RU2845017C1 - Sulfone derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or pharmaceutically acceptable salts thereof, which are inhibitors of human methionine adenosyltransferase 2A (Mat2A) and can be used in treating, preventing and/or delaying the progression of cancer. In formula I X¹ is or N, or C, X² is or N, or CR⁴, X³ is or N, or CR⁵, X⁴ is or N, or CH, provided that not more than two of X¹, X² and X³ are N; dotted lines represent a single or double bond to ensure that the six-membered rings are aromatic provided that, when X¹ is N, and X² is C=O, then connection between X¹ and X², connection between X² and X³, bonds a and c are single bonds, and the bond between X³ and CR⁷ and b are double bonds; and provided that, when X¹ is N, and X² is not C=O, then the bond between X¹ and X², the bond between X³ and CR⁷, bonds b and c are single bonds, and the bond between X² and X³ and bond a are double bonds; R¹ is -SO₂R^1a or -SOR^1b; R^1a selected from (C₁-C₃) alkyl, (C₃-C₄) cycloalkyl, (C₃-C₄) cycloalkyl-(C₁-C₃) alkyl, halogen(C₁-C₃) alkyl, hydroxy(C₁-C₃) alkyl, (C₁-C₃) alkoxy-(C₁-C₃) alkyl, NR^1' and R^1'b and oxetanyl, wherein at least one of R^1'a and R^1'b is (C₁-C₃) alkyl, and the other is H or (C₁-C₃) alkyl; R^1b is (C₁-C₆) alkyl; R^2' is hydrogen, halogen, -NH₂, (C₁-C₆) alkyl, (C₁-C₆) alkoxy or halogen(C₁-C₆) alkyl; R^2'' is hydrogen, halogen, -NH₂, (C₁-C₆) alkyl, (C₁-C₆) alkoxy or halogen (C₁-C₆) alkyl; R^3' is hydrogen; R^3'' is hydrogen, halogen or (C₁-C₃) alkyl; R⁴ is cyano, oxo, hydroxy, (C₁-C₃) alkyl, (C₁-C₃) alkoxy, halogen(C₁-C₃)alkyl, halogen(C₁-C₆) alkoxy, (C₁-C₃)alkoxy-(C₁-C₃)alkyl, (C₃-C₄) cycloalkyl, -CO₂R^4a, -CONR^4bR^4c, -SO₂R^4d, -SOR^4e, -SR^4f or -SO(NR^4h)R^4g; R^4a, R^4b and R^4c are independently selected from hydrogen, (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl, (C₃-C₆)cycloalkyl-(C₁-C₆)alkyl, halogen(C₁-C₆)alkyl and oxetanyl; R^4d, R^4e and R^4f are independently selected from (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl, (C₃-C₆)cycloalkyl-(C₁-C₆)alkyl, halogen(C₁-C₆)alkyl and oxetanyl; R^4h and R^4g are independently selected from hydrogen, (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyl-(C₁-C₆) alkyl, halogen(C₁-C₆) alkyl and oxetanyl; R⁵ is hydrogen, halogen, (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl or (C₁-C₆) alkoxy; R⁶ is halogen, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, cyano, halogen (C₁-C₆) alkyl, halogen(C₁-C₆) alkoxy, (C₃-C₆) cycloalkyl, oxetanyl or thiophenyl, or -SO₂R^6a; R^6a is (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl or halogen(C₁-C₆) alkyl; R⁷ is hydrogen, halogen or hydroxy.

EFFECT: invention also relates to specific compounds and a pharmaceutical composition containing said compounds.

50 cl, 1 tbl, 120 ex

Description

The present invention provides compounds that are inhibitors of human methionine adenosyltransferase 2A (Mat2A) for use in the treatment, prevention and/or delay of cancer progression.

In particular, the present invention relates to compounds of formula I

Where

X ¹ is either N or C,

X ² is either N or CR ⁴ ,

X ³ is either N or CR ⁵ ,

X ⁴ is either N or CH,

provided that no more than two of X ¹ , X ² and X ³ represent N;

the dotted lines represent a single or double bond to ensure that six-membered rings are aromatic, provided that when X ¹ is N and X ² is C=O, then the bond between X ¹ and X ² , the bond between X ² and X ³ , bonds a and c are single bonds and the bond between X ³ and CR ⁷ and b are double bonds; and provided that when X ¹ is N and X ² is not C=O, then the bond between X ¹ and X ² , the bond between X ³ and CR ⁷ , bonds b and c are single bonds and the bond between X ² and X ³ and bond a are double bonds;

R ¹ is -SO ₂ R ^1a or -SOR ^1b ;

R ^1a and R ^1b are independently selected from (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, 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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₆ )alkyl and the other is H or (C ₁ -C ₆ )alkyl; or

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'' represents 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'' represents 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 ;

R ^4a , R ^4b and R ^4c are independently selected from 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 selected from (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 ^4h and R ^4g are independently selected from 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 selected from 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 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 ;

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 , where one of R ^7'a and R ^7'b 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 ;

or its pharmaceutically acceptable salts.

Unless defined otherwise, all 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 pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.

All publications, patent applications, patents and other references cited in this document are incorporated by reference in their entirety.

The nomenclature used in this application is based on the IUPAC system nomenclature unless otherwise stated.

Any free valence occurring on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of hydrogen unless otherwise noted.

"Halo" or "halogen" means fluorine, chlorine, bromine or iodine, particularly chlorine or fluorine.

"Hydroxy" refers to the OH group.

