmaceutical composition 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 either alone or in association with other drugs, for the treatment, prevention and / or delay of the progression of Mat2A-related diseases, in particular cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma , squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, carcinoma of the esophagus, glioblastoma multiforme, and mesothelioma, more particularly adenocarcinoma of the lung, squamous cell carcinoma of the lung, glioblastoma multiforme and squamous cell carcinoma of the head and neck. A particular embodiment of the present invention relates to pharmaceutical compositions comprising compounds of Formula I, la, Ib, le, Id or le or their pharmaceutically acceptable salts, as defined above, and one or more acceptable excipients. from a pharmaceutical point of view, for use in the treatment, prevention and / or delay of the progression of cognitive deficiencies associated with cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck , squamous cell carcinoma of the lung, carcinoma of the esophagus, glioblastoma multiforme and mesothelioma, more particularly adenocarcinoma of the lung, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck. Another embodiment includes a pharmaceutical composition comprising a compound according to the invention described herein, for use in the treatment, prevention and / or delay of the progression of, more particularly in the treatment of Mat2A-related diseases. Another embodiment includes a pharmaceutical composition comprising a compound according to the invention described herein, for use in the treatment, prevention and / or delay of the progression of, more particularly in the treatment of Mat2A-related diseases. In another embodiment, the present invention provides for the manufacture of compounds of Formula I, la, Ib, le, Id or le as described herein. The preparation of the compounds of Formula I, la, Ib, le, Id or le of the present invention can be carried out in sequential or convergent synthesis routes. The following general diagram shows a synthesis of the invention. The skills necessary to carry out the reaction and purification of the resulting products are known to those in the mid-level trade. In the event that a mixture of enantiomers or diastereoisomers is produced during a reaction, these enantiomers or diastereoisomers can be separated by methods described herein or known to those of ordinary skill in the art, such as, for example, chiral chromatography or crystallization. CCfrQ Ln / Zznz / E / YIAI Furthermore, the compounds of the present invention can be prepared from commercially available starting materials or by use of general synthetic techniques and procedures that are known to those of ordinary skill in the art. Suitable reaction schemes for the preparation of such compounds are set out below. The substituents and indices used in the following description of the processes have the meaning given herein. More information can be found in the specific examples detailed below. General Summary In more detail, the compounds of Formula I, la, Ib, le, Id or le and their intermediates can be prepared by Schemes 1 to 2 and by the description of specific examples. A subgroup of compounds of Formula I, la, Ib, le, Id or le, where X is halo, X1 is C, X4 is CH, R2 and R3' are H, and R7 is H and ”, R4, R5 and R6 are as defined above, they can be prepared as set out in schemes 1-2 below. CCfrQ Ln / Zznz / E / YIAI Scheme 1 o i t · R' 0 R R , i U A ΝΉ J i, I,* ------* J3 |T^ x H Vil VIII X OH l3 T II PG= protecting group * R<: x' J ----- --* J 3 1 -N V RG RU o-s-o .4: B 0 ^0 lh Ib R R r'3 OJZO R3 R6 13 1 N VI PG where X is halo, Rbes H o is cyclized to form the pinacol ester and X2, X3 and R6 are as defined above. Dihalide A is deprotonated with strong bases (e.g. n-BuLI, LDA, LÍHDMS, TMPMgCI.LiCI) at low temperature (-78 °C) in THF and subsequently reacts with either aldaldehydes to obtain alcohol II (as shown). described in Synthesis, 1988, p. 803 - 805), or with the appropriate esters to directly obtain ketone III (as described in Journal of Organic Chemistry, 2007 p. 2501 - 2507). Alternatively, alcohol II can be oxidized to ketone III using common oxidizing agents (e.g. MnO2, Dess-Martin periodinane, TEMPO / Phl(OAc)2) in dichloromethane. Ketone III can subsequently react with hydrazine (aqueous or monohydrate) at room temperature or low temperature in THF, dioxane or ethanol to obtain pyrazoles IV (as described in Journal of Medicinal Chemistry, 2019 p. 531 - 551). Alternatively, ketone III can be coupled with ester or boronic acids )) in the presence of carbonate bases (e.g., K2CO3, CS2CO3) to obtain ketone Vil which, in turn, is cyclized to pyrazole VIII with hydrazine. Alternatively, pyrazole IV can be protected at the N atom (e.g. SEM, THP or Triphyllum) under standard conditions, reacted similarly with boronic acid or esters or TFA) to obtain pyrazole VIII. Scheme 2 CCfrQ Ln / Zznz / E / YIAI o=s=o PG= protective group ix where X is halo, Rbes H o is cyclized to form the pinacol ester. Alternatively, the pyrazole III core can be formed from A1 anilines as 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 at the N atom of pyrazole IV (e.g. SEM, THP or Trityl) under standard conditions then allows subsequent reaction of the halogen (e.g. Suzuki reaction) to obtain pyrazole VI. Halogenation of VI can be carried out using halo-succinimides, as above, to obtain pyrazole VI which is then coupled with boronic acids and esters and deprotonated as described in Scheme 1. A subgroup of compounds of Formula I or la, wherein X is halo, X1 is N, X2 is C-O, , can be prepared as set out in scheme 3 below. Scheme 3 CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ PG= protective group Pyridone structures are prepared by first protecting the pyrazole or pyrrole nitrogens of A2 with suitable protecting groups, for example (THP, SEM, Trityl) under standard conditions to obtain II. Derivatization of the halogen what its reinstatement is needed to obtain IV. Chan-Lam coupling of boronic acids V with copper(II) acetate-dependent catalysis with a mixture of pyridine and triethylamine produces derivative VI which, after standard removal of the protecting group (e.g., 4N HCl in dioxane, TFA ) produces the final compounds Vil. General Procedures Scheme 4 Y=OR, X,CN CCfrQ Ln / Zznz / E / YIAI where X is halo and X2, X3 and R6 are as defined above. General Procedure A: Aryl / heteroaryl functionalization To a solution of aryl or heteroarylaldehyde cooled to -78 °C (Ec: 1) in anhydrous THF (0.1 M) under Ar, lithium diisopropylamide or nBuLi (Ec: 1.1-1.5) is added dropwise. After stirring for the appropriate period of time (10 minutes to 1 h), the required electrophile (aldehyde, ester or chloroformate Ec: 1.5-2) is added and the reaction is stirred for an additional period of time (10 minutes to 1 h) at the same temperature. After such time the reaction is stopped at -78 °C by adding saturated aqueous amino chloride, the reaction is brought to room temperature, diluted with ethyl acetate, the organic fraction is washed with water, brine, dried ( Na2SO4) and concentrate. The crude product can be used directly in the next step or purified by flash column chromatography. Scheme 5 where X is halo and X2, X3, and R6 are as defined above. General Procedure B1: Oxidation of Benzyl alcohol with Dess-Martin periodinane To a solution of benzyl alcohol (Ec: 1) in dichloromethane (0.1 M) Dess-Martin periodinane (Ec: 1.3) is added and the reaction is stirred until the reaction is complete (1 h). The reaction is diluted with dichloromethane, washed with saturated aqueous NaHCOs, dried (Na2SO4) and concentrated. The residue is purified by flash column chromatography. General Procedure B2: Oxidation of Benzyl alcohol with TEMPO To a solution of benzyl alcohol (Ec: 1) in dichloromethane (0.1 M) TEMPO (Ec: 0.1) followed by (diacetoxyiodo)benzene (Eq: 1.1) and the reaction is stirred until the reaction is complete (3h). The reaction is diluted with dichloromethane, washed with saturated aqueous NaHCOs, dried (Na2SÜ4) and concentrated. The residue is purified by flash column chromatography. CCfrQ Ln / Zznz / E / YIAI Scheme 6 where X is halo and X2, X3 and R6 are as defined above. General Procedure C: Cyclization of Pyrazole To a solution of ketone or ester (Ec: 1) dissolved in THF, dioxane or ethanol (0.1 M) at room temperature or with cooling, hydrazine (Ec: 2-5) is added in the presence / absence of additional bases (EtsN Eq. 1.5) and the reaction is stirred until the reaction is complete (1h). The reaction is diluted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated. The residue is purified by flash column chromatography. General Procedure D: Suzuki Coupling To a solution of halide (Ec: 1) dissolved in dioxane: water (0.1 M, 4:1-10:1) potassium carbonate (Ec: 3-6), the required boronic acid or ester (Ec: 1-6) and the mixture is degassed by sonication while Ar is bubbled through the sample. The 1,1'bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride adduct (Ec: typically 0.05, and for difficult cases 0.5) is added and the mixture is heated under an Ar atmosphere. at 100-120 °C until the starting material is consumed (0.5 h-16 h). The reaction is diluted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated. Alternatively, the reaction mixture can be absorbed directly onto silica gel and concentrated. The residue is purified by flash column chromatography. General Procedure E1: Protection with SEM To a solution of pyrazole (Ec: 1) dissolved in anhydrous DMF or THF (0.1 M) under Ar was added sodium hydride (60% dispersion in mineral oil, Ec: 2), the reaction was stirred for 15 minutes before Add SEM-CI (Eq: 1.8) and the reaction was stirred until the starting material was completely consumed (1 h). The reaction was then diluted with ethyl acetate, extracted with water, dried (Na2SO4) and concentrated. The residue is purified by flash column chromatography. General Procedure E2: Protection with SEM To a solution of pyrazole (Ec: 1) dissolved in dichloromethane (0.1 M) under Ar, DIPEA (Ec: 1.2) and SEM-CI (Ec: 1.2) were added and the reaction was stirred until the starting material was completely consumed. (1 hour). The reaction was then concentrated and the residue was purified by flash column chromatography. Scheme 7 CCfrQ Ln / Zznz / E / YIAI where X is halo and R1, R2', R2", R3' and R3" are as defined herein. General Procedure F: Conversion of Aryl Halides to Boronates To a solution of aryl halide (Ec: 1) dissolved in dioxane (0.1 M) bis(pinacolato)diboron (Ec: 1.1), potassium acetate (Ec: 3) is added and the mixture is degassed by bubbling. with Ar under sonication. The adduct [1,1'-bis(diphenlyphosphino)ferrocene]dichloropalladium(ll) dichloromethane (Ec: 0.1) was added and the reaction was heated (80 °C-100 °C) until the conversion was completed. The reaction was then diluted with ethyl acetate, washed with brine, dried (NasSO^ and concentrated. The residue was purified by flash column chromatography General Procedure F: Oxidation of sulfides To an ice-cooled solution of sulfide (Ec: 1) in dichloromethane (0.1 M) is added mchloroperbenzoic acid (Ec: 1- 2.5, depending on whether sulfoxide or sulfone is required), the ice bath is removed and Allow the reaction to reach room temperature. Stirring is maintained until the conversion is complete, after which time the reaction is diluted in dichloromethane, washed with 1N NaOH, dried (Na2SO4) and concentrated. The residue is purified by flash column chromatography. General Procedure F: Trityl Deprotection The trityl-protected compound (Ec: 1) is dissolved in trifluoroacetic acid (0.1 M) and triethylsilane (Ec: 1.5) is added and the reaction is stirred at room temperature until complete. The mixture is then carefully poured onto saturated aqueous sodium hydrogencarbonate, and extracted with dichloromethane, the organic extracts are combined and washed with brine, dried (Na2SÜ4) and concentrated. The residue is purified by flash column chromatography or preparative reverse phase HPLC. General Procedure 11: Deprotection of THP The THP-protected compound (Ec: 1) is dissolved in dichloromethane (0.1 M), trifluoroacetic acid (Ec: 10) is added and the reaction is stirred at room temperature until complete. The mixture is then diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate, dried (Na2SO4) and concentrated. The residue is purified by flash column chromatography or preparative reverse phase HPLC. General Procedure 12: Deprotection of THP The THP-protected compound (Eq: 1) is dissolved in 4 N HCl in dioxane (0.1 M) and the reaction is stirred at room temperature until complete. The mixture is then diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate, dried (Na2SO4) and concentrated. The residue is purified by flash column chromatography or preparative reverse phase HPLC. General Procedure J: Deprotection of SEM / MOM The compound protected with SEM / MOM (Ec: 1) is dissolved in trifluoroacetic acid (0.1 M) and the CCfrQ Ln / Zznz / E / YIAI reaction is stirred at room temperature until complete. Deprotection is completed by evaporation of trifluoroacetic acid followed by redissolution of the reaction in dichloromethane or dioxane (0.1 M) and addition of ethylenediamine (Ec: 10). The mixture is concentrated and purified by flash column chromatography or preparative reverse phase HPLC. General Procedure J2: SEM Deprotection The SEM-protected compound (Ec: 1) is dissolved in a solution of 1 M TBAF in THF (Ec: 10) and the reaction is heated to 50 °C until completion. The reaction is completed with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried (Na2SÜ4) and concentrated. The residue is purified by flash column chromatography or preparative reverse phase HPLC. A specific embodiment of the invention relates to a process for the preparation of compounds of Formula (I) and its pharmaceutically acceptable salts as defined in accordance with the present invention, comprising the deprotection of a compound of Formula (la) wherein X1, TFA) or an inorganic acid (e.g. aqueous HCl), as shown in Scheme 8. Scheme 8 (the I) The compounds were investigated according to the test given below. Determination of Mat2A activity Measurement of Mat2A inhibition is performed using an absorbance-based assay in 384-well format. Recombinant human Mat2a (12.5 nM) and compounds serially diluted in DMSO (concentration range 10 pM to 508 pM) or controls (DMSO) are incubated for 15 minutes at room temperature (RT) in assay buffer containing 50 mM HEPES pH 7.5, 50 mM KOI, 50mM MgCI2, 0.01% Tween 20 and 10 mM DTT. The reaction is initiated by adding the combined substrates ATP and Methionine, each at a final concentration of 100 μΜ. The final assay conditions are 12.5 nM Mat2A, 100 pM of the substrates ATP and Methionine and 2% DMSO. After 120 minutes of incubation at RT, the reaction is stopped by the addition of Biomol Green. The absorbance signal is measured at λ =635 nm with a multiplate reader (BMG Pherastar reader or equivalent) after 30 minutes of equilibration at RT. The table below shows the data for selected compounds: CCfrQ Ln / Zznz / E / YIAI Example number MAT2A_LEC IC50 (uM) (No.) 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 4 8 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 CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 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 0.013 108 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 CCfrQ Ln / Zznz / E / YIAI Experimental section The following examples are provided by way of illustration of the invention. They should not be considered as limiting the scope of the invention, but rather as representing it. General Analytical methods HPLC (ultrafast_gradient_LCMS_method) Column: Agilent Zorbax Eclipse Plus C18, Fast Resolution HT, 2.1x30 mm, 1.8 pm, Part. no. 959731 / -902 Solvent A: Water 0.01% formic acid; Solvent B: acetonitrile (MeCN) Gradients: Time [min] Flow Rate [ml / min] % A % B Initial 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 In the experimental section the following abbreviations were used: Ar = argon; nBuLi = n-butyl lithium; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMSO = dimethyl sulfoxide; DMF = dimethylformamide; EtOH = ethanol; ExampleNumber = ExampleNumber; 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.= Preparation; SEM = [2-(trimethylosilyl)ethox)methyl] acetal; TBTU = 2-(1 H-Benzotriazol-1-yl)-1,1,3,3-tetramethylamino tetrafluoroborate; THF = tetrahydrofuran; TEMPO = 2,2,6,6-tetramethylpiperidinyloxyl; TBAF = tetra-n-butyl ammonium fluoride; TLC = thin layer chromatography; Starting material Basic chemical reagents and solvents were purchased and used without further purification. Some intermediates are commercially available or can be synthesized using methods known in the art. Intermediaries Intermediate 1: 4-chloro-3-cyclopropyl-1 H-pyrazolo[4,3-c]pyridine CCfrQ Ln / Zznz / E / YIAI The title 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)-1Hpyrazolo[3,4-c]pyridine Step 1: 3-iodo-5-methoxy-1 -((2-(trimethylsiIyl)ethoxy)methyl)-1 H-pyrazolo[3,4-c]pyridine 3-iodo-5-methoxy-1 H-plrazolo[3,4-c]pyridine (76006-07-0: WO2015 / 25025 A1) was converted to the title compound ([M+H]+406.2) by the use of General Procedure E1 (accompanied by 20% of the regioisomer). Step 2: 3-cyclopropyl-5-methoxy-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazolo[3,4-c]pyridine 3-iodo-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (step 1) is reacted with cyclopropyl boronic acid (6 eq), carbonate of low potassium (3 eq), catalysis with the rbis(diphenylphosphino)ferrocene-palladium (II) dichloride adduct dichloromethane (0.1 eq) for 4 h according to general procedure D to obtain the title compound ([M+H ]+320.3). Step 3: 4-bromo-3-cyclopropyl-5-methoxy¡-1 -((2-(trimethyls¡l¡l)ethoxy)methyl)-1 H-pyrazolo[3,4-c]pyrád na To a solution of 3-cyclopropyl-5-methoxy-1-((2-(trimethyllos¡lyl)ethoxy)methyl)-1 H-pyrazolo[3,4-c]pyridine (Step 2, 20 mg , 63 pmol) in DCM (1 ml) / V-bromosuccinimide (12 mg, 70 pmol) was added and the reaction was stirred for 4 h. The reaction was then absorbed 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-(trimethylosilyl)ethoxy)methyl)-1H-pyrazolo[4,3c]pyridine CCfrQ Ln / Zznz / E / YIAI Step 1: 4-chloro-3-(thfluoromethyl)-1 H-pyrazolo[4,3-c]pyridine 2,4-Dichloropyridine was deprotonated with nBuLi (1.3 eq) for 30 minutes and reacted with ethyl 2,2,2-trifluoroacetate (2 eq) according to general procedure A to obtain 1 -(2,4dichloropyridine -3-yl)-2,2,2-trifluoroethane-1 -one which was reacted directly with hydrazine hydrate (5 eq) in THF for 16 h, initially at -40 °C and reaching room temperature, according to with general procedure C to obtain the title compound ([M+H, Cl]+220.0). Step 2: 4-chloro-3-(trifIuoromethyl)-1 -((2-(trimethiIsiliI)ethoxy)methyl)-1 H-pyrazolo[4,3-c]pyridine The title compound ([M+H, Cl]+352.2) was prepared from 4-chloro-3-(trifluoromethyl)-1Hpyrazolo[4,3-c]pineapple (Step 1) by use of the general procedure E2. Intermediate 4: 4-chloro-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,2c]pyridine CCfrQ Ln / Zznz / E / YIAI Step 1: 3-bromo-4-chloro-1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrrolo[3,2-c]pyridine 3-Bromo-4-chloro-1 H-pyrrolo[3,2-c]pyridine was converted to the title compound ([M+H, Br, Cl]+361.1) by using the general procedure E1. Step 2: 4-chloro-3-cyclopropyl-1 -((2-(trimethyls¡l¡l)ethoxy)methyl)-1 H-pyrrolo[3,2-c]pyridine 3-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol[3,2-c]pyrdina (step 1) is reacts with cyclopropyl boronic acid (6 eq), potassium carbonate (6 eq) under catalysis with the dichloride adduct of 1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane (0.15 eq) for 1 h at 100 °C , according to general procedure D, to obtain the title compound ([M+H, CL]+323.2). Intermediate 5: 4-bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile Stage 1: 3-bromo-4-(cyclopropanecarbonyl)-5-fluoropicolinonitrile 3-Bromo-5-fluoropicolinonítrilo is treated with LDA (2 eq) for 10 minutes before the addition of cyclopropanecarbaldehyde according to general procedure A, to obtain 3-bromo-4(cyclopropyl( Crude hydroxy)methyl)-5-fluoropicolinonitrile, which is then oxidized to form the title compound ([M-H, Br]' 265.3) by using the general procedure E2. Step 3: 4-bromo-3-cyclopropyl-1 H-pyrazolo[3,4-c]pyridine-5-carbonátrilo 3-Bromo-4-(cyclopropanecarbonyl)-5-fluoropicolinonítrile (step 2) is reacted with hydrazine hydrate (2 eq) in EtOH, initially at 0 °C and reaching room temperature for 1 h , according to general procedure C, to obtain the title compound ([M+H, Br]+263.1). Intermediate 6: 4-chloro-3-(1,1-difluoroethyl)-1 H-pyrazolo[4,3-c]pyridine CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ Step 1: 1-(2-chloro-4-fluorop¡ridín-3-¡l)-2,2-difluoropropan-1-one 2-Chloro-4-fluoropyridine is deprotonated with nBuLi (1.3 eq) for 1 h and reacted with ethyl 2,2difluoropropanoate (1.3 eq), according to general procedure A, to obtain the title compound ([ M+H, Cl]+224.1. Step 2: 4-chloro-3-(1,1-difluoroethyl)-1 H-pyrazolo[4,3-c]pyridine 1-(2-Chloro-4-fluoropyridin-3-yl)-2,2-difluoropropan-1-one (Step 1) is reacted with hydrazine hydrate (5 eq) in THF at room temperature for 15 minutes, according to general procedure C, to obtain the title compound ([M+H, Cl]+218.1). Intermediate T\2-[[4-chloro-3-(difluoromethyl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyltrimethylsilane Step 1: 1-(2-chloro-4-fluoropyridin-3-yl)-2,2-difluoropropan-1-one 2-Chloro-4-fluoropyridine was deprotonated with LDA (2 eq) for 3 h and reacted with ethyl 2,2difluoroacetate (1.3 eq) for 3 h, according to general procedure A, to obtain the compound of title ([M-H, Cl]- 206.1. Step 2: 4-chloro-3-(trifluoromethyl)-1 H-pyrazolo[4,3-c]pyridine React 1-(2-chloro-4-fluoropyridin-3-!l)-2,2-difluoropropan-1-one (Step 1) with hydrazine hydrate (5 eq) in THF at -40 °C for 1 h, according to general procedure C, to obtain the title compound ([M+H, Cl]+204.0). Step 3: 4-chloro-3-(1,1-difluoroethyl)-1 H-pyrazolo[4,3-c]pyridine 4-Chloro-3-(difluoromethyl)-1 H-pyrazolo[4,3-c]pyridine (step 2) was converted to the title compound ([M+H, Cl]+324.1) by using of General Procedure E2, accompanied by its regioisomer. Intermediate 8: 4-chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[4,3-c]pyridine CCfrQ ίη / ζζηζ / Ε / γΐΛΐ Step 1: 4-chloro-1 H-pyrazolo[4,3-c]pyridin-3-ol To a solution of methyl 2-chloro-4-fluoro-pyridine-3-carboxylate carboxylate (950 mg, 5.0 mmol) in dioxane (9.5 ml) was added hydrazine monohydrate (325 mg, 6.5 mmol) and triethylamine (1.4 mi, 10.0 mmol) and the mixture was heated at 70 °C for 16 h. The reaction was diluted with 2-methoxy-2-methylpropane (5 ml) and the precipitate was removed by filtration to obtain the title compound (900 mg, 95%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ = 11.36 - 9.59 (m, 2H), 8.01 - 7.85 (m, 1H), 7.38 - 7.03 (m, 2H). Step 2: 4-chloro-1-trityl-1 H-pyrazolo[4,3-c]pyridin-3-ol To a solution of 4-chloro-1 H-pyrazolo[4,3-c]pyridín-3-ol (step 1) (700 mg, 3.7 mmol), triphenylmethyl chloride (1035 mg, 3.7 mmol) in DMF (100 ml) under Ar, triethylamine (1.55 mL, 11.5 mmol) was added and the reaction was stirred at 30 °C for 4 h, after which time it was diluted with water and extracted repeatedly with ethyl acetate. The combined organic fractions were dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 1:6-3:1) gave (620 mg, 41%) as a yellow solid, 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.77 (d, J = 6.1 Hz, 1H), 7.33 - 7.27 (s, 15H), 6.13 (d, J = 6.1 Hz, 1H). Step 3: 4-chloro-3-(difluoromethox¡)-1-tritll-pyrazolo[4,3-c]pyridine A suspension of 4-chloro-1-tntil-pyrazolo[4,3-c]pyridín-3-ol (Step 2) (100 mg, 0.2 mmol), cesium carbonate (158 mg, 0.5 mmol) and 2-chloro-2,2-dlfluoro-acetyl)oxysodium (74 mg, 0.45 mmol) in acetonitrile was heated at 80 °C for 2 h. The reaction mixture was filtered and concentrated in vacuo to obtain 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 CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ Stage 1: (2,4-dichloro-3-pyrid¡l)-(oxetan-3-¡l)methanol 2,4-Dichloropyridine was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with oxetane-3carbaldehyde (1.5 eq) for 1 h, according to general procedure A, to obtain the title compound ([M+H , Cl]+233.8. Step 2: (2,4-dichloro-3-pyrid¡l)-(oxetan-3-yl)methanone (2,4-Dichloro-3-pyridyl)-(oxetan-3-yl)methanol (step 1) was oxidized by using general procedure B1 to obtain the title compound. [M+H Cl]+= 231.7. Step 3: 4-chloro-3-(oxetan-3-yl)-1 H-pyrazolo[4,3-c]pyridine (2,4-Dichloro-3-pyridyl)-(oxetan-3-yl)methanone (step 2) was reacted with hydrazine monohydrate (1.5 eq) and triethylamine (1.5 eq) in dioxane at 60 °C for 1 h , according to general procedure C, to obtain the title compound ([M+H, Cl]+209.8). Step 4: 4-chloro-3-(oxetan-3-yl)-1-tetrahydroxiran-2-yl-pyrazol[4,3-c]pyrdina A solution of 4-chloro-3-(oxetan-3-yl)-1 H-pyrazolo[4,3-c]pyridine (step 3) (200.0 mg, 0.95 mmol), sulfonic acid p-toluene 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 at 60 °C for 16 h. The reaction was neutralized by addition of triethylamine (0.2 ml) and the concentrate was dried. Purification by preparative TLC: (nHeptane:ethyl acetate 1:1) gave the title compound (150 mg, 53%) as a light yellow solid.1H NMR (400MHz, CHLOROFORM-d) δ = 8.08 (d, J =6.0 Hz, 1H), 7.35 (d, J=5.9 Hz, 1H), 5.63 (dd, J=2.7, 9.0 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-1 H-pyrazolo[4,3-c]pyridine Step 1: Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone 2,4), DMAP (300 mg, 1.64 mmol, Eq: 1) was deprotonated with LDA (0.9 eq) for 1 h and react cyclopropanecarbaldehyde (1.5 eq) for 1.5 h in accordance with general procedure A, to obtain crude cyclopropyl(2,4,6-trichloropyridin-3-yl)methanol, which was directly oxidized by the use of general procedure B1 to obtain the title compound. ([M+H, 2CI]+250.1. Step 2: 4,6-dichloro-3-cyclopropyl-1 H-pyrazolo[4,3-c]pyridine Cyclopropyl(2,4,6-trichlorop¡rid¡n-3-yl)methanone (step 2) was reacted with hydrazine monohydrate (5 eq) in THF at 0 °C for 2 h and then 2 h at room temperature. , according to general procedure C, to obtain the title compound ([M+H, 2CI]+228.1). Intermediate 11: 4-bromo-5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2Hpyrazolo[3,4-c]pyridine CCfrQ Ln / Zznz / E / YIAI Step 1: 3-iodo-5-methoxy¡-2-((2-(tr¡met¡ls¡l¡l)ethoxy¡)met¡l)-2H-p¡razolo[3,4-c]p ¡r¡dina 3-iodo-5-methoxy¡-1 H-pyrazolo[3,4-c]pyridine (WO2015 / 25025 A1) was converted to the title compound ([M+H]+406.2) by using of the general procedure accompanied by its regioisomer. Step 2: 5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylosilyl)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) iodine (164 mg, 0.86 mmol) and potassium fluoride (50 mg, 0.17 mmol) in NMP (1 mi) was added (trifluromethyl)trimethylslane (0.13 mL, 0.86 mmol) and the mixture was heated under Ar at 50 °C for 1 h. The reaction was then diluted in water, filtered through Celite ®, extracted with ethyl acetate and the organic fraction was dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 1:4) afforded the title compound (32 mg, 53%) as a viscous yellow oil ([M+H]+348.3) Step 3: 4-bromo-5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylos¡l)ethoxy)methyl)-2H-pyrazol[3,4c ]pyridine 5-Methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine (step 2) (32 mg, 0.9 mmol) in 1,2-dichloroethane (0.5 ml), N-bromosuccinamide (18 mg, 1.0 mmol) added and the mixture was heated at 70 °C for 2 h. The reaction was concentrated and purified by flash column chromatography (ethyl acetate: n-Heptane 1:4) to obtain the title compound (20 mg, 51%) as a yellow solid ([M+H, Br]+428.3 ) Intermediate 12: 4-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrroloyl3,2 c]pyridine CCfrQ Ln / Zznz / E / YIAI Step 1: 4-chloro-3-(trifluoromethyl)-1 H-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) were dissolved sulfoniotrifluoromethanesulfonate (436 mg, 1.1 mmol) in DMF (2 ml) and copper (138 mg, 2.2 mmol) was added and the mixture was stirred in a closed tube under Ar for 6 h at 60 °C. The reaction was diluted with ethyl acetate, the organic fraction was washed with water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 0:1) afforded the title compound (18 mg, 22%) as a white solid ([M+H, Cl]+221.0) Step 2: 4-chloro-3-(trifluoromethyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrrolo[3,2-c]pyridine 4-Chloro-3-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridine was converted to the title compound ([M+H,CI]+351.2) by using the general procedure E1 . Intermediate 13: 4-bromo-3-cyclopropyl-5-(methoxymethyl)-1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazolo[3,4-c]pyridine Step 1: 4-bromo-3-cyclopropyl-1 -(tetrahydro-2H-pyran-2-¡l)-1 H-pyrazolo[3,4-¡ l)pyridi n a-5carboxylic acid 4-Bromo-3-cyclopropyl-1H-pyrazol[3,4-c]pyridine-5-carbonatetrile (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 at 100 °C for 15 h. The reaction was then acidified with conc. HCl. and the resulting solid was separated by filtration, yielding the title compound (435 mg, 77%) as a light brown solid ([M+H, Br]+ 282.1). Step 2: Methyl 4-bromo-3-cyclopropyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxylate 4-Bromo-3-cyclopropyl-1 H-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, 5.3 mol) and ptoluenesulfonic acid monohydrate (20 mg, 0.1 mmol) was added. The reaction was stirred for 4 h after which time it was diluted with ethyl acetate, washed with 1 N HCl, dried (Na2SO4) and concentrated. 4Bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-l)-1 H-pyrazolo[3,4-c]pyridine-5-carboxylic acid was dissolved crude (389 mg, 1.1 mmol) in a DCM / MeOH mixture (6 ml / 3ml) and trimethylsilyldiazomethane (5.3 ml, 2M in hexanes, 10.6 mmol) was added. The reaction was stirred for 15 h after which time 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)-1 H-pyrazolo[3,4-c]pyridin-5-yl)methanol Methyl 4-bromo-3-cyclopropyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[3,4-c]pyridi n a-5carboxylate (Step 2) (320 mg) was dissolved , 0.8 mmol) in THF (10 ml) and cooled -78 °C before the addition of diisobutylaluminum hydride (3.37 ml, 1 M in THF, 3.4 mmol) and the reaction was stirred for 90 minutes before adding a second portion of diisobutylaluminum hydride (3.37 ml, 1 M in THF, 3.4 mmol) and the mixture was stirred for an additional 3 h. The reaction was stopped by adding a few drops of water, acidified by adding 1N HCl, extracted with ethyl acetate, dried (Na2SÜ4) 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)-1 H-pyrazolo[3,4c]pyridine (4-bromo-3-cyclopropyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[3,4-c]p¡ñdin-5-yl)methanol (step 3) was dissolved ( 60 mg, 0.17 mmol) in dichloromethane (2 ml), triethylamine (49 μΙ, 0.3 mmol) was added followed by methanesulfonyl chloride (16 pL, 0.2 mmol) and the reaction was stirred for 30 minutes. A second 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 (2.0 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 fraction 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]+368.2) Intermediate 14: 4-bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1-((2-(trimethylosilyl)ethoxy)methyl)1H-indazole CCfrQ ίη / ζζηζ / Ε / γΐΛΐ CCfrQ Ln / Zznz / E / YIAI Step 1: 1 -(2-bromo-6-fluoro-3-(methylsulfonyl)phenyl)-2,2,2-trifluoroethane-1 -one (2-Bromo-4-fluorophenyl)(methyl)sulfane was deprotonated with LDA (1.3 eq) for 30 minutes and reacted with ethyl 2,2,2-thinfluoroacetate (2 eq) according to the general procedure A to obtain crude 1-(2-bromo-6-fluoro-3-(methylthio)phenyl)-2,2,2-trifluoroethane-1-one which was used directly. Crude 1-(2-bromo-6-fluoro-3-(methylthio)phenyl)-2,2,2-trifluoroethane-1-one (1.8 g, 5.1 mmol) was dissolved in dichloromethane (25 ml) and cooled. at 0 °C. mCPBA (3.5 g, 11.2 mmol) was added to the mixture, brought to room temperature and stirred for 3 h. The reaction was diluted with dichloromethane, washed repeatedly with 1 N NaOH, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 7:3) gave (1.0 g, 56%) as a yellow oil. Step 32 4-bromo-5-(methylsulfoníl)-3-(trifluoromethyl)-1 H-indazole 1-(2-bromo-6-fluoro-3-(methylsulfonyl)phenyl)-2,2,2-trifluoroethane-1-one (Step 1) was reacted with hydrazine monohydrate (5 eq) in THF for 1 h at room temperature according to general procedure C to obtain the title compound ([M+H, Br]+343.1). Step 3: 4-bromo-5-(methylsulfonyl)-3-(tñfluoromethyl)-1 -((2-(trimethiIsiIyl)ethoxy)methyl)-1 H-indazole 4-Bromo-5-(methylsulfon¡l)-3-(trifluoromethyl)-1 H-indazole (Step 3) was converted to the title compound ([M+H,CI]+351.2) by using of the general procedure E2.1H NMR (CHLOROFORM-d, 300 MHz) δ 8.37 (d, 1H, J=9.1 Hz), 7.83 (d, 1H, J=9.1 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)-1 H-pyrazolo[3,4c]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), TBTU (4068 mg, 12.7 mmol) was added and the mixture was stirred for 4 p.m. The reaction was diluted with ethyl acetate and washed with water, dried (Na2SO4) and concentrated. Preparative reverse phase HPLC gave the title compound (1.6 g, 51%) as a white solid ([M+H, Br]+296.0). Intermediate 16: 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1 H-indazole CCfrQ Ln / Zznz / E / YIAI Step 1: ethyl 2-bromo-6-fluoro-3-(methylthio)benzoate (2-Bromo-4-fluorophenyl)(methyl)sulfane was deprotonated with LDA (1.1 eq) for 30 minutes and reacted with ethyl chloroformate (1.2 eq) according to general procedure A to obtain the compound of qualification. [M+H,Br]+= 292.3. Step 2: Ethyl 2-bromo-6-fluoro-3-(methylsulfoníl)benzoate To a solution of ethyl 2-bromo-6-fluoro-3-(methylthio)benzoate (step 1) (100 mg, 0.3 mmol) in dichloromethane (3 ml), mCPBA (153 mg, 0.7 mmol) was added and the reaction It was stirred at room temperature for 16 h. The reaction was then diluted with DCM, washed with 1 N NaOH, dried (Na2SO4), and concentrated to obtain the title compound (111 mg, quant.) as a light yellow oil. ([M+H, Br]+325.0). Step 3: 4-bromo-5-(methylsulfonyl)-1,2-methyl-pyridin-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 pL, 3.2 mmol) followed by triethylamine (0.45 ml, 0.8 mmol) and the reaction was brought to room temperature. It was then heated at 80 °C for 2 h, after which time it was cooled to room temperature, the desired product was precipitated and separated 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 -triti 1-1 H-lndazol-3-ol To an ice-cold solution of 4-bromo-5-(methylsulfonyl)-1,2-dihydro-3H-ndazol-3-one was added (step 3) (540 mg, 1.9 mmol) in DMF (20 ml). triphilyl 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 room 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) gave (460 mg, 43%) as a colorless solid. ([M-H, Br] 533.3). Step 5: 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1 H-indazole To a solution of 4-bromo-5-(methylsulfonyl)-1-trityl-1 H-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 at 80 °C for 30 minutes. The reaction was then diluted with ethyl acetate, washed with water, dried (NazSO^ and concentrated. Flash column chromatography (ethyl acetate: n-Heptane -5:95-1:0) gave the compound of titer (192 mg, 70%) as a light yellow solid.([M+H-Tr, Br]+339.1). Intermediate 17: 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile CCfrQ Ln / Zznz / E / YIAI Step 1: ethyl 3-bromo-2-cyano-5-fluoro-pyridine-4-carboxylate 3-Bromo-5-fluoropicolinonitrile was deprotonated with a solution of the complex 2,2,6,6tetramethylpiperidinylmagnesium chloride and lithium chloride (2.5 eq) in THF at -78 °C for 1 h and then reacted with ethyl cyanoformate, in accordance with general procedure A, to obtain the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.6 (s, 1H), 4.60 -4.44 (m, 1H), 4.60 - 4.44 (m, 2H), 1.43 (d, J = 7.2 Hz, 3H). Stage 2: 4-bromo-3-oxo-1,2-di¡hydro¡razolo[3,4-c]pyrádine-5-carbon¡trilo To a solution of ethyl 3-bromo-2-cyano-5-fluoro-pyridine-4-carboxylate (Step 1) (5.0 g, 18.3 mmol) in ethanol (50 ml) was added hydrazine (1.9 ml, 36.6 mmol) and the reaction was heated at 70 °C for 2 h. The reaction was concentrated to dryness and the residue was purified by reverse phase HPLC to obtain 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 sodium chloride. triphenylmethyl (4286 mg, 15.4 mmol) and triethylamine (6.1 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), giving the title compound (400 mg, 6%) as a solid. yellow. [M-H,Br]'= 533.3.1H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.44 (t, 1H), 7.39-7.35 (m, 9H), 7.21 - 7.17 (m, 6H ). Step 4: 4-bromo-3-(difluoromethoyxy)-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-carbon¡trilo (step 3) (50 mg, 0.1 mmol) in acetonitrile (1.5 ml), (2-chloro-2,2-difluoro-acetyl)oxysodium (32 mg, 0.2 mmol) and cesium carbonate (68 mg, 0.2 mmol) were added and the mixture was heated to 80 °C for 2 h. The reaction was diluted with ethyl acetate, filtered and concentrated to obtain the title compound (50 mg, 91%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.49 (s, 1H), 7.45 - 7.16 (m, 16H). Intermediate 18: 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane CCfrQ Ln / Zznz / E / YIAI Step 1: (4-bromo-2-methylphenyl)(cyclopropyl)sulfane 4-Bromo-2-methylbenzenethiol (600 mg, 3.0 mmol) was dissolved in DMF (12 mL), sprayed with Ar under sonication before the addition of potassium tert-butoxide (398 mg, 3.6 mmol) and cyclopropyl bromide. (0.5 ml, 5.9 mmol) and the mixture was heated at 100 °C for 26 h. The reaction was diluted with ethyl acetate, washed repeatedly with water, dried (Na2SO4), and concentrated to obtain the title compound (737 mg, 59%) as a light brown oil. 1H NMR (300 MHz, CHLOROFORM-d) δ 7.4-7.4 (m, 1H), 7.37.3 (m, 1H), 7.2-7.3 (m, 2H), 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 -(cyclopropylsulfoníl)-2-methylpyridine Convert (4-bromo-2-methylphenyl)(cyclopropyl)sulfane (step 1) to the title compound by using the 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 Convert 4-bromo-1-(cyclopropylsulfonyl)-2-methylbenzene (step 2) to the title compound using general procedure F. ([M+H]+323.2). Intermediate 19: 2-(4-(cyclopropylsulfonyl)-3-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane CL 4-Bromo-1-(cyclopropylsulfonyl)-2-methylbenzene (CAS: 1310947-51-3, US2011 / 237791 A1) is converted to the title compound using general procedure F. ([M+H]+343.2). Intermediate 20: 2-chloro-N,N,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzenesulfonamide CCfrQ Ln / Zznz / E / YIAI Stage 1: 4-bromo-N,2-dimethyl-propanamide To a solution of methylamine dihydrochloride (2.1 g, 25.9 mmol) and diispropylethylamine (6.5 ml, 17.2 mmol) in dichloromethane (40 ml) was added 4-bromo-2-chlorobenzenesulfonyl chloride (5.0 g, 17.2 mmol) and the mixture It was stirred at room temperature for 2 h. The reaction was then washed with water, brine, dried (Na2SO4) and concentrated to obtain the title compound (4.3 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 Convert 4-bromo-2-chloro-N,N-dimethyl-benzenesulfonamide (step 1) to the title compound using general procedure F. ([M+H]+ 346.1). Intermediate 21: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane Stage 1: (2-(difluoromethyl)phenyl)(methyl)sulfane To a degassed solution of bromo-2-(difluoromethyl)benzene (400 mg, 1.9 mmol) in DMF (6 ml) sodium thiomethoxide (271 mg, 3.9 mmol) was added and the mixture was heated at 100 °C for 3 h. . It was then diluted with ethyl acetate, washed with water, brine, dried (Na2SO4), and concentrated to obtain the title compound (0.22 g, 44%) as a yellow oil. 1H NMR (CHLOROFORM-d, 300 MHz) δ 8.0-8.0 (m, 1H), 7.61 (m, 1H), 7.4-7.5 (m, 2H), 7.3-7.3 (m, 1H), 7.02 (m, 1H), 2.5-2.5 (m, 3H). Stage 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 bromide (93 pL, 1.8 mmol) and the reaction was warmed to room temperature and stirred for 4 days. The reaction was diluted with DCM, washed with aqueous sodium thiosulfate, brine, dried (Na2SO4), and concentrated to obtain the title compound (0.29 g, 67%) as a yellow oil. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.74 (br d, 1 H, J=2.2 Hz), 7.55 (tdd, 1H, J=1.0, 2.2, 8.5 Hz), 7.2-7.3 (m, 2H), 6.95 (t, 1H, J=1.0 Hz), 2.48 (s, 3H) Step 3: 4-bromo-2-(difluoromethyl)-1 -(methylsulfonyl)benzene Convert 4-bromo-2-(difluoromethyl)phenyl)(methyl)sulfane (step 2) to the title compound using general procedure G. 1H NMR (CHLOROFORM-d, 300 MHz) δ 8.0- 8.1 (m, 1H), 8.0-8.0 (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 Convert 4-bromo-2-(difluoromethyl)-1-(methylsulfonyl)benzene (Step 3) to the title compound using general procedure F. ([M+H-CeHi2]+500.2). Intermediate 22: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane CCfrQ Ln / Zznz / E / YIAI Stage: 4-bromo-2-(fluoromethyl)-1-(methylsulfoníl)benzene To a solution (5-bromo-2-(methylsulfonyl)phenyl)methanol (CAS: 773134-43-3, WO2011 / 138751 A2) (780 mg, 2.9 mmol) cooled to -78 °C is added diethylaminosulfide (0.5 ml, 3.5 mmol) and the reaction was stirred for 1 h before reaching the temperature at 0 °C for 2 h. The reaction was then washed with saturated aqueous sodium hydrogen carbonate, dried (Na2SCU) and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 3:7) gave the title compound (400 mg, 6%) as a yellow solid. ([M-H, Br]' 533.3). to obtain the title compound (0.62 g, 75%) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 7.9-8.0 (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-(methylsulfon¡l)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-2-(fluoromethyl)-1-(methylsulfoníl)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), 5.706.00 (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)-1,3,2dioxaborolane Step 1: 3-((4-bromo-2-methylphenyl)thio)oxetane A degassed solution of 4-bromo-2-methylbenzenethiol (200 mg, 0.9 mmol) and oxetan-3-yl-4methylbenzenesulfonate (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) gave the title compound (185 mg, 71%) as a colorless oil. ([M+H, Br]+261.0). Stage 2: 3-((4-bromo-2-methylphenyl)sulfonyl)oxetane 3-((4-bromo-2-methylphenyl)thio)oxetane (step 2) was converted to the title compound by using general procedure G. ([M+H+ MeCN, Br]+334.1). Step 4: 4,4,5,5-tetramethyl-2-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1,3,2-dioxaborolane 3-((4-bromo-2-methylphenyl)sulfonyl)oxetane 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 CCfrQ Ln / Zznz / E / YIAI Stage 1: 4-bromo-1-ethylsulfan¡l-2-methyl-benzene Bromide ( 40.0 g, 256.0 mmol) and subsequently the reaction was stirred at room temperature for 1 h. The reaction was concentrated to obtain the title compound (40.0 g, 87%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.34 Hz, 3 H) 2.23 (s, 3 H) 2.93 (q, J=7.34 Hz, 2 H) 7.18 (d, J=8.31 Hz, 1H) 7.31 - 7.41 (m, 2H) Stage 2: 4-bromo-1-ethylsulfonyl-2-methyl-benzene Convert 4-bromo-1-ethylsulfanyl-2-methyl-benzene (step 1) to the title compound by 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) Stage 3: 2-(4-ethylsulfonyl-3-methyl-phenyl)- 4,4,5,5tetramethyl-1,3,2-dioxaborolane Convert 4-bromo-1-ethylsulfonyl-2-methyl-benzene (Step 2) to the title compound using general procedure F. ([M+H]+229.1) Intermediate 25: 2-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane Stage 1: 1-bromo-2-fluoro-5-methyl-4-methylsulfonyl-benzene 1-bromo-2-fluoro-5-methyl-4-methylsulfanyl-benzene (CAS: 1351167-83-3, document WO2011 / 146335 A1) to the title compound using the general procedure G. ([M+H+ MeCN. Br]+267.0). Step 2: 2-(2-fluoro-5-methyl-4-methylsulfonyl-pheni 1)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Convert 1-bromo-2-fluoro-5-methyl-4-methylsulfonyl-benzene (Step 1) to the title compound using general procedure F at 70 °C. ([Μ+Η-ΟεΗιψ 233.1). Intermediate 26: 2-(2,5-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane CCfrQ Ln / Zznz / E / YIAI Stage 1: 1-bromo-2,5-dlmethyl-4-methylsulfonyl-benzene To a mixture of ,4-dlbromo-2,5-dimethylbenzene (2.0 g, 7.6 mmol), L-proline (0.7 g, 6.1 mmol) and copper (I) iodide (1.2 g, 6.1 mmol) in DMSO (20 mL) sodium hydroxide (0.2 g, 6.1 mmol) and sodium methanesulfinate (1.0 g, 9.9 mmol) were added. The mixture was stirred at 120 °C for 20 h under a nitrogen atmosphere, after which time it was diluted with water and extracted repeatedly with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 1:4) gave the title compound (627 mg, 13%) as a yellow solid. ([M+H, Br]+263.0). Step 2: 2-(2,5-(difluoromethyl)-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 using general procedure F at 95 °C. ([M+H]+311.2). Intermediate 27: 2-[4-(difluoromethylsulfoníl)-3-methylsulfoníl-pheníl]-4,4,5,5-tetramethyl-1,3,2dioxaborolane Stage 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) (15.0 g, 86.1 mmol) in heptane (162 ml) was added bromine (15.1 g, 94.7 mmol) and the mixture was stirred at room temperature for 12 h after which time the reaction was diluted with ethyl acetate, washed with saturated sodium bisulfite, dried (Na2SO4) and concentrated to obtain the title compound (15.0 g, 69%) as a yellow liquid. 1H NMR (400MHz, CHLOROFORM-d6) δ = 7.50 (d, J=1.9 Hz, 1H), 7.51 (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 by using general procedure G. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.89 (d, J= 9.0 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 1-1,3,2-dioxaborolane 4-Bromo-1-(difluoromethylsulfanyl)-2-methyl-benzene (step 1) was converted to the title compound using general procedure F at 80 °C. 1 H 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-(cyclopropylmethylSLylphonyl)-3-methylsulfonyl-phenyl]-4,4,5,5-tetramethyl-1,3,2dioxaborolane CCfrQ Ln / Zznz / E / YIAI Step 1: 1-(cyclopropylmethylsulfanyl)-2-methyl-benzene To solution of o-thiocresol (2.0 g, 16.1 mmol) in acetonitrile (20 mL) was added potassium carbonate (4.4 g, 32.2 mmol) and (bromomethyl)cyclopropane (1.6 mL, 16.1 mmol). The mixture was stirred at 50 °C for 12 h. The reaction was then diluted with ethyl acetate, filtered and concentrated to obtain the title compound (3.0 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) Stage 2: 4-bromo-1 -(cyclopropylmethylsulfanyl)-2-methyl-benzene To a solution of 1-(cyclopropylmethylsulfanyl)-2-methyl-benzene (step 1) (3.0 g, 16.8 mmol) in hexane (35 ml) was added bromine (2.7 g, 16.9 mmol) and the mixture was stirred at room temperature for 3 h after which time the reaction was diluted with ethyl acetate, washed with saturated sodium bisulfite, dried (Na2SO4) and concentrated to obtain the title compound (3.7 g, 86%) as a liquid yellow.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 by using general procedure G. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.13 - 0.18 (m, 2 Η) 0.53 - 0.58 (m, 2 Η) 0.90 - 1.03 (m, 1 Η) 2.65 (s, 3 Η) 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-methylsulfonyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-1-(cyclopropylmethylsulfonyl)-2-methylbenzene (step 3) was converted to the title compound using 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, 1H) Intermediate 29: 4,4,5,5-tetramethyl·2-(3-methyl-4-propylsulfonyl-phenyl)-1,3,2-dioxaborolane CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ Stage 1: 1-methyl-2-propylsulfanyl-benzene To a solution of o-thiocresol (2.0 g, 16.1 mmol) in acetonitrile (20 mL), potassium carbonate (4.4 g, 32.2 mmol) and 1-iodopropane (4.3 mL, 16.1 mmol) were added. The mixture was stirred at 60 °C for 12 h. The reaction was then diluted with ethyl acetate, filtered and concentrated to obtain 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). Stage 2: 4-bromo-2-methyl-1-propylsulfanyl-benzene To a solution of 1-(cyclopropylmethylsulfanyl)-2-methylbenzene (step 1) (2.5 g, 15.0 mmol) in hexane (25 ml) was added bromine (2.6 g, 16.5 mmol) and the mixture was stirred at room temperature for 3 h after which time the reaction was diluted with ethyl acetate, washed with saturated sodium bisulfite, dried (NazSO4) and concentrated to obtain 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 =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: Convert 4-bromo-2-methyl-1-propylsulfonyl-benzene4-bromo-2-methyl-1-propylsulfanylbenzene (step 2) to the title compound by 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-dioxaborolane-4bromo-1-(cycloprop) is converted lomethylsulfoníl)-2-methylíl-benzene (step 3) 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 CCfrQ Ln / Zznz / E / YIAI Stage 1: 1-isopropílosulfaníl-2-methyl-benzene To a solution of o-thiocresol (2.0 g, 16.1 mmol) in acetonitrile (20 mL), potassium carbonate (4.4 g, 32.2 mmol) and 2-bromopropane (3.1 mL, 29.1 mmol) were added. The mixture was stirred at 60 °C for 2 h. The reaction was then diluted with ethyl acetate, filtered and concentrated to obtain 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-methylbenzene (step 1) (2.5 g, 15.0 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 time the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (Na2SO4) and concentrated to obtain the title compound (3.6 g, 98%) as a yellow liquid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.35 (d, J=2.0 Hz, 1H), 7.30 -7.26 (m, 1H), 7.24 - 7.20 (m, 1H) , 3.33 (td, J = 6.7, 13.3 Hz, 1H), 2.38 (s, 3H), 1.31 (s, 3H), 1.29 (s, 3H) Stage 3: 4-bromo-1-isopropylsulfonyl-2-methyl-benzene Convert 4-bromo-2-methyl-1-propylsulfanyl-benzene (step 2) to the title compound by using the 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-dioxaborolane-4bromo-1- is converted. (cyclopropylmethylsulfonyl)-2-methylbenzene (step 3) to the title compound using general procedure F at 90 °C. ([M+H]+325.1). Intermediate 31: N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)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 thetilamine (2.5 mL, 17.8 mmol) and 4-bromo-2-methylbenzene-1-sulfonyl chloride (2.0 g, 7.4 mmol) and the reaction was stirred for 1 h at room temperature. The reaction was diluted with dichloromethane, washed with brine, dried (Na2SO4) and concentrated to obtain the title compound (1.9 g, 92%) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.82 (d, J = 8.3 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¡l)benzenesulfonamide-4-bromo-N,2- is converted dimethyl-benzenesulfonamide (step 2) to the title compound using general procedure F at 90 °C. ([M+H]+312.1). Intermediate 32: tert-butyl-dimethyl-[2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]sulfonylethoxy]silane CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ Step 1: tert-butyl-dimethyl-[2-(o-tolylsulfanyl)ethoxy]silane To solution of o-thiocresol (2.0 g, 16.1 mmol) in acetonitrile (30 mL) was added potassium carbonate (4.4 g, 32.2 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (6.0 mL, 29.0 mmol). The mixture was stirred at 60 °C for 2 h. The reaction was then diluted with ethyl acetate, filtered and concentrated to obtain 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-butyldimethyl-[2-(o-tolylsulfanyl) ethoxy]silane (step 1) (7.5 g, 13.3 mmol) in dichloromethane (50 ml) bromine (2.3 g, 14.6 mmol) was added and the mixture was stirred at room temperature for 3 h after which time the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (NasSO^ and concentrated to obtain the title compound (9.0 g, 65%) as a yellow liquid which was used directly in the next step. Step 3: 2-(4-bromo-2-methyl-phenyl)sulfon-letoxy-tert-butyl-dimethyl-silane Convert 2-(4-bromo-2-methyl-phenyl)sulfan-letoxy-tert-butyl-dimethyl-silane (step 2) to the title compound by using general procedure G. .([M+H]+393.0). Step 4: tert-butyl-dimethyl-[2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]sulfonylethoxy]silane Convert 2-(4-bromo-2-methyl-phenyl)sulfonylethoxy-tert-butyl-dimethyl-silane (step 3) to the title compound using general procedure F at 90 °C. ([M+H]+ 441.1). Intermediate 33: 4,4,5!5-tetramethyl-2-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1,3,2dioxaborolane CCfrQ Ln / Zznz / E / YIAI 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 (2.18 mL , 1 M in THF, 2.18 mmol) and the mixture was stirred for 1 h before the addition of iodomethane (515 mg, 3.6 mmol) and the mixture was heated to 20 °C and stirred for another 15 h. The mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated. Purification by prepa TLC. (petroleum ether:ethyl acetate 5:1) to obtain 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 Convert 4-bromo-2-methyl-1-(1-methylcyclopropyl)sulfonyl-benzene (step 2) to the title compound using 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-(cyclopropylmethylsulfonyl)-3-methylsulfonyl-phenyl]-4,4,5,5-tetramethyl-1,3,2dioxaborolane Step 1: 4-bromo-1-(methoxymethylsulfonyl)-2-methyl-benzene To a solution of chloromethyl methyl ether (0.28 mL, 3.7 mmol) in acetonitrile (3 mL), potassium carbonate (680 mg, 4.9 mmol) and 4-bromo-2-methyl-benzenethiol (500 mg, 2.5 mmol) were added. 