Sulfone Derivatives

Abstract

The present invention relates to a compound of formula (I) TIFF2023531020000152.tif80170[where, X 1 , X 2 , X 3 , X 4 , R 1 , R 1a , R 1b , R 2’ , R 2’’ , R 3’ , R 3’’ , R 6 , and R 7 is as described herein, and pharmaceutically acceptable salts thereof. The present invention further relates to the preparation of compounds of formula (I), pharmaceutical compositions containing those compounds, and their use as medicaments.

Description

[Technical Field]

[0001] The present invention provides compounds that are inhibitors of human methionine adenosyltransferase 2A (Mat2A) for use in treating, preventing and / or delaying the progression of cancer.

[0002] In particular, the present invention provides compounds of formula I TIFF0007731381000001.tif61170[In the formula, X 1 is either N or C, X 2 is N or CR 4 Either X 3 is N or CR 5 Either X 4 is either N or CH, However, X 1 , X 2 , and X 3 Two or fewer of these represent N; The dotted line is an X 1 is N and X 2 If C=O, then X 1 and X 2 The bond between X 2 and X 3 The bond between, bond a and bond c is a single bond, and X 3 and CR 7 and bond b are double bonds; and X 1 is N and X 2 If is not C=O, then X 1 and X 2 The bond between X 3 and CR 7 The bond between X and X, bond b and bond c are single bonds. 2 and X 3 represents a single or double bond that renders the six-membered ring aromatic, provided that the bond between and bond a is a double bond; R 1 Ha-SO2R 1a or -SOR1b and; R 1a and R 1b are independently (C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, NR 1’a R 1’b , oxetanyl, furanyl, and pyranyl; R 1’a and R 1’b at least one of is (C1-C6) alkyl and the other is H or (C1-C6) alkyl; R 2’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 2’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C1-C6) alkoxy-(C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, -CO2R 4a , -CONR 4b R 4c , -SO2R 4d , -SOR 4e , -SR4f , -SO(NR 4h )R 4g , or -SO2(NR 4i )R 4j and; R 4a , R 4b , and R 4c is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4d , R 4e , and R 4f is independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4h and R 4g is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4i and R 4j is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 5 is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 6 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C3-C6) cycloalkyl, oxetanyl, or thiophenyl, or -SO2R 6a and; R 6ais (C1-C6)alkyl, (C3-C6)cycloalkyl, or halo(C1-C6)alkyl; R 7 is hydrogen, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, halo-(C1-C6) alkyl, halo-(C1-C6) alkoxy, or NR 7’a R 7’b and R 7’a and R 7’b one of which is hydrogen and the other is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, -(C1-C6) alkyl-O-(C1-C6) alkyl-NHCO-(C1-C6) alkyl, -(C1-C6) alkyl-O-(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NHCO-(C1-C6) alkyl, or -(C1-C6) alkyl-NH2] and pharmaceutically acceptable salts thereof.

[0003] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.

[0004] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0005] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0006] Any open valency appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein indicates the presence of a hydrogen, unless otherwise indicated.

[0007] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo, especially chloro or fluoro.

[0008] "Hydroxy" refers to the group --OH.

[0009] "(C1-C6) alkyl" means a branched or straight hydrocarbon chain of 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl.

[0010] "(C1-C6)" alkoxy is a group of the formula -OR a means the part of R a is a (C1-C6) alkyl moiety as defined herein. Examples of (C1-C6) alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0011] The term "(C3-C6)"cycloalkyl means a saturated monovalent monocyclic hydrocarbon radical of 3 to 6 ring carbon atoms. Examples of monocyclic (C3-C6)cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, or cyclohexyl. A particular example of (C3-C6)cycloalkyl is cyclopropyl.

[0012] "(C3-C6)cycloalkyl-(C1-C6)alkyl" means a (C1-C6)alkyl as defined above substituted with one or more (C3-C6)cycloalkyl groups, in particular one (C3-C6)cycloalkyl group. In particular, "(C3-C6)cycloalkyl-(C1-C6)alkyl" means means TIFF0007731381000002.tif21170.

[0013] The term "perhalo(C1-C3)alkyl" means a (C1-C3)alkyl group as defined above, in which all hydrogen atoms have been replaced by halogen atoms. In particular, "(C1-C3)perhaloalkyl" is a (C1-C3)perfluoroalkyl, most preferably trifluoromethyl.

[0014] "Halo-(C1-C6)alkyl" means (C1-C6)alkyl as defined above substituted with one or more halogen atoms, particularly 1 to 3 halogen atoms. In particular, halo-(C1-C6)alkyl is chloro-(C1-C6)alkyl and fluoro-(C1-C6)alkyl. In some particular embodiments, halo-(C1-C6)alkyl means perhalo(C1-C3)alkyl as defined herein. In particular, halo-(C1-C6)alkyl is trifluoromethyl, difluoromethyl, or fluoromethyl.

[0015] "Halo-(C1-C6)alkoxy" means (C1-C6)alkoxy as defined above substituted with one or more halogen atoms, particularly 1 to 3 halogen atoms. In particular, halo-(C1-C6)alkoxy is chloro-(C1-C6)alkoxy and fluoro-(C1-C6)alkoxy. In some particular embodiments, halo-(C1-C6)alkoxy means perhalo(C1-C3)alkoxy, for example, trifluoromethoxy or difluoromethoxy.

[0016] "Hydroxy-(C1-C6)alkyl" means (C1-C6)alkyl as defined above substituted with one or more hydroxy groups, in particular with one hydroxy group. In particular, hydroxy-(C1-C6)alkyl means methyl hydroxide or ethyl hydroxide.

[0017] "(C1-C6)alkoxy-(C1-C6)alkyl" means a (C1-C6)alkyl as defined above substituted with one or more (C1-C6)alkoxy groups as defined herein, in particular one (C1-C6)alkoxy group. In particular, (C1-C6)alkoxy-(C1-C6)alkyl means -CH2-O-CH3 or -CH2CH2-O-CH3.

[0018] "Halo-(C1-C6)alkoxy" means alkoxy as defined above substituted with one or more halogen atoms, in particular with 1 to 3 halogen atoms. In particular, halo-(C1-C6)alkoxy is chloro-(C1-C6)alkoxy and fluoro-(C1-C6)alkoxy.

[0019] "Heteroaryl" means a monovalent monocyclic or bicyclic moiety of 5 to 12 ring atoms having at least one aromatic ring containing 1, 2, or 3 ring heteroatoms each independently selected from N, O, or S (preferably N or O), the remaining ring atoms being C, and it is understood that the point of attachment of the heteroaryl moiety is on the aromatic ring. In particular, the term heteroaryl includes, but is not limited to, pyridinyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, or benzothienyl, imidazo[1,2-a]-pyridinyl, imidazo[2,1-b]thiazolyl, and derivatives thereof. In particular, "N-heteroaryl" refers to the heteroaryl defined above that contains at least one nitrogen atom. The attachment point of N-heteroaryl to the rest of the molecule can be via a nitrogen atom or a carbon ring atom. Examples of N-heteroaryl are pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl.

[0020] The terms "heterocycloalkyl" or "heterocyclic" mean a monovalent saturated or partially unsaturated, monocyclic ring system of 4 to 9 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon. Examples of heterocycloalkyl are pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolane, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. In particular, heterocycloalkyl means dihydrofuryl, 1,3-dioxolyl, dihydropyryl, dihydrothiophyl, dihydropyrazolyl, dihydroisoxazolyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazyl, 1,2,3,4-tetrahydropyrazyl.

[0021] The term "therapeutically effective amount" refers to the amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder described herein, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder. A therapeutically effective amount will vary depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0022] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl may be present but need not be present, and that the description includes situations where the aryl group is substituted with an alkyl group and situations where the aryl group is not substituted with an alkyl group.

[0023] The term "individual" or "subject" refers 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 certain embodiments, the individual or subject is a human.

[0024] The terms "compound of this invention" and "compound of the present invention" mean compounds disclosed herein, as well as their stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts).

[0025] When the compounds of the invention are solids, those skilled in the art will understand that the compounds, and their solvates and salts, may exist in different solid forms, particularly different crystalline forms, all of which are included within the scope of the invention and the specified formula.

[0026] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0027] The term "pharmaceutically acceptable acid addition salts" refers to pharmaceutically acceptable salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid) and with organic acids of the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes (e.g., formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, 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).

[0028] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0029] The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule in a pharmaceutical composition that has a specific biological activity.

[0030] The terms "pharmaceutical composition" or "pharmaceutical formulation" (or "formulation") refer to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients, used interchangeably, and administered to a mammal, e.g., a human, in need thereof.

[0031] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" are used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition used in the formulation of a pharmaceutical product, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant, that has no therapeutic activity and is non-toxic to a subject to which it is administered.

[0032] The terms "treating" or "treatment" of a condition include suppressing the condition, i.e., arresting the development of the condition or its clinical symptoms, or alleviating the condition, i.e., temporary or permanent regression of the condition or its clinical symptoms.

[0033] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the spatial arrangement of their atoms are called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when one carbon atom is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center, described by the Cahn-Ingold-Prelog R / S rule, or by the way the molecule rotates the plane of polarized light, called dextrorotatory or levorotatory (i.e., (+)-isomer or (-)-isomer, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal ratios of enantiomers is called a "racemic mixture."

[0034] The compound of formula I may have one or more asymmetric centers or axes. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include individual epimers, atropisomers, and mixtures thereof, as well as individual enantiomers, atropisomers, and racemic or other mixtures thereof. Methods for identifying stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th Edition, J. March, John Wiley and Sons, New York, 1992).

[0035] Certain compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate individual tautomers usually result in mixtures whose chemical and physical properties match those of the compound. The position of the equilibrium depends on the chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. Common prototropic tautomers include keto / enol (-C(=O)-CH-⇔-C(-OH)=CH-), amide / imidic acid (-C(=O)-NH-⇔-C(-OH)=N-), and amidine (-C(=NR)-NH-⇔-C(-NHR)=N-). The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention encompasses all tautomeric forms of the compounds.

[0036] The present compounds of formula I have now been found to be inhibitors of Mat2A, and as such may be of therapeutic interest for the treatment of cancer disorders including lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma.

[0037] 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 to produce S-adenosylmethionine (SAM), the principal methyl donor in cells. MAT1A is a liver-specific SAM-producing enzyme, while MAT2A is ubiquitously expressed except in the liver. MAT2A is found in a complex with MAT2B (methionine adenosyltransferase II beta), an allosteric regulator of MAT2A, which acts like a rheostat on MAT2A enzymatic activity. Binding of MAT2B to MAT2A changes the conformation of MAT2A, increasing its affinity for methionine and SAM. The net effect is that when bound to MAT2B, MAT2A is more active at low concentrations of methionine but is inhibited at high concentrations of methionine.

[0038] Loss-of-function mutations in tumor suppressor genes are crucial in the molecular pathogenesis of cancer, yet effective targeting of tumor suppressors has been difficult to achieve. This is primarily because mutant proteins cannot be directly inhibited for therapeutic benefit, and restoration of mutant function (e.g., restoration of mutant p53 function) has not been possible to date. The recent clinical success of PARP inhibition in patients with BRCA1 / 2 deficiency has demonstrated that targeting conditional synthetic lethality (CSL) resulting from loss-of-function mutations in tumor suppressors is a viable clinical approach for cancer treatment. 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 suppressors and are lost when that region is deleted. Methylthioadenosine phosphorylase (MTAP) is one such gene, located near the tumor suppressor CDKN2A and deleted in approximately 15% of all cancers. MTAP is deleted in approximately 53% of glioblastoma multiforme (GBM), 25% of pancreatic adenocarcinoma (PDAC), 25% of melanoma, 23% of lung squamous cell carcinoma, 20% of head and neck squamous cell carcinoma, and 15% of lung adenocarcinoma. Indeed, this deletion occurs across multiple indications, many of which represent areas of high unmet medical need with limited effective therapies. In glioblastoma, median survival is 14 months, and recent approved therapies have not significantly extended overall survival (OS), with the standard of care (SoC) remaining the same for over a decade. The same is true for the majority of PDAC patients, whose OS is less than one year. MTAP deletion is a truncal event that occurs early in tumor development and likely persists throughout tumor progression, including metastasis. Its loss is therefore an alteration that is not affected by tumor heterogeneity, genetic background, or resistance to any approved drug in clinical practice. The CSL relationships identified for MTAP deficiency may represent a real hotbed for multiple tumor indications.

[0039] MTAP is located near the tumor suppressor CDKN2A on chromosome 9. Loss of CDKN2A frequently results in co-deletion of MTAP. Loss of MTAP is considered a bystander effect and is phenotypically neutral. MTAP is the basis of the intracellular adenine and methionine salvage pathway. The methionine salvage pathway feeds into the SAM production pathway, and SAM levels are a key regulator of cancer cell growth that must be tightly controlled because significant changes in SAM concentration, either elevated or depressed, lead to cell cycle arrest. The importance of SAM levels to cancerous growth lies in its central role in methylating proteins, DNA, and RNA, which acts as a checkpoint for cell health; decreased SAM levels can be interpreted as hypomethylation, and increased SAM levels can be interpreted as hypermethylation. Cells lacking MTAP accumulate methylthioadenosine (MTA) and decarboxylated SAM (dcSAM) without adversely affecting the levels of any salvage metabolites / products, including SAM. This accumulation poses a new stress on cells, where MTA acts as a competitive inhibitor of SAM-dependent reactions due to its structural similarity. Loss of MTAP forces cells to adapt to the new MTA / SAM paradigm without the associated loss of viability that MTAP-expressing cells do not have to deal with. This adaptation creates a tight dependency on methionine adenosyltransferase II alpha 2 (MAT2A), one of the enzymes that produces SAM, in MTAP-deficient cells. This conditional synthetic lethality (CSL) relationship between MTAP loss and MAT2A dependency was identified in three large-scale shRNA screens (Marjon Cell Reports 2016, Kryukov Science 2016, and Mavrakis Science 2016).

[0040] Targeting MAT2A with small molecule inhibition may benefit genetically defined patient populations representing many areas of high unmet medical need. Summary of the Invention

[0041] The object of the present invention is the use of compounds of formula I, the use of such compounds for the preparation of medicaments for the treatment, prevention and / or delay of progression 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, in particular for the treatment of cancer, including lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme and head and neck squamous cell carcinoma, the manufacture thereof, and medicaments based on compounds of formula I according to the invention.

[0042] A further object of the present invention are the compounds of formula I in all forms, optically pure enantiomers, racemates or diastereomeric mixtures.

[0043] In particular, the present invention provides compounds of formula Ia TIFF0007731381000003.tif68170[In the formula, X 1 is either N or C; X 3 is N or CR 5 Either The dotted line is an X 1 is N and R 4 is oxo, represents a double bond that renders the six-membered ring aromatic, provided that the bond is a single bond; R 1 Ha-SO2R 1a or -SOR 1b and; R 1a and R 1b are independently (C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, NR 1’a R 1’b , oxetanyl, furanyl, and pyranyl; R1’a and R 1’b at least one of is (C1-C6) alkyl and the other is H or (C1-C6) alkyl; R 2’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 2’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C1-C6) alkoxy-(C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, -CO2R 4a , -CONR 4b R 4c , -SO2R 4d , -SOR 4e , -SR 4f , -SO(NR 4h )R 4g , or -SO2(NR 4i )R 4j and; R 4a , R 4b , and R 4c is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4d , R 4e , and R 4f is independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4h and R 4g is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4i and R 4j is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 5 is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 6 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C3-C6) cycloalkyl, oxetanyl, or thiophenyl, or -SO2R 6a and; R 6a is (C1-C6)alkyl, (C3-C6)cycloalkyl, or halo(C1-C6)alkyl; R 7 is hydrogen, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, halo-(C1-C6) alkyl, halo-(C1-C6) alkoxy, or NR 7’a R 7’b and R 7’a and R 7’bone of which is hydrogen and the other is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, -(C1-C6) alkyl-O-(C1-C6) alkyl-NHCO-(C1-C6) alkyl, -(C1-C6) alkyl-O-(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NHCO-(C1-C6) alkyl, or -(C1-C6) alkyl-NH2] and pharmaceutically acceptable salts thereof.

[0044] In particular, the present invention provides compounds of formula Ib TIFF0007731381000004.tif66170[In the formula, X 3 is N or CR 5 Either R 1 Ha-SO2R 1a or -SOR 1b and; R 1a and R 1b are independently (C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, NR 1’a R 1’b , oxetanyl, furanyl, and pyranyl; R 1’a and R 1’b at least one of is (C1-C6) alkyl and the other is H or (C1-C6) alkyl; R 2’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 2’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C1-C6) alkoxy-(C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, -CO2R 4a , -CONR 4b R 4c , -SO2R 4d , -SOR 4e , -SR 4f , -SO(NR 4h )R 4g , or -SO2(NR 4i )R 4j and; R 4a , R 4b , and R 4c is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4d , R 4e , and R 4f is independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4h and R 4g is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R4i and R 4j is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 5 is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 6 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C3-C6) cycloalkyl, oxetanyl, or thiophenyl, or -SO2R 6a and; R 6a is (C1-C6)alkyl, (C3-C6)cycloalkyl, or halo(C1-C6)alkyl; R 7 is hydrogen, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, halo-(C1-C6) alkyl, halo-(C1-C6) alkoxy, or NR 7’a R 7’b and R 7’a and R 7’b one of which is hydrogen and the other is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, -(C1-C6) alkyl-O-(C1-C6) alkyl-NHCO-(C1-C6) alkyl, -(C1-C6) alkyl-O-(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NHCO-(C1-C6) alkyl, or -(C1-C6) alkyl-NH2] and pharmaceutically acceptable salts thereof.

[0045] In another embodiment, the present invention provides a compound of formula Ic TIFF0007731381000005.tif67170[In the formula, R 1 Ha-SO2R 1a or -SOR 1band; R 1a and R 1b are independently (C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, NR 1’a R 1’b , oxetanyl, furanyl, and pyranyl; R 1’a and R 1’b at least one of is (C1-C6) alkyl and the other is H or (C1-C6) alkyl; R 2’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 2’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 5 is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 6 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C3-C6) cycloalkyl, oxetanyl, or thiophenyl, or -SO2R 6a and; R6a is (C1-C6)alkyl, (C3-C6)cycloalkyl, or halo(C1-C6)alkyl; R 7 is hydrogen, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, halo-(C1-C6) alkyl, halo-(C1-C6) alkoxy, or NR 7’a R 7’b and R 7’a and R 7’b one of which is hydrogen and the other is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, -(C1-C6) alkyl-O-(C1-C6) alkyl-NHCO-(C1-C6) alkyl, -(C1-C6) alkyl-O-(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NHCO-(C1-C6) alkyl, or -(C1-C6) alkyl-NH2; and and pharmaceutically acceptable salts thereof.

[0046] In another embodiment, the present invention provides a compound of formula Id: TIFF0007731381000006.tif68170[In the formula, R 1 Ha-SO2R 1a or -SOR 1b and; R 1a and R 1b are independently (C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, NR 1’a R 1’b , oxetanyl, furanyl, and pyranyl; R 1’a and R 1’b at least one of is (C1-C6) alkyl and the other is H or (C1-C6) alkyl; R 2’is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 2’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C1-C6) alkoxy-(C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, -CO2R 4a , -CONR 4b R 4c , -SO2R 4d , -SOR 4e , -SR 4f , -SO(NR 4h )R 4g , or -SO2(NR 4i )R 4j and; R 4a , R 4b , and R 4c is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4d , R 4e , and R 4fis independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4h and R 4g is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4i and R 4j is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 5 is hydrogen, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 6 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C3-C6) cycloalkyl, oxetanyl, or thiophenyl, or -SO2R 6a and; R 6a is (C1-C6)alkyl, (C3-C6)cycloalkyl, or halo(C1-C6)alkyl; R 7 is hydrogen, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, halo-(C1-C6) alkyl, halo-(C1-C6) alkoxy, or NR 7’a R 7’b and R 7’a and R 7’bone of which is hydrogen and the other is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, -(C1-C6) alkyl-O-(C1-C6) alkyl-NHCO-(C1-C6) alkyl, -(C1-C6) alkyl-O-(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NHCO-(C1-C6) alkyl, or -(C1-C6) alkyl-NH2; and and pharmaceutically acceptable salts thereof.

[0047] In another embodiment, the present invention provides a compound of formula Ie TIFF0007731381000007.tif68170[In the formula, R 1 Ha-SO2R 1a or -SOR 1b and; R 1a and R 1b are independently (C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, NR 1’a R 1’b , oxetanyl, furanyl, and pyranyl; R 1’a and R 1’b at least one of is (C1-C6) alkyl and the other is H or (C1-C6) alkyl; R 2’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 2’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 3’’ is hydrogen, halogen, —NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; R 4 is hydrogen, cyano, oxo, hydroxy, halogen, -NH2, (C1-C6) alkyl, (C1-C6) alkoxy, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C1-C6) alkoxy-(C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, -CO2R 4a , -CONR 4b R 4c , -SO2R 4d , -SR 4f , -SO(NR 4h )R 4g , or -SO2(NR 4i )R 4j and; R 4a , R 4b , and R 4c is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4d , R 4e , and R 4f is independently selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4h and R 4g is independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 4i and R 4jis independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, and oxetanyl; R 6 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C3-C6) cycloalkyl, oxetanyl, or thiophenyl, or -SO2R 6a and; R 6a is (C1-C6)alkyl, (C3-C6)cycloalkyl, or halo(C1-C6)alkyl; R 7 is hydrogen, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, halo-(C1-C6) alkyl, halo-(C1-C6) alkoxy, or NR 7’a R 7’b and R 7’a and R 7’b one of which is hydrogen and the other is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, -(C1-C6) alkyl-O-(C1-C6) alkyl-NHCO-(C1-C6) alkyl, -(C1-C6) alkyl-O-(C1-C6) alkyl-NH2, -(C1-C6) alkyl-NHCO-(C1-C6) alkyl, or -(C1-C6) alkyl-NH2; and and pharmaceutically acceptable salts thereof.

[0048] Furthermore, the specific X 1 , X 2 , X 3 , X 4 , R 1 , R 1a , R 1b , R 1’a , R 1’b , R 2’ , R 2’’ , R 3’ , R 3’’ , R 4 , R 4a , R 4b , R 4c, R 4d , R 4e , R 4f , R 4h , R 4g , R 4i , R 4j , R 5 , R 6 , R 6a , R 7 , R 7’a , and R 7’b All embodiments relating to other X disclosed herein may be used in combination with 1 , X 2 , X 3 , R 1 , R 1a , R 1b , R 1’a , R 1’jjb , R 2’ , R 2’’ , R 3’ , R 3’’ , R 4 , R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4h , R 4g , R 4i , R 4j , R 5 , R 6 , R 6a , R 7 , R 7’a , and R 7’b It is understood that the above embodiments can be combined with any of the other embodiments.

[0049] One particular embodiment of the present invention is a compound of formula 4 is N.

[0050] One particular embodiment of the present invention is a compound of formula 1 is N or C, and X 2 is N or CR 4 and X 3 is N or CR 5 The present invention relates to compounds of formula I,

[0051] One particular embodiment of the present invention is a compound of formula 1 is C.

[0052] One particular embodiment of the present invention is a compound of formula 2 is CR 4 The present invention relates to compounds of formula I,

[0053] One particular embodiment of the present invention is a compound of formula 3 is N.

[0054] One particular embodiment of the present invention is a compound of formula 1 SO2R 1a The present invention relates to a compound of formula I, Ia, Ib, Ic, Id, or Ie, wherein

[0055] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Ic, Id, or Ie, wherein R 1a and R 1b are independently (C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, NR 1’a R 1’b , oxetanyl, furanyl, and pyranyl; R 1’a and R 1’b at least one of which is (C1-C6) alkyl and the other is H or (C1-C6) alkyl, in particular R 1a is (C1-C3) alkyl, (C3-C4) cycloalkyl, (C3-C4) cycloalkyl-(C1-C3) alkyl, halo(C1-C3) alkyl, hydroxy(C1-C3) alkyl, (C1-C3) alkoxy-(C1-C3) alkyl, NR 1’a R 1’b and oxetanyl, and R 1’a and R 1’b at least one of which is (C1-C3) alkyl and the other is H or (C1-C3) alkyl, in particular R 1ais methyl, ethyl, propyl, i-propyl, i-butyl, cyclopropyl, TIFF0007731381000008.tif23170, fluoromethyl, difluoromethyl, fluoro-ethyl(ethanyl), difluoro-ethyl(ethanyl), 1,2-difluoroethyl(difluoroethanyl), 1,1,2-trifluoroethyl(trifluoroethanyl), hydroxymethyl, hydroxyethyl, methoxymethyl, methylaminyl (-NHCH3), dimethylamino (-N(CH3)2), and oxetanyl, in particular R 1a is selected from ethyl, propyl, i-propyl, i-butyl, cyclopropyl, fluoromethyl, difluoromethyl, fluoro-ethyl(ethanyl), difluoro-ethyl(ethanyl), 1,2-difluoroethyl(difluoroethanyl), 1,1,2-trifluoroethyl(trifluoroethanyl), and 1,2,2-trifluoroethyl(trifluoroethanyl), in particular R 1a is selected from methyl, ethyl, cyclopropyl, and difluoromethyl.

[0056] One particular embodiment of the present invention is a compound of formula 1b is (C1-C6) alkyl, in particular (C1-C3) alkyl, especially methyl.

[0057] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Ic, Id, or Ie [R 2’ is other than hydrogen as defined herein, R 3’ is hydrogen, R 2’’ is hydrogen, and R 3’’ is as defined herein, and conversely, R 2’’ If is other than hydrogen, R 3’’ is hydrogen, R 2’ is hydrogen, and R3’ is as defined herein.

[0058] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Ic, Id, or Ie, wherein R 2’ and R 2’’ one of which is hydrogen, halogen, —NH2, (C1-C2)alkyl, (C1-C2)alkoxy, or halo(C1-C2)alkyl, and the other is hydrogen, particularly in the formula 2’ is hydrogen, halogen, -NH2, methyl, ethyl, methoxyfluoromethyl, difluoromethyl, fluoro-ethanyl, difluoro-ethanyl, or 1,2-difluoroethyl; R 2’’ is hydrogen, in particular, R 2’ is methyl, ethyl, fluoromethyl, difluoromethyl, fluoro-ethyl, difluoro-ethyl, 1,2 difluoroethyl, and R 2’’ is hydrogen, in particular, R 2’ is methyl or difluoromethyl, and R 2’’ is hydrogen.

[0059] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Ic, Id, or Ie, wherein R 3’ and R 3’’ one of which is hydrogen, halogen, —NH2, (C1-C3)alkyl, (C1-C3)alkoxy, or halo(C1-C3)alkyl and the other is hydrogen, in particular R 3’’ is hydrogen, halogen, or (C1-C3) alkyl, and R 3’ is hydrogen, in particular, R 3’’ is hydrogen or fluorine, and R 3’ is hydrogen, in particular, R 3’ and R 3’’ and both are hydrogen.

[0060] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Id, or Ie, wherein R 4 is cyano, oxo, hydroxy, (C1-C3) alkyl, (C1-C3) alkoxy, halo(C1-C3) alkyl, halo(C1-C6) alkoxy, (C1-C3) alkoxy-(C1-C3) alkyl, (C3-C4) cycloalkyl, -CO2R 4a , --CONR 4b R 4c , -SO2R 4d , -SOR 4e , -SR 4f , -SO(NR 4h )R 4g , or -SO2(NR 4i )R 4j In particular, in the formula R 4 is cyano, oxo, hydroxy, (C1-C2)alkoxy, halo(C1-C2)alkyl, halo(C1-C2)alkoxy, (C1-C2)alkoxy-(C1-C2)alkyl, cyclopropyl, -CO2H, --CONR 4b R 4c , -SO2R 4d , -SOR 4e , -SR 4f or —SO(NH)CH3, in particular, where R 4 is cyano, oxo, hydroxy, methoxy, -CF3, -OCF3, -methyl-methoxy, cyclopropyl, -CO2H, --CONR 4b R 4c , -SO2R 4d , -SOR 4e , or -SR 4f , especially R 4 Cyano, oxo, -CONHR 4c , or -SO2R 4d [is] related to.

[0061] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Id, or Ie, wherein R 4a , R 4b and R 4c are independently selected from hydrogen, (C1-C3) alkyl, (C3-C4) cycloalkyl, and oxetanyl, particularly where R4a , R 4b and R 4c are independently selected from hydrogen, (C1-C3) alkyl, cyclopropyl, and oxetanyl, in particular R 4a , R 4b and R 4c are independently selected from hydrogen, (C1-C3) alkyl, and cyclopropyl, in particular R 4a and R 4b is hydrogen and R 4c is hydrogen or methyl.

[0062] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Id, or Ie, wherein R 4d , R 4e and R 4f are independently selected from (C1-C3) alkyl, (C3-C4) cycloalkyl, and oxetanyl, particularly where R 4d , R 4e and R 4f are independently selected from (C1-C3) alkyl, cyclopropyl, and oxetanyl, in particular R 4d , R 4e and R 4f are independently selected from (C1-C3) alkyl and cyclopropyl, in particular R 4d is methyl or cyclopropyl.

[0063] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Id, or Ie, wherein R 4h and R 4g are independently selected from hydrogen and (C1-C6) alkyl, in particular hydrogen and (C1-C3) alkyl, in particular in the formula 4h is hydrogen and R 4g is (C1-C3) alkyl, in particular, 4h is hydrogen and R 4g is methyl].

[0064] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Id, or Ie, wherein R4i and R 4j are independently selected from hydrogen and (C1-C6) alkyl, in particular hydrogen and (C1-C3) alkyl, in particular in the formula 4i is hydrogen and R 4j is (C1-C3) alkyl, in particular, 4i is hydrogen and R 4j is methyl].

[0065] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Ic, or Id, wherein R 5 is hydrogen, halogen, (C1-C6) alkyl, (C1-C6) alkoxy, or (C3-C6) cycloalkyl, in particular R 5 is hydrogen, halogen, (C1-C2) alkyl, (C1-C2) alkoxy, or (C3-C4) cycloalkyl, in particular R 5 is hydrogen, fluoro, chloro, cyclopropyl, methyl, or methoxy, in particular R 5 is hydrogen].

[0066] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Ic, Id, or Ie, wherein R 6 is halogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, (C3-C6) cycloalkyl, thiophenyl, oxetanyl, or -SO2R 6a where R 6a is (C1-C6) alkyl, in particular, R 6 is bromo, (C1-C3) alkyl, (C1-C3) alkoxy, cyano, halo(C1-C3) alkyl, halo(C1-C3) alkoxy, (C3-C4) cycloalkyl, thiophenyl, oxetanyl, or -SO2R 6a where R 6a is (C1-C6) alkyl, in particular, R 6 is halo(C1-C3)alkyl, halo(C1-C3)alkoxy, or (C3-C4)cycloalkyl, in particular R 6is trifluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl.

[0067] One particular embodiment of the present invention is a compound of formula 6a is (C1-C6) alkyl, particularly R 6a is methyl.

[0068] One particular embodiment of the present invention is a compound of formula 7 is hydrogen, halogen, hydroxy, or (C1-C6) alkyl, particularly R 7 is hydrogen, halogen, or hydroxy, especially R 7 is hydrogen.

[0069] One particular embodiment of the present invention is a compound of formula I, Ia, Ib, Ic, Id, or Ie, wherein R 7’a and R 7’b is hydrogen and the other is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, -(C1-C3) alkyl-O-(C1-C3) alkyl-NHCO-(C1-C3) alkyl, -(C1-C3) alkyl-O-(C1-C3) alkyl-NH2, -(C1-C3) alkyl-NHCO-(C1-C3) alkyl, or -(C1-C3) alkyl-NH2, particularly in the formula R 7’a and R 7’b is hydrogen and the other is hydrogen, (C1-C6) alkyl, or (C1-C6) alkoxy, particularly 7’a and R 7’b one of which is hydrogen, and the other is hydrogen, (C1-C3) alkyl, or (C1-C3) alkoxy. Particular compounds of formula I of the present invention are: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(3-methoxy-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(methylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(4-(methylsulfonyl)-3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N,2-trimethylbenzenesulfonamide; 3-Cyclopropyl-5-methoxy-4-(4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine; 3-Cyclopropyl-4-(4-(cyclopropylsulfonyl)-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(cyclopropylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine; 2-chloro-4-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N-dimethylbenzenesulfonamide; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine; 4-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(3-(fluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine; 3-Cyclopropyl-4-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline; 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(1,1-difluoroethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile; 3-(Difluoromethyl)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Isopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(2,5-dimethyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile; 3-Cyclopropyl-4-(3-methyl-4-methylsulfinyl-phenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-ol 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-5-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-Ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(Difluoromethoxy)-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine; 4-[4-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-(Difluoromethoxy)-4-(3-methyl-4-propylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(Difluoromethoxy)-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 3-(Difluoromethoxy)-4-(4-isopropylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N,2-dimethyl-benzenesulfonamide; 3-Methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(Difluoromethoxy)-4-[3-methyl-4-(oxetan-3-ylsulfonyl)phenyl]-1H-pyrazolo[4,3-c]pyridine; 2-[4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-methyl-phenyl]sulfonylethanol 3-Cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine 2,2,2-trifluoroacetic acid; 3-(Difluoromethoxy)-4-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-Cyclopropyl-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyridazine; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfinyl)-1H-indazole; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-(Difluoromethoxy)-4-[4-(methoxymethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[4,3-c]pyridine formic acid; 5-Methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 3-Cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3,6-Dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-Cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-Cyclopropyl-N,N-dimethyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-Cyclopropyl-5-(methoxymethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3,5-Dicyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine; N,3-Dicyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-Cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indole-5-carbonitrile; 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-Cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide; 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide; 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1#H!-indazole-5-carbonitrile; 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-5-one; 4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-(difluoromethyl)-N,N-dimethyl-benzenesulfonamide; 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-Cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole; 3-Cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(Difluoromethoxy)-4-[5-(difluoromethyl)-2-methyl-4-methylsulfinyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-5-methoxy-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-5-methylsulfonyl-1H-indazole; 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole; [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-imino-methyl-oxo-sulfane; [3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methylimino-oxo-λ 6 -Sulfane; 3-Cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide; 3-Cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide; 4-(4-Cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-5-(methylsulfonyl)-1H-indazole; 5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole; 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1H-indazole; or 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide, and pharmaceutically acceptable salts thereof. Particular compounds of formula I of the present invention are: 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-Cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole; 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-Cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole; 3-Cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; or 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide, and pharmaceutically acceptable salts thereof.

[0070] In other embodiments, the present invention provides a compound according to Formula I, Ia, Ib, Ic, Id, or Ie, as described herein, for use as a therapeutically active substance.

[0071] In yet another embodiment, the present invention provides a compound according to Formula I, Ia, Ib, Ic, Id, or Ie, as described herein, for the treatment, prevention, and / or delay of progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0072] In another embodiment, the present invention provides the use of a compound according to Formula I, Ia, Ib, Ic, Id, or Ie, as described herein, for the preparation of a medicament for the treatment, prevention, and / or delay of progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0073] In one aspect, the present application provides a method for treating a Mat2A disorder in a subject having a Mat2A-associated disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described above.

[0074] In another embodiment, the present invention provides a method of treating, preventing, and / or delaying the progression of, particularly treating, cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, comprising administering an effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, or Ie, as described herein.

[0075] In certain embodiments, the present invention provides a method of treating, preventing, and / or delaying the progression of, particularly treating, cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, comprising administering an effective amount of a compound according to Formula I, Ia, Ib, Ic, Id, or Ie, as described herein.

[0076] In particular, the Mat2A disorder or Mat2A-associated disease is cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, in particular lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0077] In one aspect, the application provides a pharmaceutical composition comprising a compound of any one of the above embodiments in admixture with at least one pharmaceutically acceptable carrier, e.g., an excipient or diluent.

[0078] In another embodiment, the present invention provides the use of a compound of formula I, Ia, Ib, Ic, Id, or Ie in the preparation of a medicament for the treatment, prevention and / or delay of progression of a disease associated with Mat2A, particularly for the treatment.

[0079] In yet another embodiment, the present invention also provides an object of a medicament containing a compound of formula I, Ia, Ib, Ic, Id or Ie as defined herein or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier, as well as a process for the preparation thereof, which process comprises incorporating one or more compounds of formula I, Ia, Ib, Ic, Id or Ie and / or a pharmaceutically acceptable acid addition salt thereof, and optionally one or more other therapeutically valuable substances, together with one or more therapeutically inert carriers, into a galenical dosage form.

[0080] Other embodiments provide pharmaceutical compositions or medicaments comprising a compound of the invention and a therapeutically inert carrier, diluent or pharmaceutically acceptable excipient, as well as methods for preparing such compositions and medicaments using the compounds of the invention.

[0081] Composition is prepared in a manner consistent with medical practice standards, divided into appropriate amounts, and administered.In this context, the points to consider include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of individual patient, the cause of disorder, the delivery site of drug, administration method, administration schedule and other factors known to medical practitioners.For example, this amount can be below the amount that is toxic to normal cells or mammals as a whole.

[0082] The compounds of the present invention may be administered by any suitable means, such as oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, pulmonary, intradermal, intrathecal, and epidural and intranasal, as well as by local therapeutic, intralesional administration, as appropriate. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0083] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, coated tablets, dragees, powders, capsules (hard and soft gelatin capsules), solutions (i.e., injectable solutions), dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, eye drops, ear drops, etc. Such compositions may contain conventional ingredients in pharmaceutical preparations, such as diluents, carriers, pH modifiers, sweeteners, fillers, and additional active agents.

[0084] Typical formulations are prepared by mixing the compound of the present invention with pharmaceutically acceptable carriers or excipients.Suitable pharmaceutically acceptable carriers and excipients are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.Pharmaceutical acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances that also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating material. In powders, the carrier is generally a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding capacity in appropriate proportions and compressed in the desired shape and size. Powders and tablets preferably contain from 1 percent to about 70 percent of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like.

[0085] The dosage that the compounds of the present invention can be administered can vary within a wide range and will of course be adapted to the individual requirements of each particular case.Generally, for oral administration, a daily dose of about 0.01-1000 mg per person of the compound of formula I, Ia, Ib, Ic, Id or Ie is appropriate, but if necessary, the above upper limit can be exceeded.

[0086] One example of a suitable oral dosage form is a tablet containing about 100 mg to 500 mg of a compound of the invention, formulated with about 30 to 90 mg of anhydrous lactose, about 5 to 40 mg of croscarmellose sodium, about 5 to 30 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg of magnesium stearate. The powdered ingredients are first blended and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablets using conventional equipment.

[0087] An example of an aerosol formulation can be prepared by dissolving, for example, 10 to 100 mg of a compound of the present invention in an appropriate buffer solution, such as phosphate buffer, and optionally adding a tonicifier, such as a salt such as sodium chloride. To remove impurities and contaminants, the solution may be filtered, for example, using a 0.2 μm filter.

[0088] Thus, one embodiment includes a pharmaceutical composition comprising a compound according to the invention described herein, or a stereoisomer thereof. A further embodiment 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.

[0089] The compounds of the present invention can be used, either alone or in combination with other drugs, for the treatment, prevention and / or delay of progression of Mat2A-related diseases, particularly cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma multiforme, and mesothelioma, in particular lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0090] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula I, Ia, Ib, Ic, Id or Ie or a pharmaceutically acceptable salt thereof as defined above, and one or more pharmaceutically acceptable excipients, for use in the treatment, prevention and / or delay of progression of cognitive impairment associated with cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme and mesothelioma, in particular lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme and head and neck squamous cell carcinoma.

[0091] Other embodiments include pharmaceutical compositions comprising compounds according to the invention as described herein for use in the treatment, prevention and / or delay of progression, particularly the treatment, of Mat2A-related diseases.Other embodiments include pharmaceutical compositions comprising compounds according to the invention as described herein for use in the treatment, prevention and / or delay of progression, particularly the treatment, of Mat2A-related diseases.

[0092] In other embodiments, the present invention provides for the preparation of a compound of Formula I, Ia, Ib, Ic, Id, or Ie, as described herein.

[0093] The preparation of the compounds of formula I, Ia, Ib, Ic, Id, or Ie of the present invention can be carried out in sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reaction and purify the resulting product are known to those skilled in the art. If a mixture of enantiomers or diastereoisomers is produced during the reaction, the enantiomers or diastereoisomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization.

[0094] Additionally, the compounds of the present invention can be prepared from commercially available starting materials or by common synthetic techniques and procedures known to those skilled in the art. Reaction schemes suitable for preparing such compounds are outlined below. The substituents and indices used in the following description of the methods have the meanings described herein. Further illustration can be found in the specific examples detailed below. DETAILED DESCRIPTION OF THE INVENTION

[0095] general synthesis More specifically, compounds of Formula I, Ia, Ib, Ic, Id, or Ie, and intermediates thereto, can be prepared according to Schemes 1-2 and as described in the specific examples.

[0096] A compound of formula I, Ia, Ib, Ic, Id, or Ie, wherein X is halo and X 1 is C and X 4 is CH and R 2’’ and R 3’ is H and R 7 is H and X 2 , X 3 , R 1a , R 2’ , R 3’’ , R 4 , R 5 and R 6 The subgroup of [wherein R is as defined above] can be prepared as outlined in Schemes 1-2 below. TIFF0007731381000009.tif241170 [wherein X is halo and R b is cyclized to H or pinacol ester, and X 2 , X 3 , and R 6 is as defined above]

[0097] Dihalide A can be deprotonated with a strong base (e.g., n-BuLi, LDA, LiHDMS, TMPMgCl, LiCl) in THF at low temperature (-78 °C) and then reacted with an aldehyde to give alcohol II (as described in Synthesis, 1988, pp. 803-805) or with an appropriate ester to give ketone III directly (as described in Journal of Organic Chemistry, 2007, pp. 2501-2507). Alternatively, alcohol II can be oxidized to ketone III using common oxidizing agents (e.g., MnO, Dess-Martin periodinane, TEMPO / PhI(OAc)) in dichloroethane. Ketone III can subsequently be reacted with hydrazine (aqueous or monohydrate) in THF, dioxane, or ethanol at ambient or reduced temperatures to afford pyrazole IV (as described in Journal of Medicinal Chemistry, 2019, pp. 531-551). Alternatively, ketone III can be coupled with boronate ester or boronic acid X in a Suzuki-Miyaura coupling under palladium catalysis (e.g., Pd(dppf)) in the presence of a carbonate base (e.g., KCO, CsCO) at elevated temperatures (e.g., 80-120 °C) in a dioxane / water mixture to afford ketone VII, which can then be similarly cyclized with hydrazine to afford pyrazole VIII. Alternatively, pyrazole IV can be N-protected under standard conditions (e.g., SEM, THP, or trityl) and similarly reacted with boronic acid or boronic ester X, followed by deprotection with strong acid (e.g., 4N HCl in dioxane or TFA) to afford pyrazole VIII. TIFF0007731381000010.tif148170 [wherein X is halo and R b is cyclized to H or pinacol ester]

[0098] Alternatively, the pyrazole core III can be constructed from aniline A1 as described in Journal of the American Chemical Society, 1954, 1176. Subsequent halogenation with a halosuccinimide in a polar solvent (e.g., DMF) provides the halopyrazole IV. N-protection under standard conditions (e.g., SEM, THP, or trityl) then allows subsequent reaction of the halogen (e.g., Suzuki coupling) to provide pyrazole VI. Halogenation of VI can be carried out using a halosuccinimide as described above to provide pyrazole VII, which is then coupled with a boronic ester or boronic acid and deprotected as described in Scheme 1.

[0099] A compound of formula I or Ia, wherein X is halo and X 1 is N and X 2 is C=O and X 3 is CH and R 2’’ and R 3’ is H and R 7 is H and X 4 , R 1a , R 2’ , R 3’’ , R 4 , R 5 and R 6 A subgroup of [wherein R is as defined above] can be prepared as outlined in Scheme 3 below. TIFF0007731381000011.tif102170

[0100] The pyridone structure is first prepared by protecting the pyrazole or pyrrole nitrogen of A2 with an appropriate protecting group (THP, SEM, trityl) under standard conditions to give II. Derivatization of the halogen X (e.g., via Suzuki coupling) leads to III, which can be converted to the pyridone by treatment with strongly acidic conditions (e.g., hydrochloric acid in dioxane). This treatment sometimes leads to removal of the protecting group (PG), necessitating reinstallation of the protecting group to give IV. Chang-Lam coupling of boronic acid V with a mixture of pyridine and triethylamine under copper(II) acetate catalysis gives derivative VI, which, after standard removal of the protecting group (e.g., 4N HCl in dioxane or TFA), gives the final compound VII.

[0101] General Procedure TIFF0007731381000012.tif98170 [wherein X is halo and X 2 , X 3 , and R 6 is as defined above]

[0102] General Procedure A: Aryl / Heteroaryl Functionalization To a solution of aryl or heteroaryl dihalide (Eq: 1) in anhydrous THF (0.1 M) cooled to -78 °C under Ar, lithium diisopropylamine or nBuLi (Eq: 1.1-1.5) is added dropwise. After stirring for an appropriate time (10 min to 1 h), the required electrophile (aldehyde, ester, or chloroformate Eq: 1.5-2) is added, and the reaction is stirred at the same temperature for an additional time (10 min to 1 h). After that time, the reaction is quenched at -78 °C by the addition of saturated aqueous ammonium chloride. The reaction is allowed to reach room temperature, diluted with ethyl acetate, and the organic layer is washed with water, brine, dried (NaSO), and concentrated. The crude product can be used directly in the next step or purified by flash column chromatography. TIFF0007731381000013.tif46170 [wherein X is halo and X 2 , X3 , and R 6 is as defined above]

[0103] General Procedure B1: Oxidation of benzylic alcohols with Dess-Martin periodinane To a solution of the benzylic alcohol (Eq: 1) in dichloromethane (0.1 M), Dess-Martin periodinane (Eq: 1.3) is added and stirred until the reaction is complete (1 h). The reaction is diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated. The residue is purified by flash column chromatography.

[0104] General Procedure B2: Oxidation of benzylic alcohols with TEMPO To a solution of the benzylic alcohol (Eq: 1) in dichloromethane (0.1 M), TEMPO (Eq: 0.1) is added followed by (diacetoxyiodo)benzene (Eq: 1.1) and stirred until the reaction is complete (3 h). The reaction is diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated. The residue is purified by flash column chromatography. TIFF0007731381000014.tif45170 [wherein X is halo and X 2 , X 3 , and R 6 is as defined above]

[0105] General Procedure C: Pyrazole Cyclization To a solution of ketone or ester (Eq. 1) dissolved in THF, dioxane, or ethanol (0.1 M) at ambient temperature or with cooling, hydrazine (Eq. 2-5) is added in the presence or absence of additional base (Et3N Eq. 1.5) and stirred until the reaction is complete (1 h). The reaction is diluted with ethyl acetate, washed with water, dried (Na2SO4), and concentrated. The residue is purified by flash column chromatography.

[0106] General Procedure D: Suzuki Coupling To a solution of the halide (Eq: 1) dissolved in dioxane:water (0.1 M, 4:1–10:1), potassium carbonate (Eq: 3–6) and the required boronic acid or boronic ester (Eq: 1–6) are added. Ar is bubbled through the mixture, and the mixture is degassed by sonication. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (Eq: typically 0.05, 0.5 in difficult cases) is added, and the mixture is heated to 100–120 °C under Ar until the starting material is consumed (0.5–16 h). The reaction is diluted with ethyl acetate, washed with water, dried (NaSO), and concentrated. Alternatively, the reaction mixture can be directly absorbed onto silica gel and concentrated. The residue is purified by flash column chromatography.

[0107] General Procedure E1: SEM Protection To a solution of pyrazole (Eq: 1) dissolved in anhydrous DMF or THF (0.1 M) under Ar, sodium hydride (60% dispersion in mineral oil, Eq: 2) was added and the reaction was stirred for 15 min, followed by the addition of SEM-Cl (Eq: 1.8) and stirring 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 was purified by flash column chromatography.

[0108] General procedure E2: SEM protection To a solution of pyrazole (Eq: 1) dissolved in dichloromethane (0.1 M) under Ar, DIPEA (Eq: 1.2) and SEM-Cl (Eq: 1.2) were added and stirred until the starting material was completely consumed (1 h). The reaction was then concentrated and the residue was purified by flash column chromatography. TIFF0007731381000015.tif76170 [wherein X is halo and R 1 , R 2’’ , R 3’ and R 3’’ is as defined herein]

[0109] General Procedure F: Conversion of Aryl Halides to Boronates To a solution of aryl halide (Eq: 1) dissolved in dioxane (0.1 M), bis(pinacolato)diboron (Eq: 1.1) and potassium acetate (Eq: 3) were added and degassed by injecting Ar under sonication. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (Eq: 0.1) was added and the reaction was heated (80-100 °C) until complete conversion. The reaction was then diluted with ethyl acetate, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography.

[0110] General Procedure G: Sulfide Oxidation To an ice-cold solution of the sulfide (Eq: 1) in dichloromethane (0.1 M) is added m-chloroperbenzoic acid (Eq: 1-2.5, depending on whether the sulfoxide or sulfone is required), the ice bath is removed, and the reaction is allowed to warm to room temperature. Stirring is continued until complete conversion, after which the reaction is diluted with dichloromethane, washed with 1N NaOH, dried (Na2SO4), and concentrated. The residue is purified by flash column chromatography.

[0111] General Procedure H: Trityl Deprotection The trityl-protected compound (Eq: 1) is dissolved in trifluoroacetic acid (0.1 M), triethylsilane (Eq: 1.5) is added, and the mixture is stirred at room temperature until the reaction is complete. The mixture is then carefully poured onto saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the combined organic extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is purified by flash column chromatography or reverse-phase preparative HPLC.