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) gave 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-methylbenzene (step 2) was converted to the title compound by using general procedure G. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.86 (d, J=8.3 Hz, 1H), 7.56 - 7.49 (m, 2H), 4.54 (s, 2H), 3.54 (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-methylbenzene (step 3) was converted to the title compound using general procedure F at 70°C and used crude in the next step. Intermediate 35: 2-[5-(difluoromethyl)-2-methyl·4-methylsulfinyl-phenyl]-4,4,5,5-tetramethyl-1,3,2dioxaborolane CCfrQ Ln / Zznz / E / YIAI Stage 1: 2-bromo-1-(difluoromethyl)-4-methyl-benzene To a solution of 2-bromo-4-methylbenzaldehyde (5.0 g, 25.1 mmol) in dichloromethane (75 mL) diethylaminosulfide trifluoride (6.1 g, 37.7 mmol) was added slowly over 0.5 h and the reaction was stirred for 16 h. The reaction was diluted with dichloromethane, washed carefully with saturated aqueous sodium hydrogen carbonate and concentrated. Flash column chromatography (n-heptane) gave 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 (7.2 mL, 2.5 M in hexanes, 18 mmol) and the mixture was stirred for 0.5 h before (methyldisulfan¡l)methane (2.0 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 room temperature and extracted repeatedly with ethyl acetate. The combined organic fraction was concentrated to obtain 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 time the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (Na2SO4) and concentrated to obtain the title compound (90 mg , 63 %) as a yellow liquid.1H NMR (400MHz, CHLOROFORM-d) δ 7.75 (s, 1H), 7.25 (s, 1H), 7.11 - 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) (1.0 g, 3.7 mmol) in dichloromethane (20 mL) cooled to 0 °C, 3-chloro-benzenecarboperoxoic acid (0.6 g, 3.0 mmol) was added and the mixture was stirred at 0 °C for 0.5 h after which time the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, saturated aqueous sodium hydrogen carbonate , brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-heptane 3:7) gave the title compound (800 mg, 57%) as a white solid. ([M+H, Br]+282.0). 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]+331.2). Intermediate 36: 4-bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-trityl-1H-indazole CCfrQ Ln / Zznz / E / YIAI Stage 1: Ethyl 2-bromo-6-fluoro-3-methylsulfanyl-benzoate 2-Bromo-4-fluoro-1-methylsulfanyl-benzene was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with ethyl chloroformate (1.5 eq) for 1 h according to general procedure A to obtain 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 = 7.1 Hz, 2H), 2.48 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H) Stage 2: Ethyl 2-bromo-6-fluoro-3-methylsulfonyl-benzoate Ethyl 2-bromo-6-fluoro-3-methylsulfanyl-benzoate was converted to the title compound by 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 then the reaction was heated to 80 °C for 4 h. After cooling to room temperature, the title compound was filtered off (5.0 g mg, 52%) as an off-white solid. ([M+Na, Br]+314.8). Step 4: 4-bromo-5-methylsulfonyl-1-trityl-ndazol-3-ol To a solution of 4-bromo-5-methylsulfonyl-1,2-dihldroindazol-3-one (step 3) (200 mg, 0.7 mmol) in DMF (5 mL) was added sodium hydride (41 mg, 60% dispersion). % in mineral oil, 1.0 mmol) and triphenylmethyl chloride (211 mg, 0.8 mmol) at 0 °C under a nitrogen atmosphere. The cooling bath was removed and the reaction was stirred for 2 h upon reaching room temperature. The reaction was stopped by addition of saturated aqueous ammonium chloride, extracted repeatedly with ethyl acetate, and the combined organic extracts were washed with brine and concentrated. Flash column chromatography (1:1 ethyl acetate: n-heptane) gave 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-1 H-indazole To a solution of 4-bromo-5-methylsulfonyl-1-trityl-indazol-3-ol (step 4) (1.0 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 at 80 °C for 30 min. The reaction was filtered and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:3) gave the title compound (0.9 g, 71%) as a white solid. ([M+Na, Br]+605.0). Intermediate 37: 4-chloro-3-cyclopropyl-2-trimethylsilyl-1-(2-trimethylsilylethoxymethyl)indole-5carbonitrile CCfrQ Ln / Zznz / E / YIAI 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)-1 H-indole A mixture of 4-bromo-3-chloro-2-iodoaniline (step 1) (441 mg, 1.3 mmol), (cyclopropylethynyl)trimethylsilane (159 μΙ, 1.5 mmol), lithium chloride (56 mg, 1.33 mmol) and sodium carbonate (281 mg, 2.7 mmol) in DMF (5 ml) was bubbled with argon, then the [1,1'1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride adduct was added (49 mg, 66 pmol). The reaction was heated in a closed tube at 100 °C for 16 h, after which time the reaction was diluted with ethyl acetate, washed with aqueous sodium thiosulfate, brine, dried (NazSO^ and concentrated. Chromatography on a flash column (ethyl acetate: n-Heptane 4:1) gave 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-(trimethylsiIII)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-indole 5-Bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1 H-indole was converted to the title compound by using the general procedure E1 in THF.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-cycloprop¡l-2-(trimethylsil¡l)-1 -((2-(trimethylsil¡l)ethoxy¡)methyl)-1 H- 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 bubbled with argon and the reaction was heated in a microwave at 150SC for 30 min. The reaction was diluted with water and extracted repeatedly with ethyl acetate. The combined organic fractions were washed with water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 4:1) gave 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-2yl)benzenesulfonamide CCfrQ Ln / Zznz / E / YIAI Stage 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 was added. -bromo-2-(difluoromethyl)-1-fluoro-benzene (3.0 g, 13.3 mmol) and the reaction was stirred for an additional 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 colorless liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.77 (d, J = 2.1 Hz, 1H), 7.49 (td, J = 1.1, 8.3 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.27 7.22 ( m, 2H), 7.18-7.15 (m, 2H), 7.07 - 6.75 (m, 1H), 4.03 (s, 2H) Stage 2: 4-bromo-2-(difluoromethyl)benzenesulfonyl chloride To an ice-cold solution of 1-benzylsulfanyl-4-bromo-2-(difluoromethyl)benzene (200 mg, 0.6 mmol) in acetonitrile (5 mL) is added acetic acid (182 mg, 3.0 mmol) and water (0.05 mL, 3 mmol), N-chlorosuccinimide (243 mg, 1.8 mmol) was added and the mixture was stirred for 1 h. The reaction was diluted with ethyl acetate, washed with water, brine and concentrated. Flash column chromatography (1:10 ethyl acetate:heptane) gave the title compound (150 mg, 65%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.16 - 8.12 (m, 1H), 8.03 (d, J = 8.6 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 methylamine dihydrochloride (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) gave 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-2yl)benzenesulfonamide Convert 4-bromo-2-chloro-N,N-dimethyl-benzenesulfonamide (step 3) to the title compound using general procedure F at 80 °C. ([M+H]+362.2). CCfrQ Ln / Zznz / E / YIAI EXAMPLES Ex. No. Structure Product name Molecular weight found From intermediates Prep. 1 I o=s=o IX ιι 3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediariol) and 3-methyl-4(methylsulfonyl) phenyl boronic acid D 2 I o=s=o A / L ιι X H 3-cyclopropyl- 4-(3- methoxy¡-4(methylsulfonyl)phenyl)-1 Hpyrazolo[4,3-c]pyridine [M+H]+ 344.1 4-chloro-3-cyclopropyl-1Hpyrazolo[4,3-c]pyri¡ d¡na (Intermediate 1) and 4- methanesulfonyl-3methoxyphenyl boronic acid D 3 I o=s=o N'^V'V ιι X H 4-(3-chloro-4(methylsulfonyl)phenyl)-3cyclopropyl-1 Hpyrazolo [4,3-c]pyridine [M+H, Cl]+ 348.1 4-chloro-3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 3-chloro-4methanesulfonylphenyl boronic acid D 4 F O =?=O F- / XX ιι -chloro-3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediariol) and 4-methanesulfonyl-3(trifluoromethyl)phenyl boronic acid D 5 I o=s=o ιι T / N H 4-(3-cyclopropyl-1 Hpyrazolo[4,3-c]pyridin-4-yl)-N,N,2-trimethylbenzenesulfonamide [M+H] + 357.1 4-chloro-3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediate 1) and N,N,2trimethyl-4-(4,4,5,5-tetramethyl1,3,2-dioxoborolan-2yl )benzenesulfonamide D 6 \ o / z=O=v° i / írr / —\ — ° IZ __, z xy 3-cyclopropyl-5-methoxy¡4-(4-methylsulfoniI-phenyl)1H-pyrazolo[3,4c ]pyridine [M+H]+ 344.1 4-bromo-3-cyclopropyl-5methoxy¡-1-((2- (trimethyls¡l¡l)ethoxy¡)methyl)-1 Hpyrazolo[3, 4-c]pyridine (Intermediate 2) and 4-(methanesulfonyl)phenyl boronic acid D, J 7 Y o=s=o Ό N^Vv- X H 3-cyclopropyl-4-(4(cyclopropyl- sulfonyl)-3methylphenyl)-1 Hpyrazolo[4,3-c]pyridine [M+H]+ 354.1 4-chloro-3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 2-(4( cyclopropylsulfonyl)-3methylphenyl)-4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 18) D 8 Y o=s=o . i N^YvV' ιι 3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 2-(4(cyclopropylsulfonyl)-3chlorophenyl)-4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 19) D 9 ''--Z> ZI \ ° / —\ )—( O 2-chloro-4-(3cyclopropyl-1 Hpyrazolo[4,3-c]pyridin-4yl)-N,N-dimethylbenzenesulfonamide [M+H]+ 377.1 4-chloro-3-cyclopropyl-1 Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 2-chloroN,N-dimethyl-4-(4,4,5,5tetramethyl-1,3,2dioxaborolan-2yl )benzenesulfonamide (Intermediate 20) D CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 10 I o=s=o [i chloro-3-(trif I uoromethyl)-1 ((2-(trimethyl Isilyl) ethoxy)methyl)1 H-pyrazolo[4,3-c]pyridine (Intermediate 3) and boronic acid 3-methyl-4(methylsulfonyl)phenyl D, J 11 I o=s=o ÓF / F rF h XyN \í^-N H 4-(4- (methylsulfonyl)phenyl)-3(trifluoromethyl)-l Hpyrazolo[4 ,3-c]pyridine [M+H]+ 342.0 4-chloro-3-(trifluoromethyl)-1 ((2-(trimethylsilyl)ethoxy)methyl)1 H-pyrazolo[4,3-c] pyridine (Intermediate 3) and 4-(methanesulfonyl)phenyl boronic acid D, J 12 I F O=S=O OX H 3-cyclopropyl-4-(3methoxy¡-4-(methylsulfonyl)pheníl)-1 Hpyrazolo[4 ,3-c]pyridine [M+H]+ 364.1 4-chloro-3-cyclopropyl-1 Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 2-(3(difluoromethyl)-4(methylsulfonyl)phenyl) -4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 21) D 13 I o=s=o fxtS v [i X / N H 3-cyclopropyl-4-(3(fluoromethyl)-4(methylsulfonyl)phenyl )-1 Hpyrazolo[4,3-c]pyridine [M+H]+ 346.1 4-chloro-3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 2 -(3(difluoromethyl)-4(methylsulfonyl)pheníl)-4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 22) D 14 I o=s=o Ίχ] h 1 and H 3-cyclopropyl -4-(3-methyl4-(methylsulfonyl)phenyl)- 1 H-pyrrolo[3,2c]pyridine [M+H]+ 327.2 4-chloro-3-(trifluoromethyl)-1 ((2-( trimethylsilyl)ethoxy)methyl)1 H-pyrazolo[3,2-c]pyridine (Intermediate 3) and 3-methyl-4(methylsulfonyl)phenyl boronic acid D, J 15 / =^=0^ i, v° ) —\ — ° IZ xz \7 3-cyclopropyl-4-(3-methyl-4-(oxetan-3ylsulfonyl)phenyl)-1 Hpyrazolo[4,3-c]pyridine [M+H] + 370.2 4-chloro-3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 4,4,5,5tetramethyl-2-(3-methyl-4(oxetan-3-ylsulfonyl)phenyl)1 ,3,2-Dioxaborolane (Intermediate 23) D CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 16 I o=s=o V? Y Y ]+ 353.1 4-bromo-3-cyclopropyl-1 Hpyrazolo[3,4-c]pyridine-5carbonitrile (Intermediate 5) and 3methyl-4-(methylsulfonyl)phenyl boronic acid D 17 I o=s=o uF ! H -3-(1,1 -difluoroethyl)1 H-pyrazolo[4,3-c]pyridine (Intermediate 6) and 3-methyl-4(methylsulfonyl)phenyl boronic acid D 18 VXXX” / --\ - Π— ° IZ Λ--- / xz \ 3-(difluoromethyl)-4-(3methyl-4- methylsulfonylpheníl)-1 Hyrazolo[4,3-c]pyridine [M+H]+ 338.1 2- [[4-chloro-3- (difluoromethyl)pyrazolo[4,3c]pyrid i n-1 -i I] m ethoxy]eryltrimethylsilane (Intermediate 7) and 3methyl-4-(methylsulfonyl)phen boronic acid ¡lo D, J 19 I O=S=O ii 330.1 4-chloro-3-isopropyl-1 Hpyrazolo[4,3-c]pyridine and 3-methyl-4(methylsulfonyl)phenyl boronic acid D 20 o=s=o Ό [M+H]+ 314.9 4-chloro -3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 2-(4(ethylsulfonyl-3-methyl-phenyl)4,4,5,5-tetramethyl-1,3,2dioxaborolane (Intermediate 24) D N^Yr-Y t CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 21 / =^ / =0 )—\ / — ° iz z 346.1 4-chloro-3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 2-(2(fluoro-5-methyl-4-methi Isu Ifon i I-1 -phenyl)-4,4 ,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 25) D 22 I o=s=o ii T / N H 3cyclopropyl-4-(2,5dimethyl-4-methylsulfonylphenyl)-1 H-pyrazolo[4,3clpyridine hydrochloride [M+H]+ 342.1 4-chloro-3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 2-(2,5dimethyl-4-methylsulfonyl-phenyl)4, 4,5,5-tetramethyl-1,3,2dioxaborolane (Intermediate 26) D 23 1 zi οΛ=ΑΆ= / 3cyclopropyl-4-(3-methyl-4methylsulfon¡l-phenyl)-1 Hpyrazolo[4] hydrochloride ,3-c]pyridine [M+H]+ 312.2 4-chloro-3-cyclopropyl-1Hpyrazolo[4,3-c]pyridine (Intermediate 1) and 3-methyl-4( boronic acid methylthio)phenyl D, G (1 eq) 24 \ O / 7=0=0 vrU-r / —\ — ° 12 7—-^—1 3-cyclopropyl-5-methoxy¡- 4-(3- methyl-4- (methylsulfonyl)phenyl)-1 Hpyrazolo[3,4-c]pyridine [M+H]+ 358.3 4-bromo-3-cyclopropyl-5- methoxy¡-1-((2- (trimethylsili l)ethoxy)methyl)-1Hpyrazolo[3,4-c]pyridine (Intermediate 2) and 3-methyl-4(methylsulfonyl)phenyl boronic acid D, J 25 v o=s=o Xi 7 0^\ 1 / f N'^-vv h JO H 3-(difluorome-toxy¡)-4[4-(difluoromethylsulfonyl)-3-methyl-phen¡l]-1 Hpyrazolo[4,3-c]pyridine [M+H]+ 390.1 4-chloro-3-(difluoromethoxy)-1 trityl-pyrazolo[4,3-c]pyridine (Intermediate 8) and 2-[4(difluoromethylsulfonyl)-3methyl-phenyl] -4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 27) D, CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 26 Y o=s=o Yj f ob I / f ιι T / N H 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3(difluorome-toxy)-l Hpyrazolo[4,3-c]pyridine [M +H]+ 380.1 4-chloro-3-(difluoromethoxy)-1 trityl-pyrazol[4,3-c]pyridine (Intermediate 8) and 2-(4(cyclopropylsulfonyl)-3methylphenyl)-4,4, 5,5tetramethyl-1,3,2dioxaborolane (Intermediate 18) D, H 27 O=S=O Yj F ob I / f N bl \^~~N H 3-(difluorome-toxy)-4(4-ethylsulfonyl-3 -methylphenyl)-1 H-pyrazolo[4,3-c]pyridine [M+H]+ 368.0 4-chloro-3-(difluoromethoxy¡)-1 trityl-pyrazolo[4,3-c]pyridine (Intermediate 8) and 2-[4-(4ethylsulfonyl-3-methyl-phenyl)4,4,5,5-tetramethyl-1,3,2dioxaborolane (Intermediate 24) D, H 28 i / iYr / —\ — ° IZ z X / ° 4-(3-methyl-4methylsulfonyl-phenyl)-3(oxetan-3-yl)-1 Hpyrazolo[4,3-c]pyridine [M+H]+ 344.0 4-chloro -3-(oxetan-3-yl)-1 tetrahydropyran-2-ylpyrazolo[4,3-c]pyridine (Intermediate 9) and (3-methyl-4(methylsulfonyl)phenyl boronic acid D, 11 29 b o =s=o Yj F b o—\ I / f ii Y H 4-[4-(cyclopropylmethylsulfonyl)-3-methylphenyl]-3-(difluoromethoxy¡)-1 H-pyrazolo[4,3c]pyridine [ M+H]+ 394.1 4-chloro-3-(difluoromethoxy¡)-1 trityl-pyrazolo[4,3-c]pyridine (Intermediate 8) and 2-[4(cyclopropylmethylsulfonyl)-3methyl-phenyl] -4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 28) D, H 30 O=S=O Yj F ob 1 / F ii Y H 3-(difluoromethox¡)-4-[3(difluoromethox¡) -4methylsulfonylphenyl]-1 Hpyrazolo[4,3-c]pyridine [M+H]+ 382.2 4-chloro-3-(difluoromethoxy)-1 trityl-pyrazolo[4,3-c]pyr Dynane (Intermediate 8) and 4,4,5,5tetramethyl-2-(3-methyl-4propylsulfonyl-phenyl)-1,3,2dioxaborolane (Intermediate 29) D, H 31 1 F O=S=O Y j ] ob 1 / F nYY Η Γ zN YY H 3-(difluorome-toxy)-4(4-(isopropylsulfonyl-3methyl-phenyl)-1 Hpyrazolo[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) -4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 21) D, H CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 32 o=s=o Yj F Y Ο'Λ I / F ii + 382.0 4-chloro-3-(difluoromethoxy)-1 trityl-pyrazolo[4,3-c]pyridine (Intermediate 8) and 2-[4-(4isopropylsulfonyl-3-methylphenyl)-4,4,5, 5-tetramethyl1,3,2-dioxaborolane (Intermediate 30) D, H 33 ^NH I o-s-o Yj j oY I / F |i Y ” H 4-[3-(difluoromethox¡)1H-pyrazolo[4,3c]pyridin -4-yl]-N,2dimethyl-benzenesulfonamide [M+H]+ 369.0 4-chloro-3-(difluoromethox¡)-1 trityl-pyrazolo[4,3-c]pyridine (Intermediate 8) and N,2dimethyl- 4-(4,4,5,5-tetramet¡l1,3,2-dioxaborolan-2¡l)benzenesulfonamide (Intermediate 30) D, H 34 1 o=s=o N^YY ii T / N CYY 6- chloro-3-cyclopropyl-4(3-methyl-4-methylsulfonylphenyl)-1 H-pyrazolo[4,3c]pyridine [M+H]+ 362.3 4,6-dichloro-3-cyclopropyl-1 Hpyrazolo[4 ,3-c]pyridine (Intermediate 10) and 3-methyl-4(methylsulfonyl)phenyl boronic acid D 35 o Ϋ o=s=o H 3-(difluorome-toxy¡)-4[3-methyl- 4-(oxetan-3ylsulfonyl)phenyl]-1 Hpyrazolo[4,3-c]pyridine [M+H]+ 396.1 4-chloro-3-(difluoromethox¡)-1 trityl-pyrazolo[4,3-c]pyridine (Intermediate 8) and 4,4,5,5tetramethyl-2-(3-methyl-4(oxetan-3-ylsulfonyl)phenyl)1,3,2-dioxaborolane (Intermediate 23) D, H 36 OH o= s=o Yj j oY 1 / p ü Y / N \íí^N H 2-[4-[3-(difluoromethox¡)-1 H-pyrazolo[4,3c]pyridin-4-yl]-2-methylphenyl] sulfo-nylethanol [M+H]+ 384.1 4-chloro-3-(difluoromethox¡)-1 trityl-pyrazolo[4,3-c]pyridine (Intermediate 8) and tert-butyl-dimethyl-[2 -[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]sulfon¡letoxy¡]si-lane (Intermediate 32) D, H CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 37 / —\ — ° 3-(difluoromethoxy¡)-4-[3methyl-4-(1-methylcyclopropyl)sulfonylphenyl]-1 Hpyrazolo[4,3-c]pyridine [M+H]+ 394.1 4-chloro-3 -(difluoromethoxy)-1 trityl-pyrazolo[4,3-c]pyridine (Intermediate 8) and 4,4,5,5tetramethyl-2-[3-methyl-4-(1 methylcyclopropyl)sulfonylphenyl]- 1,3,2-dioxaborolane (Intermediate 33) D, H 38 I 0^ o=s=o / o—\ I / f N'^r^s Η T / N \í^-N H 3-(difluoromethox¡ )-4-[4(methoxyme-tylsulfonyl)3-methyl-phenyl]-1 Hpyrazolo[4,3-c]pyridine [M+H]+ 384.1 4-chloro-3-(difluoromethoxy)-1 tritile -pyrazolo[4,3-c]pyridine (Intermediate 8) and 2-[4(methoxymethylsulfonyl)-3methyl-phenyl]-4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 34) D, H 39 i o=s=o uF \rF J. / r ¡na [M+H]+ 386.3 4-bromo-5-methoxy-3(trifluoromethyl)-2-((2(trimethylsilyl)ethoxy¡)methyl)-2Hpyrazolo[3,4-c]pyrádi¡ na (Intermediate 11) and 3-methyl-4(methylsulfon¡l)phenyl boronic acid D, J 40 I o=s=o XTj f \-F 1 Λ F H 1 7 H 4-(3- methyl-4(methylsulfonyl)phenyl)-3(trifluoromethyl)-l Hpyrrolo[3,2-c]pyridine [M+H]+ 355.2 4-chloro-3-(trif I uoromethyl)-1 ((2-(trimet ¡ls¡lyl)ethoxy)methyl)1 H-pyrrolo[3,2-c]pyridine (Intermediate 12) and 3-methyl-4(methylsulfonyl)phenyl boronic acid D, J 41 / or / Z=V / = O γΗ / Τ / —\ — ° IZ _ 'z \7 3-cyclopropyl-5(methoxymethyl)-4-(3methyl-4- (methylsulfonyl)phenyl)-1 Hpyrazolo[3,4-c]pyridine [M+ H]+ 372.2 4-bromo-3-cyclopropyl-5(methoxymethyl)-l -(tetrahydro2H-pyran-2-yl)-1 Hpyrazolo[3,4-c]pyridine (Intermediate 13) and boronic acid of (3- methyl-4(methylsulfonyl)phenyl D, 11 42 ^-y ZI 3-cyclopropyl-4-(4-ethylsulfonyl-3-methylphenyl)-1 H-pyrazolo[3,4c]pyridine-5-carbon trilo [M+H]+ 367.0 4-bromo-3-cyclopropyl-1 Hpyrazolo[3,4-c]pyridine-5carbonitrile (Intermediate 5) and (4-(ethylsulfonyl-3-methylphenyl)-4, 4,5,5-tetramethyl1,3,2-dioxaborolane (Intermediate 24) D CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 43 Y o=s=o T / n^^n' H 3-cyclopropyl-4-(4cyclopropyl-sulfonyl-3methyl-phenyl)-1 Hpyrazolo[3,4-c]pyridine5-carbonitrile [M+H]+ 379.0 4-bromo-3-cyclopropyl-1 Hpyrazolo[3,4-c]pyridine-5carbonitrile (Intermediate 5) and 2-(4-(cyclopropylsulfoníl)-3methylphenyl)-4,4,5,5tetramethyl-1,3 ,2dioxaborolane (Intermediate 18) D 44 I o=s=o XX F ,f i ° I i > H 4-(3-methyl-4(methylsulfonyl)phenyl)-5(methylsulfonyl)-3(trifluoromethyl)-1Hindazol [M +H]+ 433.2 4-bromo-5-(methylsulfon¡l)-3- (trifluoromethyl)-l-((2- (trimethylsili l)ethoxy) methyl)-1Hindazol (Intermediate 14) and boronic acid of (3- methyl4-(methylsulfonyl)phenyl D, J 45 / / , / / ​​o / \ \ ii vXv^íi / —\ — ° IZ 3-cyclopropyl-4-(3-methyl- 4-methylsulfonylphenyl)- 1 H-indole-5-carbonitrile [M+H]+ 351.2 3-cyclopropyl-4-(3-methyl-4- (methylsulfonyl)phenyl)-2- (trimethylsilyl)-l -((2- (trimethylsilyl) )ethoxy)methyl)-1Hindol-5-carbonitrile (Intermediate 37) and (3-methyl-4(methylsulfonyl)phenyl boronic acid D, J2 46 / TZ )^° / Z —( ,--( O / 7 Ά / \ 11 \ i—(\ / )— \— / / / II / —— ° ZZ A- _, sz^^7 3-cyclopropyl-4-(4cyclopropyl-sulfonyl-3methyl-phenyl)-N-methyl- 1 Hpyrazolo[3,4-c]pyridine5-carboxamide [M+H]+ 411.2 4-bromo-3-cyclopropyl-Nmethyl-1 H-pyrazolo[3,4c]pyridine-5-carboxamide (Intermediate 15) and 2-(4(cyclopropylsulfonyl)-3methylphenyl)-4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 18) D 47 A / z=\ θ \\ 7--W — v X \— / ii ?—\ —\ ° IZ zK.__, ' ζ'Λχ 3-cyclopropyl-4-(2fluoro-5-methyl-4methylsulfon¡l-phen¡l)-1 Hpyrazolo[3,4-c]pyridine5-carbonitrile [ M+H]+ 371.0 4-bromo-3-cyclopropyl-1 Hpyrazolo[3,4-c]pyridine (Intermediate 5) and 2-(2(fluoro-5-methyl-4- methi Isu Ifon i I-1 - phenyl)-4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 25) D 48 1 F O=S=O ,Λά λ 1 0-A 1 J F íl X 'N H 4-[3-(difluoromethoxí )1H-pyrazolo[4,3c]pyridin-4-yl]-2(difluoromethyl)-N,Ndimethyl-benzenesulfonamide [M+H]+ 419.1 4-chloro-3-(difluoromethoxy)-1 trit¡l- pyrazolo[4,3-c]pine (Intermediate 8) and 2(difluoromethyl)-N,N-dimethyl4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2yl) Benzenesulfonamide (Intermediate 38) D, H CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 49 o, / / ​​o / \ / \ 11 vZvj^íí / —\ — ° 3-(difluoromethoxy¡)-4-(3methyl-4-(methylsulfonyl)phen¡l)-5(methylsulfonyl)-l Hindazol [M +H]+ 430.1 4-bromo-3-(difluoromethoxy¡)5-(methylsulfonyl)-1-trityl-1 Hindazole (Intermediate 16) and 3-methyl-4(methylsulfonyl)phenyl boronic acid D, H 50 v o=s=o hK Y / IiTÁ n^nz H 3-cyclopropyl-4-[4(difluoromethylsulfonyl)3-methyl-phenyl]-1 Hpyrazolo[3,4-c]pyridine5-carbonitrile [M+H] + 389.0 4-bromo-3-cyclopropyl-1 Hpyrazolo[3,4-c]pyridine-5carbonitrile (Intermediate 5) and [4- (difluoromethylsulfonyl)-3methyl-phenyl]-4,4,5,5tetramethyl-1, 3,2dioxaborolane (Intermediate 27) D 51 1 F O=S=O F^ó 0 r Η ll N H 3-cyclopropyl-4-[3(difluoromethyl)-4methylsulfoníl-pheníl]-Nmethyl-1 H-pyrazolo[ 3,4c]pyridine-5carboxamide [M+H]+ 421.2 4-bromo-3-cyclopropyl-Nmethyl-1 H-pyrazolo[3,4c]pyridíne-5-carboxamide (Intermediate 15) and 2-( 3- (difluoromethyl)-4- (methylsulfonyl)phenyl)-4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 21) D 52 1 o=s=o U J T pF VH n^Anz H 3-(difluoromethox ¡)-4-(3methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4c]pyrádina-5-carbonitrilo [M+H]+ 379.1 4-bromo-3-(difluoromethoxy)1 - trityl-pyrazolo[3,4-c]pyridine5-carbonitrile (Intermediate 17) and 3methyl-4-(methylsulfonyl)phenyl boronic acid D, H 53 o. / F YY J Vi y y ^ílV^N H 3-(difluoromethox¡)-4-[5(difluoromethyl)-2-methyl4-methylsulfinyl-phenyl]-1 Hpyrazolo[3,4-c]pyridine5-carbonitrile [M +H]+ 413.1 4-bromo-3-(difluoromethox¡)1 -trityl-p¡razolo[3,4c]pyrádine-5-carbonitrile (Intermediate 17) and 4bromo-3-(difluoromethox¡)- 1 trityl-pyrazol[3,4-c]pyridine5-carbonitrile (Intermediate 35) D, H 54 \ X O >—-n / =0=0 Í / ÍO / --\ -Π— ° “v / Yn 4-[3-(difluoromethyl)-4methylsulfonyl-phenyl]-5methoxy-3(trifluoromethyl)-l Hpyrazolo[3,4-c]pyridine [M+H]+ 422.2 4-bromo-5- methoxy¡-3- (trifluoromethyl)-2-((2- (trimethyls¡l¡l)ethoxy)methyl)-2Hpyrazolo[3,4-c]pyridine (Intermediate 11) and 2-(3- (difluoromethyl)-4- (methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (Intermediate 21) D, J CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 55 ll \— / \— / θ / o., / / \ o 4-(4-cyclopropylsulfoníl-3-methylphenyl)-3(difluorome-toxy¡)-5methylsulfonyl-1 Hindazole [M+H]+ 457.1 4-bromo-3-(difluoromethoxy¡)5-methylsulfonyl-1-trityl-indazole (Intermediate 36) and 2-(4(cyclopropylsulfonyl)-3methylphenyl)-4,4,5,5tetramethyl-1,3,2dioxaborolane (Intermediate 18) D, J Example 56: 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[4,3-c]pyrid ¡na 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c¡r¡dina (CAS: 1416713-66-0, document US2014 / 128374 A1) is reacted with 3-methyl-4-(methylsulfon¡l)phenyl boronic acid (1.1 eq) at 100 °C using general procedure D. ([M+H]+372.2). Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine 4-(3-methyl-4-(methylsulfonyl)phenyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[4,3-c]pyridine was dissolved (step 1) ( 40 mg, 0.1 mmol) in dioxane / DCM (2.0 / 0.5 ml) and HCl (50 pL, 4 N in dioxane, 0.2 mmol) was added. The reaction was stirred for 16 h after which time it was washed with saturated sodium hydrogen carbonate, water, brine, dried (NaaSCU) and concentrated to obtain the title compound (23 mg, 6-7%) as an off-white solid. ([M+H]+288.1). Step 3: 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine 4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine (step 2) (23 mg, 0.1 mmol) was suspended in DCM (1.5 ml) and added N-bromosuccinimide (14 mg, 0.1 mmol). The reaction was stirred for 2 h after which time it was concentrated to dryness. Flash column chromatography (ethyl acetate: n-heptane 4:6-1:0) gave the title compound (185 mg, 71%) as a white solid. ([M+H, Br]+366.1). Example 57 and 58: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3c]pyridine and 3-methoxy-4-(3-methyl-4-( methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine CCfrQ Ln / Zznz / E / YIAI 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 eq) and triethylamine (1 eq) in ethanol at 80 °C, according to general procedure C, to obtain the title compound. ([M+H,CI] + = 170.0). Step 2: 4-chloro-1 -trityl-1 H-pyrazolo[4,3-c]pyri¡d¡η-3-ol 4-Chloro-1,2-dihydro-3H-pyrazol[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 a nitrogen atmosphere. The cooling bath was removed and the reaction was stirred for 2 h upon reaching room temperature. The reaction was stopped by addition of saturated aqueous ammonium chloride, extracted repeatedly with ethyl acetate, and the combined organic extracts were washed with brine and concentrated. Flash column chromatography (ethyl acetate: nHeptane 1:1) gave 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-1 H-pyrazolo[4,3-c]pyridiη-3-ol The title compound ([M+H]+546.2) was prepared from Suzuki coupling of 4-chloro-1trityl-1 H-pyrazolo[4,3-c]pyridín-3-ol (step 2 ) and 3-methyl-4-(methylsulfon¡l)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-1 H-plrazolo[4,3-c]pyridine and 3methoxy)-4 -(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1 H-pyrazolo[4,3-c]pyridine To a mixture of 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1 H-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) methyl 2-chloro-2,2difluoroacetate (20 pL, 0.2 mmol) was added. The reaction was shaken in a sealed tube at 80 °C for 30 min. The reaction was diluted with ethyl acetate, washed with water, brine, dried (NasSCU) and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 0:1-1:4) gave the title compounds as a mixture (4:1) (27 mg, 35%) as a white solid. ([M+H]+= 560.3 and 560.3). Step 57: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-plrazolo[4,3-c]pyridine and 3 -methoxy¡4-(3-metll-4-(methylsulfon¡l)phenyl)-1 H-pyrazolo[4,3-c]pyridine The mixture of 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1 Hpyrazolo[4,3-c]pyridine and 3-methoxy-4-( 3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1 H-pyrazolo[4,3-c]pyridine (step 4) by using general procedure H to obtain the title compounds, separated by HPLC preparative reverse phase. ([M+H]+354.1 and 318.2). Example 59: 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline CCfrQ Ln / Zznz / E / YIAI Step 1: 3-cyclopropyl-4-(3-fluoro-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine The title compound ([M+H]+332.1) was prepared from Suzuki coupling of 4-chloro-3cycloproyl-1 H-pyrazolo[4,3-c]pyridine (step 1) and 3-methyl boronic acid -4-(methylsulfonyl)phenyl with potassium carbonate at 100 °C according to general procedure D. Step 2: 5-(3-cyclopropyl-1 H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline In a pressure tube, 3-cyclopropyl-4-(3-fluoro-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3c]pyridine (step 1) (30 mg, 0.1 mmol) was added, ammonium was condensed. (approx. 