[0112] General Procedure I1: THP Deprotection The THP-protected compound (Eq:1) is dissolved in dichloromethane (0.1 M), trifluoroacetic acid (Eq:10) is added, and the mixture is stirred at room temperature until the reaction is complete. The mixture is diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), and concentrated. The residue is purified by flash column chromatography or reverse-phase preparative HPLC.

[0113] General Procedure I2: THP Deprotection The THP-protected compound (Eq:1) is dissolved in 4N HCl in dioxane (0.1 M) and stirred at room temperature until the reaction is complete. The mixture is then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried (NaSO), and concentrated. The residue is purified by flash column chromatography or reverse-phase preparative HPLC.

[0114] General Procedure J: SEM / MOM Deprotection The SEM / MOM-protected compound (Eq:1) was dissolved in trifluoroacetic acid (0.1 M) and stirred at room temperature until the reaction was complete. Following evaporation of the trifluoroacetic acid, the compound was redissolved in dichloromethane or dioxane (0.1 M) and deprotection was completed by the addition of ethylenediamine (Eq:10). The mixture was then concentrated and purified by flash column chromatography or reverse-phase preparative HPLC.

[0115] General Procedure J2: SEM Deprotection The SEM-protected compound (Eq:1) is dissolved in a 1M TBAF (Eq:10) solution in THF and heated to 50°C until the reaction is complete. The reaction is diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried (NaSO), and concentrated. The residue is purified by flash column chromatography or reverse-phase preparative HPLC.

[0116] One particular embodiment of the present invention is a process for preparing compounds of formula (I) as defined in accordance with the present invention, and pharmaceutically acceptable salts thereof, in particular by reacting compounds of formula (Ia) [wherein X 1 , X 2 , X 3 , X 4 , R 1 , R 2’ , R 2’’ , R 3’ , R 3’’ , R 4 , R 5 , R 6 , and R 7 is as defined herein]. TIFF0007731381000016.tif80170

[0117] The compounds were investigated according to the tests described below.

[0118] Identification of Mat2A activity Mat2A inhibition is measured in an absorbance-based assay in a 384-well format.

[0119] Recombinant human Mat2a (12.5 nM) and serially diluted compounds in DMSO (concentration range: 10 μM to 508 pM) or control (DMSO) are incubated for 15 min at room temperature (RT) in assay buffer containing 50 mM HEPES (pH 7.5), 50 mM KCl, 50 mM MgCl2, 0.01% Tween 20, and 10 mM DTT. The reaction is initiated by the addition of combined substrates, ATP and methionine, to a final concentration of 100 μM each. Final assay conditions are 12.5 nM Mat2A, 100 μM ATP and methionine (substrates), and 2% DMSO. After 120 min of incubation at RT, the reaction is stopped by the addition of Biomol Green. The absorbance signal is measured at λ = 635 nm using a multiplate reader (BMG Pherastar reader or equivalent) after 30 min of equilibration at RT.

[0120] The table below shows data for selected compounds. TIFF0007731381000017.tif255170TIFF0007731381000018.tif255170TIFF0007731381000019.tif255170TIFF0007731381000020.tif133170

[0121] Experimental part The following examples are provided to illustrate the invention and should not be construed as limiting the scope of the invention, but rather as merely representative.

[0122] overview Analysis method HPLC (Method LCMS_fastgradient) Column: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1x30mm, 1.8µm, part number 959731-902

[0123] Solvent A: Water with 0.01% formic acid; Solvent B: Acetonitrile (MeCN) gradient: TIFF0007731381000021.tif51170

[0124] Abbreviation The following abbreviations are used in the experimental section: Ar = argon; nBuLi = n-butyllithium; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMSO = dimethyl sulfoxide; DMF = dimethylformamide; EtOH = ethanol; Ex. No. = Example number; HCl = hydrochloric acid; HPLC = high performance liquid chromatography; LDA = lithium diisopropylamide; LiHMDS = lithium bis(trimethylsilyl)amide; mCPBA = metachloroperbenzoic acid; Mol = molecule; MOM = methoxymethyl; NMP = N-methyl-2-pyrrolidone; Prep. = preparation; SEM = [2-(trimethylsilyl)ethoxy)methyl]acetal; TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate; THF = tetrahydrofuran; TEMPO = 2,2,6,6-tetramethylpiperidinyloxyl; TBAF = tetra-n-butylammonium fluoride; TLC = thin layer chromatography;

[0125] Starting materials Basic chemicals and solvents were purchased and used as is without further purification. Some intermediates are commercially available or can be synthesized using methods known in the art.

[0126] Intermediates Intermediate 1: 4-chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000022.tif45170

[0127] Title compound ([M+H,Cl] + 194.1) was prepared as described in WO 2010 / 1063331.

[0128] Intermediate 2: 4-Bromo-3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine TIFF0007731381000023.tif50170

[0129] Step 1: 3-iodo-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine Using general procedure E1, 3-iodo-5-methoxy-1H-pyrazolo[3,4-c]pyridine (76006-07-0: WO 2015 / 25025) was converted to the title compound ([M+H] + 406.2) (with 20% of the regioisomer).

[0130] Step 2: 3-Cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine According to general procedure D, 3-iodo-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (step 1) was reacted with cyclopropylboronic acid (6 eq), potassium carbonate (3 eq) catalyzed by 1' bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.1 eq) for 4 h to give the title compound ([M+H] + 320.3).

[0131] Step 3: 4-Bromo-3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine To a solution of 3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (Step 2, 20 mg, 63 μmol) in DCM (1 ml) was added N-bromosuccinimide (12 mg, 70 μmol) and the reaction was stirred for 4 h. The reaction was then absorbed onto silica gel and concentrated. Flash column chromatography (ethyl acetate:n-heptane 4:1) gave the title compound (18 mg, 65%) as a brown oil [M+H, Br]. + 400.2)

[0132] Intermediate 3: 4-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000024.tif44170

[0133] Step 1: 4-chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine According to general procedure A, 2,4-dichloropyridine was deprotonated with nBuLi (1.3 eq) for 30 min and reacted with ethyl 2,2,2-trifluoroacetate (2 eq) to give 1-(2,4-dichloropyridin-3-yl)-2,2,2-trifluoroethan-1-one, which was reacted directly with hydrazine hydrate (5 eq) in THF, initially at −40° C. and then at ambient temperature for 16 h, according to general procedure C, to give the title compound ([M+H,Cl] + 220.0).

[0134] Step 2: 4-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine General procedure E2 was used to obtain the title compound ([M+H,Cl] + 352.2) was prepared from 4-chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine (step 1).

[0135] Intermediate 4: 4-chloro-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine TIFF0007731381000025.tif55170

[0136] Step 1: 3-Bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine Using general procedure E1, 3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine was prepared to give the title compound ([M+H,Br,Cl] + 361.1).

[0137] Step 2: 4-chloro-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine According to general procedure D, 3-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (step 1) was reacted with cyclopropylboronic acid (6 eq), potassium carbonate (6 eq) catalyzed by 1' bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.15 eq) at 100 °C for 1 h to give the title compound ([M+H,Cl] + 323.2).

[0138] Intermediate 5: 4-Bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile TIFF0007731381000026.tif49170

[0139] Step 1: 3-Bromo-4-(cyclopropanecarbonyl)-5-fluoropicolinonitrile According to General Procedure A, 3-bromo-5-fluoropicolinonitrile was treated with LDA (2 eq) for 10 min followed by the addition of cyclopropanecarbaldehyde to give crude 3-bromo-4-(cyclopropyl(hydroxy)methyl)-5-fluoropicolinonitrile, which was then converted to the title compound ([MH,Br]) using General Procedure E2. - 265.3).

[0140] Step 3: 4-Bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile Following general procedure C, 3-bromo-4-(cyclopropanecarbonyl)-5-fluoropicolinonitrile (step 2) was reacted with hydrazine hydrate (2 eq) in EtOH initially at 0° C. and then allowed to warm to ambient temperature for 1 h to give the title compound ([M+H, Br] + 263.1).

[0141] Intermediate 6: 4-chloro-3-(1,1-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000027.tif51170

[0142] Step 1: 1-(2-chloro-4-fluoropyridin-3-yl)-2,2-difluoropropan-1-one Following general procedure A, 2-chloro-4-fluoropyridine was deprotonated with nBuLi (1.3 eq) for 1 h and reacted with ethyl 2,2-difluoropropanoate (1.3 eq) to give the title compound ([M+H,Cl] + I got 224.1.

[0143] Step 2: 4-chloro-3-(1,1-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine According to general procedure C, 1-(2-chloro-4-fluoropyridin-3-yl)-2,2-difluoropropan-1-one (step 1) was reacted with hydrazine hydrate (5 eq) in THF at ambient temperature for 15 minutes to give the title compound ([M+H,Br] + 218.1).

[0144] Intermediate 7: 2-[[4-chloro-3-(difluoromethyl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl-trimethylsilane TIFF0007731381000028.tif41170

[0145] Step 1: 1-(2-chloro-4-fluoropyridin-3-yl)-2,2-difluoroethan-1-one According to general procedure A, 2-chloro-4-fluoropyridine was deprotonated with LDA (2 eq) for 3 h and reacted with ethyl 2,2-difluoroacetate (1.3 eq) to give the title compound ([M+H,Cl] - 206.1).

[0146] Step 2: 4-chloro-3-(difluoromethyl)-1H-pyrazolo[4,3-c]pyridine According to general procedure C, 1-(2-chloro-4-fluoropyridin-3-yl)-2,2-difluoroethan-1-one (step 1) was reacted with hydrazine hydrate (5 eq) in THF at −40° C. for 1 h to give the title compound ([M+H,Cl] + 204.0).

[0147] Step 3: 4-chloro-3-(1,1-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine Using general procedure E2, 4-chloro-3-(difluoromethyl)-1H-pyrazolo[4,3-c]pyridine (step 2) was converted to the title compound ([M+H,Cl] + 324.1) and its positional isomer was concomitant.

[0148] Intermediate 8: 4-Chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[4,3-c]pyridine TIFF0007731381000029.tif73170

[0149] Step 1: 4-chloro-1H-pyrazolo[4,3-c]pyridin-3-ol To a solution of methyl 2-chloro-4-fluoro-pyridine-3-carboxylate (950 mg, 5.0 mmol) in dioxane (9.5 mL), hydrazine monohydrate (325 mg, 6.5 mmol) and triethylamine (1.4 mL, 10.0 mmol) were added, and the mixture was heated to 70 °C for 16 h. The reaction was diluted with 2-methoxy-2-methylpropane (5 mL), and the precipitate was isolated by filtration to give the title compound (900 mg, 95%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.36 - 9.59 (m, 2H), 8.01 - 7.85 (m, 1H), 7.38 - 7.03 (m, 1H).

[0150] Step 2: 4-Chloro-1-trityl-pyrazolo[4,3-c]pyridin-3-ol To a solution of 4-chloro-1H-pyrazolo[4,3-c]pyridin-3-ol (Step 1) (700 mg, 3.7 mmol), triphenylmethyl chloride (1035 mg, 3.7 mmol) in DMF (100 ml) under Ar, triethylamine (1.55 mL, 11.5 mmol) was added, and the reaction was stirred at 30 °C for 4 h before being diluted with water and repeatedly extracted with ethyl acetate. The combined organic layers were dried (NaSO) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:6 to 3:1) afforded the title compound (620 mg, 41%) as a yellow solid. H 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).

[0151] Step 3: 4-chloro-3-(difluoromethoxy)-1-trityl-pyrazolo[4,3-c]pyridine A suspension of 4-chloro-1-trityl-pyrazolo[4,3-c]pyridin-3-ol (step 2) (100 mg, 0.2 mmol), cesium carbonate (158 mg, 0.5 mmol), and 2-chloro-2,2-difluoro-acetyl)oxysodium (74 mg, 0.45 mmol) in acetonitrile was heated to 80° C. for 2 h. The reaction mixture was filtered and concentrated in vacuo to afford the title compound (100 mg, 89%) as a yellow solid that was used without further purification. 1 H 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)

[0152] Intermediate 9: 4-chloro-3-(oxetan-3-yl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine TIFF0007731381000030.tif58170

[0153] Step 1: (2,4-Dichloro-3-pyridyl)-(oxetan-3-yl)methanol According to general procedure A, 2,4-dichloropyridine was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with oxetane-3-carbaldehyde (1.5 eq) for 1 h to give the title compound ([M+H, Cl] + 233.8).

[0154] Step 2: (2,4-Dichloro-3-pyridyl)-(oxetan-3-yl)methanone Using General Procedure B1, (2,4-dichloro-3-pyridyl)-(oxetan-3-yl)methanol (Step 1) was oxidized to give the title compound. ([M+H,Cl] + 231.7.

[0155] Step 3: 4-chloro-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine According to general procedure C, (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 to give the title compound ([M+H,Cl] + 209.8).

[0156] Step 4: 4-chloro-3-(oxetan-3-yl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine A solution of 4-chloro-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine (Step 3) (200.0 mg, 0.95 mmol), p-toluenesulfonic acid monohydrate (18.2 mg, 0.1 mmol), and 3,4-dihydro-2H-pyran (0.44 mL, 4.77 mmol) in THF (20 mL) was heated to 60 °C for 16 h. The reaction was neutralized by the addition of triethylamine (0.2 mL) and concentrated to dryness. Purification by preparative TLC (n-heptane:ethyl acetate 1:1) afforded the title compound (150 mg, 53%) as a light yellow solid. 1 H NMR (400 MHz, 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).

[0157] Intermediate 10: 4,6-Dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000031.tif43170

[0158] Step 1: Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone According to General Procedure A, 2,4,6-trichloropyridine (300 mg, 1.64 mmol, Eq: 1) was deprotonated with LDA (0.9 eq) for 1 h and reacted with cyclopropanecarbaldehyde (1.5 eq) for 1.5 h to give crude cyclopropyl(2,4,6-trichloropyridin-3-yl)methanol, which was directly oxidized using General Procedure B1 to give the title compound. ([M+H, 2Cl] + 250.1.

[0159] Step 2: 4,6-Dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine According to general procedure C, cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone (step 2) was reacted with hydrazine hydrate (5 eq) in THF at 0° C. for 2 h and then at ambient temperature for 2 h to give the title compound ([M+H, 2Cl] + 228.1).

[0160] Intermediate 11: 4-Bromo-5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine TIFF0007731381000032.tif59170

[0161] Step 1: 3-iodo-5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine Using general procedure E1, 3-iodo-5-methoxy-1H-pyrazolo[3,4-c]pyridine (WO 2015 / 25025) was converted to the title compound ([M+H] + 406.2) and its positional isomer was concomitant.

[0162] Step 2: 5-Methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine To a suspension of 3-iodo-5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine (Step 1) (70 mg, 0.17 mmol), copper(I) iodide (164 mg, 0.86 mmol), and potassium fluoride (50 mg, 0.17 mmol) in NMP (1 mL) was added (trifluromethyl)trimethylsilane (0.13 mL, 0.86 mmol), and the mixture was heated to 50 °C under Ar for 1 h. The reaction was then diluted with water, filtered through Celite®, extracted with ethyl acetate, and the organic layer was dried (NaSO) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:4) gave the title compound (32 mg, 53%) as a yellow viscous oil [M+H]. + 348.3).

[0163] Step 3: 4-Bromo-5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine 5-Methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine (Step 2) (32 mg, 0.9 mmol) was dissolved in 1,2-dichloroethane (0.5 ml), N-bromosuccinamide (18 mg, 1.0 mmol) was added, and the mixture was heated to 70° C. for 2 h. The reaction was concentrated and purified by flash column chromatography (ethyl acetate:n-heptane 1:4) to give the title compound (20 mg, 51%) as a yellow solid [M+H, Br]. + 428.3).

[0164] Intermediate 12: 4-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine TIFF0007731381000033.tif45170

[0165] Step 1: 4-chloro-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine 4-Chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (CAS: 1190313-39-3) (100 mg, 0.4 mmol) and diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (436 mg, 1.1 mmol) were dissolved in DMF (2 ml), copper (138 mg, 2.2 mmol) was added, and the mixture was stirred in a sealed tube under Ar at 60 °C for 6 h. The reaction was diluted with ethyl acetate, and the organic layer was washed with water, brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 0:1 to 6:1) afforded the title compound (18 mg, 22%) as a white solid ([M+H, Cl]). + 221.0).

[0166] Step 2: 4-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine Using general procedure E1, 4-chloro-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine was prepared to give the title compound ([M+H,Cl] + 351.2).

[0167] Intermediate 13: 4-Bromo-3-cyclopropyl-5-(methoxymethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine TIFF0007731381000034.tif52170

[0168] Step 1: 4-Bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid 4-Bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Intermediate 5) (500 mg, 1.9 mmol) was suspended in water (15 ml), sodium hydroxide (380 mg, 9.5 mmol) was added, and the reaction was heated to 100° C. for 15 h. The reaction was then acidified with concentrated HCl, and the resulting solid was isolated by filtration to give the title compound (435 mg, 77%) as a light brown solid ([M+H, Br] + 282.1).

[0169] Step 2: 4-Bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylate methyl 4-Bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Step 1) (300 mg, 1.1 mmol) was suspended in dichloromethane (2 mL) and 3,4-dihydro-2H-pyran (0.5 mL, 5.3 mol) and p-toluenesulfonic acid monohydrate (20 mg, 0.1 mmol) were added. The reaction was stirred for 4 h, then diluted with ethyl acetate, washed with 1N HCl, dried (NaSO), and concentrated. Crude 4-bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (389 mg, 1.1 mmol) was dissolved in a mixture of DCM / MeOH (6 mL / 3 mL) and trimethylsilyldiazomethane (5.3 mL, 2 M in hexanes, 10.6 mmol) was added. The reaction was stirred for 15 h and then concentrated to dryness. Flash column chromatography (ethyl acetate:n-heptane 4:6) gave the title compound (320 mg, 90%) as a colorless gum ([M+H,Br] + 380.2).

[0170] Step 3: (4-bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)methanol Methyl 4-bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylate (Step 2) (320 mg, 0.8 mmol) was dissolved in THF (10 ml) and cooled to −78° C. before adding diisobutylaluminum hydride (3.37 ml, 1 M in THF, 3.4 mmol) and stirring the reaction for 90 minutes. A second portion of diisobutylaluminum hydride (3.37 ml, 1 M in THF, 3.4 mmol) was then added and the mixture stirred for a further 3 h. The reaction was quenched by adding a few drops of water, acidified by adding 1N HCl, extracted with ethyl acetate, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:7) gave the title compound (60 mg, 19%) as a light grey solid ([M+H, Br] + 354.2).

[0171] Step 4: 4-Bromo-3-cyclopropyl-5-(methoxymethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (4-Bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)methanol (Step 3) (60 mg, 0.17 mmol) was dissolved in dichloromethane (2 ml) and triethylamine (49 μL, 0.3 mmol) was added followed by methanesulfonyl chloride (16 μL, 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 a further 3 h. The reaction was concentrated to dryness and 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 bicarbonate, extracted with DCM, and the combined organic layers were dried (NaSO) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:1) gave the title compound (40 mg, 64%) as a colorless solid ([M+H,Br] + 368.2).

[0172] Intermediate 14: 4-Bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole TIFF0007731381000035.tif37170

[0173] Step 1: 1-(2-bromo-6-fluoro-3-(methylsulfonyl)phenyl)-2,2,2-trifluoroethan-1-one According to general procedure A, (2-bromo-4-fluorophenyl)(methyl)sulfane was deprotonated with LDA (1.3 eq) for 30 min and reacted with ethyl 2,2,2-trifluoroacetate (2 eq) to give crude 1-(2-bromo-6-fluoro-3-(methylthio)phenyl)-2,2,2-trifluoroethan-1-one, which was used directly.

[0174] Crude 1-(2-bromo-6-fluoro-3-(methylthio)phenyl)-2,2,2-trifluoroethan-1-one (1.8 g, 5.1 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0 °C. mCPBA (3.5 g, 11.2 mmol) was added, and the mixture was brought to ambient temperature and stirred for 3 h. The reaction was diluted with dichloromethane, washed repeatedly with 1 N NaOH, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 7:3) afforded the title compound (1.0 g, 56%) as a yellow oil.

[0175] Step 32 4-Bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole According to general procedure C, 1-(2-bromo-6-fluoro-3-(methylsulfonyl)phenyl)-2,2,2-trifluoroethan-1-one (step 1) was reacted with hydrazine hydrate (5 eq) in THF at ambient temperature for 1 h to give the title compound ([M+H, Br] + 343.1).

[0176] Step 3: 4-Bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole Using general procedure E2, 4-bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole (step 3) was converted to the title compound ([M+H,Cl] + 351.2). 1 H 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).

[0177] Intermediate 15: 4-Bromo-3-cyclopropyl-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000036.tif35170

[0178] To a solution of 4-bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Intermediate 13, Step 1) (3000 mg, 10.6 mmol), methylamine hydrochloride (1070 mg, 15.8 mmol), and diisopropylethylamine (4 mL, 42.2 mmol) in DMF (60 mL) was added TBTU (4068 mg, 12.7 mmol) and the mixture was stirred for 16 h. The reaction was then diluted with ethyl acetate, washed with water, dried (NaSO), and concentrated. Reverse-phase preparative HPLC gave the title compound (1.6 g, 51%) as a white solid ([M+H, Br] + 296.0).

[0179] Intermediate 16: 4-Bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole TIFF0007731381000037.tif62170

[0180] Step 1: 2-bromo-6-fluoro-3-(methylthio)benzoate ethyl Following general procedure A, (2-bromo-4-fluorophenyl)(methyl)sulfane was deprotonated with LDA (1.1 eq) for 30 min and reacted with ethyl chloroformate (1.2 eq) to give the title compound. ([M+H,Br] + 292.3).

[0181] Step 2: 2-Bromo-6-fluoro-3-(methylsulfonyl)benzoate ethyl To a solution of ethyl 2-bromo-6-fluoro-3-(methylthio)benzoate (Step 1) (100 mg, 0.3 mmol) in dichloromethane (3 mL) was added mCPBA (153 mg, 0.7 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction was then diluted with DCM, washed with 1N NaOH, dried (NaSO), and concentrated to give the title compound (111 mg, quantitative yield) as a light yellow oil. ([M+H, Br] + 325.0).

[0182] Step 3: 4-Bromo-5-(methylsulfonyl)-1,2-dihydro-3H-indazol-3-one To an ice-cold solution of ethyl 2-bromo-6-fluoro-3-(methylsulfonyl)benzoate (Step 2) (1050 mg, 3.2 mmol) in ethanol (13 mL) was added hydrazine monohydrate (157 μL, 3.2 mmol), followed by triethylamine (0.45 mL, 0.8 mmol), and the reaction was allowed to warm to ambient temperature. It was then heated to 80° C. for 2 h before being cooled to ambient temperature, whereupon the desired product precipitated and was isolated by filtration. The title compound (192 mg, 70%) was obtained as a light yellow solid. ([M+H, Br] + 290.9).

[0183] Step 4: 4-Bromo-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol 4-Bromo-5-(methylsulfonyl)-1,2-dihydro-3H-indazol-3-one in DMF (20 ml) To an ice-cold solution of (step 3) (540 mg, 1.9 mmol), trityl chloride (517 mg, 1.9 mmol) was added followed by sodium hydride (89 mg, 60% dispersion in mineral oil, 2.2 mmol). The cooling bath was removed and the reaction was stirred at ambient temperature for 2 h. The reaction was then diluted with ethyl acetate, washed with water, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:9 to 1:0) afforded the title compound (460 mg, 43%) as a colorless solid. ([MH,Br] - 533.3).

[0184] Step 5: 4-Bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole To a solution of 4-bromo-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol (Step 4) (250 mg, 0.5 mmol) in DMF (7.5 ml) was added sodium chlorodifluoroacetate (143 mg, 0.9 mmol) and potassium carbonate (194 mg, 1.4 mmol), and the mixture was heated to 80° C. for 30 minutes. The reaction was then diluted with ethyl acetate, washed with water, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 5:95 to 1:0) afforded the title compound (192 mg, 70%) as a light yellow solid. ([M+H-Tr,Br] + 339.1).

[0185] Intermediate 17: 4-Bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile TIFF0007731381000038.tif58170

[0186] Step 1: Ethyl 3-bromo-2-cyano-5-fluoro-pyridine-4-carboxylate Following general procedure A, 3-bromo-5-fluoropicolinonitrile was deprotonated with 2,2,6,6-tetramethylpiperidinylmagnesium chloride-lithium chloride complex solution (2.5 eq) in THF at −78 °C for 1 h, followed by reaction with ethyl cyanoformate to give the title compound. 1H NMR (400 MHz, chloroform-d) δ = 8.6 (s, 1H), 4.60–4.44 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0187] Step 2: 4-Bromo-3-oxo-1,2-dihydropyrazolo[3,4-c]pyridine-5-carbonitrile To a solution of ethyl 3-bromo-2-cyano-5-fluoro-pyridine-4-carboxylate (Step 1) (5.0 g, 18.3 mmol) in ethanol (50 ml), hydrazine monohydrate (1.9 ml, 36.6 mmol) was added and the reaction was heated to 70 °C for 2 h. The reaction was concentrated to dryness and the residue was purified by reverse phase HPLC to give the title compound (3.5 g, 80%) as a yellow solid. H NMR (400 MHz, DMSO-d) δ = 13.15 (s, 1H), 11.74 (s, 1H), 8.88 (s, 1H).

[0188] Step 3: 4-Bromo-3-hydroxy-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile To 4-bromo-3-oxo-1,2-dihydropyrazolo[3,4-c]pyridine-5-carbonitrile (Step 2) (3500 mg, 14.6 mmol) in DMF (200 mL) was added triphenylmethyl chloride (4286 mg, 15.4 mmol) and triethylamine (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 to 1:3) to afford the title compound (400 mg, 6%) as a yellow solid. ([MH,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).

[0189] Step 4: 4-Bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile To a solution of 4-bromo-3-hydroxy-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Step 3) (50 mg, 0.1 mmol) in acetonitrile (1.5 ml) was added (2-chloro-2,2-difluoro-acetyl)oxysodium (32 mg, 0.2 mmol) and cesium carbonate (68 mg, 0.2 mmol), and the mixture was heated to 80 °C for 2 h. The reaction was diluted with ethyl acetate, filtered, and concentrated to give the title compound (50 mg, 91%) as a yellow solid. H NMR (400 MHz, DMSO-d) δ = 7.49 (s, 1H), 7.45 - 7.16 (m, 16H).

[0190] Intermediate 18: 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000039.tif30170

[0191] Step 1: (4-bromo-2-methylphenyl)(cyclopropyl)sulfane 4-Bromo-2-methylbenzenethiol (600 mg, 3.0 mmol) was dissolved in DMF (12 ml) and the solution was sparged with Ar under sonication, then potassium tert-butoxide (398 mg, 3.6 mmol) and cyclopropyl bromide (0.5 ml, 5.9 mmol) were added and the mixture was heated to 100° C. for 26 h. The reaction was diluted with ethyl acetate, washed repeatedly with water, dried (NaSO), and concentrated to give the title compound (737 mg, 59%) as a light brown oil. 1H NMR (chloroform-d, 300 MHz) δ 7.4-7.4 (m, 1H), 7.3-7.3 (m, 1H), 7.2-7.3 (m, 1H), 2.2-2.2 (m, 3H), 2.0-2.1 (m, 1H), 1.1-1.1 (m, 2H), 0.6-0.7 (m, 2H)

[0192] Step 2: 4-Bromo-1-(cyclopropylsulfonyl)-2-methylbenzene Convert (4-bromo-2-methylphenyl)(cyclopropyl)sulfane (Step 1) to the title compound using general procedure G. 1H NMR (chloroform-d, 300 MHz) δ 7.7-7.8 (m, 1H), 7.5-7.5 (m, 2H), 2.7-2.7 (m, 3H), 2.5-2.6 (m, 1H), 1.3-1.4 (m, 2H), 1.0-1.1 (m, 2H).

[0193] Step 3: 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Using general procedure F, 4-bromo-1-(cyclopropylsulfonyl)-2-methylbenzene (Step 2) is converted to the title compound. ([M+H] + 323.2).

[0194] Intermediate 19: 2-(4-(cyclopropylsulfonyl)-3-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000040.tif28170

[0195] Using general procedure F, 4-bromo-1-(cyclopropylsulfonyl)-2-methylbenzene (CAS: 1310947-51-3, U.S. Patent Application Publication No. 2011 / 237791) is converted to the title compound. ([M+H] + 343.2).

[0196] Intermediate 20: 2-chloro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide TIFF0007731381000041.tif29170

[0197] Step 1: 4-Bromo-2-chloro-N,N-dimethyl-benzenesulfonamide To a solution of dimethylamine hydrochloride (2.1 g, 25.9 mmol) and diisopropylethylamine (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 was stirred at ambient temperature for 2 h. The reaction was then washed with water, brine, dried (NaSO), and concentrated to give the title compound (4.3 g, 84%) as a light brown solid. ([M+H, Br, Cl] + 299.9).

[0198] Step 2: 2-chloro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide Using general procedure F, 4-bromo-2-chloro-N,N-dimethyl-benzenesulfonamide (Step 1) is converted to the title compound. ([M+H] + 346.1).

[0199] Intermediate 21: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000042.tif42170

[0200] Step 1: (2-(difluoromethyl)phenyl)(methyl)sulfane To a degassed solution of bromo-2-(difluoromethyl)benzene (400 mg, 1.9 mmol) in DMF (6 ml) was added sodium thiomethoxide (271 mg, 3.9 mmol) and the mixture was heated to 100 °C for 3 h. It was then diluted with ethyl acetate, washed with water, brine, dried (Na SO ), and concentrated to give the title compound (0.22 g, 44%) as a yellow oil. H NMR (chloroform-d, 300 MHz) δ 8.0-8.0 (m, 1H), 7.61 (s, 1H), 7.4-7.5 (m, 2H), 7.3-7.3 (m, 1H), 7.02 (s, 1H), 2.5-2.5 (m, 3H).

[0201] Step 2: 4-Bromo-2-(difluoromethyl)phenyl)(methyl)sulfane To an ice-cold solution of 2-(difluoromethyl)phenyl)(methyl)sulfane (Step 1, 224 mg, 1.3 mmol) in DCM (4.5 mL) was added bromine (93 μL, 1.8 mmol), and the reaction was allowed to warm to ambient temperature and stirred for 4 days. The reaction was diluted with DCM, washed with aqueous sodium thiosulfate, brine, dried (NaSO), and concentrated to give the title compound (0.29 g, 67%) as a yellow oil. H NMR (chloroform-d, 300 MHz) δ 7.74 (br d, 1H, 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).

[0202] 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).

[0203] Step 4: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Using general procedure F, convert 4-bromo-2-(difluoromethyl)-1-(methylsulfonyl)benzene (Step 3) to the title compound. ([M+H-CH 12 ] + 500.2).

[0204] Intermediate 22: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000043.tif34170

[0205] Step 1: 4-Bromo-2-(fluoromethyl)-1-(methylsulfonyl)benzene To a solution of (5-bromo-2-(methylsulfonyl)phenyl)methanol (CAS: 773134-43-3, WO 2011 / 138751) (780 mg, 2.9 mmol) cooled to -78 °C, diethylaminosulfur trifluoride (0.5 ml, 3.5 mmol) was added and the reaction was stirred for 1 h before the temperature was raised to 0 °C and stirred for 2 h. The reaction was then washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), and concentrated. Flash column chromatography (ethyl acetate: n-heptane 3:7) afforded the title compound (400 mg, 6%) as a yellow solid. ([MH,Br] -533.3) to give the title compound (0.62 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).

[0206] Step 2: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Convert 4-bromo-2-(fluoromethyl)-1-(methylsulfonyl)benzene (Step 1) to the title compound using general procedure F. 1H NMR (chloroform-d, 300 MHz) δ 7.90-8.10 (m, 3H), 5.70-6.00 (m, 2H), 3.14 (s, 3H), 1.37 (s, 12H).

[0207] Intermediate 23: 4,4,5,5-tetramethyl-2-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1,3,2-dioxaborolane TIFF0007731381000044.tif29170

[0208] 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 4-methylbenzenesulfonate (CAS: 26272-83-3, WO 2012 / 138678) (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 (NaSO), and concentrated. Flash column chromatography (ethyl acetate: n-heptane 3:7) afforded the title compound (185 mg, 71%) as a colorless oil. ([M+H, Br] + 261.0).

[0209] Step 2: 3-((4-bromo-2-methylphenyl)sulfonyl)oxetane Using general procedure G, 3-((4-bromo-2-methylphenyl)thio)oxetane (Step 2) is converted to the title compound. ([M+H+MeCN,Br] + 334.1).

[0210] Step 4: 4,4,5,5-tetramethyl-2-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1,3,2-dioxaborolane Using general procedure F, convert 3-((4-bromo-2-methylphenyl)sulfonyl)oxetane to the title compound. ([M+H+MeCN] + 380.3).

[0211] Intermediate 24: 2-(4-ethylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000045.tif33170

[0212] Step 1: 4-Bromo-1-ethylsulfanyl-2-methyl-benzene To a solution of 1-ethylsulfanyl-2-methyl-benzene (CAS: 3695-36-1) (30.0 g, 197.0 mmol) in dichloromethane (300 ml) at 0 °C, bromine (40.0 g, 256.0 mmol) was added, and the reaction was stirred at ambient temperature for 1 h. The reaction was concentrated to give 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, 1 H), 7.31 - 7.41 (m, 2 H).

[0213] Step 2: 4-Bromo-1-ethylsulfonyl-2-methyl-benzene Convert 4-bromo-1-ethylsulfonyl-2-methyl-benzene (Step 1) to the title compound using general procedure G. 1H NMR (400MHz, chloroform-d) δ = 7.89 - 7.82 (m, 1H), 7.55 - 7.50 (m, 2H), 3.17 - 3.11 (m, 2H), 2.67 (s, 3H), 1.27 (t, 3H).

[0214] Step 3: 2-(4-ethylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Using general procedure F, 4-bromo-1-ethylsulfonyl-2-methyl-benzene (Step 2) is converted to the title compound. ([M+H] + 229.1)

[0215] Intermediate 25: 2-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000046.tif34170

[0216] Step 1: 1-Bromo-2-fluoro-5-methyl-4-methylsulfonyl-benzene Using general procedure G, 1-bromo-2-fluoro-5-methyl-4-methylsulfanyl-benzene (CAS: 1351167-83-3, WO 2011 / 146335) is converted to the title compound. ([M+H+MeCN,Br] + 267.0).

[0217] Step 2: 2-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Using general procedure F, convert 1-bromo-2-fluoro-5-methyl-4-methylsulfonyl-benzene (Step 1) to the title compound at 70° C. ([M+H-CH 12 ] + 233.1).

[0218] Intermediate 26: 2-(2,5-dimethyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000047.tif36170

[0219] Step 1: 1-Bromo-2,5-dimethyl-4-methylsulfonyl-benzene To a mixture of 1,4-dibromo-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) was added sodium hydroxide (0.2 g, 6.1 mmol) and sodium methanesulfinate (1.0 g, 9.9 mmol). The mixture was stirred under a nitrogen atmosphere at 120 °C for 20 h, then diluted with water and repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:4) afforded the title compound (627 mg, 13%) as a yellow solid. ([M+H, Br] + 263.0).

[0220] Step 2: 2-(2,5-dimethyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Using general procedure F, 1-bromo-2,5-dimethyl-4-methylsulfonyl-benzene (Step 1) is converted to the title compound at 95° C. ([M+H] + 311.2).

[0221] Intermediate 27: 2-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000048.tif31170

[0222] Step 1: 4-Bromo-1-(difluoromethylsulfanyl)-2-methyl-benzene To a solution of 1-(difluoromethylsulfanyl)-2-methyl-benzene (CAS: 1450743-54-0, Organic Letters, 2013, pp. 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 ambient temperature for 12 h, after which the reaction was diluted with ethyl acetate, washed with saturated sodium bisulfite, dried (NaSO), and concentrated to give the title compound (15.0 g, 69%) as a yellow liquid. 1H NMR (400MHz, chloroform-d) δ = 7.50 (d, J=1.9 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.40 - 7.31 (m, 2H), 6.97 - 6.61 (m, 1H), 2.50 (s, 3H)

[0223] Step 2: 4-Bromo-1-(difluoromethylsulfonyl)-2-methyl-benzene Using general procedure G, convert 4-bromo-1-(difluoromethylsulfanyl)-2-methyl-benzene (Step 1) to the title compound. 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).

[0224] Step 3: 2-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Using general procedure F, convert 4-bromo-1-(difluoromethylsulfonyl)-2-methyl-benzene (Step 1) to the title compound at 80° C. 1H NMR (400MHz, chloroform-d) δ = 7.99 (d, J = 7.8 Hz, 1H), 7.86 - 7.79 (m, 2H), 6.38 - 5.97 (m, 1H), 2.71 (s, 3H), 1.36 (s, 12H).

[0225] Intermediate 28: 2-[4-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000049.tif35170

[0226] Step 1: 1-(cyclopropylmethylsulfanyl)-2-methyl-benzene To a 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 give the title compound (3.0 g, quantitative yield) as a yellow liquid. 1 H NMR (400 MHz, chloroform-d) δ ppm 0.24 - 0.30 (m, 2H) 0.56 - 0.63 (m, 2H) 1.01 - 1.15 (m, 1H) 2.40 (s, 3H) 2.84 (d, J=7.00 Hz, 2H) 7.05 - 7.12 (m, 1H) 7.12 - 7.20 (m, 2H) 7.27 - 7.33 (m, 1H)

[0227] Step 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 ambient temperature for 3 h, after which the reaction was diluted with ethyl acetate, washed with saturated sodium bisulfite, dried (NaSO), and concentrated to give the title compound (3.7 g, 86%) as a yellow liquid. 1H NMR (400 MHz, Chloroform-d) δ ppm 0.01 - 0.07 (m, 2 H) 0.34 - 0.42 (m, 2 H) 0.76 - 0.90 (m, 1 H) 2.14 (s, 3 H) 2.16 - 2.19 (m, 1 H) 2.17 - 2.18 (m, 1 H) 2.59 (d, J=7.00 Hz, 2 H) 2.62 (d, J=7.00 Hz, 1 H) 6.93 (d, J=8.25 Hz, 1 H) 6.91 - 6.94 (m, 1 H) 7.03 - 7.06 (m, 1 H) 7.08 - 7.10 (m, 1H) 7.09 (d, J=2.25 Hz, 1 H)

[0228] Step 3: 4-Bromo-1-(cyclopropylmethylsulfonyl)-2-methyl-benzene General procedure G is used to convert 4-bromo-1-(cyclopropylmethylsulfanyl)-2-methyl-benzene (Step 2) to the title compound. 1 H NMR (400 MHz, chloroform-d) δ ppm 0.13 - 0.18 (m, 2 H) 0.53 - 0.58 (m, 2 H) 0.90 - 1.03 (m, 1 H) 2.65 (s, 3 H) 3.04 (d, J=7.25 Hz, 2 H) 7.49 - 7.54 (m, 2 H) 7.88 (d, J=8.25 Hz, 1 H)

[0229] Step 4: 2-[4-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Convert 4-bromo-1-(cyclopropylmethylsulfonyl)-2-methyl-benzene (Step 3) 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 (quintet, J=7.65, 7.65, 7.65, 7.65, 4.85, 4.85 Hz, 1 H) 1.36 (s, 12 H) 2.68 (s, 3 H) 3.05 (d, J=7.13 Hz, 2 H) 7.74 (s, 1 H) 7.77 (d, J=7.88 Hz, 1 H) 8.01 (d, J=7.88 Hz, 1 H)

[0230] Intermediate 29: 4,4,5,5-tetramethyl-2-(3-methyl-4-propylsulfonyl-phenyl)-1,3,2-dioxaborolane TIFF0007731381000050.tif29170

[0231] Step 1: 1-Methyl-2-propylsulfanyl-benzene To a 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 1-iodopropane (4.3 mL, 29.0 mmol). The mixture was stirred at 60 °C for 12 h. The reaction was then diluted with ethyl acetate, filtered, and concentrated to give the title compound (2.5 g, 94%) as a yellow liquid. 1 H 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).

[0232] Step 2: 4-Bromo-2-methyl-1-propylsulfanyl-benzene To a solution of 1-methyl-2-propylsulfanyl-benzene (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 ambient temperature for 3 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (NaSO), and concentrated to give the title compound (3.6 g, 98%) as a yellow liquid. 1 H 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, 1H) 7.09 (d, J=2.25 Hz, 1 H)

[0233] Step 3: 4-Bromo-2-methyl-1-propylsulfonyl-benzene General procedure G is used to convert 4-bromo-2-methyl-1-propylsulfanyl-benzene (step 2) to the title compound. 1 H 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).

[0234] Step 4: 4,4,5,5-tetramethyl-2-(3-methyl-4-propylsulfonyl-phenyl)-1,3,2-dioxaborolane Using general procedure F, 4-bromo-1-(cyclopropylmethylsulfonyl)-2-methyl-benzene (step 3) is converted to the title compound at 90° C. ([M+H] + 311.2).

[0235] Intermediate 30: 2-(4-isopropylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000051.tif35170

[0236] Step 1: 1-Isopropylsulfanyl-2-methyl-benzene To a 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 2-bromopropane (3.1 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 give the title compound (2.5 g, 94%) as a yellow liquid. 1 H 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).

[0237] Step 2: 4-Bromo-2-methyl-1-propylsulfanyl-benzene To a solution of 1-isopropylsulfanyl 2-methyl-benzene (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 ambient temperature for 3 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (NaSO), and concentrated to give the title compound (3.6 g, 98%) as a yellow liquid. 1H NMR (400 MHz, chloroform-d) δ = 7.35 (d, J = 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).

[0238] Step 3: 4-Bromo-1-isopropylsulfonyl-2-methyl-benzene General procedure G is used to convert 4-bromo-2-methyl-1-propylmethylsulfanyl-benzene (step 2) to the title compound. 1 H 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)

[0239] Step 4: 2-(4-isopropylsulfonyl-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Using general procedure F, 4-bromo-1-(cyclopropylmethylsulfonyl)-2-methyl-benzene (step 3) is converted to the title compound at 90° C. ([M+H] + 325.1).

[0240] Intermediate 31: N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide TIFF0007731381000052.tif28170

[0241] Step 1: 4-Bromo-N,2-dimethyl-benzenesulfonamide To a solution of methylamine hydrochloride (0.6 g, 8.9 mmol) in dichloromethane (30 mL) was added triethylamine (2.5 mL, 17.8 mmol) and 4-bromo-2-methylbenzene-1-sulfonyl chloride (2.0 g, 7.4 mmol), and the reaction was stirred at ambient temperature for 1 h. The reaction was diluted with dichloromethane, washed with brine, dried (NaSO), and concentrated to give the title compound (1.9 g, 92%) as a white solid. 1 H 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)

[0242] Step 2: N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide Using general procedure F, 4-bromo-N,2-dimethyl-benzenesulfonamide (Step 2) is converted to the title compound at 90° C. ([M+H] + 312.1).

[0243] Intermediate 32: tert-butyl-dimethyl-[2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylethoxy]silane TIFF0007731381000053.tif39170

[0244] Step 1: tert-butyl-dimethyl-[2-(o-tolylsulfanyl)ethoxy]silane To a 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 give the title compound (7.5 g, 82%) as a colorless liquid. 1H NMR (400 MHz, chloroform-d) δ = 7.32 (d, J = 7.6 Hz, 1H), 7.18 - 7.14 (m, 2H), 7.12 - 7.07 (m, 1H), 3.81 (t, J = 7.2 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H).

[0245] Step 2: 2-(4-Bromo-2-methyl-phenyl)sulfanylethoxy-tert-butyl-dimethyl-silane To a solution of tert-butyl-dimethyl-[2-(o-tolylsulfanyl)ethoxy]silane (Step 1) (7.5 g, 13.3 mmol) in dichloromethane (50 ml) was added bromine (2.3 g, 14.6 mmol) and the mixture was stirred at ambient temperature for 3 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (NaSO), and concentrated to give the title compound (9.0 g, 65%) as a yellow liquid that was used directly in the next step.

[0246] Step 3: 2-(4-Bromo-2-methyl-phenyl)sulfonylethoxy-tert-butyl-dimethyl-silane Using general procedure G, 2-(4-bromo-2-methyl-phenyl)sulfanylethoxy-tert-butyl-dimethyl-silane (step 2) is converted to the title compound. ([M+H] + 393.0).

[0247] Step 4: tert-butyl-dimethyl-[2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylethoxy]silane Using general procedure F, 2-(4-bromo-2-methyl-phenyl)sulfonylethoxy-tert-butyl-dimethyl-silane (step 3) is converted to the title compound at 90° C. ([M+H] + 441.1).

[0248] Intermediate 33: 4,4,5,5-tetramethyl-2-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1,3,2-dioxaborolane TIFF0007731381000054.tif27170

[0249] 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, then iodomethane (515 mg, 3.6 mmol) was added and the mixture was warmed to 20° C. and stirred for an additional 15 h. The mixture was diluted with ethyl acetate, washed with water, dried (NaSO), and concentrated. Purification by preparative TLC (petroleum ether:ethyl acetate 5:1) afforded the title compound (0.45 g, 86%) as a colorless gum. 1 H 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)

[0250] 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)

[0251] Intermediate 34: 2-[4-(methoxymethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000055.tif37170

[0252] Step 1: 4-Bromo-1-(methoxymethylsulfanyl)-2-methyl-benzene To a solution of chloromethyl methyl ether (0.28 mL, 3.7 mmol) in acetonitrile (3 mL) was added potassium carbonate (680 mg, 4.9 mmol) and 4-bromo-2-methyl-benzenethiol (500 mg, 2.5 mmol). The mixture was stirred at 50 °C for 12 h. The reaction was then diluted with ethyl acetate, washed with water, dried (Na SO ), and concentrated. Flash column chromatography (n-heptane) afforded the title compound (220 mg, 36%) as a light yellow oil. 1 H 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)

[0253] Step 2: 4-Bromo-1-(methoxymethylsulfonyl)-2-methyl-benzene General procedure G is used to convert 4-bromo-1-(methoxymethylsulfanyl)-2-methyl-benzene (Step 2) to the title compound. 1H NMR (400MHz, chloroform-d) δ = 7.86 (d, J=8.3 Hz, 1H), 7.56 - 7.49 (m, 2H), 4.54 (s, 2H), 3.64 (s, 3H), 2.67 (s, 3H)

[0254] Step 3: 2-[4-(methoxymethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Using general procedure F, 4-bromo-1-(methoxymethylsulfonyl)-2-methyl-benzene (step 3) is converted to the title compound at 70° C. and the crude product is used in the next step.

[0255] Intermediate 35: 2-[5-(difluoromethyl)-2-methyl-4-methylsulfinyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF0007731381000056.tif39170

[0256] Step 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) was added diethylaminosulfur trifluoride (6.1 g, 37.7 mmol) 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 bicarbonate, and concentrated. Flash column chromatography (n-heptane) afforded the title compound (3.6 g, 65%) as a yellow liquid. 1 H 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)

[0257] 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, n-butyllithium (7.2 mL, 2.5 M in hexanes, 18 mmol) was added and the mixture was stirred for 0.5 h, then (methyldisulfanyl)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 ambient temperature and repeatedly extracted with ethyl acetate. The combined organic layers were concentrated to give the title compound (2.5 g, 82%) as a yellow liquid. 1 H 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)

[0258] 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 ambient temperature for 12 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (NaSO), and concentrated to give the title compound (90 mg, 63%) as a yellow liquid. 1 H 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)

[0259] 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-chloroperbenzoic acid (0.6 g, 3.0 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. After that, the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, saturated aqueous sodium bicarbonate, brine, dried (Na SO ), and concentrated. Flash column chromatography (ethyl acetate: n-heptane 3:7) afforded the title compound (800 mg, 57%) as a white solid. ([M+H, Br] + 282.0).

[0260] Step 5: 2-[5-(difluoromethyl)-2-methyl-4-methylsulfinyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Using general procedure F, 1-bromo-5-(difluoromethyl)-2-methyl-4-methylsulfinyl-benzene (step 4) is converted to the title compound at 80° C. ([M+H] + 331.2).

[0261] Intermediate 36: 4-Bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-trityl-indazole TIFF0007731381000057.tif55170

[0262] Step 1: 2-Bromo-6-fluoro-3-methylsulfanyl-benzoate ethyl Following general procedure A, 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 to give the title compound. 1 H 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)

[0263] Step 2: 2-Bromo-6-fluoro-3-methylsulfonyl-benzoate ethyl Using general procedure G, ethyl 2-bromo-6-fluoro-3-methylsulfanyl-benzoate is converted to the title compound. ([M+H,Br] + 326.9).

[0264] Step 3: 4-Bromo-5-methylsulfonyl-1,2-dihydroindazol-3-one To a solution of ethyl 2-bromo-6-fluoro-3-methylsulfonylbenzoate (Step 2) (10.8 g, 33.2 mmol) in ethanol (120 mL) at 0° C. was added hydrazine hydrate (2.2 g, 44.4 mmol) and triethylamine (4.6 mL, 33.2 mmol), and the reaction was then heated to 80° C. for 4 h. After cooling to ambient temperature, the title compound (5.0 g, 52%) was isolated as an off-white solid by filtration. ([M+Na,Br] + 314.8).