3 mL) at -78 °C. The tube was then sealed and then allowed to warm to room temperature and stirred for 8 days. Evaporation of ammonium and flash column chromatography (ethyl acetate: n-heptane 1:1-1:0) gave the title compound (6 mg, 21%) as a white solid. ([M+H]+329.1). 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-íl)-1 H-pyrazolo[4,3c]pyridine To a mixture of 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine (Product 56) (648 mg, 1.8 mmol) in THF (20 mi) 3,4-dihydro-2H-pyran (1.6 ml, 17.7 mmol) and ptoluenesulfonic acid monohydrate (34 mg, 0.2 mmol) were added and the reaction mixture was stirred at 70 °C for 36 h after which time concentrated in vacuo. The residue was redissolved with ethyl acetate and washed with water, dried (Na2SO4) and concentrated. Flash column chromatography (DCM: MeOH 1:0-9:1) gave the title compound (689 mg, 78%) as a yellow solid. ([M+H]+452.1). Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1 H -pyrazolo[4,3c]pyridine 3-bromo-4-(3-methyl-4-(methylsulfon¡l)phen¡l)-1-(tetrahydro-2H-pyran-2-¡l)-1 H-pyrazolo[4,3 -c]pyridine (step 1) (102 mg, 0.2 mmol) was dissolved in DMSO (2.5 ml). 2-Methyl-2-thiopsuedourea sulfate (63 mg, 0.2 mmol) and cesium carbonate (295 mg, 0.9 mmol) were added. The reaction mixture was heated at 100 °C for 15 h. The reaction mixture was allowed to cool to RT, then silica gel was added. The suspension was concentrated under high vacuum. The crude mixture was purified by flash column chromatography (0:1-1:0 ethylom acetate-heptane) to obtain the title compound (40 mg, 42% yield) as a light yellow gum. ([M+H]+418.1). Step 3: 4-(3-methyl-4-(methylsulfon¡l)phen¡l)-3-(met¡l)-1 -(tetrahydro-2H-pyran-2-¡l)-1 H-pyrazolo[4,3c]plridina 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1 H was oxidized -pyrazolo[4,3c]pyridine (step 2) to the title compound by using general procedure G. ([M+H]+450.2). Step 4: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1 H-pyrazolo[4,3-c]pyridine 4-(3-methyl-4-(methi Isu Ifon i l)pheni l)-3-(methi Iti o)-1 -(tetrahydro-2 H-pi ran-2-¡ I) -1Hpyrazolo[4, 3-c]pyridine (Step 3) by using general procedure I to obtain the title compound. ([M+H]+366.0). Example 61: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile CCfrQ Ln / Zznz / E / YIAI Step 1: 4-(3-methyl-4-(methylsulfon¡l)phenyl)-1 -(tetrahydro-2H-pyran-2-¡l)-1 H-pyrazolo[4,3-c]pyr¡ dyne-3carbonitrile 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 Hpyrazolo[4,3-c]pyridine (Intermediate 60) was resuspended , step 1) (40 mg, 0.1 mmol), zinc cyanide (10 mg, 0.1 mmol) and tetrakistriphenylphosphine palladium (15 mg, 0.01 mmol) in DMF (1 ml) at room temperature. The reaction mixture was heated at 150 °C for 0.5 h in a microwave reactor. Silica gel was added to the reaction mixture and concentrated. The crude mixture was purified by flash column chromatography (0:1-1:0 ethylom acetate-heptane) to obtain the title compound (16 mg, 44% yield) as a yellow solid. ([M+H]+ 397.2). Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazol[4,3-c]pyridine-3-carbonyl 4-(3-methyl-4-(met¡ Isu Ifon i l)phen¡ I)-3-(met¡ Iti o)-1 -(tetrahydro-2H-pyran-2-¡l)-1 Hpyrazolo[ was deprotonated 4,3-c]pyridine (Step 1) by using general procedure I to obtain the title compound. ([M+H]+313.1). Example 62: 3-cyclopropyl·4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine-5carboxylic acid CCfrQ Ln / Zznz / E / YIAI 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrol was suspended (Example 16 ) (20 mg, 0.1 mmol) in aqueous sodium hydroxide solution (0.5 ml, 6 M, 3.0 mmol) and the mixture was heated at 100 °C for 16 h. The reaction was cooled to room temperature, acidified with 37% HCl, and concentrated. Purification by preparative reverse phase HPLC provided 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-(cycloprop¡l(hydroxy¡)methyl)-4-fluorobenzonítrile 2-Bromo-4-fluorobenzonitrile is treated with LDA (1.3 eq) for 10 minutes before the addition of cyclopropanecarbaldehyde (1.4 eq) according to general procedure A.1H NMR (CHLOROFORM-d, 300 MHz) δ 7.62 (dd, 1H, J=5.2, 8.7 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-fluorobenzonitetrile was oxidized by using general procedure B1 to obtain 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)benzonium The title compound ([M+H]+358.2) was prepared from Suzuki coupling of 2-bromo-3(cyclopropanecarbonyl)-4-fluorobenzonitrile (Step 2) and 3-methyl-4-(methylsulfonyl) boronic acid. phenyl with potassium carbonate at 90 °C in accordance with 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 eq) in THF at room temperature. , in accordance with general procedure C, to obtain 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 CCfrQ Ln / Zznz / E / YIAI Step 1: 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridine A mixture of N-bromosuccinimide (109 mg, 0.6 mmol), 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1 H-pyrazolo[4,3-c]p Radina (Example 1) (100 mg, 0.3 mmol) in DMF (2 mL) was stirred at 80 °C for 24 h. The reaction was purified directly by preparative reverse phase HPLC which provided the title compound (30 mg, 24%) as a green solid. ([M+H, Br]+405.8). Step 2: 3-cyclopropyl-4-(3-methyl-4-(methylsulfoniyphenyl)-1 H-pyrazolo[4,3-c]pyridin-7-ol To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-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), tBuXFos (4 mg, 0.01 mmol, 0.060 eq) in dioxane (1.5 mL) and water (1 mL) and the mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. 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 O=S=O Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1 -(tetrahydro-2H-pyran-2-¡l)-3-(thiophen-3-yl)-1 H-pyrazolo[4, 3c]pyridine 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazolo[4,3-c]pyridine was reacted (Intermediate 60, step 1) with thiophene-3-boronic acid 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)-1 H-pyrazolo[4,3-c]piñdine 4-(3-methyl-4-(methi Isulfoni l)phenyl)-1 -(tetrahydro-2H-pyran-2-yl)-3-(thiophen-3-yl)-1 Hpyrazolo[4,3- c]pyridine (Step 1) by using the general procedure I2 to obtain the title compound. ([M+H]+370.2). Example 66: 3-ethoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine CCfrQ Ln / Zznz / E / YIAI o=s=o 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), cesium carbonate (120 mg, 0.4 mmol) and iodoethane (0.04 mL, 0.6 mmol) were added and the reaction mixture was stirred at 80 °C for 2 h. The reaction was filtered and concentrated. Purification by flash column chromatography (3:1 heptane:ethyl acetate) to obtain the title compound (60 mg, 54%) as a white solid. ([M+H]+574.3). Step 2: 3-ethoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine 3-Ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-pyrazolo[4,3-c]pyridine is deprotonated by using general procedure H to obtain the title compound . ([M+H]+332.1). Example 67: 3-cyclopropyl-7-fluoro-4-(3-methyl-4-(methylsulfonyl-phenyl)-1H-pyrazol[4,3-c]pyri d¡n 7-ol CCfrQ Ln / Zznz / E / YIAI 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 eq) for 30 minutes before the addition of cyclopropanecarbaldehyde (1.4 eq) according to general procedure A. ([M+H, Br]+280.0) Step 2: 2-bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanone 2-Bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanol was oxidized by using general procedure B1 to obtain the title compound. ([M+H, Br]+278.0). Step 3: [4-chloro-5-fluoro-2-(3-methyl-4-methylsulfonyl-phenyl)-3-pyridyl]-cyclopropyl -methanone The title compound ([M+H]+368.1) was prepared from Suzuki coupling of 2-bromo-4chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanone (step 2) and 3-methyl boronic acid -4-(methylsulfonyl)phenyl with potassium carbonate at 100 °C, according to general procedure D. Step 4: 3-cyclopropyl-7-fluoro-4-(3-methyl-4-(methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyr dna 4-Chloro-5-fluoro-2-(3-methyl-4-methylsulfonyl-phenyl)-3-pyridyl]-cyclopropyl-methanone (step 3) was reacted with hydrazine hydrate (5 eq) in dioxane at 60 °C, according to general procedure C, to obtain the title compound. ([M+H]+346.1). Example 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 eq) for 0.5 h and reacted with ethyl chloroformate (1.2 eq) for 0.5 h, according to general procedure A, to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (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-1 H-indazole-5-carbonitrile Ethyl 2-bromo-3-cyano-6-fluorobenzoate (Step 1) was reacted with hydrazine hydrate (1 eq) and triethylamine (1 eq) in ethanol at 80 °C, according to general procedure C, to obtain the title compound. ([M+H, Br]+240.0). Step 3: 4-bromo-3-hydroxy¡-1 -trityl-1 H-indazole-5-carbonitrile 4-bromo-3-oxo-2,3-dihydro-1 H-indazol-5-carbonitrillo (step 2) (180 mg, 0.8 mmol) in DMF (5 mL) sodium hydride (36 mg, dispersion at 60% in mineral oil, 0.9 mmol) and triphenylmethyl chloride (232 mg, 0.8 mmol) at 0 °C under a nitrogen atmosphere. The cooling bath was removed and the reaction was stirred for 2 h upon reaching room temperature. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-heptane 0:1-1:1) gave the title compound (136 mg, 36%) as a white solid. ([M+Na]+502.1). Step 4: 3-hydroxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1 H-indazole-5-carbonitrile The title compound ([M-H] 568.4) was prepared from Suzuki coupling of 4-bromo-3hydroxy-1-trityl-1 H-indazole-5-carbonitrile (step 3) and 3-methyl-4-boronic acid. (methylsulfonyl)phenyl with cesium carbonate at 100 °C according to general procedure D. Step 5: 3-methoxy-4-(3methyl-4-(methylsulfonyl)phenyl)-1 H-lndazol-5-carbonitrillo and 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)1 H-indazole-5-carbonitrile To a mixture of 3-hydroxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1 H-indazole-5-carbonitrile (step 3) (49 mg, 0.1 mmol) and potassium carbonate (48 mg, 0.3 mmol) in DMF (1 mL) methyl 2-chloro-2,2difluoroacetate (20 pL, 0.2 mmol) was added. The reaction was shaken in a sealed tube at 80 °C for 50 min. The reaction was diluted with ethyl acetate, washed with water, brine, dried (NazSCU) and concentrated to obtain 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl. -1H-indazol-5-carbonitrile and 3methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazol-5-carbonitrile as a crude mixture that was used directly . The mixture of 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1 H-indazole-5carbonitrile and 3-methoxy-4-(3-methyl-) is deprotonated. 4-(methylsulfonyl)phenyl)-1-trityl-1 H-indazol-5-carbonitrile (step 4) using general procedure H to obtain the title compounds, is separated by preparative reverse phase HPLC. ([M+H]+342.2 and 378.2). Example 70: 3-cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine CCfrQ Ln / Zznz / E / YIAI CCfrQ Ln / zznz / E / YiAi Step 1: cycloprop¡l(2,4,6-trichlorop¡r¡din-3-¡l)methanone 2,4,6-Trichloropyridine was deprotonated with LDA (0.9 eq) for 1 h and cyclopropanecarbaldehyde (1.5 eq) was reacted for 1.5 h according to general procedure A, to obtain cyclopropyl(2,4,6-trichloropyridine-3 Crude -yl)methanol, which was directly oxidized by using general procedure B1 to obtain the title compound. ([M+H Cl]+= 250.1). Step 2: 4,6-dichloro-3-cyclopropyl-1 H-prázolo[4,3-c]pindina Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone (etapal) was reacted with hydrazine hydrate (5 eq) in ethanol at room temperature, according to general procedure C, to obtain the title compound. ([M+H Cl]+= 228.1). 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 4,6dichloro-3-cycloproyl-1 H-pyrazolo[4,3-c]pyridine (step 2) and 3-methyl-4-(methylsulfon¡l)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)-1 H-pyrazolo[4,3-c]pyridine was protected ( step 3) (50 mg, 0.1 mmol) with SEM by using general procedure E2. The crude product was dissolved in 2 M sodium methoxide in MeOH (2mL) and the reaction was heated in a microwave at 130 °C for 30 minutes. 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 obtain 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 I o=s=o CCfrQ Ln / Zznz / E / YIAI Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1 -tritiI-1 H-pyrazolo[4,3-c]pyridine To a mixture of 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1 H-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) 1(trifluoromethyl)-113-benzo[d][1,2]odaoxol-3(1H)-one was added ( 40 mg, 0.3 mmol). The reaction was at room temperature for 16 h after which time a second portion of potassium carbonate (35 mg, 0.3 mmol) and 1-(trifluoromethyl)-l l3-benzo[d][1,2]iodaoxol-3 were added. (1 H)-one (40 mg, 0.3 mmol) and the mixture was stirred for an additional 16 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 1:1-1:4) gave the title compound (12 mg, 22%) as a colorless gum. ([M+H]+614.4). Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1 H-pyrazolo[4,3-c]pyridine 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1-trityl-1 H-pyrazolo[4,3-c]pyridine was deprotonated (step 1) using general procedure H to obtain the title compound. ([M+H]+372.2). Example 72: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5carboxamide Step 1: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1 Hp¡razolo[3,4-c]pine acid n-5-carboxylic acid To a solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine-5carboxylic acid (Example 62) (147 mg, 0.4 mmol) in dichloromethane (4ml) 3,4-dihydro-2H-pyran (73 μΙ, 0.8 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.1 mmol) were added and the reaction was stirred for 7 h. Concentration of the reaction gave the crude compound (181 mg, quant.) as a brown foam. ([M+H]+456.3). Step 2: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide A acid 3-cyclopropyl-4-(3-methyl-4-(methylsulfoníl)phenyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[3,4c]pyridina- 5-carboxylic acid (45 mg, 0.1 mmol) in DMF (1 ml) TBTU (48 mg, 0.2 mmol) was added followed by triethylamine (41 pL, 0.3 mmol). After 0.5 h, ammonium hydroxide (39 pL, 1 mmol) was added and the mixture was stirred for 30 min. The reaction was concentrated, redissolved in HCl (0.5 ml, 4 N in dioxane, 2 mmol) and the reaction was stirred for 6 h at 50 °C after which time the reaction was again concentrated to dryness. Purification by reverse phase HPLC gave the title compound (3 mg, 8%) as an off-white solid. ([M+H]+371.3). Example 73: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5carboxamide I o=s=o CCfrQ Ln / Zznz / E / YIAI 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)-1 H-pyrazolo[3,4-c]pyridine-5carboxylic acid (Example 72, step 1) and methylamine hydrochloride. Example 74: 3-cyclopropyl-4-(3-methylsulfon-4-(methylsulfonyl)phenyl)-1H-pyrazol[3,4-d]pyr dazna Step 1: Methyl 3-cyclopropyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carboxylate To a solution of methyl 3-cyclopropyl-1 H-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 (3:7 heptane:ethyl acetate) gave the title compound (374 mg, 82%) as a colorless oil. ([M+H]+251.1). Step 2: (3-cyclopropyl-1 - (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl)methanol To a solution of cooled methyl 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carboxylate (step 1) (1.1 g, 4.6 mmol) in THF (34 ml). At -78 °C under argon, diisobutylaluminum hydride (9.11 ml, 1 M in THF, 9.1 mmol) was added and the mixture was stirred at this temperature for 30 min before reaching room temperature. The reaction was cooled again to -78 °C and water (0.3 ml) was added and the reaction returned to room temperature again, addition of Na2SÜ4 followed by filtration and concentration gave the title compound (670 mg, 63% ) as a white solid. ([M+H]+223.2). Step 3: 3-cyclopropyl-1 -(tetrahydro-2H-pyran-2-iI)-5-(((tetrahydro-2H-pyran-2-yl)ox¡)methyl)-1 H-pyrazole To a solution of (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-¡l)-1 H-pyrazol-5-yl)methanol (step 2) (300 mg, 1.4 mmol) in DCM (5 ml), 3,4-dihydro-2H-pyrane (136 μΙ, 1.6 mmol) and ptoluenesulfonic acid monohydrate (26 mg, 0.1 mmol) were added 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) gave the title compound (354 mg, 66%) as a light yellow oil. ([M+H]+307.1). Step 4: 3-cyclopropyl-1 -iodo-1 -(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-¡l)ox¡)met¡ l)-1 Hpyrazole To a solution of 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)ox¡)methyl)1 H-pyrazole (step 3) (402 mg, 1.3 mmol) in dichloromethane (2.5 ml) N-iodosuccinimide (413 mg, 1.8 mmol) was added and the reaction was stirred at room 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) gave the title compound (400 mg, 68%) as a light yellow oil. ([M+H]+433.1). Step 5: (3-cyclopropyl-1 - (tetrah id ro-2H-pi ran-2-yl)-5-(((tetrah idro-2H-pyran-2-yl)oxy) methi I) -1Hpyrazole-4 -¡l)(3-methyl-4-(methylsulfonyl)phen¡l)methanol To an ice-cold solution of 3-cyclopropyl-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro2H-pyran-2-yl)oxy)met ¡l)-1 H-pyrazole (step 4) (50 mg, 0.1 mmol) in THF (0.2 ml) under an argon atmosphere the isopropylmagnesium chloride-lithium chloride complex (98 μΙ, 1.3 M in THF, 0.1 mmol The reaction was warmed to room temperature for 5 min and then cooled to 0 °C before stopping with a solution of 3-methyl-4-(methylsulfonyl)benzaldehyde (28 mg, 0.1 mmol) dissolved in THF (0.1 e) and subsequently the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, water, brine, dried (Na2SO4) and concentrated. Column chromatography Ultrafast (ethyl acetate: n-heptane 1:9-4:1) gave the title compound (40 mg, 62%) as an off-white solid ([M+H]+505.4). Step 6: (3-cyclopropyl-5-(hydroxymethyl)-1 H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol CCfrQ Ln / Zznz / E / YIAI (3-cyclopropyl-1 - (tetrah id ro-2H-pi ran-2-yl)-5-(((tetrah idro-2H-pyran-2-yl)oxy) methi I) -1Hpyrazole-4- was dissolved ¡l)(3-methyl-4-(methylsulfon¡l)phenyl)methanol (step 5) (41 mg, 0.1 mmol) in HCl (1.0 ml, 4 N in dioxane, 4.1 mmol) and water was added ( 15 μΙ, 0.1 mmol). The reaction mixture was subsequently stirred at 45 °C for 5 min after which time it was concentrated to obtain the crude title compound (40 mg, quant.) as a light yellow gum. ([M+H]+337.2). Step 7: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-d]pyridazine To a solution of (3-cyclopropyl-5-(hydroxymethyl)-1 H-pyrazol-4-yl)(3-methyl-4(methylsulfonyl)phenyl)methanol (step 6) (30 mg, 0.1 mmol) in dichloromethane ( 0.4 ml) Dess-Martin periodinan (76 mg, 0.2 mmol) was added and the mixture was stirred at room temperature for 10 min. Hydrazine monohydrate (48 μΙ, 0.5 mmol) was then added and the reaction was stirred for an additional 16 h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate, water, dried (Na2SO4) and concentrated. Flash column chromatography (DCM: MeOH 1:0-1:1) gave the title compound (3 mg, 9%) as a light yellow solid. ([M+H]+329.2). Example 75: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole CCfrQ Ln / Zznz / E / YIAI Stage 1: (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanol (2-Bromo-4-fluorophenyl)(methyl)sulfane was reacted with LDA (1.1 eq) for 1 h before the addition of cyclopropanecarbaldehyde (1.2 eq) 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 by using general procedure B1 to obtain the title compound. ([M+H, Br]+291.0). Step 3: cyclopropyl(3-fluoro-3'-methyl-4'-(methylsuIfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone The title compound ([M+H, Cl]+379.2) was prepared from Suzuki coupling of 4,6dichloro-3-cycloproyl-1 H-pyrazolo[4,3-c]pyridine (step 2) and boronic acid of 3-methyl-4-(methylsulfonyl)phenyl with cesium carbonate at 100 °C according to general procedure D. Step 4: 3-cyclopropyl-4-(3-methyl-4-(methysulfonyl)phenyl)-5-(methylthio)-1 H-indazole Cyclopropyl(3-fluoro-3'-methyl-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2yl) was reacted. methanone (step 2) with hydrazine hydrate (15 eq) in ethanol at 150 °C (microwave), according to general procedure C, to obtain the title compound. ([M+H]+373.2). Example 76: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfinyl)-1H-indazole Yo CCfrQ Ln / Zznz / E / YIAI To an ice-cold solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1 Hindazol (Example 74) (23 mg, 0.1 mmol) in DCM (1 ml) was added to a mchloroperbenzoic acid solution (124 pl, 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, water, dried (Na2SO4) and concentrated. Flash column chromatography (DCM: MeOH 1:0-1:9) gave the title compound (15 mg, 59%) as a yellow solid. ([M+H]+389.2). Example 77: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole O=S=O To an ice-cold solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1 Hindazol (Example 74) (26 mg, 0.1 mmol) in DCM (1 ml ) a mchloroperbenzoic acid solution (263 μΙ, 0.5 M in DCM, 0.1 mmol) was added 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, water, dried (Na2SO4) and concentrated. Flash column chromatography (DCM: MeOH 1:0-1:9) gave the title compound (18 mg, 61%) as a yellow solid. ([M+H]+405.2). Example 78: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5 one o=s=o CCfrQ Ln / Zznz / E / YIAI Step 1: 3-iodo-5-methoxy¡-1-trit¡l-p¡razolo[4,3-b]pyridine To an ice-cold solution of 3-iodo-5-methoxy¡-1 H-pyrazolo[4,3-b]pyridine (WO2018 / 11628 A1) (1.0 g, 3.6 mmol) in DMF (20 mL) under an argon atmosphere, triphenylmethyl chloride (12.2 g, 4.4 mmol) and sodium hydride (175 mg, 60% dispersion in mineral oil, 4.4 mmol) were added and the reaction mixture was warmed to room temperature and stirred. for 3 hours. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, brine, dried (Na2SÜ4) and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:10) gave the title compound (0.9 g, 46%) as a white solid. ([M+Na]+518.0). Step 2: 5-methoxy¡-1-trityl-pyrazolo[4,3-b]pyridin-3-οI A mixture of 3-iodo-5-methoxy¡-1-trit¡l-p¡razolo[4,3-b]pyridine (step 1) (50 mg, 0.1 mmol), potassium hydroxide (16 mg, 0.3 mmol), t-BuBrettFos (8 mg, 0.02 mmol), t-BuBrettfos 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 a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse phase HPLC provided the title compound (20 mg, 51% yield) as a white solid. ([M+Na]+408.1). 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, 1.0 mmol), sodium 2-chloro-2,2-difluoroacetate (224 mg , 1.5 mmol), cesium carbonate (640 mg, 2.0 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 provided the title compound (400 mg, 89% yield) as a yellow solid. ([M+H]+458.1) Step 4: 3-(difluoromethoxy)-1,3a,4,7a-tetrahydropyrazolo[4,3-b]pyridin-5-one 3-(difluoromethoxy)-5-methoxy-1-tntil-pyrazolo[4,3-b]pyridine (step 3) (300 mg, 0.7 mmol) HCl (15 mL, 4N in dioxane, 60 mmol) was dissolved and stirred at 80 °C for 3 h. The reaction mixture was concentrated to dryness and purified by preparative reverse phase HPLC to obtain the title compound (100 mg, 75%) as a gray solid. ([M+H]+ 202.1). Step 5: 3-(difluoromethox¡)-1-tetrahydro¡ran-2-¡l-4H-pyrazolo[4,3-b]pyrid¡ran-5-one A mixture of 3-(difluoromethox¡)-1,4-dihydro¡razolo[4,3-b]pyr¡din-5-one (200 mg, 1.0 mmol), 3,4dlhydro -2H-pyrane (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 time the reaction was concentrated. The purification by Preparative reverse phase HPLC provided the title compound (150 mg, 52% yield) as a white solid. ([M+H]+286.0). Stage 6: 3-(difluoromethox¡)-4-(3-methyl¡l-4-met¡lsulfon¡l·phen¡l)-1-tetrah¡drop¡ran-2-¡l-p¡razol[4 ,3b]pyridín-5-one To a solution of 3-(difluoromethox¡)-1-tetrahydro¡drop¡ran-2-¡l-4H-párazolo[4,3-b]pyridín-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 room temperature under air. After 12 h, an additional 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 stirred for an additional 16 h before the reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated. Preparative reverse phase HPLC gave the title compound (70 mg, 44%) as a brown solid. ([M+H]+454.1). Step 5: 3-(difluoromethoxy¡)-4-(3-methyl-4-met¡isulfonyl-phenyl)-1 H-pyrazolo[4,3-b]pyrid¡n-5-one 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-l-pyrazol[4,3b]pyridin-5 was deprotected -one (step 4) by using general procedure 11 to obtain the title compound. ([M+H]+370.1). Example 79: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4cjpyridine CCfrQ Ln / Zznz / E / YIAI 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 eq) for 1 h before the addition of cyclopropanecarbaldehyde (1.2 eq), according to general procedure A, to obtain crude (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-¡l)(cyclopropyl)methanol which was directly oxidized by using the general procedure B1 to obtain the title compound. ([M+H, Br]+312.1). Step 2: cyclopropyl(5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)pyridin-4-yl)methanone The title compound ([M+H]+402.2) was prepared from Suzuki coupling of (3-bromo-5fluoro-2-(trifluoromethyl)pyridin-4-¡l)(c ¡cloprop¡l)methanone (step 1) and 3-methyl-4(methylsulfon¡l)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)-1 H-pyrazolo[3,4-c]pyridine 3-Cyclopropyl(5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)pyridin-4yl)methanone (step 2) was reacted with hydrazine hydrate (5 eq) in THF at room temperature, according to general procedure C, to obtain the title compound. ([M+H]+396.2). Example 80: 3-cyclopropyl-6-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-b]pyridin-5-one CCfrQ Ln / Zznz / E / YIAI O=S=O Step 1: 3-iodo-5-methoxy-1-tetrahydroplran-2-l-p¡razol[4,3-b]pyrdina 3, 4-dihydro-2H-pyran (3.0 g, 35.6 mmol) and ptoluenesulfonic acid monohydrate (100.0 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, dried (Na2SO4) and concentrated. Flash column chromatography (heptane:ethyl acetate 7:3) gave 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-l-pyrazol[4,3-b]pyridine The title compound ([M+H]+274.0) was prepared from Suzuki coupling of 3-iodo-5methoxy-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine (step 1) and cyclopropylboronic acid (8 eq) with potassium carbonate (4 eq) at 100 °C according to general procedure D. Step 3: 3-cyclopropyl-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one 3-Cyclopropyl-5-methoxy¡-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine (step 2) (270 mg, 1.0 mmol) was dissolved in HCL (30 mL, 4N in dioxane, 120 mmol) and heated at 100 °C for 15 h. The mixture was concentrated and the residue was redissolved in DCM (9 mL) and DMF (3 mL). 