[0265] Step 4: 4-Bromo-5-methylsulfonyl-1-trityl-indazol-3-ol To a solution of 4-bromo-5-methylsulfonyl-1,2-dihydroindazol-3-one (step 3) (200 mg, 0.7 mmol) in DMF (5 mL) at 0 °C under a nitrogen atmosphere was added sodium hydride (41 mg, 60% dispersion in mineral oil, 1.0 mmol) and triphenylmethyl chloride (211 mg, 0.8 mmol). The cooling bath was removed and the reaction was stirred for 2 h upon reaching ambient temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted repeatedly with ethyl acetate. The combined organic extracts were washed with brine and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:1) afforded the title compound (150 mg, 41%) as a white solid. ([M+Na,Br] + 556.9).

[0266] Step 5: 4-Bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-trityl-indazole To a solution of 4-bromo-5-methylsulfonyl-1-trityl-indazol-3-ol (step 4) (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 to 80° C. for 30 minutes. The reaction was filtered and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:3) afforded the title compound (0.9 g, 71%) as a white solid. ([M+H, Br] + 605.0

[0267] Intermediate 37: 4-chloro-3-cyclopropyl-2-trimethylsilyl-1-(2-trimethylsilylethoxymethyl)indole-5-carbonitrile TIFF0007731381000058.tif45170

[0268] Step 1: 4-Bromo-3-chloro-2-iodoaniline was prepared as described in WO 2013 / 33228.

[0269] Step 2: 5-Bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-indole A mixture of 4-bromo-3-chloro-2-iodoaniline (Step 1) (441 mg, 1.3 mmol), (cyclopropylethynyl)trimethylsilane (159 μl, 1.5 mmol), lithium chloride (56 mg, 1.33 mmol), and sodium carbonate (281 mg, 2.7 mmol) in DMF (5 mL) was sparged with argon, followed by the addition of [1,1′-1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (49 mg, 66 μmol). The reaction was heated to 100° C. in a sealed tube for 16 h, after which the reaction was diluted with ethyl acetate, washed with aqueous sodium thiosulfate, brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 4:1) afforded the title compound (185 mg, 39%) as a yellow solid. ([M+H, Cl, Br] + 342.2).

[0270] Step 3: 5-Bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole 5-Bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-indole was converted to the title compound in THF using general procedure E1. 1 H 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)

[0271] Step 4: 4-chloro-3-cyclopropyl-2-trimethylsilyl-1-(2-trimethylsilylethoxymethyl)indole-5-carbonitrile 5-Bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (Step 3) (170 mg, 0.3 mmol) and zinc cyanide (34 mg, 0.3 mmol) were suspended in DMF (3 ml). The reaction mixture was sparged with argon and the reaction was heated in a microwave at 150° C. for 30 minutes. The reaction was diluted with water and repeatedly extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 4:1) afforded the title compound (57 mg, 46%) as a yellow solid. ([M+H,Cl] + 301.2).

[0272] Intermediate 38: 2-(Difluoromethyl)-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide TIFF0007731381000059.tif39170

[0273] Step 1: 1-Benzylsulfanyl-4-bromo-2-(difluoromethyl)benzene To an ice-cold solution of benzyl mercaptan (2.4 g, 19.4 mmol) in DMF (20 mL) was added sodium hydride (0.8 g, 60% dispersion in mineral oil, 20 mmol), and after 0.5 h, 4-bromo-2-(difluoromethyl)-1-fluoro-benzene (3.0 g, 13.3 mmol) was added, 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 to 5:95) afforded the title compound (3.8 g, 83%) as a colorless oil. 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).

[0274] Step 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) was added acetic acid (182 mg, 3.0 mmol) and water (0.05 mL, 3.0 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 (ethyl acetate:heptane 1:10) afforded 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)

[0275] Step 3: 4-Bromo-2-(difluoromethyl)-N,N-dimethyl-benzenesulfonamide To an ice-cold solution of 4-bromo-2-(difluoromethyl)benzenesulfonyl chloride (Step 2) (2.6 g, 6.8 mmol) in acetonitrile (20 mL) was added dimethylamine hydrochloride (1.7 g, 20.4 mmol) followed by pyridine (1.65 mL, 20.4 mmol), and the mixture was stirred for 0.5 h. The reaction was diluted with ethyl acetate, washed with 1N HCl, brine, and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:5) afforded the title compound (1.6 g, 71%) as a white solid. ([M+H, Br] + 315.9).

[0276] Step 4: 2-(Difluoromethyl)-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide Using general procedure F, 4-bromo-2-(difluoromethyl)-N,N-dimethyl-benzenesulfonamide (step 3) is converted to the title compound at 80° C. ([M+H] + 362.2). [Example]

[0277] TIFF0007731381000060.tif228170TIFF0007731381000061.tif255170TIFF0007731381000062.t if255170TIFF0007731381000063.tif231170TIFF0007731381000064.tif255170TIFF00077313810 00065.tif255170TIFF0007731381000066.tif245170TIFF0007731381000067.tif255170TIFF000 7731381000068.tif201170TIFF0007731381000069.tif201170TIFF0007731381000070.tif255170 TIFF0007731381000071.tif241170TIFF0007731381000072.tif255170TIFF0007731381000073.t if255170TIFF0007731381000074.tif201170TIFF0007731381000075.tif255170TIFF00077313810 00076.tif232170TIFF0007731381000077.tif233170TIFF0007731381000078.tif217170TIFF000 7731381000079.tif255170TIFF0007731381000080.tif233170TIFF0007731381000081.tif240170

[0278] Example 56: 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000082.tif39170

[0279] Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine Using general procedure D, 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (CAS: 1416713-66-0, U.S. Patent Application Publication No. 2014 / 128374) is reacted with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid (1.1 eq) at 100° C. ([M+H] + 372.2).

[0280] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Step 1) (40 mg, 0.1 mmol) was dissolved in dioxane / DCM (2.0 / 0.5 ml) and HCl (50 μL, 4N in dioxane, 0.2 mmol) was added. The reaction was stirred for 16 h before being washed with saturated aqueous sodium bicarbonate, water, brine, dried (NaSO), and concentrated to give the title compound (23 mg, 67%) as an off-white solid. ([M+H] + 288.1).

[0281] Step 3: 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine 4-(3-Methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (Step 2) (23 mg, 0.1 mmol) was suspended in DCM (1.5 ml) and N-bromosuccinimide (14 mg, 0.1 mmol) was added. The reaction was stirred for 2 h and then concentrated to dryness. Flash column chromatography (ethyl acetate:n-heptane 4:6 to 1:0) afforded the title compound (185 mg, 71%) as a white solid. ([M+H, Br] + 366.1).

[0282] Examples 57 & 58: 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine & 3-Methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000083.tif57170

[0283] Step 1: 4-chloro-1,2-dihydro-3H-pyrazolo[4,3-c]pyridin-3-one Following general procedure C, ethyl 2-chloro-4-fluoronicotinate was reacted with hydrazine hydrate (1 eq) and triethylamine (1 eq) in ethanol at 80° C. to give the title compound. ([M+H,Cl] + 170.0).

[0284] Step 2: 4-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol To 4-chloro-1,2-dihydro-3H-pyrazolo[4,3-c]pyridin-3-one (20 mg, 0.1 mmol) in DMF (1 mL) at 0°C under a nitrogen atmosphere was added sodium hydride (6 mg, 60% dispersion in mineral oil, 0.1 mmol) and triphenylmethyl chloride (33 mg, 0.1 mmol). The cooling bath was removed and the reaction was stirred for 2 h upon reaching ambient temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted repeatedly with ethyl acetate. The combined organic extracts were washed with brine and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:1) afforded the title compound (19 mg, 37%) as a light yellow solid. ([M+H] + 412.3).

[0285] Step 3: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol Suzuki coupling of 4-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol (step 2) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using potassium carbonate at 100 °C according to general procedure D gave the title compound ([M+H] + 546.2) was prepared.

[0286] Step 4: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine & 3-methoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine

[0287] To a mixture of 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol (Step 3) (51 mg, 0.1 mmol) and potassium carbonate (39 mg, 0.3 mmol) in DMF (1.5 mL) was added methyl 2-chloro-2,2-difluoroacetate (20 μL, 0.2 mmol). The reaction was stirred in a sealed tube at 80 °C for 30 min. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na SO ), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 0:1 to 1:4) afforded the title compound as a 4:1 mixture (27 mg, 35%) as a white solid. ([M+H] + 596.3&560.3).

[0288] Step 5: 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine & 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

[0289] Using general procedure H, the mixture of 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (step 4) is deprotected to give the title compounds, which are separated by reverse-phase preparative HPLC. ([M+H] + 354.1&318.2).

[0290] Example 59: 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline TIFF0007731381000084.tif39170

[0291] Step 1: 3-Cyclopropyl-4-(3-fluoro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine Suzuki coupling of 4-chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (Intermediate 1) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using cesium carbonate at 100 °C according to general procedure D gave the title compound ([M+H] + 332.1) was prepared.

[0292] Step 2: 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline In a pressure tube, 3-cyclopropyl-4-(3-fluoro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (Step 1) (30 mg, 0.1 mmol) and condensed ammonia (approximately 3 mL) were added at -78 °C. The tube was then sealed, warmed to ambient temperature, and stirred for 8 days. Evaporation of the ammonia and flash column chromatography (ethyl acetate: n-heptane 1:1 to 1:0) afforded the title compound (6 mg, 21%) as a white solid. ([M+H] + 329.1).

[0293] Example 60: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000085.tif39170

[0294] Step 1: 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine To a mixture of 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (product 56) (648 mg, 1.8 mmol) in THF (20 ml), 3,4-dihydro-2H-pyran (1.6 ml, 17.7 mmol) and p-toluenesulfonic acid monohydrate (34 mg, 0.2 mmol) were added, and the reaction mixture was stirred at 70 °C for 36 h before being concentrated in vacuo. The residue was redissolved in ethyl acetate, washed with water, dried (Na SO ), and concentrated. Flash column chromatography (DCM:MeOH 1:0 to 9:1) afforded the title compound (689 mg, 78%) as a yellow solid. ([M+H] + 452.1).

[0295] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine 3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Step 1) (102 mg, 0.2 mmol) was dissolved in DMSO (2.5 ml). 2-Methyl-2-thiopseudourea sulfate (63 mg, 0.2 mmol) and cesium carbonate (295 mg, 0.9 mmol) were added. The reaction mixture was heated to 100° C. for 15 h. The reaction mixture was allowed to cool to RT, and then silica gel was added. The suspension was concentrated under high vacuum. The crude mixture was purified by flash column chromatography (ethyl acetate:n-heptane 0:1 to 1:0) to afford the title compound (40 mg, 42% yield) as a light yellow gum. ([M+H] + 418.1).

[0296] Step 3: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine Using general procedure G, 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Step 2) was oxidized to the title compound. ([M+H] + 450.2).

[0297] Step 4: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine Using general procedure I, 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (step 3) was deprotected to give the title compound. ([M+H] + 366.0).

[0298] Example 61: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile TIFF0007731381000086.tif42170

[0299] Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile At ambient temperature, 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 60, Step 1) (40 mg, 0.1 mmol), zinc cyanide (10 mg, 0.1 mmol), and tetrakistriphenylphosphine palladium (15 mg, 0.01 mmol) were suspended in DMF (1 ml). The reaction mixture was heated to 150 °C in a microwave reactor for 0.5 h. Silica gel was added to the reaction mixture, which was then concentrated. The crude mixture was purified by flash column chromatography (ethyl acetate:n-heptane 0:1 to 1:0) to afford the title compound (16 mg, 44% yield) as a light yellow solid. ([M+H] + 397.2).

[0300] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile Using general procedure I, 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile (step 1) was deprotected to give the title compound. ([M+H] + 313.1).

[0301] Example 62: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid TIFF0007731381000087.tif58170

[0302] 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 16) (20 mg, 0.1 mmol) was suspended in aqueous sodium hydroxide (0.5 mL, 6 M, 3.0 mmol) and the mixture was heated to 100° C. for 16 h. The reaction was cooled to ambient temperature, acidified with 37% HCl, and concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (8 mg, 36% yield) as a white solid. ([M+H] + 372.2).

[0303] Example 63: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile TIFF0007731381000088.tif61170

[0304] Step 1: 2-Bromo-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile According to general procedure A, 2-bromo-4-fluorobenzonitrile is treated with LDA (1.3 eq) for 10 min before the addition of cyclopropanecarbaldehyde (1.4 eq). 1 H 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).

[0305] Step 2: 2-Bromo-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile Using general procedure B1, 2-bromo-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile was oxidized to give the title compound. 1H NMR (chloroform-d, 300 MHz) δ 7.7-7.8 (m, 1H), 7.2-7.3 (m, 1H), 2.24 (dtt, 1H, J=1.0, 4.5, 7.8 Hz), 1.4-1.5 (m, 2H), 1.2-1.3 (m, 2H).

[0306] Step 3: 3-(cyclopropanecarbonyl)-4-fluoro-2-(3-methyl-4-methylsulfonylphenyl)benzonitrile Suzuki coupling of 2-bromo-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile (step 2) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using potassium carbonate at 90 °C according to general procedure D afforded the title compound ([M+H] + 358.2) was prepared.

[0307] Step 4: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile According to general procedure C, 3-(cyclopropanecarbonyl)-4-fluoro-2-(3-methyl-4-methylsulfonylphenyl)benzonitrile (step 3) was reacted with hydrazine hydrate (5 eq) in THF at ambient temperature to give the title compound. ([M+H] + 352.3).

[0308] Example 64: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-ol TIFF0007731381000089.tif32170

[0309] Step 1: 7-Bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine A mixture of N-bromosuccinimide (109 mg, 0.6 mmol), 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine (Example 1) (100 mg, 0.3 mmol) in DMF (2 mL) was stirred at 80° C. for 24 h. The reaction was directly purified by reverse-phase preparative HPLC to afford the title compound (30 mg, 24%) as a green solid. ([M+H, Br] + 405.8).

[0310] Step 2: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-ol 7-Bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine (Step 3) (60 mg, 0.2 mmol), potassium hydroxide (33 mg, 0.6 mmol), Pd(dba) (5 mg, 0.03 mmol), tBuXPhos (4 mg, 0.01 mmol, 0.060 eq) in dioxane (1.5 mL) and water (1 mL) was stirred at 90 °C under nitrogen atmosphere for 1 h. The reaction mixture was filtered and concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (6 mg, 10%) as a yellow solid. ([M+H] + 343.9).

[0311] Example 65: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000090.tif65170

[0312] Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine According to general procedure D, 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Intermediate 60, Step 1) is reacted with thiophene-3-boronic acid using potassium carbonate as a base at 90° C. ([M+H] + 454.2).

[0313] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine Using general procedure I2, 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine (Step 1) was deprotected to give the title compound. ([M+H] + 370.2).

[0314] Example 66: 3-Ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000091.tif68170

[0315] Step 1: 3-Ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-pyrazolo[4,3-c]pyridine To a solution of 4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-pyrazolo[4,3-c]pyridin-3-ol (Example 57, Step 3) (100 mg, 0.2 mmol) in acetonitrile (2 mL) was added cesium carbonate (120 mg, 0.4 mmol) and iodoethane (0.04 mL, 0.6 mmol), and the reaction mixture was stirred at 80° C. for 2 h. The reaction was filtered and concentrated. Purification by preparative TLC (heptane:ethyl acetate 3:1) afforded the title compound (60 mg, 54%) as a white solid. ([M+H] + 574.3).

[0316] Step 2: 3-ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine Deprotection of 3-ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-pyrazolo[4,3-c]pyridine using general procedure H gives the title compound. ([M+H] + 332.1).

[0317] Example 67: 3-Cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000092.tif63170

[0318] Step 1: 2-Bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanol According to general procedure A, 2-bromo-4-chloro-5-fluoro-pyridine was reacted with LDA (1.2 eq) for 30 min, followed by the addition of cyclopropanecarbaldehyde (1.4 eq). ([M+H, Br] + 280.0)

[0319] Step 2: 2-Bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanone Using general procedure B1, 2-bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanol was oxidized to give the title compound. ([M+H,Br] + 278.0)

[0320] Step 3: [4-chloro-5-fluoro-2-(3-methyl-4-methylsulfonyl-phenyl)-3-pyridyl]-cyclopropyl-methanone Suzuki coupling of 2-bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropyl-methanone (step 2) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using potassium carbonate at 100 °C according to general procedure D to give the title compound ([M+H] + 368.1) was prepared.

[0321] Step 4: 3-Cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine According to general procedure C, 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. to give the title compound. ([M+H] + 346.1).

[0322] Examples 68 & 69: 3-Methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile & 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile TIFF0007731381000093.tif56170

[0323] Step 1: 2-bromo-3-cyano-6-fluorobenzoate ethyl According to general procedure A, 2-bromo-4-fluorobenzonitrile was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with ethyl chloroformate (1.2 eq) to give 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).

[0324] Step 2: 4-Bromo-3-oxo-2,3-dihydro-1H-indazole-5-carbonitrile According to general procedure C, 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. to give the title compound. ([M+H,Br] + 240.0).

[0325] Step 3: 4-Bromo-3-hydroxy-1-trityl-1H-indazole-5-carbonitrile To 4-bromo-3-oxo-2,3-dihydro-1H-indazole-5-carbonitrile (Step 2) (180 mg, 0.8 mmol) in DMF (5 mL) at 0 °C under a nitrogen atmosphere was added sodium hydride (36 mg, 60% dispersion in mineral oil, 0.9 mmol) and triphenylmethyl chloride (232 mg, 0.8 mmol). The cooling bath was removed and the reaction was stirred for 2 h upon reaching ambient temperature. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 0:1 to 1:1) afforded the title compound (136 mg, 36%) as a white solid. ([M+Na] + 502.1).

[0326] Step 4: 3-hydroxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile Suzuki coupling of 4-bromo-3-hydroxy-1-trityl-1H-indazole-5-carbonitrile (step 3) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using cesium carbonate at 100 °C according to general procedure D afforded the title compound ([M+H] + 568.4) was prepared.

[0327] Step 5: 3-Methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile & 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile To a mixture of 3-hydroxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile (Step 3) (49 mg, 0.1 mmol) and potassium carbonate (48 mg, 0.3 mmol) in DMF (1 mL) was added 2-chloro-2,2-difluoromethyl acetate (20 μL, 0.2 mmol). The reaction was stirred in a sealed tube at 80 °C for 50 minutes. The reaction was diluted with ethyl acetate, washed with water, brine, dried (NaSO), and concentrated to give 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile as a crude mixture that was used directly.

[0328] Using general procedure H, the mixture of 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile & 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile (step 4) is deprotected to give the title compounds, which are separated by reverse phase preparative HPLC. ([M+H] + 342.2&378.2).

[0329] Example 70: 3-Cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000094.tif59170

[0330] Step 1: Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone According to General Procedure A, 2,4,6-trichloropyridine was deprotonated with LDA (0.9 eq) for 1 h and reacted with cyclopropanecarbaldehyde (1.2 eq) for 1.5 h to give crude cyclopropyl(2,4,6-trichloropyridin-3-yl)methanol, which was directly oxidized using General Procedure B1 to give the title compound. ([M+H,Cl] + 250.1)

[0331] Step 2: 4,6-Dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine According to general procedure C, cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone (step 1) was reacted with hydrazine hydrate (5 eq) in ethanol at ambient temperature to give the title compound. ([M+H,Cl] + 228.1).

[0332] Step 3: 3-Cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine Suzuki coupling of 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (step 2) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using potassium carbonate at 100 °C according to general procedure D afforded the title compound ([M+H] + 362.3) was prepared.

[0333] Step 4: 6-chloro-3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine Using general procedure E2, 6-chloro-3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (Step 3) (50 mg, 0.1 mmol) was SEM protected. The crude product was dissolved in 2M sodium methoxide in MeOH (2 mL) and the reaction was heated to 130° C. in a microwave for 30 minutes. The reaction mixture was concentrated and redissolved in trifluoroacetic acid (1 mL), ethylenediamine (0.1 ml, 1.4 mmol) was added, and the mixture was stirred for 1 hour. The reaction was concentrated and the residue was purified by reverse phase chromatography to give the title compound (3 mg, 5%) as a white solid. ([M+H] + 358.2).

[0334] Example 71: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine TIFF0007731381000095.tif57170

[0335] Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine To a mixture of 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol (Example 57, Step 3) (45 mg, 0.1 mmol) and potassium carbonate (35 mg, 0.3 mmol) in DMF (0.8 mL) was added 1-(trifluoromethyl)-113-benzo[d][1,2]iodoxol-3(1H)-one (40 mg, 0.3 mmol). After 16 h of reaction at ambient temperature, a second portion of potassium carbonate (35 mg, 0.3 mmol) and 1-(trifluoromethyl)-113-benzo[d][1,2]iodoxol-3(1H)-one (40 mg, 0.3 mmol) was added, and the mixture was stirred for an additional 16 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 0:1 to 1:4) afforded the title compound (12 mg, 22%) as a colorless gum. ([M+H] + 614.4).

[0336] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine Using general procedure H, 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (step 1) was deprotected to give the title compound. ([M+H] + 372.2).

[0337] Example 72: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000096.tif52170

[0338] Step 1: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid To a solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 62) (147 mg, 0.4 mmol) in dichloromethane (4 ml), 3,4-dihydro-2H-pyran (73 μl, 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 afforded the crude title compound (181 mg, quantitative yield) as a brown foam. ([M+H] + 456.3).

[0339] Step 2: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide To 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (45 mg, 0.1 mmol) in DMF (1 ml) was added TBTU (48 mg, 0.2 mmol), followed by triethylamine (41 μL, 0.3 mmol). After 0.5 h, ammonium hydroxide (39 μL, 1 mmol) was added and the mixture was stirred for 30 min. The reaction was concentrated and redissolved in HCl (0.5 ml, 4N in dioxane, 2 mmol), and the reaction was stirred at 50° C. for 6 h before being concentrated to dryness again. Purification by reverse-phase HPLC afforded the title compound (3 mg, 8%) as an off-white solid. ([M+H] + 371.3).

[0340] Example 73: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000097.tif54170

[0341] The title compound ([M+H]) was obtained from 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, Step 1) and methylamine hydrochloride in a manner similar to that of Example 72. + 385.3) was prepared.

[0342] Example 74: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyridazine TIFF0007731381000098.tif52170

[0343] Step 1: methyl 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate To a solution of methyl 3-cyclopropyl-1H-pyrazole-5-carboxylate (300 mg, 1.8 mmol) in dichloromethane (5 ml), 3,4-dihydro-2H-pyran (197 μl, 2.2 mmol) and p-toluenesulfonic acid monohydrate (35 mg, 0.2 mmol) were added and the reaction was stirred for 1 h. Concentration of the reaction and flash column chromatography (heptane:ethyl acetate 3:7) afforded the title compound (374 mg, 82%) as a colorless oil. ([M+H] + 251.1).

[0344] Step 2: (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol To a solution of methyl 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate (Step 1) (1.1 g, 4.6 mmol) in THF (34 ml) cooled to −78° C. under argon was added diisobutylaluminum hydride (9.11 ml, 1 M in THF, 9.1 mmol) and the mixture was stirred at that temperature for 30 minutes until it reached ambient temperature. The reaction was cooled again to −78° C., water (0.3 ml) was added, and the reaction was allowed to warm to ambient temperature again. Following the addition of NaSO, it was filtered and concentrated to give the title compound (670 mg, 63%) as a white solid. ([M+H] + 223.2).

[0345] Step 3: 3-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole To a solution of (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol (Step 2) (300 mg, 1.4 mmol) in DCM (5 ml) was added 3,4-dihydro-2H-pyran (136 μl, 1.6 mmol) and p-toluenesulfonic acid monohydrate (26 mg, 0.1 mmol), and the reaction was stirred for 16 h. Addition of a few drops of triethylamine, concentration of the reaction, and flash column chromatography (heptane:ethyl acetate 1:1) afforded the title compound (354 mg, 66%) as a light yellow oil. ([M+H] + 307.1).

[0346] Step 4: 3-cyclopropyl-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole To a solution of 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (Step 3) (402 mg, 1.3 mmol) in dichloromethane (2.5 ml) was added N-iodosuccinimide (413 mg, 1.8 mmol) and the reaction was stirred at ambient temperature for 20 h. The reaction was diluted with dichloromethane, washed with 10% aqueous sodium thiosulfate, water, brine, dried (Na2SO4), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:3) afforded the title compound (400 mg, 68%) as a yellow oil. ([M+H] + 433.1).

[0347] Step 5: (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol To an ice-cold solution of 3-cyclopropyl-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (Step 4) (50 mg, 0.1 mmol) in THF (0.2 ml) under an argon atmosphere was added isopropylmagnesium chloride·lithium chloride complex (98 μl, 1.3 M in THF, 0.1 mmol). The reaction was allowed to warm to ambient temperature for 5 min, then cooled again to 0° C. before being diluted with THF. The reaction was quenched with a solution of 3-methyl-4-(methylsulfonyl)benzaldehyde (28 mg, 0.1 mmol) dissolved in hexane (0.1 ml), and the reaction was then stirred at ambient temperature for 30 minutes. The reaction was diluted with ethyl acetate, washed with saturated ammonium chloride, water, brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:9 to 4:1) afforded the title compound (40 mg, 62%) as an off-white solid. ([M+H] + 505.4).

[0348] Step 6: (3-cyclopropyl-5-(hydroxymethyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol (3-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol (Step 5) (41 mg, 0.1 mmol) was dissolved in HCl (1.0 ml, 4N in dioxane, 4.1 mmol) and water (15 μl, 0.1 mmol) was added. The reaction was then stirred at 45° C. for 5 minutes before being concentrated to give the crude title compound (40 mg, quantitative yield) as a light yellow gum. ([M+H] + 337.2).

[0349] Step 7: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyridazine To a solution of (3-cyclopropyl-5-(hydroxymethyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol (Step 6) (30 mg, 0.1 mmol) in dichloromethane (0.4 ml) was added Dess-Martin periodinane (76 mg, 0.2 mmol) and the mixture was stirred at ambient temperature for 10 minutes. Hydrazine monohydrate (48 μl, 0.5 mmol) was then added and the reaction was stirred for an additional 16 hours. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, water, dried (NaSO), and concentrated. Flash column chromatography (DCM:MeOH 1:0 to 1:9) afforded the title compound (3 mg, 9%) as a light yellow solid. ([M+H] + 329.2).

[0350] Example 75: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole TIFF0007731381000099.tif51170

[0351] Step 1: (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanol According to general procedure A, (2-bromo-4-fluorophenyl)(methyl)sulfane was reacted with LDA (1.1 eq) for 1 h, followed by the addition of cyclopropanecarbaldehyde (1.2 eq). 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).

[0352] Step 2: (2-Bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanone Using General Procedure B1, (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanol (Step 1) was oxidized to give the title compound. ([M+H,Br] + 291.0)

[0353] Step 3: Cyclopropyl(3-fluoro-3'-methyl-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone Suzuki coupling of 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (step 2) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using cesium carbonate at 100 °C according to general procedure D afforded the title compound ([M+H] + 379.2) was prepared.

[0354] Step 4: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole According to general procedure C, cyclopropyl(3-fluoro-3'-methyl-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone (step 2) was reacted with hydrazine hydrate (15 eq) in ethanol at 150°C (microwave) to give the title compound. ([M+H] + 373.2).

[0355] Example 76: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfinyl)-1H-indazole TIFF0007731381000100.tif55170

[0356] To an ice-cold solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole (Example 74) (23 mg, 0.1 mmol) in DCM (1 ml) was added a solution of m-chloroperbenzoic acid (124 μl, 0.5 M in DCM, 0.1 mmol), and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, dried (NaSO), and concentrated. Flash column chromatography (DCM:MeOH 1:0 to 1:9) afforded the title compound (15 mg, 59%) as a white solid. ([M+H] + 389.2).

[0357] Example 77: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole TIFF0007731381000101.tif62170

[0358] To an ice-cold solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole (Example 74) (26 mg, 0.1 mmol) in DCM (1 ml) was added a solution of m-chloroperbenzoic acid (263 μl, 0.5 M in DCM, 0.1 mmol), and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, water, dried (NaSO), and concentrated. Flash column chromatography (DCM:MeOH 1:0 to 1:9) afforded the title compound (18 mg, 61%) as a white solid. ([M+H] + 405.2).

[0359] Example 78: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one TIFF0007731381000102.tif51170

[0360] Step 1: 3-iodo-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine To an ice-cold solution of 3-iodo-5-methoxy-1H-pyrazolo[4,3-b]pyridine (WO 2018 / 11628) (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 ambient temperature and stirred for 3 h. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:10) afforded the title compound (0.9 g, 46%) as a white solid. ([M+Na] + 518.0).

[0361] Step 2: 5-Methoxy-1-trityl-pyrazolo[4,3-b]pyridin-3-ol A mixture of 3-iodo-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine (Step 1) (50 mg, 0.1 mmol), potassium hydroxide (16 mg, 0.3 mmol), t-BuBrettPhos (8 mg, 0.02 mmol), t-BuBrettPhos Pd G3 (10 mg, 0.02 mmol) in dioxane (2 mL) and water (0.5 mL) was stirred at 80° C. under a nitrogen atmosphere for 18 h. The reaction mixture was filtered and concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (20 mg, 51%) as a white solid. ([M+Na] + 408.1)

[0362] 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), and cesium carbonate (640 mg, 2.0 mmol) in acetonitrile (20 mL) was stirred for 2 h at 50° C. The reaction mixture was filtered and concentrated.

[0363] Purification by reverse-phase preparative HPLC afforded the title compound (400 mg, 89%) as a yellow solid. ([M+H] + 458.1)

[0364] Step 4: 3-(Difluoromethoxy)-1,3a,4,7a-tetrahydropyrazolo[4,3-b]pyridin-5-one 3-(Difluoromethoxy)-5-methoxy-1-trityl-pyrazolo[4,3-b]pyridine (Step 3) (300 mg, 0.7 mmol) was dissolved in HCl (15 mL, 4N in dioxane, 60 mmol) and stirred at 80° C. for 3 h. The reaction mixture was concentrated to dryness and purified by reverse-phase preparative HPLC to give the title compound (100 mg, 75%) as a gray solid. ([M+H] + 202.1)

[0365] Step 5: 3-(Difluoromethoxy)-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one A mixture of 3-(difluoromethoxy)-1,4-dihydropyrazolo[4,3-b]pyridin-5-one (200 mg, 1.0 mmol), 3,4-dihydro-2H-pyran (0.14 mL, 1.5 mmol), and p-toluenesulfonic acid monohydrate (86 mg, 0.5 mmol) in THF (5 mL) was stirred at 60° C. for 12 h, after which the reaction was concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (150 mg, 52%) as a white solid. ([M+H] + 286.0)

[0366] Step 6: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one To a solution of 3-(difluoromethoxy)-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one (step 5) (100 mg, 0.4 mmol) in dichloromethane (3 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol), pyridine (0.06 mL, 0.7 mmol), triethylamine (0.1 mL, 0.7 mmol), and copper(II) acetate (128 mg, 0.7 mmol) and the reaction was stirred under air at ambient temperature. 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, then the reaction was diluted with ethyl acetate, washed with water, brine, dried (NaSO), and concentrated. Reverse-phase preparative HPLC afforded the title compound (7 mg, 44%) as a brown solid. ([M+H] + 454.1).

[0367] Step 5: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one Using general procedure I1, 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (step 4) was deprotected to give the title compound. ([M+H] + 370.1).

[0368] Example 79: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine TIFF0007731381000103.tif55170

[0369] Step 1: (3-Bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanone According to General Procedure A, 3-bromo-5-fluoro-2-(trifluoromethyl)pyridine was reacted with LDA (1.1 eq) for 1 h, followed by the addition of cyclopropanecarbaldehyde (1.2 eq) to give crude (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanol, which was directly oxidized using General Procedure B1 to give the title compound. ([M+H,Br] + 312.1)

[0370] Step 2: Cyclopropyl(5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)pyridin-4-yl)methanone Suzuki coupling of (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanone (step 1) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using potassium carbonate at 100 °C according to general procedure D to give the title compound ([M+H] + 402.2) was prepared.

[0371] Step 3: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine According to general procedure C, 3-cyclopropyl(5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)pyridin-4-yl)methanone (step 2) was reacted with hydrazine hydrate (5 eq) in THF at ambient temperature to give the title compound. ([M+H] + 396.2).

[0372] Example 80: 3-Cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one TIFF0007731381000104.tif57170

[0373] Step 1: 3-iodo-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine To a solution of 3-iodo-5-methoxy-1H-pyrazolo[4,3-b]pyridine (WO 2018 / 11628) (1.6 g, 5.8 mmol) in dichloromethane (40 mL) was added 3,4-dihydro-2H-pyran (3.0 g, 35.6 mmol) and p-toluenesulfonic acid monohydrate (100.0 mg, 0.6 mmol), and the mixture was stirred at ambient temperature for 15 h. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried (NaSO), and concentrated. Flash column chromatography (heptane:ethyl acetate 7:3) afforded the title compound (1.8 g, 82%) as a brown viscous oil. ([M+H] + 359.9).

[0374] Step 2: 3-Cyclopropyl-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine Suzuki coupling of 3-iodo-5-methoxy-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine (step 1) with cyclopropylboronic acid (8 eq) using potassium carbonate (4 eq) at 100 °C according to general procedure D gave the title compound ([M+H] + 274.0) was prepared.

[0375] 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 to 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) were added, 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 bicarbonate, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate) afforded the title compound (170 mg, 62%) as a colorless viscous oil. ([M+H] + 260.3).

[0376] Step 4: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one To a solution of 3-(difluoromethoxy)-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one (step 3) (100 mg, 0.4 mmol) in DCM (3 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (150 mg, 0.7 mmol), pyridine (0.06 mL, 0.7 mmol), triethylamine (0.1 mL, 0.7 mmol), and copper(II) acetate (128 mg, 0.7 mmol) and the reaction was stirred under air at ambient temperature. 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, then 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, and the reaction was diluted with ethyl acetate, washed with water, brine, dried (NaSO), and concentrated. Purification by preparative TLC (ethyl acetate) provided the title compound (90 mg, 50%) as a brown gum. ([M+H] + 428.1).

[0377] Step 5: 6-Bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one To a solution of 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (50 mg, 0.09 mmol) (step 4) in DMF (2.5 mL) was added N-bromosuccinimide (33 mg, 0.2 mmol). After stirring the reaction for 24 h, the reaction was diluted with ethyl acetate, washed with water, brine, dried (NaSO), and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:1) afforded the title compound (40 mg, 68%) as a white solid. ([M+H,Br] + 506.0).

[0378] Step 6: 3-Cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one Suzuki coupling of 6-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (step 5) with trimethylboroxine using potassium carbonate at 100 °C according to general procedure D to give the title compound ([M+H] + 422.1) was prepared.

[0379] Step 7: 3-Cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one Using general procedure I1, 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (step 6) was deprotected to give the title compound. ([M+H] + 358.1).

[0380] Example 81: 3,6-Dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one TIFF0007731381000105.tif53170

[0381] Step 1: 3,6-Dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one Suzuki coupling of 6-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one (Example 81, step 5) with cyclopropylboronic acid (10 eq) using potassium carbonate (4 eq) at 100° C. according to general procedure D to give the title compound ([M+H] +468.1) was prepared.

[0382] Step 2: 3-Cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine Using general procedure I1, 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-one was deprotected to give the title compound. ([M+H] + 384.2).

[0383] Example 82: 3-Cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine TIFF0007731381000106.tif54170

[0384] Step 1: (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanol Following general procedure A, 3-bromo-2-(difluoromethoxy)-5-fluoropyridine was reacted with LDA (1.2 eq) for 1 h, followed by the addition of cyclopropanecarbaldehyde (3 eq) to give the title compound. ([M+H, Br] + 312.1).

[0385] Step 2: (3-Bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanone (3-Bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanol (Step 1) was directly oxidized using General Procedure B1 to give the title compound. 1H NMR (chloroform-d, 300 MHz) δ 8.06 (s, 1H), 7.61 (s, 0.25H), 7.37 (s, 0.5H), 7.13 (s, 0.25H), 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).

[0386] Step 3: Cyclopropyl(2-(difluoromethoxy)-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone Suzuki coupling of (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanone (step 2) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using potassium carbonate at 90 °C according to general procedure D to give the title compound ([M+H] + 400.3) was prepared.

[0387] Step 4: 3-Cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine According to general procedure C, cyclopropyl(2-(difluoromethoxy)-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone (step 3) was reacted with hydrazine hydrate (5 eq) in THF at ambient temperature to give the title compound. ([M+H] + 394.4).

[0388] Example 83: 3-Cyclopropyl-N,N-dimethyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000107.tif54170

[0389] The title compound ([M+H]) was obtained from 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, Step 1) and dimethylamine hydrochloride in a manner similar to that of Example 72. + 399.3) was prepared.

[0390] Example 84: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000108.tif51170

[0391] The title compound ([M+H]) was obtained from 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, Step 1) and 3-oxetanamine in a similar manner to Example 72. + 425.4) was prepared.

[0392] Example 85: 3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000109.tif49170

[0393] Step 1: 3-chloro-2-cyclopropyl-5-fluoropyridine 2-Bromo-3-chloro-5-fluoropyridine (300 mg, 1.4 mmol), potassium cyclopropyltrifluoroborate (232 mg, 1.6 mmol), palladium(II) acetate (6 mg, 29 μmol), and butyldi-1-adamantylphosphine (31 mg, 86 μmol), and cesium carbonate (1.4 g, 4.3 mmol) in a mixture of toluene (10 ml) and water (1.5 ml) was evacuated and filled with argon. The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was filtered directly through Dicalite®, washed with ethyl acetate, and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:9) afforded the title compound (81 mg, 31%) as a colorless oil. ([M+H] + 172.0).

[0394] Step 2: (3-chloro-2-cyclopropyl-5-fluoropyridin-4-yl)(cyclopropyl)methanone According to General Procedure A, 3-chloro-2-cyclopropyl-5-fluoropyridine was reacted with LDA (1.1 eq) for 1 h, followed by the addition of cyclopropanecarbaldehyde (1.2 eq) to give crude (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanol, which was directly oxidized using General Procedure B1 to give the title compound. ([M+H,Cl] + 240.1)

[0395] Step 3: Cyclopropyl(2-cyclopropyl-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone Suzuki coupling of (3-bromo-2(3-chloro-2-cyclopropyl-5-fluoropyridin-4-yl)(cyclopropyl)methanone (step 2) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using potassium carbonate at 120 °C according to general procedure D gave the title compound ([M+H] + 374.2) was prepared.

[0396] Step 4: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide According to general procedure C, cyclopropyl(2-cyclopropyl-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone (step 3) was reacted with hydrazine hydrate (100 eq) in THF at 170° C. (microwave) to give the title compound. ([M+H] + 368.2).

[0397] Example 86: N,3-Dicyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000110.tif52170

[0398] The title compound ([M+H]) was obtained from 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 72, Step 1) and cyclopropylamine in a similar manner to Example 72. + 425.4) was prepared.

[0399] Example 87: 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide TIFF0007731381000111.tif59170

[0400] Step 1: 6-chloro-2,4-difluoro-3-(triethylsilyl)benzonitrile To a solution of 2-chloro-4,6-difluorobenzonitrile (100 mg, 0.6 mmol) dissolved in THF (2 ml) cooled to -78 °C under Ar, LDA (0.3 ml, 0.7 mmol) was added, and the mixture was stirred for 5 min. After that, chlorotrimethylsilane (0.1 ml, 0.6 mmol) was added, and the reaction was stirred for an additional 30 min. The reaction was quenched by the addition of saturated aqueous ammonium chloride, allowed to reach ambient temperature, extracted with ethyl acetate, dried (Na SO ), and concentrated. Flash column chromatography (heptane) afforded the title compound (127 mg, 73%) as a colorless oil. H NMR (chloroform-d, 300 MHz) δ 7.03 (dd, 1H, J=1.4, 8.1 Hz), 0.9-1.0 (m, 15H).

[0401] Step 2: 2-chloro-3-(cyclopropyl(hydroxy)methyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile Following general procedure A, 6-chloro-2,4-difluoro-3-(triethylsilyl)benzonitrile (Step 1) was reacted with LDA (1.2 eq) for 0.25 h, followed by the addition of cyclopropanecarbaldehyde (1.3 eq) to give the title compound. ([M+H,Cl] + 381.2).

[0402] Step 3: 2-chloro-3-(cyclopropanecarbonyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile Using general procedure B1, 2-chloro-3-(cyclopropyl(hydroxy)methyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile (step 2) was oxidized to give the title compound. 1H NMR (chloroform-d, 300 MHz) δ 2.22 (dtt, 1H, J=1.3, 4.5, 7.8 Hz), 1.37 (t, 2H, J=3.9 Hz), 1.1-1.2 (m, 2H), 0.9-1.0 (m, 15H).

[0403] Step 4: 6-(Cyclopropanecarbonyl)-3,5-difluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile Suzuki coupling of 2-chloro-3-(cyclopropanecarbonyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile (step 3) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using potassium carbonate at 120 °C according to general procedure D afforded the title compound ([M+H] + 376.4) was prepared.

[0404] Step 5: 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide According to general procedure C, 6-(cyclopropanecarbonyl)-3,5-difluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile (step 4) was reacted with hydrazine hydrate (2 eq) in THF at ambient temperature to give the title compound. ([M+H] + 370.2).

[0405] Examples 88 & 89: 3-Cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide & 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000112.tif53170

[0406] 3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile (Example 87) (20 mg, 54 μmol) was suspended in sodium hydroxide (3 mL, 3 M in water, 9 mmol) and heated to 150° C. in a microwave for 4.5 h. The reaction was acidified with 6 N hydrochloric acid, extracted with ethyl acetate, and the combined organic layers were dried (NaSO) and concentrated to give a crude mixture of 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide and 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (1:1). Reaction with ethylamine hydrochloride, prepared similarly to Example 72, followed by reverse phase preparative HPLC afforded the two title compounds. ([M+H] + 402.3&388.2).

[0407] Example 90: 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile TIFF0007731381000113.tif68170

[0408] Step 1: 2,6-Dichloro-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile Following general procedure A, 2,6-dichloro-4-fluorobenzonitrile was reacted with LDA (1.0 eq) for 1 h, followed by the addition of cyclopropanecarbaldehyde (1.2 eq) to give the title compound. ([M-HO,2Cl] + 242.1).

[0409] Step 2: 2,6-Dichloro-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile Using general procedure B1, 2,6-dichloro-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile (Step 1) was oxidized to give the title compound. ([M+H, 2Cl]+ 258.1).

[0410] Step 3: 3-chloro-6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile Suzuki coupling of 2-chloro-32,6-dichloro-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile (step 2) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using cesium carbonate at 100 °C according to general procedure D afforded the title compound ([M+H] + 392.2) was prepared.

[0411] Step 4: 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile According to general procedure C, 3-chloro-6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile (step 3) was reacted with hydrazine hydrate (15 eq) in THF at ambient temperature to give the title compound. ([M+H,Cl] + 386.2).

[0412] Example 91: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one TIFF0007731381000114.tif53170

[0413] 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 potassium carbonate (438 mg, 3.2 mmol) and 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1001 mg, 3.2 mmol). After the mixture was stirred at 25 °C for 16 h, a second portion of potassium carbonate (438 mg, 3.2 mmol) and 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1001 mg, 3.2 mmol) was added, and the reaction was stirred for an additional 12 h. The reaction was diluted with water and repeatedly extracted with ethyl acetate. The combined organic layer was washed with brine, dried (NaSO), and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:10) afforded the title compound (110 mg, 21%) as a white solid. ([M+H] + 476.1).

[0414] Step 2: 3-(trifluoromethoxy)-1-trityl-4H-pyrazolo[4,3-b]pyridin-5-one A solution of 5-methoxy-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridine (Step 1) (110 mg, 0.2 mmol) in 4 M HCl in dioxane (20.0 mL, 80 mmol) was stirred at 80° C. for 24 h. The reaction was concentrated and purification by preparative TLC (heptane:ethyl acetate 1:1) afforded the title compound (60 mg, 53%) as a white solid. ([M+H] + 462.1).

[0415] Step 3: 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridin-5-one To a solution of 3-(trifluoromethoxy)-1-trityl-4H-pyrazolo[4,3-b]pyridin-5-one (Step 2) (55 mg, 0.1 mmol) in DCM (4 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (51 mg, 0.2 mmol), pyridine (0.02 mL, 0.2 mmol), triethylamine (0.03 mL, 0.2 mmol), and copper(II) acetate (43 mg, 0.2 mmol), and the reaction was stirred at ambient temperature under an oxygen atmosphere (balloon). After 12 h, an additional portion of (3-methyl-4-methylsulfonyl-phenyl)boronic acid (51 mg, 0.2 mmol), pyridine (0.02 mL, 0.2 mmol), and triethylamine (0.03 mL, 0.2 mmol) was added, and the mixture was stirred for an additional 12 h, after which the reaction was diluted with ethyl acetate and filtered. Purification by preparative TLC afforded the title compound (90 mg, 63%) as a white solid. ([M+H] + 630.1).

[0416] Step 4: 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one Using general procedure I1, 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1-trityl-pyrazolo[4,3-b]pyridin-5-one was deprotected to give the title compound. ([M+H] + 388.1).

[0417] Example 92: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-5-one TIFF0007731381000115.tif61170

[0418] Step 1: 3-Bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridine To a solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (1.0 g, 6.75 mmol, 1 eq) in DMF (20 mL) at 25 °C was added N-bromosuccinimide (1.4 g, 7.1 mmol), and the reaction mixture was stirred at ambient temperature for 16 h. The reaction was diluted with water and repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Flash column chromatography (ethyl acetate:n-heptane = 0:1 to 1:8) afforded the title compound (1.2 g, 76%) as a white solid. ([M+H, Br] + 227.0).

[0419] Step 2: 2-[(3-bromo-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane Using general procedure E1, 3-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridine (step 1) was converted to the title compound in THF. ([M+H,Br] + 357.1)

[0420] Step 3: 2-[(3-cyclopropyl-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane Suzuki coupling of 2-[(3-bromo-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (step 2) with cyclopropylboronic acid (10 eq) using potassium carbonate (8 eq) at 100 °C according to general procedure D gave the title compound ([M+H] + 319.2) was prepared.

[0421] Step 4: 3-Cyclopropyl-1-(methoxymethyl)-4H-pyrrolo[3,2-b]pyridin-5-one A solution of 2-[(3-cyclopropyl-5-methoxy-pyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (Step 3) (320 mg, 1 mmol) in 4 M HCl in dioxane (20.0 mL, 80 mmol) was stirred at 90° C. for 5 h. The reaction was concentrated and purification by preparative TLC (heptane:ethyl acetate 1:1) afforded the title compound (140 mg, 58%) as an off-white solid. ([M+H] + 219.1).

[0422] Step 5: 3-Cyclopropyl-1-(methoxymethyl)-4-(3-methyl-4-methylsulfonyl-phenyl)pyrrolo[3,2-b]pyridin-5-one To a solution of 3-cyclopropyl-1-(methoxymethyl)-4H-pyrrolo[3,2-b]pyridin-5-one (step 4) (140 mg, 0.6 mmol) in dichloromethane (6 mL) was added (3-methyl-4-methylsulfonyl-phenyl)boronic acid (250 mg, 1.2 mmol), pyridine (0.09 mL, 1.2 mmol), triethylamine (0.16 mL, 1.2 mmol), and copper(II) acetate (212 mg, 1.2 mmol) and the reaction was stirred under an oxygen atmosphere (balloon) at ambient temperature. 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 mixture was stirred for an additional 2 h, after which a third, identical re-addition of boronic acid and triethylamine was added, and the reaction was stirred for an additional 12 h. The reaction mixture was then filtered and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:1) afforded the title compound (170 mg, 68%) as a yellow solid. ([M+H] + 387.1).

[0423] Step 6: 3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-5-one Using general procedure J, 3-cyclopropyl-1-(methoxymethyl)-4-(3-methyl-4-methylsulfonyl-phenyl)pyrrolo[3,2-b]pyridin-5-one (step 5) was deprotected to give the title compound. ([M+H] + 343.2).

[0424] Example 93: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole TIFF0007731381000116.tif55170

[0425] Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol Suzuki coupling of 4-bromo-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol (Intermediate 16, Step 4) with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using potassium carbonate at 100 °C according to general procedure D to give the title compound ([MH] + 621.5) was prepared.

[0426] Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1-trityl-1H-indazole To a solution of 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol (Step 1) (206 mg, 0.3 mmol) in DMF (3 mL) was added potassium carbonate (137 mg, 1.0 mmol) and 1-(trifluoromethyl)-113-benzo[d][1,2]iodoxol-3(1H)-one (165 mg, 0.5 mmol), and the mixture was stirred at ambient temperature for 18 h. The reaction was concentrated to dryness, suspended in ethyl acetate, washed with water, dried (NaSO), and concentrated. Flash column chromatography (heptane:ethyl acetate 1:9 to 0:1) afforded the title compound (46 mg, 20%) as a white solid. ([M+NH4 + ] + 708.5)

[0427] Step 3: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole Using general procedure I1, 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1-trityl-1H-indazole (step 2) was deprotected to give the title compound. ([M+H] + 449.2).

[0428] Example 94: 3-Cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole TIFF0007731381000117.tif54170

[0429] Step 1: Cyclopropyl(3'-(difluoromethyl)-3-fluoro-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone Suzuki coupling of (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanone (Example 75, Step 2) with 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 21) using potassium carbonate at 100 °C according to general procedure D to afford the title compound ([M+H] + 415.2) was prepared.

[0430] Step 2: Cyclopropyl(3'-(difluoromethyl)-3-fluoro-4',6-bis(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methanone Using general procedure G, cyclopropyl(3'-(difluoromethyl)-3-fluoro-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone (Step 1) is converted to the title compound. ([M+H] + 447.3).