4-dihydro-2H-pyran (80 mg, 1.0 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.3 mmol) and the reaction was stirred for 16 h. A second portion of 4-dihydro-2H-pyran (80 mg, 1.0 mmol) was added and the reaction was stirred for an additional 12 h. The reaction was diluted with DCM, washed with saturated aqueous sodium hydrogen carbonate, dried (Na2SÜ4) and concentrated. Flash column chromatography (ethyl acetate) gave the title compound (170 mg, 62%) as a colorless viscous oil. ([M+H]+ 260.3). Step 4: 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridín-5one To a solution of 3-(difluoromethox¡)-1-tetrahydro¡drop¡ran-2-¡l-4H-pyrazolo[4,3-b]pyr¡d¡n-5-one (step 3) ( 100 mg, 0.4 mmol) in dichloromethane (3 mL) 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 room temperature under air. After 12 h an additional 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 an additional 16 h before add an additional portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) and the mixture was stirred for an additional 16 h, the reaction was diluted with acetate of ethyl, washed with water, brine, dried (NasSCU) 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[4,3b]plridín-5-one To a solution of 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydrochloran-2-yl-pyrazol[4, 3b]pyridin-5-one (50 mg, 0.09 mmol) (step 4) in DMF (2.5 mL) N-bromosuccinimide (33 mg, 0.2 mmol) was added. The reaction was stirred for 24 h after which time the reaction was diluted with ethyl acetate, washed with water, brine, dried (NazSCU) and concentrated. Purification by preparative TLC (1:1 heptane:ethyl acetate) gave the title compound (40 mg, 68%) as a white solid. ([M+H, Br]+506.0). Step 6: 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-l-pyrazolo[4,3b]pyridin-5-one The title compound ([M+H]+ 422.1) was prepared from Suzuki coupling of 6-bromo-3cyclopropi I-4-(3-methyl-4-methi Isu Ifon i l-phenyl) -1 -tetrah idropi ran-2-yl-pyrazolo[4,3-b]pyrid i n-5-one (step 5) and trimethylboroxine with potassium carbonate at 100 °C according to general procedure D. Step 7: 3-cyclopropyl-6-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-b]pyridin-5-one 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3b]pyridin-5-one (step 6) was deprotected by using general procedure 11 to obtain the title compound. ([M+H]+358.1). Example 81: 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one CCfrQ Ln / Zznz / E / YIAI o=s=o Step 1: 3,6-dicyclopropyl-4-(3-methyl-4-methiIsuIfonyl-pheniI)-1 -tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin5-one The title compound ([M+H]+ 468.1) was prepared from Suzuki coupling of 6-bromo-3cyclopropy I-4-(3-methyl-4-methi Isu Ifon i l-phenyl) -1 -tetrah¡ drop¡ran-2-¡l-pyrazolo[4,3-b]pyr¡din-5-one (step 5) and trimethylboroxine with potassium carbonate at 100 °C according to general procedure D. Step 2: 3-cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsilphonyl-phenyl)-1H-pyrazolo[3,4-c]pi rádina 3,6-Dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3b]pyridín-5-one was deprotected (step 4) by using of general procedure 11 to obtain the title compound. ([M+H]+384.2). Step 82: 3-cyclopiOpil-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4c]pyridine CCfrQ Ln / Zznz / E / YIAI Step 1: (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-l)(cyclopropyl)methanol 3-Bromo-2-(difluoromethoxy)-5-fluoroprídine was reacted with LDA (1.2 eq) for 1 h before the addition of cyclopropanecarbaldehyde (3 eq) according to general procedure A to obtain the title compound. ([M+H, Br]+312.1). Step 2: (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-l)(cyclopropyl)methanone (3-bromo-2-(difluoromethoxy¡)-5-fluoropyridín-4-¡l)(cyclopropyl)methanol (step 1) was directly oxidized by using the general procedure B1 to obtain the compound of qualification. 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]+400.3) was prepared from Suzuki coupling of (3-bromo-2fluoro-2-(trifluoromethyl)pyridín-4-¡l)(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)-1 H-pyrazolo[3,4-c ]p¡r¡dina Cycloprop¡l(2-(difluoromethoxy¡)-5-fluoro-3-(3-methyl-4-(methylsulfon¡l)phen¡l)-2(trifluoromethyl) was reacted )pyridín-4-íl)methanone (step 3) with hydrazine hydrate (5 eq) in THF at room temperature, according to general procedure C, to obtain the title compound. ([M+H]+394.4). Example 83: 3-cyclopropyl·N,N-dimethyl-4-(3-methyl·4-(methylsulfoníl)phenyl)-1H-pyrazolo[3,4c]pyridine-5-carboxamide CCfrQ Ln / Zznz / E / YIAI The title compound ([M+H]+399.3) was prepared analogously to Example 72 from 3-cyclopropyl-4-(3-methylsulfonyl)phenyl acid. )-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[3,4-c]pyridine-5carboxylic acid (Example 72, step 1) and methylamine hydrochloride. Example 84: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4c]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)-1 H-pyrazolo[3,4-c]pyridine-5carboxylic acid (Example 72, step 1) and methylamine hydrochloride. Example 85: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1 H-pyrazolo[3,4c]pyridine-5-carboxamide Stage 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 pmol) and butyldi-1-adamantylphosphine (31 mg, 86 pmol) and cesium carbonate (1.4 g, 4.3 mmol) in a mixture of toluene (10 ml) and water (1.5 mi) was evacuated and bubbled with argon. The reaction mixture was stirred for 2 h at 80 °C. The reaction mixture was filtered directly over Dicalite®, washed with ethyl acetate and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 1:9) gave the title compound (81 mg, 31%) as a colorless oil. ([M+H]+172.0). Step 2: (3-chloro-2-cyclopropyl-5-fluoropyridin-4-yl)(cyclopropyl)methanone 3-Chloro-2-cyclopropyl-5-fluoropyridine was reacted with LDA (1.1 eq) for 1 h before the addition of cyclopropanecarbaldehyde (1.2 eq), according to general procedure A, to obtain (3-bromo-5 crude -fluoro-2-(trifluoromethyl)pyridn-4-¡l)(cyclopropyl)methanol which was directly oxidized by using the general procedure B1 to obtain the compound of qualification. ([M+H, Cl]+= 240.1). Step 3: cyclopropyl(2-cyclopropyl-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyrdin-4 -l)methanone The title compound ([M+H]+374.2) was prepared from Suzuki coupling of (3-bromo2(3-chloro-2-cyclopropyl-5-fluorop¡rid¡n-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)-1 H-pyrazolo[3,4-c]pyridine-5carboxamide Cyclopropyl(2-cyclopropyl-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4yl)methanone (step 3) was reacted with hydrazine hydrate (100 eq) in THF at 170 °C (microwave), according to general procedure C, to obtain the title compound. ([M+H]+368.2). Example 86: N,3-dicyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5carboxamide CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ 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)-1 H-pyrazolo[3,4-c]pyridine-5carboxylic acid (Example 72, step 1) and cyclopropylamine. Example 87: 3-cyclopropyl-6-tluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5carboxamide CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ Step 1: 6-chloro-2,4-difluoro-3-(triethylsilyl)benzoniumtrile To a solution of 2-chloro-4,6-difluorobenzonitrile (100 mg, 0.6 mmol) dissolved in THF (2 ml) under Ar and cooled to -78 °C, LDA (0.3 ml, 0.7 mmol) was added and the The mixture was stirred for 5 min after which time chlorotrimethylsilane (0.1 ml, 0.6 mmol) was added and the reaction was stirred for an additional 30 min. The reaction was stopped by addition of saturated aqueous ammonium chloride, allowed to reach room temperature, extracted with ethyl acetate, dried (Na2SO4) and concentrated. Flash column chromatography (heptane) gave the title compound (127 mg, 73%) as a colorless oil. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.03 (dd, 1H, J=1.4, 8.1 Hz), 0.9-1.0 (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 eq) for 0.25 h before adding cyclopropanecarbaldehyde (1.3 eq), according to general procedure A, to obtain the title compound. ([M+H Cl]+381.2). Step 3: 2-chloro-3-(cyclopropanecarbonyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile 2-Chloro-3-(cyclopropyl(hydroxyl)methyl)-4,6-difluoro-5-(triethylsilyl)benzonitrich was oxidized (step 2 ) by using the general procedure B1 to obtain 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(cyclopropanecarbon¡l)-4,6-difluoro-5-(triethyls¡l ¡l)benzonítrile (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)-1 H-indazole-5-carboxamide 6-(cyclopropanecarbonyl)-3,5-difluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2carbonitrile (step 4) was reacted with hydrazine hydrate (2 eq) in THF at room temperature, according to general procedure C, to obtain the title compound. ([M+H]+370.2). Example 88 and 89: 3-cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5carboxamide and 3-cyclopropyl-4-(4-cyclopropylsulfoníl -3-methyl-phenyl)-N-methyl-1 H-pyrazolo[3,4-c]pyridine5-carboxamide CCfrQ Ln / Zznz / E / YIAI 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile (Example 87) (20 mg, 54 pmol) was suspended in sodium hydroxide (3 ml, 3M in water, 9 mmol) and heated at 150 °C in a microwave for 4.5 h. The reaction was acidified with 6 N hydrochloric acid and extracted with ethyl acetate, the organic fraction was dried (NasSCU) and concentrated to obtain the crude mixture (1:1) of 3cyclopropyl-4-(4-cyclopropylsuIphonyl-3 -methyl-phenyl)-N-methiI-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide and 3cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl- 1 H-pyrazolo[3,4-c]pyridine-5-carboxylic acid. Reaction with methylamine hydrochloride was prepared analogously to Example 72 followed by preparative reverse phase HPLC provided the two title compounds. ([M+H]+402.3 and 388.2). Example 90: 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile o=s=o Step 1: 2,6-dichloro-3-(cyclopropyl(hydrox¡)methyl)-4-fluorobenzonitrile 2,6-Dichloro-4-fluorobenzonitrile was reacted with LDA (1.0 eq) for 1 h before adding cyclopropanecarbaldehyde (1.2 eq), according to general procedure A, to obtain the title compound. ([M-H2O, 2CI]+242.1). Step 2: 2,6-dichloro-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile 2,6-Dichloro-3-(cycloprop¡l(hydrox¡)methyl)-4-fluorobenzonitrile (step 1) was oxidized by using the general procedure B1 to obtain the title compound. ([M+H, 2CI]+258.1). Step 3: 3-chloro-6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2 carbonitrile The title compound ([M+H]+392.2) was prepared from Suzuki coupling of 2-chloro32,6-dichloro-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile (step 2) and boronic acid of 3-methyl-4(methylsulfonyl)phenyl with cesium carbonate at 100 °C according to general procedure D. Step4: 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-carbonitrile 3-Chloro-6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]2-carbonitrile (step 3) was reacted with hydrate of hydrazine (15 eq) in THE at room temperature, according to general procedure C, to obtain the title compound. ([M+H,CI]+= 386.2). Example 91: 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5one I o=s=o CCfrQ Ln / Zznz / E / YIAI Step 1: 5-methoxy-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridine 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 sodium carbonate. potassium (438 mg, 3.2 mmol) and 1-trifluoromethyl-1,2benziodoxol-3-(1 H)-one (1001 mg, 3.2 mmol). The mixture was stirred at 25 °C for 16 h, after which time a second portion of potassium carbonate (438 mg, 3.2 mmol) and 1-tnfluoromethyl-1,2benziodoxol-3-(1 H)-one ( 1001 mg, 3.2 mmol) 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 fractions were washed with brine, dried (Na2SCU), and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:10) gave the title compound (110 mg, 21%) as a white solid. ([M+H]+476.1). Step 2: 3-(tñfluoromethoxy)-1-tñt¡l-4H-pyrazolo[4,3-b]piñdin-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 (20.0 mL, 80 mmol) was stirred at 80 °C for 24 h. The reaction was concentrated and purification by preparative TLC (1:1 heptane:ethyl acetate) gave the title compound (60 mg, 53%) as a white solid. ([M+H]+462.1). Step 3: 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(tnfluoromethoxy)-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 acid ( 3-methyl-4-methylsulfonyl-phenyl)boronic (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 room temperature under an oxygen atmosphere (balloon). After 12 h, an additional portion of boronic acid (3-methyl-4-methylsulfonyl-phenyl (51 mg, 0.2 mmol), pyridine (0.02 mL, 0.2 mmol), triethylamine (0.03 mL, 0.2 mmol) and the mixture were added. Stirred for a further 12 h before the reaction was diluted with ethyl acetate and filtered. Purification by preparative TLC gave (90 mg, 63%) as a white solid. ([M+H]+630.1). Step 4: 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy¡)-1 H-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 deprotonated by using general procedure 11 to obtain the compound of the title. ([M+H]+388.1). Example 92: 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,2-b]pyridin-5-one CCfrQ Ln / Zznz / E / YIAI Step 1: 3-bromo-5-methoxy-1 H-pyrrolo[3,2-c]pyridine To a solution of 5-methoxy-1 H-pyrrolo[3,2-b]pyridine (1.0 g, 6.75 mmol, 1 eq) in DMF (20 mL) was added A / -bromosuccinamide (1.4 g, 7.1 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 fractions were washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-heptane 0:1-1:8) gave the title compound (1.2 g, 76%) as a white solid. ([M+H, Br]+227.0). Step 2: 2-[(3-bromo-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyll-silane 3-Bromo-5-methoxy-1 H-pyrrolo[3,2-b]pyridine (step 1) was converted to the title compound using the general procedure E1 in THF. ([M+H, Br]+357.1). Step 3: 2-[(3-cyclopropyl-5-methoxy¡-pyrrolo[3,2-b]pyridín-1-yl)methoxy¡]ethyl-trimethyll-silane The title compound ([M+HI]+319.2) was prepared from Suzuki coupling of 2-[(3bromo-5-methoxy¡-pyrrolo[3,2-b]pyrid¡n-1- ¡l)methoxy]ethyl-trimethyl-silane (step 2) and cylcopropyl boronic acid (10 eq) with potassium carbonate (8 eq) 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 4M HCl in dioxane (20.0 mL, 80 mmol) was stirred at 90 °C for 5 h. The reaction was concentrated and purification by preparative TLC (1:1 Heptane:ethyl acetate) gave the title compound (140 mg, 58%) as an off-white solid. ([M+H]+219.1). Step 5: 3-cyclopropyl-1 -(methoxymethyl)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-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 acid 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 room temperature under an oxygen atmosphere (tank). After 2 h, an additional 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 The mixture was stirred for an additional 2 h before a third identical readdition of added boronic acid and triethylamine and the reaction was stirred for an additional 12 h. The reaction was then filtered and concentrated. Purification by preparative TLC (1:1 heptane:ethyl acetate) gave the title compound (170 mg, 68%) as a white solid. ([M+H]+ 387.1). Step 6: 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrrolo[3,2-b]pyridin-5-one 3-Cyclopropyl-1-(methoxylmethyl)-4-(3-methyl-4-methylsulfonyl-phenyl)pyrrolo[3,2-b]pyridin-5one (step 5) was deprotonated using the procedure general J to obtain the title compound. ([M+H]+343.2). Example 93: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1 H-indazole I o=s=o CCfrQ Ln / Zznz / E / YIAI Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1-trityl-1 H-indazol-3-ol The title compound ([M-H]' 621.5) was prepared from Suzuki coupling of 4-bromo-5(methylsulfonyl)-l-trityl-1 H-indazol-3-ol (Intermediate 16, step 4) and boronic acid of 3-methyl-4(methylsulfonyl)phenyl with potassium carbonate at 100 °C according to general procedure D. Step 2: 4-(3-methylsulfonyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1-trityl-1 H-indazole To a solution of 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1-trityl-1 H-indazol-3-ol (step 1) (206 mg, 0.3 mmol) in DMF (3 ml) potassium carbonate (137 mg, 1.0 mmol) and 1 -(trifluoromethyl)113-benzo[d][1,2]iodaoxol-3(1H)-one (165 mg, 0.5 mmol) were added and the The mixture was stirred for 18 h at room temperature. The reaction was concentrated to dryness, suspended in ethyl acetate, washed with water, dried (NaaSCU) and concentrated. Purification by flash column chromatography (heptane:ethyl acetate 1:9-0:1) provided the title compound (46 mg, 20%) as a white solid. ([M+NH4+]+708.5) Step 3: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1 H-indazole 4-(3-methiI-4-(methylsulfonyl)pheny 1)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1-trityl-1 H-indazole was deprotonated (step 2) by using general procedure 11 to obtain the title compound. ([M+H]+449.2). Example 94: 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfoníl)phenyl)-5-(methylsulfonyl)-1Hindazol Yo F O=S=O CCfrQ Ln / Zznz / E / YIAI Step 1: cyclopropyl(3'-(difluoromethyl)-3-fluoro-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2yl)methanone The title compound ([M+H]+ 415.2) was prepared from Suzuki coupling of (2-bromo-6fluoro-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 with general procedure D. Step 2: cyclopropyl(3'-(difluoromethyl)-3-fluoro-4',6bis(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methanone Convert cyclopropyl(3'-(dif luoromethyl)-3-fluoro-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2yl)methanone (step 1) to the title compound by using the general procedure G. ([M+H]+447.3). Step 3: 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1 H-indazole Cyclopropyl(3'-(dif luoromethyl)-3-fluoro-4',6-bis(methylsulfonyl)-[1,1'-biphenyl]-2yl)methanone (step 2) was reacted with hydrazine hydrate (2 eq. ) in THF at room temperature, according to general procedure C, to obtain the title compound. ([M+H]+441.2). Example 95: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4c]pyridine-5-carboxamide 100 CCfrQ Ln / Zznz / E / YIAI Step 1: 3-(difluoromethoxy¡)-4-(3-methyl¡l-4-methylsulfon¡l-phenyl)-1 H-pyrazolo[3,4-c]pyrádine-5carboxylic acid A solution of 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5carbonitrile (Example 52) (100 mg , 0.3 mmol) in water (4 mL), sodium hydroxide (1.0 mL, 6 N, 6 mmol) was added and the reaction was heated at 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 fraction was dried (Na2SO4) and concentrated to obtain the title compound (100 mg, 95% ), as a light yellow solid. ([M+H]+398.0). Step 2: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5carboxamide The title compound ([M+H]+ 411.1) was prepared analogously to Example 72 from 3-(difluoromethoxy¡)-4-(3-methyl-4-methylsulfon¡l-phen¡l acid )-1 H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 4) and methylamine hydrochloride. Example 96: 3-cyclopropyl-4-(4-cycloproDylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1Hpyrazolo[3,4-c]pyridine-5-carboxamide Y o=s=o Tji r o ΪfoA U i / F H H N h Stage 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 at 100 °C for 12 h. The reaction was then extracted 101 repeatedly with ethyl acetate, the combined organic fraction was dried (Na2SO4) and concentrated, purification by preparative TLC (heptane) gave (60 mg, 51%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.29 (d, J = 9.5 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-cyclopropylsulfanyl-2-fluoro-5-methyl-benzene Convert 1-bromo-4-cyclopropylsulfanyl-2-fluoro-5-methyl-benzene (step 1) to the title compound by using general procedure G. ([M+H]+293.0). Step 3: 2-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Convert 1-bromo-4-cyclopropylsulfanyl-2-fluoro-5-methyl-benzene (step 2) to the title compound using general procedure G. ([M+H]+ 258.9). Step 4: 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5carbonitrile The title compound ([M+H]+397.2) was prepared from Suzuki coupling of 4-bromo3-(difluoromethoxy)-1 -trityl-pi razo lo [3,4-c] pyrid ina-5-carbo nitrilo (Intermediate 17), 2-(4-cyclopropí Isu Ifon i I-2fluoro-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) dichloromethane dichloride (0.5 eq) 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]pyhdine5-carboxylic acid A solution of 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5methyl-phenyl)-1 H-pyrazolo[3,4c]pyridine-5- carbonitrile (step 4) (20 mg, 0.1 mmol) in water (0.2 mL), sodium hydroxide (0.05 mL, 6 N, 0.3 mmol) was added and the reaction was heated at 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 fraction was dried (Na2SO4) and concentrated to obtain the title compound (20 mg, 95% ). ([M+H]+416.1). Step 6: 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1 H-pyrazolo[3,4c]pyridine-5-carboxamide The title compound ([M+H]+ 429.1) was prepared analogously to Example 72 from 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5- methyl-phenyl)-1 H-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[3,4c]pyridine-5-carboxamide CCfrQ Ln / zznz / E / YiAi 102 O=S=O CCfrQ Ln / Zznz / E / YIAI Step 1: 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine acid -5carboxylic To a suspension of 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4c]pyridine-5-carbonitril (Example 47) (50 mg, 0.1 mmol) in water (0.6 mL) sodium hydroxide (0.1 mL, 0.8 mmol) was added. 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 organic fraction was dried (Na2SO4) and concentrated. Purification by preparative reverse phase HPLC gave the title compound (20 mg, 34% yield) as a gray foam. ([M+H]+390.0). Step 2: 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-N-methyl-1H-pyrazolo[3,4- c]pyridine-5carboxamide The title compound ([M+H]+ 403.1) was prepared analogously to Example 72 from 3-cyclopropyl-4-(2-f I uoro-5-methyl4-methylsu Ifon i I -f acid in i I) -1 H-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-5carboxamide A solution of 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5carbonitrile (Example 52) ( 100 mg, 0.3 mmol) in ethanol (4 mL), sodium hydroxide (0.7 mL, 6 N, 0.3 mmol) was added and the reaction was heated at 100 °C for 12 h. The reaction mixture was concentrated and the residue was purified by preparative reverse phase HPLC to obtain the title compound (28 mg, 26%) as a white solid. ([M+H]+397.1). 103 Example 99: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin7-yl]amino]ethoxy]ethyl ]acetamide; formic acid salt CCfrQ Ln / Zznz / E / YIAI O-^NH Step 1: 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3b]pyrid na To a solution of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridine (Example 64, step 1) (100 mg, 0.3 mmol) in THF (1 mL), p-toluenesulfonic acid monohydrate (13 mg, 0.1 mmol) and dihydropyran (0.07 mL, 0.7 mmol) were added 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 fraction was dried (NaíSCU) and concentrated. Purification by preparative TLC (1:1 heptane:ethyl acetate) gave the title compound (60 mg, 50%) as a yellow oil. ([M+H, Br]+490.0). Step 2: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3c]pyr¡d ¡n-7-yl]amino]ethox¡]et¡l]acetam¡da To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydrochloran-2-lplrazol[4 ,3-c]pyridine (step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (5 mL) cesium carbonate (332 mg, 1.0 mmol), N-[2-( 2-aminoethoxy¡)ethyl]acetam¡de (179 mg, 1.2 mmol), xanthos (14 mg, 0.02 mmol) and Pd(OAc)2 (4.6 mg, 0.02 mmol) were stirred at 80 °C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse phase HPLC provided the title compound (40 mg, 34% yield) as a yellow solid. ([M+H]+556.2). Step 3: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyrádin-7yl] amino]ethoxy]ethyl]acetamide; formic acid salt 104 N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-íl was deprotonated ]amino]ethoxy]ethyl]acetamide (step 2) by using general procedure 11 to obtain the title compound. ([M+H]+472.3). Example 100: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]p ¡ridin-7yl]amino]propyl]acetamide; formic acid salt CCfrQ Ln / Zznz / E / YIAI Step 1: N-[3-[[3-cyclopropyl-4-(3-met¡ l-4-m ethylsulfoni l-phen i I)-1 -tetrahydropyran-2-yl-p¡razol[4,3c] pyridin-7-yl]amino]propíl]acetamide To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-ylpyrazolo[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, 1.0 mmol), N-(3-aminopropyl)ethyl]acetamide (118 mg, 1.0 mmol), xantphos ( 14 mg, 0.02 mmol) and Pd(OAc)2 (5 mg, 0.02 mmol) was stirred at 80 °C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse phase HPLC provided the title compound (60 mg, 56% yield) as a yellow solid. ([M+H]+526.0). Step 2: N-[3-[[3-cyclopropí l-4-(3-methyl-4-methylsulfonyl-phení l)-1 H-plrazolo[4,3-c]pyridin-7yl]amino]prop l]acetamide; formic acid N-[3-[[3-cyclopropyl-4-(3-methyl-4-methi Isulfonyl-phenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl] was deprotonated amino]propyl]acetamide (step 1) by using general procedure 11 to obtain the title compound. ([M+H]+441.9). Example 101: N-[2-(2-aminoethoxy)ethyl]-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1Hpyrazolo[4,3-c]pyridin-7-amine; formic acid 105 CCfrQ Ln / Zznz / E / YIAI Step 1: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfoníl-phenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c] tere-butyl p¡r¡din-7-¡l]amino]ethoxy]ethyl]carbamate To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridine (Example 99, step 1) (120 mg, 0.2 mmol) in 1,4-dioxane (4 mL) added cesium carbonate (399 mg, 1.2 mmol), N-[2-(2-aminoethoxy)ethyl]acetamide (150 mg, 0.7 mmol), xantphos (17 mg, 0.02 mmol) and Pd(OAc)z (5 mg, 0.02 mmol) were stirred at 80 °C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse phase HPLC provided the title compound (98 mg, 62% yield) as a yellow solid. ([M+H]+614.2). Step 2: N-[2-(2-am¡noethoxy¡)ethyl]-3-cycloprop¡l-4-(3-methyl-4-methylsulfon¡l-phen¡l)-1 H-pyrazolo[4,3c]plridín-7-amine; formic acid salt N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin- was deprotonated. 