[0431] Step 3: 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole According to general procedure C, cyclopropyl(3'-(difluoromethyl)-3-fluoro-4',6-bis(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methanone (step 2) was reacted with hydrazine hydrate (2 eq) in THF at ambient temperature to give the title compound. ([M+H] + 441.2).

[0432] Example 95: 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000118.tif59170

[0433] Step 1: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid To a solution of 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 52) (100 mg, 0.3 mmol) in water (4 mL) was added sodium hydroxide (1.0 mL, 6 N, 6 mmol) and the reaction was heated to 100° C. for 10 h. The reaction mixture was cooled to 0° C., acidified with concentrated aqueous HCl, extracted repeatedly with ethyl acetate, and the combined organic layers were dried (NaSO) and concentrated to give the title compound (100 mg, 95%) was obtained as a yellow solid. ([M+H] + 398.0)

[0434] Step 2: 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide The title compound ([M+H]) was obtained from 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Step 4) and methylamine hydrochloride in a manner similar to Example 72. + 411.1) was prepared.

[0435] Example 96: 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000119.tif58170

[0436] Step 1: 1-Bromo-4-cyclopropylsulfanyl-2-fluoro-5-methyl-benzene To a stirred suspension of potassium tert-butoxide (61 mg, 0.5 mmol) in DMSO (1 mL) was added 4-bromo-5-fluoro-2-methyl-benzenethiol (CAS: 1208077-77-3) (100 mg, 0.5 mmol) and cyclopropyl bromide (164 mg, 1.4 mmol), and the reaction was heated to 100 °C for 12 h. The reaction was repeatedly extracted with ethyl acetate, and the combined organic layers were dried (NaSO) and concentrated. Purification by preparative TLC (heptane) afforded the title compound (60 mg, 51%) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ = 7.29 (d, J = 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)

[0437] Step 2: 1-Bromo-4-cyclopropylsulfonyl-2-fluoro-5-methyl-benzene Using general procedure G, 1-bromo-4-cyclopropylsulfanyl-2-fluoro-5-methyl-benzene (Step 1) is converted to the title compound. ([M+H] + 293.0).

[0438] Step 3: 2-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Using general procedure F, 1-bromo-4-cyclopropylsulfonyl-2-fluoro-5-methyl-benzene (step 2) is converted to the title compound. ([M+H] + 258.9).

[0439] Step 4: 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 17), 2-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (step 4) using potassium carbonate and 1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.5 eq) at 120° C. according to general procedure D gave the title compound ([M+H] + 397.2) was prepared.

[0440] Step 5: 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid To a solution of 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Step 4) (20 mg, 0.1 mmol) in water (0.2 mL) was added sodium hydroxide (0.05 mL, 6N, 0.3 mmol) and the reaction was heated to 100° C. for 38 h. The reaction mixture was cooled to 0° C., acidified with concentrated aqueous HCl, extracted repeatedly with ethyl acetate, and the combined organic layers were dried (NaSO) and concentrated to give the title compound (20 mg, 95%). ([M+H] + 416.1)

[0441] Step 6: 3-Cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide The title compound ([M+H]) was obtained from 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Step 5) and methylamine hydrochloride in analogy to Example 72. + 429.1) was prepared.

[0442] Example 97: 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000120.tif50170

[0443] Step 1: 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid To a suspension of 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 47) (50 mg, 0.1 mmol) in water (0.6 mL) was added sodium hydroxide (0.1 mL, 0.8 mmol). The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to 0° C., acidified with concentrated aqueous HCl, extracted repeatedly with ethyl acetate, and the combined organic layers were dried (NaSO) and concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (20 mg, 34%) as a gray foam. ([M+H] + 390.0)

[0444] Step 2: 3-Cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide The title compound ([M+H]) was obtained from 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Step 1) and methylamine hydrochloride in a manner similar to Example 72. + 403.1) was prepared.

[0445] Example 98: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000121.tif52170

[0446] To a solution of 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 52) (100 mg, 0.3 mmol) in ethanol (4 mL) was added sodium hydroxide (0.7 mL, 6N, 0.3 mmol) and the reaction was heated to 100° C. for 12 h. The reaction mixture was concentrated and the residue was purified by reverse-phase preparative HPLC to afford the title compound (28 mg, 26%) as a white solid. ([M+H] + 397.1)

[0447] Example 99: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide; Formate TIFF0007731381000122.tif92170

[0448] Step 1: 7-Bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine To a solution of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine (Example 64, Step 1) (100 mg, 0.3 mmol) in THF (1 mL) was added p-toluenesulfonic acid monohydrate (13 mg, 0.1 mmol) and dihydropyran (0.07 mL, 0.7 mmol), and the reaction solution was stirred at 60 °C for 12 h. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried (NaSO) and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:1) afforded the title compound (60 mg, 50%) as a yellow oil. ([M+H, Br] + 490.0)

[0449] Step 2: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (332 mg, 1.0 mmol), N-[2-(2-aminoethoxy)ethyl]acetamide (179 mg, 1.2 mmol), Xantphos (14 mg, 0.02 mmol), and Pd(OAc) (4.6 mg, 0.02 mmol) and stirred at 80 °C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (40 mg, 34%) as a yellow solid. ([M+H] + 556.2)

[0450] Step 3: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide; formate Using general procedure I1, N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide (step 2) was deprotected to give the title compound. ([M+H] + 472.3).

[0451] Example 100: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide; Formate TIFF0007731381000123.tif82170

[0452] Step 1: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Example 99, Step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (3 mL), cesium carbonate (332 mg, 1.0 mmol), N-(3-aminopropyl)acetamide (118 mg, 1.0 mmol), Xantphos (14 mg, 0.02 mmol), and Pd(OAc) (5 mg, 0.02 mmol) were added and stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (60 mg, 56%) as a yellow solid. ([M+H] + 526.0)

[0453] Step 2: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide; formic acid Using general procedure I1, N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]]propyl]acetamide (Step 1) was deprotected to give the title compound. ([M+H] + 441.9).

[0454] Example 101: N-[2-(2-aminoethoxy)ethyl]-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-amine; formic acid TIFF0007731381000124.tif85170

[0455] Step 1: tert-butyl N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]carbamate To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Example 99, Step 1) (120 mg, 0.2 mmol) in 1,4-dioxane (4 mL), cesium carbonate (399 mg, 1.2 mmol), N-Boc-2-(2-amino-ethoxy)-ethylamine (150 mg, 0.7 mmol), Xantphos (17 mg, 0.03 mmol), and Pd(OAc) (5 mg, 0.02 mmol) were added and stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (98 mg, 62%) as a yellow solid. ([M+H] + 614.2)

[0456] Step 2: N-[2-(2-aminoethoxy)ethyl]-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-amine; formate salt Using general procedure I1, tert-butyl N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]carbamate (Step 1) was deprotected to give the title compound. ([M+H] + 430.1).

[0457] Example 102: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]butane-1,4-diamine TIFF0007731381000125.tif78170

[0458] Step 1: tert-butyl N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]carbamate To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Example 99, Step 1) (130 mg, 0.3 mmol) in 1,4-dioxane (4 mL), 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) (6 mg, 0.03 mmol) were added and stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (90 mg, 56%) as a yellow solid. ([M+H] + 598.2)

[0459] Step 2: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]butane-1,4-diamine Using general procedure I1, tert-butyl N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]]butyl]carbamate (step 1) was deprotected to give the title compound. ([M+H] + 414.1).

[0460] Example 103: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide TIFF0007731381000126.tif88170

[0461] Step 1: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Example 99, Step 1) (80 mg, 0.2 mmol) in 1,4-dioxane (2 mL), cesium carbonate (266 mg, 0.8 mmol), N-(4-aminobutyl)acetamide (106 mg, 0.8 mmol), Xantphos (11 mg, 0.02 mmol), and Pd(OAc) (4 mg, 0.02 mmol) were added and stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (60 mg, 68%) as a yellow solid. ([M+H] + 540.1)

[0462] Step 2: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide Using general procedure I1, N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]]butyl]acetamide (Step 1) was deprotected to give the title compound. ([M+H] + 499.9).

[0463] Example 104: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]propane-1,3-diamine TIFF0007731381000127.tif75170

[0464] Step 1: tert-butyl N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]carbamate To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (Example 99, Step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (4 mL), cesium carbonate (332 mg, 1.0 mmol), N-Boc-1,3-diaminopropane (107 mg, 0.6 mmol), Xantphos (14 mg, 0.02 mmol), and Pd(OAc) (5 mg, 0.02 mmol) were added and stirred at 80° C. for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reverse-phase preparative HPLC afforded the title compound (50 mg, 42%) as a brown oil. ([M+H] + 584.4)

[0465] Step 2: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]propane-1,3-diamine Using general procedure I1, N tert-butyl N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]carbamate (step 1) was deprotected to give the title compound. ([M+H] + 399.9).

[0466] Example 105: 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile TIFF0007731381000128.tif57170

[0467] Step 1: 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 17), 2-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (step 4) using potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.05 eq) at 100° C. according to general procedure D gave the title compound ([M+formate] - 701.3) was prepared.

[0468] Step 2: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile General procedure H was used to deprotect 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile to give the title compound ([M+H]) after flash column chromatography. + 415.2).

[0469] Example 106: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000129.tif57170

[0470] Step 1: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide To a solution of 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 105, Step 1) (295 mg, 0.45 mmol) in dimethyl sulfoxide (3.5 mL) was added potassium carbonate (12.4 mg, 0.09 mmol), followed by the dropwise addition of 35% aqueous hydrogen peroxide (153 μL, 10.23 mmol). The reaction was stirred for 16 h and then diluted with water, causing the product to precipitate. The suspension was allowed to settle, filtered, and the filter cake was washed with water and dried to give the title product compound (325 mg, quantitative yield) as an off-white powder. ([M+H] + 675.3)

[0471] Step 2: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide General procedure H was used to deprotect 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide to give the title compound ([M+H]) after flash column chromatography. + 433.2).

[0472] Example 107: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000130.tif57170

[0473] Step 1: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide (150 mg, 0.22 mmol) was dissolved in acetonitrile (5 mL) and heated to 80° C. tert-Butyl nitrite (132 μL, 1.11 mmol) was added and the mixture was stirred for 4 hours, after which the mixture was evaporated to dryness to give the crude title compound (208 mg) as an orange foam, which was used in the next step without further purification. ([M+H] + 434.2)

[0474] Step 2: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide The title compound ([M+H]) was obtained from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Step 1) and oxetan-3-ylamine in analogy to Example 72. + 489.2) was prepared.

[0475] Example 108: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000131.tif56170

[0476] The title compound ([M+H]) was obtained from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 107, Step 1) and methylamine hydrochloride in a manner analogous to Example 72. + 447.1) was prepared.

[0477] Example 109: 3-(Difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000132.tif57170

[0478] The title compound ([M+H]) was obtained 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 in a similar manner to Example 72. + 447.1) was prepared.

[0479] Example 110: 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000133.tif50170

[0480] Step 1: 3-(Difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid To 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 52) (238 mg, 0.6 mmol) was added 6N sodium hydroxide (2.5 mL) and the reaction was heated to 100° C. for 2.5 h, then diluted with water (9 mL) and continued heating at 90° C. for 36 h. The reaction was cooled to 0° C., acidified with 25% hydrochloric acid, and the product was isolated by filtration to give the title compound (92 mg, 30%) as a light brown solid. ([M+H] + 398.2)

[0481] Step 2: 3-(Difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide The title compound ([M+H]) was obtained from 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Step 1) and methylamine hydrochloride in a manner similar to Example 72. + 411.3) was prepared.

[0482] Example 111: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole TIFF0007731381000134.tif52170

[0483] Step 1: 3-(2-bromo-4-fluoro-phenyl)sulfanyloxetane To a stirred suspension 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 reaction was heated to 100 °C for 5 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:10 to 1:3) afforded 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, 1H).

[0484] Step 2: 2-bromo-6-fluoro-3-(oxetan-3-ylsulfanyl)benzoate ethyl According to general procedure A, 3-(2-bromo-4-fluoro-phenyl)sulfanyloxetane (Step 1) was deprotonated with LDA (1.1 eq) for 30 min and reacted with ethyl chloroformate (1.2 eq) to give 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).

[0485] Step 3: 2-bromo-6-fluoro-3-(oxetan-3-ylsulfonyl)benzoate ethyl 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) was added mCPBA (6.2 g, 30.6 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction was diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:1 to 1:1) afforded 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).

[0486] Step 4: 4-Bromo-5-(oxetan-3-ylsulfonyl)-1,2-dihydroindazol-3-one To an ice-cold solution of ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfonyl)benzoate (Step 3) (4.6 g, 12.5 mmol) in ethanol (40 mL) was added hydrazine monohydrate (689 μL, 13.9 mmol) followed by triethylamine (2.1 mL, 15.0 mmol), and the reaction was allowed to warm to ambient temperature. After heating to 80° C. for 2 h, the reaction was concentrated to dryness. Reverse-phase preparative HPLC afforded the title compound (2.8 g, 67%) as a light yellow solid. ([M+H, Br] + 335.0).

[0487] Step 5: 4-Bromo-5-(oxetan-3-ylsulfonyl)-1-trityl-indazol-3-ol 4-Bromo-5-(oxetan-3-ylsulfonyl)-1,2-dihydroindazol-3-one in DMF (30 ml) To an ice-cold solution of (step 4) (2.7 g, 8.1 mmol), trityl chloride (2.5 g, 8.9 mmol) was added followed by sodium hydride (389 mg, 60% dispersion in mineral oil, 9.7 mmol). The cooling bath was removed and the reaction was stirred at ambient temperature for 1 h. The reaction was then diluted with ethyl acetate, washed with water, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:3 to 1:0) afforded the title compound (4.1 g, 65%) as a colorless solid. ([M+Na+,Br] + 599.1).

[0488] Step 6: 4-Bromo-3-(difluoromethoxy)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole To 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 sodium chlorofluoroacetate (1.6 g, 10.4 mmol) and potassium carbonate (2.1 g, 15.6 mmol) and heated to 80 °C for 0.5 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:3 to 1:0) afforded the title compound (2.8 g, 86%) as a white solid. ([M+Na] + 649.1).

[0489] Step 7: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole (step 6), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.1 eq) at 100° C. according to general procedure D gave the title compound ([M+Na + ] + 737.4) was prepared.

[0490] Step 8: 3-(Difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole General procedure H was used to deprotect 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1-trityl-indazole (step 7) to give the title compound ([M+H] + 495.2).

[0491] Example 112: [3-Cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-imino-methyl-oxo-sulfane TIFF0007731381000135.tif53170

[0492] Step 1: (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(imino)(methyl)-16-sulfanone To a solution of cyclopropyl(3-fluoro-3'-methyl-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone (Example 75, Step 3) (250 mg, 661 μmol) in MeOH (3 mL) was added ammonium carbonate (95 mg, 991 μmol) and (diacetoxyiodo)benzene (532 mg, 1.65 mmol), and the mixture was stirred at ambient temperature for 1 h. The reaction was diluted with ethyl acetate, washed with water, dried (NaSO), and concentrated. Flash column chromatography (dichloromethane:MeOH 1:0 to 9:1) afforded the title compound (199 mg, 72%) as a white solid. ([M+H] + 410.2).

[0493] Step 2: [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-imino-methyl-oxo-sulfane To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(imino)(methyl)-16-sulfanone (Step 1) (15 mg, 36.6 μmol) in methanol (1 ml) was added hydrazine monohydrate (28 μL, 366 μmol) and the reaction was heated to 65° C. for 16 h after which the reaction was concentrated to dryness. Flash column chromatography (dichloromethane:MeOH 9:1) afforded the title compound (10 mg, 67%) as a white solid. ([M+H] + 404.1).

[0494] Example 113: [3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methylimino-oxo-λ 6 -Sulfane TIFF0007731381000136.tif51170

[0495] Step 1: (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(methyl)(methylimino)-16-sulfanone To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(imino)(methyl)-16-sulfanone (50 mg, 122 μmol) in DMF (1 ml) was added sodium hydride (7.3 mg, 183 μmol) and iodomethane (10 μl, 159 μmol), and the reaction mixture was stirred at ambient temperature for 16 h. The reaction was diluted with ethyl acetate, washed with water, dried (NaSO), and concentrated. Reverse-phase preparative HPLC afforded the title compound (22 mg, 37%) as a white solid. ([M+H] + 424.2).

[0496] Step 2: [3-Cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methylimino-oxo-λ 6 -Sulfane To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(methyl)(methylimino)-16-sulfanone (Step 1) (22 mg, 52.7 μmol) in ethanol (0.4 ml) was added hydrazine monohydrate (156 μl, 316 μmol), followed by triethylamine (11 μl, 79 μmol). The reaction was stirred at ambient temperature for 16 h before being concentrated to dryness. Flash column chromatography (dichloromethane:MeOH 1:9) afforded the title compound (19 mg, 85%) as a white solid. ([M+H] + 418.2).

[0497] Example 114: 3-Cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide TIFF0007731381000137.tif52170

[0498] 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) were added diisopropylethylamine (2.8 mL, 21.9 mmol) and dimethylamine hydrochloride (1.1 g, 14.6 mmol), and the reaction mixture was stirred at ambient temperature for 2 h. The reaction was diluted with ethyl acetate, washed with 1 M HCl, and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:10 to 3:1) afforded the title compound (1.8 g, 83%) as a white solid. ([M+H, Br] + 282.0).

[0499] Step 2: 2-Bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide Following general procedure A, 2-bromo-4-fluoro-N,N-dimethyl-benzenesulfonamide (step 1) was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with cyclopropanecarboxaldehyde (1.5 eq) for 1 h to give the title compound ([M+H(-OH),Br] + The result was 334.0.

[0500] Step 3: 2-Bromo-3-(cyclopropanecarbonyl)-4-fluoro-N,N-dimethyl-benzenesulfonamide Using general procedure B2, 2-bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide (step 2) was oxidized to give the title compound. ([M+H,Br] + 350.0.

[0501] Step 4: 4-Bromo-3-cyclopropyl-N,N-dimethyl-1H-indazole-5-sulfonamide To a solution of 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N,N-dimethyl-benzenesulfonamide (Step 3) (60 mg, 170 μmol) in ethanol (2 ml) was added hydrazine monohydrate (170 μl, 316 μmol), followed by triethylamine (30 μl, 210 μmol), and after heating to 80° C. for 16 h, the reaction was concentrated to dryness. Reverse phase preparative HPLC afforded the title compound (40 mg, 67%) as a light yellow solid. ([M+H, Br] + 346.1).

[0502] Step 5: 3-Cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide Suzuki coupling of 4-bromo-3-cyclopropyl-N,N-dimethyl-1H-indazole-5-sulfonamide (step 4), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.1 eq) at 100° C. according to general procedure D gave the title compound ([M+Na + ] + 434.2) was prepared.

[0503] Example 115: 3-Cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide TIFF0007731381000138.tif52170

[0504] 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 at ambient temperature for 2 h. The reaction was diluted with ethyl acetate, washed with 1 M HCl, and concentrated. Flash column chromatography afforded the title compound (2.6 g, 92%) as a white solid. ([M+H, Br] + 412.1).

[0505] Step 2: 2-Bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide According to general procedure A, 2-bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (step 1) was deprotonated with LDA (1.2 eq) for 0.5 h and reacted with cyclopropanecarboxaldehyde (1.5 eq) for 1 h to give the title compound ([M+Na,Br] + I got 482.1.

[0506] Step 3: 2-Bromo-3-(cyclopropanecarbonyl)-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide Using general procedure B2, 2-bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethyl-benzenesulfonamide (step 2) was oxidized to give the title compound. ([M+H,Br] + 480.2.

[0507] Step 4: 4-Bromo-3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-1H-indazole-5-sulfonamide To a solution of 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-benzenesulfonamide (Step 3) (200 mg, 440 μmol) in ethanol (4 ml) was added hydrazine monohydrate (44 μl, 880 μmol) followed by triethylamine (70 μl, 530 μmol) and the reaction was heated to 80° C. for 2 h before concentrating the reaction to dryness. Reverse phase preparative HPLC afforded the title compound (200 mg, quantitative yield) as a white solid. ([M+H, Br] + 450.0).

[0508] Step 5: 3-Cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide Suzuki coupling of 44-bromo-3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-1H-indazole-5-sulfonamide (step 4), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid using potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.1 eq) at 100° C. according to general procedure D gave the title compound ([M+Na + ] + 540.2) was prepared.

[0509] Step 6: 3-Cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide General procedure H was used to deprotect 3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide (step 5) to give the title compound ([M+H]) after flash column chromatography. + 420.0).

[0510] Example 116: 4-(4-Cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000139.tif57170

[0511] Step 1: 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Intermediate 17) with 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 8) using potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.05 eq) at 100° C. according to general procedure D gave the title compound ([M+Na] + 669.3) was prepared.

[0512] Step 2: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide To a solution of 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carbonitrile (Step 1) (220.0 mg, 0.34 mmol) in ethanol (5 mL) was added 2N aqueous NaOH (0.85 mL, 1.7 mmol) and the reaction was heated to 100° C. for 6 h. The reaction was acidified by the addition of 1N HCl, extracted with ethyl acetate, and concentrated. Preparative tlc ((ethyl acetate:n-heptane 1:2)) afforded the title compound (150 mg, 66%) as a yellow solid.

[0513] Step 3: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide General procedure H was used to deprotect 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide (step 2) to give the title compound ([M+H]) after flash column chromatography. + 423.2).

[0514] Example 117: 3-(Difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-5-(methylsulfonyl)-1H-indazole TIFF0007731381000140.tif56170

[0515] Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole (Intermediate 6) with 2-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 27) followed by deprotection by general procedure H afforded the title compound ([M+Na] + 465.1) can be prepared.

[0516] Example 118: 5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole TIFF0007731381000141.tif55170

[0517] Step 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 to 100 °C for 12 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (NaSO), and concentrated. Flash column chromatography (n-heptane) afforded the title compound (1.7 g, 41%) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ = 7.50 (dd, J = 5.6, 8.4 Hz, 1H), 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).

[0518] Step 2: 2-Bromo-3-cyclopropylsulfanyl-6-fluoro-benzoate ethyl According to general procedure A, 2-bromo-1-cyclopropylsulfanyl-4-fluoro-benzene (Step 1) was deprotonated with LDA (1.1 eq) for 30 min and reacted with ethyl chloroformate (1.2 eq) to give 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).

[0519] Step 3: 2-Bromo-1-cyclopropylsulfonyl-6-fluoro-benzoate ethyl To a solution of ethyl 2-bromo-3-cyclopropylsulfanyl-6-fluorobenzoate (Step 2) (1.9 g, 5.95 mmol) in dichloromethane (40 ml) was added mCPBA (3.6 g, 17.9 mmol) and the reaction was stirred at ambient temperature for 12 h. The reaction was then diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:5 to 1:3) afforded the title compound (2.0 g, 84%) as a white solid. ([M+H, Br] + 353.0)

[0520] Step 4: 4-Bromo-5-cyclopropylsulfonyl-1,2-dihydroindazol-3-one To an ice-cold solution of ethyl 2-bromo-3-cyclopropylsulfonyl-6-fluorobenzoate (Step 3) (2.0 g, 5.69 mmol) in ethanol (20 ml) was added hydrazine monohydrate (1130 μL, 22.6 mmol) followed by triethylamine (0.79 ml, 5.69 mmol) and the reaction was brought to ambient temperature. After heating to 80° C. for 2 h, the reaction was concentrated to dryness. Reverse phase preparative HPLC afforded the title compound (1.1 g, 58%) as an off-white solid. ([M+H, Br] + 316.8).

[0521] Step 5: 4-Bromo-5-cyclopropylsulfonyl-1-trityl-indazol-3-ol 4-Bromo-5-cyclopropylsulfonyl-1,2-dihydroindazol-3-one in DMF (20 ml) To an ice-cold solution of (step 4) (1.0 g, 3.15 mmol), trityl chloride (0.97 g, 3.47 mmol) was added followed by sodium hydride (151 mg, 60% dispersion in mineral oil, 3.78 mmol). The cooling bath was removed and the reaction was stirred at ambient temperature for 2 h. The reaction was then diluted with ethyl acetate, washed with water, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:3 to 1:1) afforded the title compound (1.1 g, 52%) as a yellow solid. ([M+Na,Br] + 583.1).

[0522] Step 6: 4-Bromo-5-cyclopropylsulfonyl-3-(difluoromethoxy)-1-trityl-indazole To a mixture of 4-bromo-5-cyclopropylsulfonyl-1-trityl-indazol-3-ol (Step 5) (1.2 g, 2.06 mmol) in DMF (30 ml) was added sodium chlorofluoroacetate (0.63 g, 4.11 mmol) and potassium carbonate (0.85 g, 6.17 mmol) and heated to 80 °C for 0.5 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (NaSO), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:5 to 1:3) afforded the title compound (1.1 g, 83%) as a light yellow solid. ([M+Na] + 633.0).

[0523] Step 7: 5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-indazole Suzuki coupling of 4-bromo-5-cyclopropylsulfonyl-3-(difluoromethoxy)-1-trityl-indazole (step 6), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adduct (0.1 eq) at 100° C. according to general procedure D gave the title compound ([M+Na + ]+ 721.1) was prepared.

[0524] Step 8: 5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole General procedure H was used to deprotect 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1-trityl-indazole (step 7) to give the title compound ([M+H] + 457.2).

[0525] Example 119: 3-(Difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1H-indazole TIFF0007731381000142.tif56170

[0526] Step 1: 3-(Difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1-trityl-indazole Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-trityl-indazole (Intermediate 36), (2-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 25) using potassium carbonate and SPhos Pd G3 (0.1 eq) at 100 °C according to general procedure D gave the title compound ([M+Na + ] + 713.2) was prepared.

[0527] Step 2: 3-(Difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1H-indazole General procedure H was used to deprotect 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1-trityl-indazole (step 1) to give the title compound ([M+H] + 448.0).

[0528] Example 120: 4-(4-Cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide TIFF0007731381000143.tif58170

[0529] Step 1: 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide To a solution of 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1-trityl-pyrazolo[3,4-c]pyridine-5-carboxamide (Example 116, Step 2) (150.0 mg, 0.23 mmol) in DMF (1 mL) at 0 °C was added NaH (5.4 mg, 0.23 mmol). After the reaction was brought to ambient temperature, iodomethane (32 mg, 0.23 mmol) was added and the mixture was stirred for an additional 2 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried (NaSO), and concentrated. Preparative tlc (ethyl acetate: n-heptane 1:3) provided the title compound (110 mg, 73%) as a white solid. ([M+H] + 679.2).

Claims

1. Compounds of Formula I [In the formula, X １ is either N or C, X ２ is N or CR ４ Either X ３ is N or CR ５ Either X ４ is either N or CH, However, X １ , X ２ , and X ３ wherein no more than two of represent N; The dotted line is an X １ is N and X ２ When is C=O, X １ and X ２ The bond between ２ and X ３ The bond between X and X, bond a and bond c are single bonds; ３ and CR ７ and bond b are double bonds; and X １ is N and X ２ If is not C=O, then X １ and X ２ The bond between ３ and CR ７ The bond between X and X, bond b and bond c are single bonds, ２ and X ３ represents a single or double bond that renders the six-membered ring aromatic, provided that the bond between and bond a is a double bond; R １ Ha-SO ２ R １ａ or -SOR １ｂ and R １ａ and R １ｂ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, hydroxy (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, NR １’ａ R １’ｂ , oxetanyl, furanyl, and pyranyl; R １’ａ and R １’ｂ At least one of (C １ ~C ６ ) alkyl, and the other is H or (C １ ~C ６ ) alkyl; R ２’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ２’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ４ is hydrogen, cyano, oxo, hydroxy, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, —CO ２ R ４ａ , -CONR ４ｂ R ４ｃ , -SO ２ R ４ｄ , -SOR ４ｅ , -SR ４ｆ , -SO(NR ４ｈ ) R ４ｇ , or -SO ２ (NR ４ｉ ) R ４ｊ and R ４ａ , R ４ｂ , and R ４ｃ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｄ , R ４ｅ , and R ４ｆ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｈ and R ４ｇ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｉ and R ４ｊ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ５ is hydrogen, halogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ６ is a halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, cyano, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C ３ ~C ６ ) cycloalkyl, oxetanyl, or thiophenyl, or —SO ２ R ６ａ and R ６ａ is (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, or halo(C １ ~C ６ ) alkyl; R ７ is hydrogen, halogen, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo-(C １ ~C ６ ) alkyl, halo-(C １ ~C ６ ) alkoxy, or NR ７’ａ R ７’ｂ and R ７’ａ and R ７’ｂ One of the groups is hydrogen, and the other is hydrogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NH ２ , -(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, or —(C １ ~C ６ ) alkyl-NH ２ is] or a pharmaceutically acceptable salt thereof.

2. The compound is a compound of formula Ia [In the formula, X １ is either N or C; X ３ is N or CR ５ Either The dotted line is an X １ is N and R ４ represents a bond that renders the six-membered ring aromatic, provided that when is oxo, the bond is a single bond; R １ Ha-SO ２ R １ａ or -SOR １ｂ and R １ａ and R １ｂ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, hydroxy (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, NR １’ａ R １’ｂ , oxetanyl, furanyl, and pyranyl; R １’ａ and R １’ｂ At least one of (C １ ~C ６ ) alkyl, and the other is H or (C １ ~C ６ ) alkyl; R ２’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ２’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ４ is hydrogen, cyano, oxo, hydroxy, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, —CO ２ R ４ａ , -CONR ４ｂ R ４ｃ , -SO ２ R ４ｄ , -SOR ４ｅ , -SR ４ｆ , -SO(NR ４ｈ ) R ４ｇ , or -SO ２ (NR ４ｉ ) R ４ｊ and R ４ａ , R ４ｂ , and R ４ｃ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｄ , R ４ｅ , and R ４ｆ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｈ and R ４ｇ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｉ and R ４ｊ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ６ is a halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, cyano, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C ３ ~C ６ ) cycloalkyl, oxetanyl, or thiophenyl, or —SO ２ R ６ａ and R ６ａ is (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, or halo(C １ ~C ６ ) alkyl; R ７ is hydrogen, halogen, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo-(C １ ~C ６ ) alkyl, halo-(C １ ~C ６ ) alkoxy, or NR ７’ａ R ７’ｂ and R ７’ａ and R ７’ｂ One of the groups is hydrogen, and the other is hydrogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NH ２ , -(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, or —(C １ ~C ６ ) alkyl-NH ２ is] 2. The compound of claim 1, wherein: Claim 3: The compound is a compound of formula Ib [In the formula, X ３ is N or CR ５ Either R １ Ha-SO ２ R １ａ or -SOR １ｂ and R １ａ and R １ｂ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, hydroxy (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, NR １’ａ R １’ｂ , oxetanyl, furanyl, and pyranyl; R １’ａ and R １’ｂ At least one of (C １ ~C ６ ) alkyl, and the other is H or (C １ ~C ６ ) alkyl; R ２’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ２’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ４ is hydrogen, cyano, oxo, hydroxy, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, —CO ２ R ４ａ , -CONR ４ｂ R ４ｃ , -SO ２ R ４ｄ , -SOR ４ｅ , -SR ４ｆ , -SO(NR ４ｈ ) R ４ｇ , or -SO ２ (NR ４ｉ ) R ４ｊ and R ４ａ , R ４ｂ , and R ４ｃ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｄ , R ４ｅ , and R ４ｆ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｈ and R ４ｇ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｉ and R ４ｊ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ５ is hydrogen, halogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ６ is a halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, cyano, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C ３ ~C ６ ) cycloalkyl, oxetanyl, or thiophenyl, or —SO ２ R ６ａ and R ６ａ is (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, or halo(C １ ~C ６ ) alkyl; R ７ is hydrogen, halogen, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo-(C １ ~C ６ ) alkyl, halo-(C １ ~C ６ ) alkoxy, or NR ７’ａ R ７’ｂ and R ７’ａ and R ７’ｂ One of the groups is hydrogen, and the other is hydrogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NH ２ , -(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, or —(C １ ~C ６ ) alkyl-NH ２ is] 2. The compound of claim 1, wherein: Claim 4: The compound is a compound of formula Ic [In the formula, R １ Ha-SO ２ R １ａ or -SOR １ｂ and R １ａ and R １ｂ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, hydroxy (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, NR １’ａ R １’ｂ , oxetanyl, furanyl, and pyranyl; R １’ａ and R １’ｂ At least one of (C １ ~C ６ ) alkyl, and the other is H or (C １ ~C ６ ) alkyl; R ２’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ２’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ５ is hydrogen, halogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ６ is a halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, cyano, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C ３ ~C ６ ) cycloalkyl, oxetanyl, or thiophenyl, or —SO ２ R ６ａ and R ６ａ is (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, or halo(C １ ~C ６ ) alkyl; R ７ is hydrogen, halogen, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo-(C １ ~C ６ ) alkyl, halo-(C １ ~C ６ ) alkoxy, or NR ７’ａ R ７’ｂ and R ７’ａ and R ７’ｂ One of the groups is hydrogen, and the other is hydrogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NH ２ , -(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, or —(C １ ~C ６ ) alkyl-NH ２ is] 2. The compound of claim 1, wherein:

5. The compound of claim 1, wherein the compound is a compound of formula Id: [In the formula, R １ Ha-SO ２ R １ａ or -SOR １ｂ and R １ａ and R １ｂ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, hydroxy (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, -, NR １’ａ R １’ｂ , oxetanyl, furanyl, and pyranyl; R １’ａ and R １’ｂ At least one of (C １ ~C ６ ) alkyl, and the other is H or (C １ ~C ６ ) alkyl; R ２’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ２’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ４ is hydrogen, cyano, oxo, hydroxy, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, —CO ２ R ４ａ , -CONR ４ｂ R ４ｃ , -SO ２ R ４ｄ , -SOR ４ｅ , -SR ４ｆ , -SO(NR ４ｈ ) R ４ｇ , or -SO ２ (NR ４ｉ ) R ４ｊ and R ４ａ , R ４ｂ , and R ４ｃ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｄ , R ４ｅ , and R ４ｆ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｈ and R ４ｇ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｉ and R ４ｊ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ５ is hydrogen, halogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ６ is a halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, cyano, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C ３ ~C ６ ) cycloalkyl, oxetanyl, or thiophenyl, or —SO ２ R ６ａ and R ６ａ is (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, or halo(C １ ~C ６ ) alkyl; R ７ is hydrogen, halogen, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo-(C １ ~C ６ ) alkyl, halo-(C １ ~C ６ ) alkoxy, or NR ７’ａ R ７’ｂ and R ７’ａ and R ７’ｂ One of the groups is hydrogen, and the other is hydrogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NH ２ , -(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, or —(C １ ~C ６ ) alkyl-NH ２ is] 2. The compound of claim 1, wherein: Claim 6: The compound is a compound of formula Ie [In the formula, R １ Ha-SO ２ R １ａ or -SOR １ｂ and R １ａ and R １ｂ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, hydroxy (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, NR １’ａ R １’ｂ , oxetanyl, furanyl, and pyranyl; R １’ａ and R １’ｂ At least one of (C １ ~C ６ ) alkyl, and the other is H or (C １ ~C ６ ) alkyl; R ２’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ２’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ３’’ is hydrogen, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, or halo(C １ ~C ６ ) alkoxy; R ４ is hydrogen, cyano, oxo, hydroxy, halogen, -NH ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, —CO ２ R ４ａ , -CONR ４ｂ R ４ｃ , -SO ２ R ４ｄ , -SOR ４ｅ , -SO(NR ４ｈ ) R ４ｇ , or -SO ２ (NR ４ｉ ) R ４ｊ and R ４ａ , R ４ｂ , and R ４ｃ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｄ , R ４ｅ , and R ４ｆ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｈ and R ４ｇ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ４ｉ and R ４ｊ are independently hydrogen, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, and oxetanyl; R ６ is a halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, cyano, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C ３ ~C ６ ) cycloalkyl, oxetanyl, or thiophenyl, or —SO ２ R ６ａ and R ６ａ is (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, or halo(C １ ~C ６ ) alkyl; R ７ is hydrogen, halogen, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, halo-(C １ ~C ６ ) alkyl, halo-(C １ ~C ６ ) alkoxy, or NR ７’ａ R ７’ｂ and R ７’ａ and R ７’ｂ One of the groups is hydrogen, and the other is hydrogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, -(C １ ~C ６ ) alkyl-O—(C １ ~C ６ ) alkyl-NH ２ , -(C １ ~C ６ ) alkyl-NHCO—(C １ ~C ６ ) alkyl, or —(C １ ~C ６ ) alkyl-NH ２ is] 2. The compound of claim 1, wherein:

7. X ４ is N, or a pharmaceutically acceptable salt thereof.

8. X １ is N or C, and X ２ is N or CR ４ and X ３ is N or CR ５ 2. The compound of claim 1, wherein:

9. R １ Ha-SO ２ R １ａ 9. The compound of any one of claims 1 to 8, wherein:

10. R １ａ and R １ｂ are independently １ ~C ６ ) alkyl, (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) cycloalkyl-(C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, hydroxy (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy-(C １ ~C ６ ) alkyl, NR １’ａ R １’ｂ , oxetanyl, furanyl, and pyranyl; R １’ａ and R １’ｂ At least one of (C １ ~C ６ ) alkyl, and the other is H or (C １ ~C ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

11. R １ａ is (C １ ~C ３ ) alkyl, (C ３ ~C ４ ) cycloalkyl, (C ３ ~C ４ ) cycloalkyl-(C １ ~C ３ ) alkyl, halo (C １ ~C ３ ) alkyl, hydroxy (C １ ~C ３ ) alkyl, (C １ ~C ３ ) alkoxy-(C １ ~C ３ ) alkyl, NR １’ａ R １’ｂ and oxetanyl, R １’ａ and R １’ｂ At least one of (C １ ~C ３ ) alkyl, and the other is H or (C １ ~C ３ 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

12. R １ａ is methyl, ethyl, propyl, i-propyl, i-butyl, cyclopropyl, Fluoromethyl, difluoromethyl, fluoro-ethyl (ethanyl), difluoro-ethyl (ethanyl), 1,2-difluoroethyl (difluoroethanyl), 1,1,2-trifluoroethyl (trifluoroethanyl), 1,2,2-trifluoroethyl (trifluoroethanyl), hydroxymethyl, hydroxyethyl, methoxymethyl, methylaminyl (—NHCH ３ ), dimethylaminyl (-N(CH ３ ) ２ 12. The compound of claim 1, wherein the compound is selected from: aryl, aryloxy, arylsulfonyl, aryloxy ...

13. R １ａ is selected from ethyl, propyl, i-propyl, i-butyl, cyclopropyl, fluoromethyl, difluoromethyl, fluoro-ethyl(ethanyl), difluoro-ethyl(ethanyl), 1,2-difluoroethyl(difluoroethanyl), 1,1,2-trifluoroethyl(trifluoroethanyl), and 1,2,2-trifluoroethyl(trifluoroethanyl), or a pharmaceutically acceptable salt thereof.

14. R １ａ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is selected from methyl, ethyl, cyclopropyl, and difluoromethyl.

15. R １ｂ However, (C １ ~C ６ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein:

16. R ２’ is halogen, —NH 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkoxy; R ３’ is hydrogen, and R ２’’ is hydrogen, and R ３’’ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, halogen, -NH2, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy.

17. R ２’ and R ２’’ One of the groups is hydrogen, halogen, or -NH ２ , (C １ ~C ２ ) alkyl, (C １ ~C ２ ) alkoxy, or halo (C １ ~C ２ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein one is alkyl and the other is hydrogen.

18. R ２’ is hydrogen, halogen, -NH ２ , methyl, ethyl, methoxyfluoromethyl, difluoromethyl, fluoro-ethyl(ethanyl), difluoro-ethyl(ethanyl), or 1,2-difluoroethyl(difluoroethanyl), and R ２’’ 18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

19. R ２’ is methyl, ethyl, fluoromethyl, difluoromethyl, fluoro-ethyl (ethanyl), difluoro-ethyl (ethanyl), 1,2-difluoroethyl (difluoroethanyl), and R ２’’ 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

20. R ２’ is methyl or difluoromethyl, and R ２’’ 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

21. R ３’ and R ３’’ One of the groups is hydrogen, halogen, or -NH ２ , (C １ ~C ３ ) alkyl, (C １ ~C ３ ) alkoxy, or halo (C １ ~C ３ 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein one is alkyl and the other is hydrogen.

22. R ３’’ is hydrogen, halogen, or (C １ ~C ３ ) alkyl, and R ３’ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

23. R ３’’ is hydrogen or fluorine, and R ３’ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

24. R ３’ and R ３’’ 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

25. R ４ is cyano, oxo, hydroxy, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) alkoxy, halo (C １ ~C ３ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C １ ~C ３ ) alkoxy-(C １ ~C ３ ) alkyl, (C ３ ~C ４ ) cycloalkyl, —CO ２ R ４ａ , --CONR ４ｂ R ４ｃ , -SO ２ R ４ｄ , -SOR ４ｅ , -SR ４ｆ , or -SO(NR ４ｈ ) R ４ｇ 25. The compound of any one of claims 1 to 24, wherein:

26. R ４ is cyano, oxo, hydroxy, (C １ ~C ２ ) alkoxy, halo (C １ ~C ２ ) alkyl, halo (C １ ~C ２ ) alkoxy, (C １ ~C ２ ) alkoxy-(C １ ~C ２ ) alkyl, cyclopropyl, —CO ２ H, --CONR ４ｂ R ４ｃ , -SO ２ R ４ｄ , -SOR ４ｅ , -SR ４ｆ , -SO(NH)CH ３ , or -SO ２ (NH)CH ３ 26. The compound of any one of claims 1 to 25, wherein:

27. R ４ is cyano, oxo, hydroxy, methoxy, -CF ３ , -OCF ３ , -methyl-methoxy, cyclopropyl, -CO ２ H, --CONR ４ｂ R ４ｃ , -SO ２ R ４ｄ , -SOR ４ｅ , or -SR ４ｆ 27. The compound of any one of claims 1 to 26, wherein:

28. R ４ cyano, oxo, -CONHR ４ｃ , or -SO ２ R ４ｄ 28. The compound of any one of claims 1 to 27, wherein:

29. R ４ａ , R ４ｂ , and R ４ｃ are independently hydrogen, (C １ ~C ３ ) alkyl, (C ３ ~C ４ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R is selected from cycloalkyl, cycloalkyl, and oxetanyl.

30. R ４ａ , R ４ｂ , and R ４ｃ are independently hydrogen, (C １ ~C ３ 30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R is selected from alkyl, cyclopropyl, and oxetanyl.

31. R ４ａ , R ４ｂ , and R ４ｃ are independently hydrogen, (C １ ~C ３ 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R is selected from: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,

32. R ４ａ 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

33. R ４ｂ is hydrogen, and R ４ｃ 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or methyl.

34. R ４ｄ , R ４ｅ , and R ４ｆ But independently, (C １ ~C ３ ) alkyl, (C ３ ~C ４ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R is selected from cycloalkyl, cycloalkyl, and oxetanyl.

35. R ４ｄ , R ４ｅ , and R ４ｆ But independently, (C １ ~C ３ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R is selected from alkyl, cyclopropyl, and oxetanyl.

36. R ４ｄ , R ４ｅ , and R ４ｆ But independently, (C １ ~C ３ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R is selected from: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,

37. R ４ｄ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein is methyl or cyclopropyl.

38. R ４ｄ 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein is methyl.

39. R ４ｈ and R ４ｇ are independently hydrogen, and (C １ ~C ６ 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein:

40. R ４ｈ and R ４ｇ are independently hydrogen, and (C １ ~C ３ 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein:

41. R ４ｈ is hydrogen, and R ４ｇ But (C １ ~C ３ 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein:

42. R ４ｈ is hydrogen, and R ４ｇ 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein is methyl.

43. R ４ｉ and R ４ｊ are independently hydrogen, and (C １ ~C ６ 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein:

44. R ４ｉ and R ４ｊ are independently hydrogen, and (C １ ~C ３ 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein:

45. R ４ｉ is hydrogen, and R ４ｊ But (C １ ~C ３ 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein:

46. R ４ｉ is hydrogen, and R ４ｊ 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein is methyl.

47. R ５ is hydrogen, halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, or (C ３ ~C ６ 47. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein:

48. R ５ is hydrogen, halogen, (C １ ~C ２ ) alkyl, (C １ ~C ２ ) alkoxy, or (C ３ ~C ４ 48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein:

49. R ５ 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, fluoro, chloro, cyclopropyl, methyl, or methoxy.

50. R ５ 50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

51. R ６ is halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, cyano, halo (C １ ~C ６ ) alkyl, halo (C １ ~C ６ ) alkoxy, (C ３ ~C ６ ) cycloalkyl, thiophenyl, oxetanyl, or —SO ２ R ６ａ 51. The compound of any one of claims 1 to 50, wherein:

52. R ６ But bromo, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) alkoxy, cyano, halo (C １ ~C ３ ) alkyl, halo (C １ ~C ３ ) alkoxy, (C ３ ~C ４ ) cycloalkyl, thiophenyl, oxetanyl, or —SO ２ R ６ａ 52. The compound of any one of claims 1 to 51, wherein:

53. R ６ But, Halo (C １ ~C ３ ) alkyl, halo (C １ ~C ３ ) alkoxy, or (C ３ ~C ４ 53. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein:

54. R ６ 53. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein is trifluoromethyl, trifluoromethoxy, difluoromethoxy, or cyclopropyl.

55. R ６ａ But (C １ ~C ６ 55. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, wherein:

56. R ６ａ 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein is methyl.

57. R ７ is hydrogen, halogen, hydroxy, or (C １ ~C ６ 57. The compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, wherein:

58. R ７ 58. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, halogen, or hydroxy.

59. R ７ 59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

60. R ７’ａ and R ７’ｂ One of the groups is hydrogen, and the other is hydrogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, -(C １ ~C ３ ) alkyl-O—(C １ ~C ３ ) alkyl-NHCO—(C １ ~C ３ ) alkyl, -(C １ ~C ３ ) alkyl-O—(C １ ~C ３ ) alkyl-NH ２ , -(C １ ~C ３ ) alkyl-NHCO—(C １ ~C ３ ) alkyl, or —(C １ ~C ３ ) alkyl-NH ２ 57. The compound of any one of claims 1 to 56, wherein:

61. R ７’ａ and R ７’ｂ One of the groups is hydrogen, and the other is hydrogen, (C １ ~C ６ ) alkyl, or (C １ ~C ６ 57. The compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, wherein:

62. R ７’ａ and R ７’ｂ One of the groups is hydrogen, and the other is hydrogen, (C １ ~C ３ ) alkyl, or (C １ ~C ３ 57. The compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, wherein:

63. The compound, 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methoxy-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(methylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(4-(methylsulfonyl)-3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N,2-trimethylbenzenesulfonamide; 3-cyclopropyl-5-methoxy-4-(4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(4-(cyclopropylsulfonyl)-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(cyclopropylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine; 2-chloro-4-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N-dimethylbenzenesulfonamide; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine; 4-(4-(methylsulfonyl)phenyl-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-(fluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-Methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(1,1-difluoroethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile; 3-(difluoromethyl)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-isopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(2,5-dimethyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid; 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile; 3-cyclopropyl-4-(3-methyl-4-methylsulfinyl-phenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride; 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridin-7-ol; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-5-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-ethoxy-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine; 4-[4-(cyclopropylmethylsulfonyl)-3-methyl-phenyl]-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(3-methyl-4-propylsulfonyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(4-isopropylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N,2-dimethyl-benzenesulfonamide; 3-Methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[3-methyl-4-(oxetan-3-ylsulfonyl)phenyl]-1H-pyrazolo[4,3-c]pyridine; 2-[4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-methyl-phenyl]sulfonylethanol; 3-cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine 2,2,2-trifluoroacetic acid; 3-(difluoromethoxy)-4-[3-methyl-4-(1-methylcyclopropyl)sulfonyl-phenyl]-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyridazine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfinyl)-1H-indazole; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-(difluoromethoxy)-4-[4-(methoxymethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[4,3-c]pyridine formic acid; 5-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-5-(methoxymethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3,5-dicyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine; N,3-dicyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole; 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indole-5-carbonitrile; 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide; 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide; 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-methylsulfonyl-phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-5-one; 4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-(difluoromethyl)-N,N-dimethyl-benzenesulfonamide; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole; 3-cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(difluoromethoxy)-4-[5-(difluoromethyl)-2-methyl-4-methylsulfinyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-5-methoxy-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methyl-phenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-5-methylsulfonyl-1H-indazole; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-N-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole; [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-imino-methyl-oxo-sulfane; [3-cyclopropyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazol-5-yl]-methyl-methylimino-oxo-λ ６ - sulfane; 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide; 3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide; 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-5-(methylsulfonyl)-1H-indazole; 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole; 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonyl-phenyl)-5-methylsulfonyl-1H-indazole; and 4-(4-cyclopropylsulfonyl-3-methyl-phenyl)-3-(difluoromethoxy)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide, 63. The compound of any one of claims 1 to 62, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

64. The compound, 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole; 3-cyclopropyl-4-[3-(difluoromethyl)-4-methylsulfonyl-phenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; and 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methyl-phenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide, 64. The compound of any one of claims 1 to 63, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

65. 65. A pharmaceutical composition comprising a compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

66. 65. A pharmaceutical for the treatment or prevention of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, comprising a compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof.

67. 65. A pharmaceutical for the treatment or prevention of lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, comprising a compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof.

68. Use of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma.

69. 65. Use of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

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