7-¡l]am¡no]ethoxy¡]ethyl¡l]carbamate (step 1) by using general procedure 11 to obtain the title compound. ([M+H]+430.1). Example 102: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7yl]butane-1,4-diamino 106 CCfrQ Ln / Zznz / E / YIAI Step 1: N-[2-[4-[[3-cycIopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-ylp¡razolo[4,3-c]) tere-butyl pyridin-7-¡l]am¡no]butyl]carbamate To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridine (Example 99, step 1) (130 mg, 0.3 mmol) in 1,4-dioxane (4 mL) added cesium carbonate (432 mg, 1.3 mmol), N-Boc-1,4-diaminobutane (150 mg, 0.8 mmol), xantphos (18 mg, 0.03 mmol) and Pd(OAc)2(6 mg, 0.03 mmol) were stirred at 80 °C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by preparative reverse phase HPLC provided the title compound (90 mg, 56% yield) as a yellow solid. ([M+H]+598.2). Step 2: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyri d¡n-7-¡l]butane-1,4diamino N-[4-[[3-cyclopropyl-4-(3-methyl-4-methyl-isulfonyl-phenyl)-1-tetrahldroplran-2-llp¡razolo[4,3-c]p was deprotonated ¡r¡din-7-¡l]am¡no]butyl]carbamate (step 1) by using general procedure 11 to obtain the title compound. ([M+H]+414.1). Example 103: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7yl]amino]butyl]acetamide 107 CCfrQ Ln / Zznz / E / YIAI Step 1: N-[4-[[3-cycloprop¡l-4-(3-methyl-4-methylsulfon¡l-phenyl)-1 -tetrahldrop¡ran-2-yl-p¡razol[ 4,3c]pyr¡din-7-¡l]am¡no]but¡l]acetam¡de To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridine (Example 99, step 1) (80 mg, 0.2 mmol) in 1,4-dioxane (3 mL) was added cesium carbonate (266 mg, 0.8 mmol), N-(4-aminobutyl)acetamide (106 mg, 0.8 mmol), xanthos (11 mg , 0.02 mmol) and Pd(OAc)2 (4 mg, 0.02 mmol) was 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, 68% yield) as a yellow solid. ([M+H]+540.1). Step 2: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridin-7yl]amino]butyl ]acetamide N-[3-[[3-cyclopropyl-4-(3-methyl-4-methi Isulfonyl-phenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino] was deprotonated butyl]acetamide (step 1) by using general procedure 11 to obtain the title compound. ([M+H]+499.9). Example 104: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridín-7yl]propane-1,3-diamine 108 CCfrQ Ln / Zznz / E / YIAI Step 1: Tere-butyl N-[3-[[3-cyclopropy l-4-(3-methyl-4-methi Isu Ifon i l-f eni I) -1 -tetrahydropy ran-2-i Ipyrazolo[4,3- c]pyrid¡n-7-yl]amino]prop¡l]carbamate To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydrochloran-2-lpyrazolo[4 ,3-c]pyridine (Example 99, step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (4 mL) added cesium carbonate (332 mg, 1.0 mmol), N-Boc-1 ,3-diaminobutane (107 mg, 0.6 mmol), xanthphos (14 mg, 0.02 mmol), and Pd(OAc)2 (5 mg, 0.02 mmol) were 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% yield) as a brown oil. ([M+H]+584.4). Step 2: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridin-7-yl]propane-1,3diamine Tere-butyl N-[3-[[3-cyclopropyl-4-(3-methyl-4-methiIsulfonyl-phenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl] was deprotonated amino]butyl]carbamate (step 1) by using general procedure 11 to obtain the title compound. ([M+H]+399.9). Example 105: 3-(difluorOmethox¡)-4-(4-((difluoromethyl)sulfon¡l)-3-methylphen¡l)-1H-pyrazolo[3,4c]pyridine -5-carbonitrile R.T. Step 1: 3-(difluoromethoxy¡)-4-(4-((difluoromethyl)sulfon¡l)-3-methylphen¡l)-1-trityl-1 H-pyrazolo[3,4c] plrídina-5-carbonitrilo 109 The title compound ([M+formate]' 701.3) was prepared from the Suzuki coupling of 4bromo-3-(difluoromethoxy)-1-tr¡t¡l-p¡razolo[3,4-c]pyri¡ d¡na-5-carbonitrile (Intermediate 17), 2-(4cyclopropylsulfon¡l-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (step 4 ) with potassium carbonate and the 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride adduct (0.05 eq) at 120 °C, according to general procedure D. Step 2: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1 H-pyrazolo[3,4-c]pyridine-5carbonitrile 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1 H-pyrazolo[3,4c]pyridine-5-carbon is deprotonated lo by using general procedure H to obtain the title compound ([M+H]+ 415.2) after flash column chromatography. Example 106: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4c]pyridine-5-carboxamide CCfrQ Ln / zznz / E / YiAi Step 1: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5carboxamide To a solution of 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4c]pyridine-5- carbonate (Example 105, step 1) (295 mg, 0.45 mmol) in dimethyl sulfoxide (3.5 mL) potassium carbonate (12.4 mg, 0.09 mmol) was added followed by dropwise addition of aqueous hydrogen peroxide to 35 % (153 pL, 10.23 mmol). The reaction was stirred for 16 h after which time it was diluted with water resulting in precipitation of the product. The suspension was reserved, filtered, the filtrate cake was washed with water and dried to obtain the title compound product (325 mg, quant) as an off-white powder. ([M+H]+675.3) Step 2: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1 H-pyrazolo[3,4-c]pyridine-5carboxamide 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4c]pyridine-5-carboxamide is deprotonated by the use of general procedure H to obtain the title compound ([M+H]+ 433.2) after flash column chromatography. Example 107: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1Hpyrazolo[3,4-c]pyridine-5-carboxamide 110 CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ Step 1: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1 H-pyrazolo[3,4c]pyridine-5-carboxylic acid 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine5-carboxamide (150 mg, 0.22 mmol) was dissolved in acetonitrile (5 mL) and heated to 80 °C. Terebutyl nitrite (132 pL, 1.11 mmol) was added and the mixture was stirred for 4 h after which time the mixture was evaporated to dryness to obtain the crude title product (208 mg) as an orange foam, which was used. in the next stage without further purification. ([M+H]+ 434.2) Step 2: 3-(difluoromethoxy¡)-4-[4-(difluoromethylsulfon¡l)-3-methyl-phen¡l]-N-(oxetan-3-¡l)-1 H- pyrazolo[3,4c]plridina-5-carboxamide The title compound ([M+H]+489.2) was prepared analogously to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl- phenyl]-1 H-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)-1Hpyrazolo[3,4-c]pyridine-5-carboxamide The title compound ([M+H]+447.1) was prepared analogously to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1 H-p¡ acid razolo[3,4-c]piñdine-5-carboxylic acid (Example 107, step 1) and methylamine hydrochloride. Example 109: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(2-methoxyethyl)1 H-pyrazolo[3,4-c]pyridine-5-carboxamide CCfrQ Ln / zznz / E / YiAi The title compound ([M+H]+447.1) was prepared analogously 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[3,4c]pyridine-5-carboxamide Step 1: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5carboxylic acid A 3-(difluoromethox¡)-4-(3-methyl-4-methylsulfon¡l-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbon¡tri (Example 52) (238 mg, 0.6 mmol) 6 N sodium hydroxide (2.5 mL) was added and the reaction was heated at 100 °C for 2.5 h, after which time it was diluted with water (9 mL) and continued to heat. for 36 h at 90 °C. The reaction was cooled to 0 °C and acidified with 25% hydrochloric acid and the product was separated by filtration to obtain the title compound (92 mg, 30%) as a light brown solid. ([M+H]+398.2). Step 2: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5carboxamide The title compound ([M+H]+411.3) was prepared analogously to Example 72 from 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-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 112 o=s=o CCfrQ Ln / Zznz / E / YIAI Stage 1: 3-(2-bromo-4-fluoro-phenyl)sulfaniloxetane To a stirred solution of 3-iodooxetane (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 The reaction was heated at 100 °C for 5 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SÜ4), filtered and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 1:10-1:3) gave the title compound (4.1 g, 83%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.37 (dd, J = 2.7, 8.1 Hz, 1H), 7.12 - 7.07 (m, 1H), 7.05 - 6.98 (m, 1H), 5.06 (t, J = 7.1 Hz, 2H), 4.68 (t, J = 6.6 Hz, 2H), 4.49 - 4.41 (m, 1 H) 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 eq) for 30 minutes and reacted with ethyl chloroformate (1.2 eq) according to general procedure A to obtain the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.12 - 7.05 (m, 2H), 5.07 (t, J = 7.1 Hz, 2H), 4.67 (t, J = 6.6 Hz, 2H), 4.50 - 4.42 (m , 3H), 1.42 (t, J = 7.1 Hz, 3H) Step 3: ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfanyl)benzoate To a solution of ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfanyl)benzoate (step 2) (4.1 g, 12.2 mmol) in dichloromethane (100 ml) mCPBA (6.2 g, 30.6 mmol) was added ) and the reaction was stirred at room temperature for 16 h. Then the reaction was diluted with DCM, washed with 1 aq sodium hydrogen carbonate solution. sat., dried (Na2SÜ4) and concentrated. Flash column chromatography (ethyl acetate: n-heptane 3:1-1:1) gave the title compound (4.6 g, 87%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.31 (dd, J = 5.6, 8.9 Hz, 1H), 7.33 (dd, J = 7.6, 8.9 Hz, 1H), 5.03 - 4.96 (m, 3H), 4.89 - 4.83 (m, 2H), 4.49 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H) Step 4: 4-bromo-5-(oxetan-3-ylsulfonyl)-1,2-dihydrondazol-3-one To an ice-cold solution of ethyl 2-bromo-6-fluoro-3-(oxetan-3ylsulfonyl)benzoate (step 3) (4.6 g, 3.2 mmol) in ethanol (40 ml) was added hydrazine monohydrate (689 pL). , 3.2 mmol) followed by triethylamine (2.1 ml, 15.0 mmol) and the reaction was brought to room temperature. It was then heated at 80 °C for 2 h after which time the reaction was concentrated to dryness. Preparative reverse phase HPLC provided (2.8 g, 67%) was obtained as a light yellow solid. ([M+H, Br]+335.0). Step 5: 4-bromo-5-(oxetan-3-ylsulfonyl)-1-trityl-indazol-3-ol To an ice-cold solution of 4-bromo-5-(oxetan-3-ylsulfonyl)-1,2-dihydroindazol-3-one (step 4) (2.7 g, 1.9 mmol) in DMF (30 ml) was added chloride of trifil (2.5 g, 1.9 mmol) followed by 113 sodium hydride (389 mg, 60% dispersion in mineral oil, 9.7 mmol), the cooling bath was removed and the reaction was stirred at room 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 -1:3-1:0) provided (4.1 g, 65%) as a colorless solid. ([M+Na, Br]+599.1). Step 6: 4-bromo-3-(difluoromethoxy)-5-(oxetan-3-ylsulfoníl)-1-trityl-indazole A mixture of 4-bromo-5-(oxetan-3-ylsulfonyl)-1-trityl-indazol-3-ol (step 5) (4.0 g, 5.21 mmol) in DMF (40 mL) was added chlorofluoroacetate Sodium (1.6 g, 10.4 mmol) and potassium carbonate (2.1 g, 15.6 mmol) were heated at 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) gave the title compound (2.8 g, 86%) as a white solid. ([M+Na]+649.1). Step 7: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole The title compound ([M+Na+]+737.4) was prepared from Suzuki coupling of 4-bromo3-(difluoromethoxy)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole (step 6), 3-methyl-4(methylsulfonyl)phenyl boronic acid with potassium carbonate and 1,1'-bis(diphenylphosphino)ferrocenepalladium(ll) dichloromethane dichloride adduct (0.1 eq) at 100 °C, accordance with the general procedure D. Step 8: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-lsulfonyl)-1 H-indazole 3-(difluoromethoxy¡)-4-(3-methyl-4-methylsulfon¡l-phen¡l)-5-(oxetan-3-¡lsulfon¡l)-1-tritylindazole is deprotonated (step 7 ) by using general procedure H to obtain the title compound ([M+H]+ 495.2) after flash column chromatography. Example 112: [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1 H-indazol-5-yl]-imino-methyl-oxo CCfrQ Ln / Zznz / E / YIAI sulfane Step 1: (6-(cyclopropanecarbon¡l)-5-fluoro-3'-methyl-4'-(methylsulfon¡l)-[1,1'-biphenyl]-2-yl)(imino)(met l)16-sulfanone To a solution of cyclopropyl(3-fluoro-3'-methyl-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2yl)methanone (Example 75, step 3) (250 mg , 661 pmol) in MeOH (3 ml), ammonium carbonate (95 mg, 991 pmol) and (diacetoxyiodo)benzene (532 mg, 1.65 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction was diluted with ethyl acetate, washed with water, dried (Na2SO4) and 114 concentrated. Purification by flash column chromatography (dichloromethane:MeOH 1:0-9:1) provided the title compound (199 mg, 72%) as a white solid. ([M+H]+410.2). Step 2: [3-cyclopropyl-4-(3-methyl-4-methylsulfonílfeníl)-1 H-indazol-5-íl]-mino-methyl-oxo-sulfane To a solution of (6-(cyclopropanecarbon¡l)-5-fluoro-3'-methyl¡l-4'-(methylsulfonyl)-[1,1'-biphenyl]-2¡I)(imino)(methyl) -l6-sulfanone (step 1) (15 mg, 36.6 pmol) in methanol (1 ml) hydrazine monohydrate (28 pL, 366 pmol) was added and the reaction was heated to 65 ° C for 16 h after which time the reaction was concentrated to dryness. Purification by flash column chromatography (9:1 dichloromethane:MeOH) provided the title compound (10 mg, 67%) as a white solid. ([M+H]+404.1). Example 113: [3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methyliminooxo-A6-sulfane O=S=O CCfrQ Ln / Zznz / E / YIAI Step 1: (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2¡I)(methyl)(methylamino )-l6-sulfanone To a solution of (6-(cyclopropanecarbon¡l)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphen¡l]-2yl)(imino)( methyl)-16-sulfanone (50 mg, 122 pmol) in DMF (1 ml), sodium hydride (7.3 mg, 183 pmol) and iodomethane (10 μΙ, 159 μmol) were added and the reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate, washed with water, dried (NasSO^ and concentrated. Preparative reverse phase HPLC gave the title compound (22 mg, 37% yield) as a white solid. ([M +H]+424.2). Step 2: [3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methylimino-oxo-A6sulfane To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2yl)(methyl)(methylimino) -16-sulfanone (step 1) (22 mg, 52.7 pmol) in ethanol (0.4 ml) hydrazine monohydrate (156 pl, 316 pmol) was added followed by triethylamine (11 pl, 79 pmol) and the reaction was stirred at temperature ambient for 16 h after which time the reaction was concentrated to dryness. Flash column chromatography (dichloromethane: MeOH 9:1) gave the title compound (19 mg, 85%) as a white solid. ([M+H]+418.2). Example 114: 3-cyclopropyl-N,N-dimethyl·4-(3-methyl·4-methylsulfonyl·phenyl)-1H-indazole·5sulfonamide 115 o=s=o CCfrQ Ln / Zznz / E / YIAI Step 1: 2-bromo-4-fluoro-N, N-dimethyl-benzenesulfonamide To a solution of 2-bromo-4-fluorobenzenesulfonyl chloride (2.0 g, 7.31 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (2.8 mL, 21.9 mmol) and methylamine dihydrochloride (1.1 g, 14.6 mmol) and the mixture reaction was stirred for 2 h at room temperature. The reaction was diluted with ethyl acetate, washed with 1M HCl and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:10-3:1) gave the title compound (1.8 g, 83%) as a white solid. ([M+H, Br]+282.0). Step 2: 2-bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide 2-Bromo-4-fluoro-N,N-dimethyl-benzenesulfonamide (etapal) was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with cyclopropanecarboxaldehyde (1.5 eq) for 1 h, according to general procedure A, to obtain the title compound ([M+H (-OH), Br]+ 334.0. Step 3: 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N,N-dimethyl-benzenesulfonamide 2-Bromo-3-[cyclopropyl(hydrox¡)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide (step 2) was oxidized by using general procedure B2 to obtain the title compound. ([M+H, Br]+350.0). 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 pmol) in ethanol (2 ml) was added hydrazine monohydrate (170 μΙ , 316 pmol) followed by triethylamine (30 μΙ, 210 μmol) and the reaction was heated to 80 °C for 16 h after which time the reaction was concentrated to dryness. Preparative reverse phase HPLC gave the title compound (40 mg, 67%) as a light yellow solid. ([M+H, Br]+346.1). Step 5: 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-indazol-5-sulfonamide The title compound ([M+Na+]+434.2) was prepared from Suzuki coupling of 4-bromo3-cyclopropyl-N,N-dimethyl-1 H-indazol-5-sulfonamide (step 4), 3-boronic acid -methyl-4(methylsulfonyl)phenyl with potassium carbonate and the dichloride adduct of 1,1'-bis(diphenylphosphino)ferrocenepalladium(ll) dichloromethane (0.1 eq) at 100 °C, in accordance with general procedure d. Example 115: 3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-sulfonamide 116 o=s=o CCfrQ Ln / Zznz / E / YIAI Step 1: 2-bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide To a solution of 2-bromo-4-fluorobenzenesulfonyl chloride (2.0 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, 11.0 mmol ) and the reaction mixture was stirred for 2 h at room temperature. The reaction was diluted with ethyl acetate, washed with 1M HCl and concentrated. Flash column chromatography gave the title compound (2.6 g, 92%) as a white solid. ([M+H, Br]+412.1). Step 2: 2-bromo-3-[cycloprop¡l(hydrox¡)met¡l]-4-fluoro-N-[(4-methoxy¡phen¡l)met¡l]-N-met benzenesulfonamide 2-Bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (etapal) was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with cyclopropanecarboxaldehyde (1.5 eq) for 1 h according to general procedure A to obtain the title compound ([M+Na, Br]+482.1. Step 3: 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide 2-Bromo-3-[cyclopropyl(li¡drox¡)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide (step 2) was oxidized by using the general procedure B2 to obtain the title compound. ([M+H, Br]+480.2). Step 4: 4-bromo-3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-1H-indazol-5-sulfonamide To a solution of 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide (step 3) (200 mg, 440 pmol ) in ethanol (4 ml) hydrazine monohydrate (44 μΙ, 880 pmol) was added followed by triethylamine (70 μΙ, 530 μmol) and the reaction was heated to 80 °C for 2 h after which time the reaction was concentrated to dryness. Preparative reverse phase HPLC gave the title compound (200 mg, quant.) as a white solid. ([M+H, Br]+450.0). Step 5: 3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)- 1H-indazole-5sulfonamide The title compound ([M+Na+]+540.2) was prepared from Suzuki coupling of 44bromo-3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-1 H -indazol-5-sulfonamide (step 4), 3-methyl-4-(methylsulfonyl)phenyl boronic acid with potassium carbonate and the adduct of 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane (0.1 eq) at 100 °C, according to general procedure D. Step 6: 3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-sulfonamide 117 3-Cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 Hindazol-5-sulfonamide is deprotonated (step 5) by using the procedure general H to obtain the title compound ([M+H]+ 420.0) after flash column chromatography. Example 116: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4c]pyridine-5-carboxamide CCfrQ Ln / Zznz / E / YIAI Step 1: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1 H-pyrazolo[3,4c]pyridine-5-carbonitol The title compound ([M+formate] 669.3) was prepared from Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Intermediate 17), 2-(4cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 8) with potassium carbonate and the dichloride adduct of 1, 1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane (0.05 eq) 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-5carboxamide To the solution of 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4c]pyridine-5-carbonite (step 1) ( 220.0 mg, 0.34 mmol) in ethanol (5 mL) aq. NaOH was added. 2N (0.85 mL, 1.7 mmol) and the reaction was heated at 100 °C for 6 h. The reaction was acidified by adding 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)-1 H-pyrazolo[3,4-c]pyridine-5carboxamide 4-(4-Cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine5-carboxamide is deprotonated (step 2) using general procedure H to obtain the title compound ([M+H]+ 423.2) after flash column chromatography. Example 117: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-5-(methylsulfonyl) 1H-indazole 118 CCfrQ ίη / ΖΖΠΖ / Ε / ΥΙΛΙ The title compound ([M+Na]+465.1) could be prepared analogously to Example 49 by Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1 H- indazole (Intermediate 6) and 2-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 27) followed by deprotection by the use of the general procedure H. Example 118: 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1Hindazol o=s=o Stage 1: 2-bromo-1-cyclopropylsulfanyl-4-fluoro-benzene To a stirred suspension of cyclopropyl bromide (6.1 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 at 100 °C for 12 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na2SÜ4), filtered and concentrated. Flash column chromatography (nheptane) gave the title compound (1.7 g, 41%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.50 (dd, J = 5.6, 8.4 Hz, 1 H), 7.30 (dd, J = 2.0, 8.1 Hz, 1H), 7.06 (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) Stage 2: Ethyl 2-bromo-3-cyclopropylsulfanyl-6-fluoro-benzoate 2-Bromo-1-cyclopropylsulfanyl-4-fluoro-benzene (Step 1) was deprotonated with LDA (1.1 eq) for 30 minutes and reacted with ethyl chloroformate (1.2 eq) according to general procedure A to obtain the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.56 (dd, J = 5.5, 8.9 Hz, 1H), 7.12 (t, J = 8.6 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 2.14 (tt, J = 4.4, 7.3 Hz, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.18 - 1.13 (m, 2H), 0.77-0.71 (m, 2H) 119 Step 3: Ethyl 2-bromo-3-cyclopropylsulfonyl-6-fluoro-benzoate To a solution of ethyl 2-bromo-3-cyclopropylsulfanyl-6-fluoro-benzoate (step 2) (1.9 g, 5.95 mmol) in dichloromethane (40 ml) mCPBA (3.6 g, 17.9 mmol) was added and the reaction was stirred at room temperature for 12 h. Then the reaction was diluted with DCM, washed with 1 aq sodium hydrogen carbonate solution. sat., dried (Na2SO4) and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:5-1:3) gave the title compound (2.0 g, 84%) as a white solid. ([M+H, Br]+ 353.0). Step 4: 4-bromo-5-cyclopropylsulfonyl-1,2-dihydroindazol-3-one To an ice-cold solution of ethyl 2-bromo-3-cyclopropylsulfonyl-6-fluoro-benzoate (step 3) (2.0 g, 5.69 mmol) in ethanol (20 ml) was added hydrazine monohydrate (1130 pL, 22.6 mmol) followed by triethylamine (0.79 ml, 5.69 mmol) and the reaction was brought to room temperature. It was then heated at 80 °C for 2 h after which time the reaction was concentrated to dryness. Preparative reverse phase HPLC gave the title compound (1.1 g, 58%) obtained as an off-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) (1.0 g, 3.15 mmol) in DMF (20 ml) was added triphyllin 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 room 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) gave the title compound (1.1 g, 52%) as a yellow solid. ([M+Na, Br]+583.1). Step 6: 4-bromo-5-cyclopropylsulfonyl-3-(difluoromethoxy)-1-trityl-indazoI 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, 4.11 mmol) and Potassium carbonate (0.85 g, 6.17 mmol) was heated at 80 °C for 0.5 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (NazSCU) and concentrated. Flash column chromatography (ethyl acetate: n-Heptane 1:5-1:3) gave the title compound (1.1 g, 83%) as a light yellow solid. ([M+Na]+633.0). Step 7: 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-indazole The title compound ([M+Na+]+721.1) was prepared from Suzuki coupling of 4-bromo5-cyclopropylsulfonyl-3-(difluoromethoxy¡)-1-trityl-indazole (step 6), 3-methyl boronic acid -4(methylsulfonyl)phenyl with potassium carbonate and the dichloride adduct of 1,1'-bis(diphenylphosphino)ferrocenepalladium(ll) dichloromethane (0.1 eq) at 100 °C, according to general procedure D. Step 8: 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-indazole 5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-indazole is deprotonated (step 7) by using general procedure H to obtain the title compound ([M+H]+ 457.2) after flash column chromatography. CCfrQ Ln / Zznz / E / YIAI 120 Example 119: 3-(difluoromethoxy)-4-(2-fluoro-5-methyl·4-methylsulfoníl-phenyl)-5-methylsulfoníl-1Hindazol CCfrQ Ln / Zznz / E / YIAI Step 1: 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1-trityl-ndazol The title compound ([M+Na+]+ 713.2) was prepared from the Suzuki coupling of 4bromo-3-(difluoromethox¡)-5-methylsulfonyl-1-triti l-indazo I (Intermediate 36), (2 -(2-fluoro-5-methyl-4methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 25) with potassium carbonate and SPhos Pd G3 (0.1 eq) at 100 °C in accordance with general procedure D. Step 2: 3-(difluoromethoxy¡)-4-(2-fluoro-5-methyl-4-methylsulfon¡l-phen¡l)-5-methylsulfon¡l-1 H-indazole 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1-tritylindazole is deprotonated (step 1) by the use of general procedure H to obtain the title compound ([M+H]+ 448.0) after flash column chromatography. Example 120: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4c]pyridine-5-carboxamide Step 1: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethox¡)-1-trityl-pyrazolo[3,4-c]pyridine-5carboxamide To a solution of 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4c]pyridine-5-carboxamide (Example 116, step 2) (150.0 mg, 0.23 mmol) in DMF (1 mL) NaH (5.4 mg, 0.23 mmol) was added at 0 °C and the reaction was allowed to reach room temperature, after which time iodomethane (32 mg, 0.23 mmol) and the mixture was stirred for an additional 2 h. The 121 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).

Claims

1. A compound of Formula I R1 (l) CChQ ίΠ / ZZΖηZ / E / YΙΛΙ where X1 is N or C, X2 is N or CR4, X3 is N or CR5, X4 is N or CH, provided that no more than two of X1, X2, and X3 represent N; the dashed lines represent a single or double bond, to enable the six-membered ring to be aromatic, on the condition that when X1 is N and X2 is C=O, then the bond between X1 and X2, the bond between X2 and X3, the bonds a and c are single bonds and the bond between X3 and CR7 and b are double bonds; and on the condition that when X1 is N and X2 is not C=O, then the bond between X1 and X2, the bond between X3 and CR7, the bonds b and c are single bonds and the bond between X2 and X3 and the bond a are double bonds; R1 is -S02R1ao-SOR1b;R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce), alkyl (CrCe), haloalkyl (Ci-Ce), haloalkoxy (Ci-Cs), hydroxyalkyl (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce), NR1a R1b, oxethanyl, furanyl, and pyranyl, wherein at least one of R1a and R1b is alkyl (Ci-Ce) and the other is H or alkyl (Ci-Ce); or R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), haloalkyl (Ci-Ce), or haloalkoxy (Ci-Ce); R2” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (CrCe), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3” is hydrogen, halogen, -NH2, alkyl (Ci-Cs), alkoxy (Ci-Ce), halo-alkyl (Ci-Cs) or halo-alkoxy (Ci-C6);123 R4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, alkyl (Ci-Cs), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-C6), -CO2R4a, -CONR4bR4c, -SO2R4b, -SOR4e, -SR4f, -SO(NR4h)R4a or -SO2(NR4i)R4i; R4a, R4b and R4c are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4d, R4e and R4f are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4h and R4g are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4' and R4i are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl;R5 is hydrogen, halogen, alkyl (Ci-Ce), cycloalkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); R6 is halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxethanyl or thiophenyl or -SO2R6a; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7a R7b, wherein one of R7a and R7b is hydrogen and the other is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), -alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce), -alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NH2, -alkyl (Ci-Ce)-NHCO-alkyl (Ci-C6) or -alkyl (Ci-Ce)-NH2; and their pharmaceutically acceptable salts.

2. A compound according to claim 1, wherein the compound is of Formula CCfrQ Ln / Zznz / E / YIAI R1 (la) wherein X1 is N or C; X3 is N or CR5 the dotted line represents a double bond to enable the six-membered ring to be aromatic on the condition that when X1 is N and R4 is oxo then the bond is a single bond; 124 R1 is -S02R1ao-SOR1b; R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce), haloalkyl (Ci-Ce), haloalkoxy (Ci-Cs), hydroxyalkyl (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce), NR1a R1b, oxethanyl, furanyl, and pyranyl, wherein at least one of R1a and R1b is alkyl (Ci-Ce) and the other is H or alkyl (Ci-Ce); or R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), haloalkyl (Ci-Ce), or haloalkoxy (Ci-Ce); R2” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce);R3' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); R3” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, alkyl (Ci-Cs), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-C6)-alkyl (Ci-C6), -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, -SO(NR4h)R49 or -SO2(NR4i)R4i; R4a, R4b and R4c are R4d, R4e and R4f are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxetanyl;R4h and R49 are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Ce-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4' and R4i are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R6 is halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxethanyl or thiophenyl or -SO2R6a; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7a R7b, wherein one of R7a and R7b is hydrogen and the other is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), -alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce), -alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NH2, -alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce) or -alkyl (Ci-Ce)-NH2; and their pharmaceutically acceptable salts.

3. The compound according to claim 1, wherein the compound is of Formula Ib CCfrQ Ln / Zznz / E / YIAI 125 CCfrQ Ln / Zznz / E / YIAI (Ib) wherein X3 is N or CR5 R1 is -S02R1ao-SOR1b; R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), hydroxy-alkyl (Ci-Ce), alkoxy (Ci-Ce)alkyl (Ci-Ce), NR1a R1b, oxethanyl, furanyl and pyranyl, wherein at least one of R1a and R1b is alkyl (Ci-Ce) and the other is H or alkyl (Ci-Ce); or R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); R2 is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (CrCe), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); R3” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce);R4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), alkoxy (Ci-Ce)-alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce)-alkyl (Ci-C6), -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f, -SO(NR4h)R49 or -SO2(NR4¡)R4¡; R4a, R4b and R4c are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4d, R4e and R4f are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4h and R49 are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4' and R4¡ are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl;126 R5 is hydrogen, halogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); R6 is halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxethanyl or thiophenyl or -SO2R6a; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7a R7b, wherein one of R7a and R7b is hydrogen and the other is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), -alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce), -alkyl (Ci-CeJ-O-alkyl (Ci-Ce)-NH2, -alkyl (Ci-Ceej-NHCO-alkyl (Ci-Ce) or -alkyl (Ci-C6)-NH2; and their pharmaceutically acceptable salts.

4. The compound according to claim 1, wherein the compound is of Formula le CCfrQ Ln / Zznz / E / YIAI (le) wherein R1 is -SO2R1ao-SOR1b; R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce), haloalkyl (Ci-Ce), haloalkoxy (Ci-Ce), hydroxyalkyl (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce), NR1a Rrb, oxethanyl, furanyl, and pyranyl, wherein at least one of R1a and R1b is alkyl (Ci-Ce) and the other is H or alkyl (Ci-Ce); or R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), haloalkyl (Ci-Ce), or haloalkoxy (Ci-C6); R2” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3 is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6);R5 is hydrogen, halogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce); 128 R4a, R4b and R4c are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4d, R4e and R4f are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4h and R4a are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4i and R4ii are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R5 is hydrogen, halogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-Ce);R6 is halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxethanyl or thiophenyl or -SO2R6a; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7a R7b, wherein one of R7a and R7b is hydrogen and the other is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), -alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce), -alkyl (Ci-Ce)O-alkyl (Ci-Ce)-NH2, -alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce) or -alkyl (Ci-Ce)-NH2; and their pharmaceutically acceptable salts.

6. The compound according to claim 1, wherein the compound is of Formula le CCfrQ Ln / Zznz / E / YIAI R1 (le) wherein R1 is -SO2R1ao-SOR1b; R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Ce), alkyl (Ci-Ce), haloalkyl (Ci-Ce), haloalkoxy (Ci-Ce), hydroxyalkyl (Ci-Ce), alkoxy (Ci-Ce), alkyl (Ci-Ce), NR1a R1b, oxethanyl, furanyl, and pyranyl, wherein at least one of R1a and R1b is alkyl (Ci-Ce) and the other is H or alkyl (Ci-Ce); or R2' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), haloalkyl (Ci-Ce), or haloalkoxy (Ci-C6); 129 R2” is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (CrCe), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3' is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (Ci-C6); R3 is hydrogen, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce) or halo-alkoxy (C1-C6);R4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), alkoxy (Ci-C6)-alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Ce-Cej-alkyl (Ci-Ce), -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SO(NR4h)R4g or -SO2(NR4i)R4i; R4a, R4b and R4c are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (Cs-Cej-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4d, R4e and R4f are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4h and R49 are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl; R4' and R4i are independently selected from hydrogen, alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce) and oxethanyl;R6 is halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), cyano, halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), cycloalkyl (Cs-Ce), oxethanyl or thiophenyl or -SO2R6a; R6a is alkyl (Ci-Ce), cycloalkyl (Cs-Ce) or halo-alkyl (Ci-Ce); R7 is hydrogen, halogen, hydroxy, alkyl (Ci-Ce), alkoxy (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce) or NR7a R7b, wherein one of R7a and R7b is hydrogen and the other is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), -alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce), -alkyl (Ci-Ce)-O-alkyl (Ci-Ce)-NH2, -alkyl (Ci-Ce)-NHCO-alkyl (Ci-Ce) or -alkyl (Ci-Ce)-NH2; and their pharmaceutically acceptable salts.

7. The compound according to claim 1, wherein X4 is N.

8. The compound according to claim 1, wherein X1 is N or C, X2 is N or CR4 and X3 is N or CR5.

9. The compound according to any one of claims 1 to 8, wherein R1 is SO2R1a.

10. The compound according to any one of claims 1 to 9, wherein R1a and R1b are independently selected from alkyl (Ci-Ce), cycloalkyl (Cs-Ce), cycloalkyl (C3-Ce)-alkyl (Ci-Ce), halo-alkyl (Ci-Ce), halo-alkoxy (Ci-Ce), hydroxy-alkyl (Ci-Ce), alkoxy (Ci-Ce)-alkyl (Ci-Ce), NR1a R1b, oxethanyl, furanyl and pyranyl, wherein at least one of R1a and R1b is alkyl (Ci-Cs) and the other is H or alkyl (Ci-Ce).

11. The compound according to any one of claims 1 to 10, wherein R1a is selected from (C1-C3) alkyl, (C3-C4) cycloalkyl, (Cs-C4)-C1-C3 cycloalkyl, (C1-C3) halo-alkyl, (C1-C3) hydroxy-alkyl, (Ci-C3) alkoxy-alkyl, R1b and oxethanyl, wherein at least one of R1a and R1b is (C1-C3) alkyl and the other is either H or (C1-C3) alkyl.

12. The compound according to any one of claims 1 to 11, wherein R1a is selected from methyl, ethyl, propyl, i-propyl, i-butyl, cyclopropyl, fluoromethyl, difluoromethyl, fluoro-ethanyl, difluoro-ethanyl, 1,2-difluoroethanyl, 1,1,2-trifluoroethanyl, 1,2,2-trifluoroethanyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methylamyl (-NHCH3), dimethylamyl (-N(CH3)2) and oxethanyl.

13. The compound according to any one of claims 1 to 12, wherein R1a is selected from ethyl, propyl, i-propyl, i-butyl, cyclopropyl, fluoromethyl, difluoromethyl, fluoro-ethanyl, difluoro-ethanyl, 1,2-difluoroethanyl, 1,1,2-trifluoroethanyl and 1,2,2-trifluoroethanyl.

14. The compound according to any one of claims 1 to 13, wherein R1a is selected from methyl, ethyl, cyclopropyl, and difluoromethyl.

15. The compound according to any one of claims 1 to 14, wherein R1b is alkyl (C1-C3), more particularly alkyl (C1-C3), with the most particularity being methyl.

16. The compound according to any one of claims 1 to 14, wherein if R2' is different from hydrogen as defined according to any one of claims 1 to 6, then R3' is hydrogen, R2" is hydrogen and R3" is as defined according to any one of claims 1 to 6.

17. The compound according to any one of claims 1 to 15, wherein one of R2' and R2” is hydrogen, halogen, -NH2, (C1-C2) alkyl, (C1-C2) alkoxy or (C1-C2) halo-alkyl, while the other is hydrogen.

18. The compound according to any one of claims 1 to 17, wherein R2' is hydrogen, halogen, -NH2, methyl, ethyl, methoxyfluoromethyl, difluoromethyl, fluoro-ethanyl, difluoro-ethanyl or 1,2 difluoroethanyl and R2 is hydrogen.

19. The compound according to any one of claims 1 to 18, wherein R2' is methyl, ethyl, fluoromethyl, difluoromethyl, fluoro-ethanyl, difluoro-ethanyl, 1,2 difluoroethanyl and R2” is hydrogen.

20. The compound according to any one of claims 1 to 19, wherein R2' is methyl or difluoromethyl and R2 is hydrogen.

21. The compound according to any one of claims 1 to 20, wherein one of R3' and R3” is hydrogen, halogen, -NH2, (C1-C3) alkyl, (C1-C3) alkoxy or (C1-C3) halo-alkyl, while the other is hydrogen.

22. The compound according to any one of claims 1 to 21, wherein R3 is hydrogen, halogen or (C1-C3) alkyl and R3' is hydrogen.

23. The compound according to any one of claims 1 to 22, wherein R3” is hydrogen or fluorine and R3’ is hydrogen. 131 24. The compound according to any one of claims 1 to 23, wherein both R3' and R3” are hydrogen.

25. The compound according to any one of claims 1 to 24, wherein R4 is cyano, oxo, hydroxy, alkyl (C1-C3), alkoxy (C1-C3), halo-alkyl (C1-C3), halo-alkoxy (Ci-Ce), alkoxy (Ci-CsJ), alkyl (C1-C3), cycloalkyl (C3-C4), -CO2R4a, -CONR4bR4c, -SO2R4d, -SOR4e, -SR4f or -SO(NR4h)R49.

26. The compound according to any one of claims 1 to 25, wherein R4 is cyano, oxo, hydroxy, alkoxy (Ci-C2), halo-alkyl (Ci-C2), halo-alkoxy (Ci-C2), alkoxy (Ci-C2)-alkyl (C1-C2), cyclopropyl, -CO2H, -CONR4bR4c, -SO2R4d, -SOR4®, -SR4f, -SO(NH)CH3 or -SO2(NH)CH3.

27. The compound according to any one of claims 1 to 26, wherein R4 is cyano, oxo, hydroxy, methoxy, -CF3, -OCFa, -methyl-methoxy, cyclopropyl, -CO2H, -CONR4bR4c, -SO2R4d, -SOR4® or -SR4f.

28. The compound according to any one of claims 1 to 27, wherein R4 is cyano, oxo, -CONHR4c or -SO2R4d.

29. The compound according to any one of claims 1 to 28, wherein R4a, R4b and R4c are independently selected from hydrogen, alkyl (C1-C3), cycloalkyl (C3-C4) and oxethanyl.

30. The compound according to any one of claims 1 to 29, wherein R4a, R4b and R4c are independently selected from hydrogen, (C1-C3) alkyl, cyclopropyl and oxethanyl.

31. The compound according to any one of claims 1 to 30, wherein R4a, R4b and R4c are independently selected from hydrogen, (C1-C3) alkyl and cyclopropyl.

32. The compound according to any one of claims 1 to 31, wherein R4a is hydrogen.

33. The compound according to any one of claims 1 to 32, wherein R4b is hydrogen and R4c is hydrogen or methyl.

34. The compound according to any one of claims 1 to 28, wherein R4d, R4e and R4f are independently selected from (C1-C3) alkyl, (C3-C4) cycloalkyl and oxethanyl.

35. The compound according to any one of claims 1 to 28, wherein R4d, R4e and R4f are independently selected from (C1-C3) alkyl, cyclopropyl and oxethanyl.

36. The compound according to any one of claims 1 to 28, wherein R4d, R4® and R4f are independently selected from (C1-C3) alkyl and cyclopropyl, with the most particularity R4d being methyl or cyclopropyl.

37. The compound according to any one of claims 1 to 28, wherein R4d is methyl or cyclopropyl.

38. The compound according to any one of claims 1 to 37, wherein R4d is methyl.

39. The compound according to any one of claims 1 to 25, wherein R4h and R4g are independently selected from hydrogen and alkyl (Oi-Ce). CChQ iP / ZZΖ / E / YILI 132 40. The compound according to any one of claims 1 to 25, wherein R4h and R49 are independently selected from hydrogen and (C1-C3) alkyl.

41. The compound according to any one of claims 1 to 25, wherein R4h is hydrogen and R4g is alkyl (C1-C3).

42. The compound according to any one of claims 1 to 25, wherein R4h is hydrogen and R4g is methyl.

43. The compound according to any one of claims 1 to 25, wherein R4i and R4¡ are independently selected from hydrogen and alkyl (Ci-Cs).

44. The compound according to any one of claims 1 to 25, wherein R4i and R4¡ are independently selected from hydrogen and (C1-C3) alkyl. CChQ ίΠ / ZZΖηZ / E / YΙΛΙ 45. The compound according to any one of claims 1 to 25, wherein R4' is hydrogen and R4 is alkyl (C1-C3).

46. ​​The compound according to any one of claims 1 to 25, wherein R4i is hydrogen and R4i is methyl.

47. The compound according to any one of the claims hydrogen, halogen, alkyl (Ci-Ce), alkoxy (Ci-Ce) or cycloalkyl (Ca-Ce).

48. The compound according to any one of the claims hydrogen, halogen, alkyl (C1-C2), alkoxy (C1-C2) or cycloalkyl (C3-C4).

49. The compound according to any one of claims 46, wherein R5 is hydrogen, fluorine, chlorine, cyclopropyl, methyl, or methoxy. 47, wherein R5 is hydrogen. 48, wherein R5 is hydrogen.

50. The compound according to any one of claims 49, wherein R5 is hydrogen.

51. The compound according to any one of claims 50, wherein R6 is halogen, alkyl (C3C3), alkoxy (C3C3), cyano, haloalkyl (C3C3), haloalkoxy (C3C3), cycloalkyl (C3C3), thiophenyl, oxethanyl, or -SO2R6a.

52. The compound according to any one of claims 1 to 51, wherein R6 is bromine, (C1-C3) alkyl, (C1-C3) alkoxy, cyano, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C3-C4) cycloalkyl, thiophenyl, oxethanyl or -SOzR63.

53. The compound according to any one of claims 1 to 52, wherein R6 is halo-alkyl (C1-C3), halo-alkoxy (C1-C3) or cycloalkyl (C3-C4).

54. A compound according to any one of claims 1 to 52, wherein R6 is trifluoromethyl, trifluoromethoxy, difluoromethoxy or cyclopropyl.

55. A compound according to any one of claims 1 to 54, wherein R6a is alkyl (Oi-Ce).

56.

57. The compound according to any one of claims 1 to 55, wherein R6a is methyl. The compound according to any one of claims 1 to 56, wherein R7 is hydrogen, halogen, hydroxy, or alkyl (Ci-Ce). 133 58. The compound according to any one of claims 1 to 57, wherein R7 is hydrogen, halogen or hydroxyl.

59. The compound according to any one of claims 1 to 58, wherein R7 is hydrogen.

60. The compound according to any one of claims 1 to 56, wherein one of R7a and R7b is hydrogen and the other is hydrogen, alkyl (Ci-Ce), alkoxy (Ci-Ce), -alkyl (Ci-C3)-O-alkyl (Ci-C3)-NHCO-alkyl (C1-C3), -alkyl (Ci-C3)-O-alkyl (Ci-C3)-NH2, -alkyl (Ci-C3)-NHCO-alkyl (C1-C3) or -alkyl (Ci-C3)-NH2.

61. The compound according to any one of claims 1 to 56, wherein one of R7a and R7bes is hydrogen and the other is hydrogen, alkyl (Ci-Ce) or alkoxy (Ci-Ce).

62. The compound according to any one of claims 1 to 56, wherein one of R7a and R7bes is hydrogen and the other is hydrogen, alkyl (C1-C3) or alkoxy (C1-C3).

63. The composition of the information with a selection of indications 1 to 62, selected from the group that consists of: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazole[4,3-c]pir¡d¡na; 3-cycloprop¡l-4-(3-methox¡-4-(met¡lsulfon¡l)phen¡l)-1 H-pyrazolo[4,3-c]pir¡d¡na; 4-(3-chloro-4-(methylsulfonyl)phenyl)-3-c¡clopropyl-1 H-pyrazolo[4,3-c]p¡rid¡na; 3-cyclopropyl-4-(4-(methylsulfonyl)-3-(trifluoromethyl)phenyl)-1 H-pyrazolo[4,3-c]pyrdine; 4-(3-cyclopropyl-1 Hp¡razolo[4,3-c]p¡r¡d¡n-4-¡l)-N,N,2-trimethylbencenosulfonamide; 3-c¡clopropyl-5-methoxy-4-(4-methylsulfonylphenyl)-1 H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(4-(cyclopropylsulfonyl)-3-methylphenyl)-1 H-pyrazolo[4,3-c]pyrdine; 4-(3-chloro-4-(cyclopropylsulfonyl)phenyl)-3-cyclopropyl-1 H-pyrazolo[4,3-c]pir¡d¡na; 2-chloro-4-(3-cyclopropyl-1 H-pyrazolo[4,3-c]pyridin-4-yl)-N,N-dimethylbencenosulfonam¡da; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(tr¡fluoromethyl)-1 H-pyrazolo[3,4-b]pyridine;4-(4-(met¡lsulfonyl)phen¡l)-3-(tr¡fluoromet¡l)-1 H-pyrazolo[4,3-c]pyr¡d¡na; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyr¡d¡na; 3-cyclopropyl-4-(3-(fluoromethyl)-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyrdine; 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyramide; 3-cyclopropyl-4-(3-methyl-4-(oxetanyl-3-sulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyrdine; 3-(difluoromethoxy)-4-(3-methyl-4-(methoxysulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyrdine; 3-methoxy-4-(3-methyl-4-(methoxysulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 5-(3-cyclopropyl-1 Hp¡razolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1 H-pyrazolo[4,3-b]pyrdine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 Hp¡razolo[3,4-c]pyr¡d¡na-5-carbonitrilo; 3-(1,1-difluoroethyl)-4-(3-methyl-4-(methylsulphonyl)phenyl)-1 H-pyrazolo[4,3-c]pyrdine;4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazole[4,3-c]p¡r¡dina-3-carbon¡tr¡lo; 3-(difluoromethyl)-4-(3-methyl-4-methylsulfonylphenyl)-1 H-pyrazolo[4,3-c]pyr¡d¡na; CCfrQ Ln / Zznz / E / YIAI 134 3-isopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-c¡clopropyl-4-(4-ethylsulfon¡l-3-methyl-phen¡l)-1 H-pyrazolo[4,3-c]pyr¡d¡na; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyrdine; 3-cyclopropyl-4-(2,5-dimethyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pridine chlorohydrate; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)fen¡l)-1 H-pyrazolo[3,4-c]pyr¡d¡na-5-carboxíl¡co acid; 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1 H-indazol-5-carbonitrilo; 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridine hydrochloride 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridine-7-ol 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(tofen-3-1)-1 H-pyrazolo[4,3-c]pyridine;3-cyclopropyl-5-methoxy-4-(3-methoxy-4-(methoxysulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-ethoxy-4-(3-methoxy-4-methoxysulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(dfluoromethoxy)-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]pyr¡dine; 3-(difluoromethoxy)-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyr¡dine; 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyr¡dine; 4-[4-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyr¡dine; 3-(difluoromethoxy)-4-(3-methyl-4-prop¡lsulfonyl-phenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-(d¡fluoromethoxy)-4-[3-(d¡fluoromethyl)-4-met¡lsulfon¡l-phen¡l]-1 H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(4-isoprop¡lsulfon¡l-3-methyl-phen¡l)-1 H-pyrazolo[4,3-c]pyridine;4-[3-(difluoromethox)-1 Hp¡razolo[4,3-c]p¡r¡d¡n-4-¡l]-N,2-dimethyl-bencenolsylfonamide; 3-methoxy-4-(3-methyl-4-(meth¡lsulfonyl)phenyl)-1 H-indazole-5-carbonitrilo; 3-(difluoromethox)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-indazole-5-carbonitrilo; 6-chloro-3-c¡cloprop¡l-4-(3-methyl-4-methylsulfonylphenyl)-1 H-pyrazolo[4,3-c]pyridine; 3-(difluoromethox¡)-4-(3-met¡l-4-(oxetan-3-¡lsulfon¡l)fen¡l)-1 H-pyrazolo[4,3-c]pyr¡d¡na; 2-[4-[3-(difluoromethox¡)-1 H-pyrazolo[4,3-c]piridin-4-yl]-2-metil-fenil]sulfon¡lethanol ácido 2,2,2-trifluoroacetico de S-ciclopropil-e-metoxi^íS-metil^-metilsulfonylfenil)-1Hpirazolo[4,3-c]pirid¡na; 3-(difluoromethoxy)-4-[3-meth-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1H-pyrazolo[4,3-c]pyrazolo; 4-(3-methyl-4-(meth-lsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyrazolo; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyrazolo-5-carboxamyl; 3-cyclopropyl-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyrazolo-5-carboxamyl;3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-pyrazolo[3,4-d]pyradazine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1 H-indazol; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfinyl)-1 H-indazol; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1 H-indazol; ácido formico de 3-(difluorometox¡)-4-[4-(metoximet¡lsulfon¡l)-3-metil-fenil]-1 H-pirazolo[4,3c]pirid¡na; CCfrQ Ln / Zznz / E / YIAI 135 5-metoxi-4-(3-metil-4-(metilsulfonyl)feniI)-3-(trifluorometil)-1 H-pirazolo[3,4-c]piridine; 4-(3-metil-4-(met¡lsulfon¡l)fenil)-3-(trifluoromet¡l)-1 H-pirrolo[3,2-c]pirid¡na; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenol)-1 H-pyrazole[3,4-c]p¡r¡d¡na; 3-c¡cloprop¡l-6-meth¡l-4-(3-methyl-4-methylsulfonyl-phen¡l)-1 H-pyrazolo[4,3-b]pir¡d¡n-5-ona; 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-b]pyridin-5-ona;3-cyclopropyl-5-(dfluoromethoxy)-4-(3-methoxy-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-methoxy-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]p¡r¡d¡na; 3-cyclopropyl-4-(3-metyl-4-(metylsulfonyl)phenyl)-N-(oxetan-3-1)-1H-pyrazolo[3,4-c]pyrazolo-5-carboxamide; 3,5-dicyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyrazolo-5-carboxamide; 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-carbonitrilo; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1 Hp¡razolo[3,4-c]pyr¡d¡na-5-carbonitrilo; 3-c¡cloprop¡l-4-(4-c¡cloprop¡lsulfon¡l-3-methyl-phen¡l)-1 H-pyrazole[3,4-c]p¡r¡dine-5-carbon¡tr¡lo;4-(3-met¡l-4-(met¡lsulfon¡l)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1 H-indazol 3-cycloprop¡l-4-(3-met¡l-4-methylsulfonylphen¡l)-1 H-indol-5-carbonitrile; 3-c¡cloprop¡l-4-(4-c¡cloprop¡lsulfon¡l·3-met¡l-phen¡l)-N-methyl·1H-p¡razolo[3,4-c]pyrid¡na-5-carboxam¡da; 3-cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1 H-indazol-5-carboxamida; 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazol-5-carboxamide; 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-carbonitrilo; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyrazolodine-5-carbonitrilo; 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trfluoromethox)-1H-pyrazolo[4,3-b]pyrdan-5-one; 3-cycloprop¡l-4-(3-meth¡l-4-methylsulfon¡l-phen¡l)-1 H-pyrrolo[3,2-b]pyrid¡n-5-one; 4-[3-(difluoromethox¡)-1 Hp¡razolo[4,3-c]pyridin-4-¡l]-2-(difluoromethyl)-N,N-dimethylbencenosulfonamide; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1 H-indazol;3-cyclopropyl-4-[4-(dfluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonyl; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-methylsulfonyl)-3-(trifluoromethoxyl)-1H-indazole; 3-ccyclopropyl-4-[3-(dfluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethox)-4-(3-meth-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrilo; 3-(difluoromethoxy)-4-[5-(difluoromethyl)-2-methyl-4-methsulfinyl-phenyl]-1H-pyrazolo[3,4-c]pind-5carbonitrilo; 4-[3-(d-fluoromethyl)-4-methsulfonyl-phenyl]-5-methox-3-(tr-fluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(3-(dfluoromethyl)-4-(methlsulfonyl)phenyl)-5-(methlsulfonyl)-1 H-indazol; 3-(dfluoromethoxyl)-N-methyl-4-(3-methl-4-methlsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; CCfrQ Ln / Zznz / E / YIAI 136 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide;4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(dfluoromethoxy)-5-methylsulfonyl-1 H-indazole; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-N-methyl-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(d¡fluoromethoxy)-4-(4-((d¡fluoromethyl)sulfon¡l)-3-methylphenyl)-1 Hp¡razolo[3,4-c]pyridine-5-carbon¡tr¡lo; 3-(difluoromethoxy)-4-[4-(d¡fluoromethylsulfon¡l)-3-methyl-phenyl]-1 H-pyrazolo[3,4-c]pyridine-5carboxamida; 3-(difluoromethox¡)-4-[4-(d¡fluorometh¡lsulfon¡l)-3-met¡l-phen¡l]-N-(oxetan-3-¡l)-1 H-pyrazolo[3,4c]pyridine¡na-5-carboxam¡da; 3-(d¡fluoromethox¡)-4-[4-(d¡fluoromethylsulfon¡l)-3-meth¡l-phen¡l]-N-rnethyl-1 H-pyrazolo[3,4-c]pyridine¡na-5carboxamida; 3-(difluoromethoxy)-4-[4-(difluoromethylsuIfonyl)-3-methyl-phenyl]-N-(2-methoxyethyl)-1 H-pyrazolo[3,4c]pyridine-5-carboxamida; 3-(difluoromethox¡)-N-met¡l-4-(3-met¡l-4-met¡lsulfonyl-phen¡l)-1 Hp¡razolo[3,4-c]pyr¡d¡na-5-carboxam¡da;3-(difluoromethoxy)-4-(3-met¡l-4-met¡lsulfonyl-phenyl)-5-(oxetane-3-ylsulfon¡l)-1 H-indazole; [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1 H-¡ndazol-5-yl]-imino-meth¡l-oxo-sulfane; [3-c¡clopropyl-4-(3-met¡l-4-methylsulfonyl-phenyl)-1 H-¡ndazol-5-yl]-met¡l-met¡l¡l¡mino-oxo-A6-sulfane; 3-c¡clopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-indazol-5-sulfonamide; 3-c¡clopropyl-N-met¡l-4-(3-methyl-4-methylsulfon¡l-phenyl)-1 H-indazole-5-sulfonamide; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1 H-pyrazolo[3,4-c]pyridine-5-carboxam¡da; 3-(difluoromethoxy)-4-(4-((d¡fluoromethyl)sulfonyl)-3-methylphenyl)-5-(meth¡lsulfonyl)-1 H-indazole; 5-c¡cloprop¡lsulfonyl-3-(d¡fluoromethoxy¡)-4-(3-met¡l-4-meth¡lsulfon¡l-phen¡l)-1 H-indazole; 3-(difluoromethoxy¡)-4-(2-fluoro-5-met¡l-4-met¡lsulfon¡l-phen¡l)-5-met¡lsulfonyl-1 H-indazole; or 4-(4-c¡cloprop¡lsulfon¡l-3-met¡l-phenyl)-3-(d¡fluoromethoxy)-N-methyl-1 H-pyrazolo[3,4-c]pindine-5carboxamide and its salts acceptable from the pharmaceutical point of view.;64. The compound according to any one of claims 1 to 63, selected from the group comprising: 3-(difluoromethoxy)-4-(3-methyl-4-(met¡lsulfonyl)phen¡l)-1 H-indazol-5-carbonitrile; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[4,3-b]pyr¡din-5-one; 3-cyclopropyl-4-(4-ethylsulfon¡l-3-methyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1 H-indazole; 3-(d¡fluoromethoxy¡)-4-(3-met¡l-4-(methylsulfon¡l)phen¡l)-5-(methylsulfon¡l)-1 H-indazole; 3-c¡cloprop¡l-4-[4-d¡fluoromethylsulfon¡l)-3-met¡l-phen¡l]-1 H-pyrazolo[3,4-c]p¡r¡d¡na-5-carbon¡tryl; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfon¡l)-3-(trifluoromethoxy)-1 H-indazole; CCfrQ Ln / Zznz / E / YIAI 137 3-cyclopropyl-4-[3-(difluoromethyl)-4-methyIsulfonyl-phenyl]-N-nnetyl-1 H-pyrazolo[3,4-c]pyridine-5carboxamide; 3-(difluoromethoxy¡)-4-(3-met¡l-4-methylsulfon¡l-phen¡l)-1 H-pyrazolo[3,4-c]p¡r¡dine-5-carbon¡tr¡lo;3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1 H-pyrazolo[3,4-c]pyridine-5-carboxamide; or 3-(difluoromethoxy¡)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1 H-pyrazolo[3,4-c]pyridine-5carboxamide and its pharmaceutically acceptable salts.; 65. A compound according to any one of claims 1 to 64 for use as a therapeutically active substance.

66. Pharmaceutical compositions comprising compounds of Formula I according to any one of claims 1 to 64 or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

67. Compounds of Formula I according to any of claims 1 to 64 above, or their pharmaceutically acceptable salts for use as therapeutically active substances.

68. Formula I compounds according to any of claims 1 to 64 or pharmaceutically acceptable salts thereof for use in the treatment, prevention and / or delay of progression of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, carcinoma of the esophagus, glioblastoma multiforme and mesothelioma.

69. Compounds according to claim 68 for use in the treatment, prevention and / or delay of progression of lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

70. A method for the treatment or prevention of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, carcinoma of the esophagus, glioblastoma multiforme, and mesothelioma, wherein the method comprises administering to a subject compounds of Formula I according to any one of claims 1 to 64 or pharmaceutically acceptable salts thereof, as defined above.

71. A method according to claim 70 for the treatment or prevention of lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme, and squamous cell carcinoma of the head and neck.

72. The use of Formula I compounds according to any one of claims 1 to 64 or their pharmaceutically acceptable salts for the treatment, prevention, and / or delay of the progression of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, carcinoma of the esophagus, glioblastoma multiforme, and mesothelioma. CCfrQ Ln / Zznz / E / YIAI 138 73. The use of compounds according to claim 72, for the treatment, prevention and / or delay of the progression of lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

74. The use of Formula I compounds according to any one of claims 1 to 64 or their pharmaceutically acceptable salts for the preparation of medicaments for the treatment or prevention of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, carcinoma of the esophagus, glioblastoma multiforme, and mesothelioma.

75. The use of compounds according to claim 74, for the treatment, prevention and / or delay of the progression of lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

76. The invention as described above in this description.