"(C ₁ -C ₆ )alkyl" refers to a branched or straight chain hydrocarbon of one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

"(C ₁ -C ₆ )alkoxy" means a moiety of the formula -OR ^a , wherein R ^a is a (C ₁ -C ₆ )alkyl moiety as defined herein. Examples of (C ₁ -C ₆ )alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

The term "(C ₃ -C ₆ )cycloalkyl" means a saturated monovalent monocyclic hydrocarbon group with 3 to 6 carbon atoms. Examples of monocyclic (C ₃ -C ₆ )cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, or cyclohexyl. One specific example of (C ₃ -C ₆ )cycloalkyl is cyclopropyl.

"( _C3 - _C6 )cycloalkyl-( _C1 - _C6 )alkyl" refers to ( _C1 - _C6 )alkyl, as defined above, substituted with one or more ( _C3 - _C6 )cycloalkyl groups, in particular one ( _C3 - _C6 )cycloalkyl group. More particularly, "( _C3 - _C6 )cycloalkyl-( _C1 - _C6 )alkyl" refers to or .

The term "perhalo(C ₁ -C ₃ )alkyl" means a (C ₁ -C ₃ )alkyl group as defined above, wherein all hydrogen atoms have been replaced by halogen atoms. More particularly, "(C ₁ -C ₃ )perhaloalkyl" is (C ₁ -C ₃ )perfluoroalkyl, most preferably trifluoromethyl.

"Halo-(C ₁ -C ₆ )alkyl" refers to (C ₁ -C ₆ )alkyl, as defined above, substituted with one or more halogen atoms, in particular one to three halogen atoms. More particularly, halo-(C ₁ -C ₆ )alkyl is chloro- and fluoro-(C ₁ -C ₆ )alkyl. In some particular embodiment, halo-(C ₁ -C ₆ )alkyl refers to perhalo(C ₁ -C ₃ )alkyl, as defined herein. More particularly, halo-(C ₁ -C ₆ )alkyl is trifluoromethyl, difluoromethyl, or fluoromethyl.

"Halogeno( _C1 - _C6 )alkoxy" refers to ( _C1 - _C6 )alkoxy, as defined above, substituted with one or more halogen atoms, in particular one to three halogen atoms. More particularly, halo( _C1 - _C6 )alkoxy is chloro- and fluoro( _C1 - _C6 )alkoxy. In some particular embodiment, halo( _C1 - _C6 )alkoxy refers to perhalogeno( _C1 - _C3 )alkoxy, such as trifluoromethoxy or difluoromethoxy.

"Hydroxy-(C ₁ -C ₆ )alkyl" refers to (C ₁ -C ₆ )alkyl, as defined above, substituted with one or more hydroxy groups, in particular one hydroxy group. More particularly, hydroxy-(C ₁ -C ₆ )alkyl refers to methyl hydroxide or ethyl hydroxide.

"( _C1 - _C6 )alkoxy-( _C1 - _C6 )alkyl" refers to ( _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. More particularly, ( _C1 - _C6 )alkoxy-( _C1 - _C6 )alkyl refers to _-CH2 -O- _CH3 or _-CH2CH2 - _O - _CH3 .

"Halogeno-(C ₁ -C ₆ )alkoxy" refers to an alkoxy as defined above substituted by one or more halogen atoms, in particular one to three halogen atoms. More particularly, halogeno-(C ₁ -C ₆ )alkoxy is chloro- and fluoro-(C ₁ -C ₆ )alkoxy.

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

The term "heterocycloalkyl" or "heterocyclic" means a monovalent saturated or partially unsaturated monoring system of 4 to 9 ring atoms containing 1, 2 or 3 ring heteroatoms selected independently from N, O and S, the remaining ring atoms being carbon. Examples of heterocycloalkyl are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiapyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolane, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. More particularly, heterocycloalkyl refers to dihydrofuryl, 1,3-dioxolyl, dihydropyryl, dihydrothiophile, dihydropyrazolyl, dihydroisoxazolyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazyl, 1,2,3,4-tetrahydropyrazyl.

The term "therapeutically effective amount" means an 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, (ii) reduces, alleviates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the occurrence of one or more symptoms of a particular disease, condition, or disorder described herein. A therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

"Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not. For example, "an aryl group optionally substituted by an alkyl group" means that the alkyl may optionally be present, and the description includes situations in which the aryl group is substituted by an alkyl group and situations in which the aryl group is not substituted by an alkyl group.

The terms "individual" or "subject" refer to a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., 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.

The terms “compound(s) of the present invention” and “compound(s) of this invention” refer to compounds as disclosed herein and their stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts).

When the compounds of the present invention are solids, those skilled in the art will appreciate that these compounds and their solvates and salts may exist in various solid forms, in particular various crystalline forms, all of which are intended to be included within the scope of the present invention and the defined formulae.

The term "pharmaceutically acceptable salts" means salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

The term "pharmaceutically acceptable acid addition salt" means pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and organic acids selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

The term "pharmaceutically acceptable base addition salt" means pharmaceutically acceptable salts formed 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 with an amine, 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 resin.

The term "active pharmaceutical ingredient" (or "API") means a compound or molecule in a pharmaceutical composition that has a specific biological activity.

The terms "pharmaceutical composition" and "pharmaceutical formulation" (or "formulation") are used interchangeably and mean a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients, for administration to a mammal, such as a human, in need thereof.

The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier" and "therapeutically inert excipient" may be used interchangeably and include any pharmaceutically acceptable ingredient in a pharmaceutical composition that does not have therapeutic activity and is non-toxic to the subject to which it is administered, such as disintegrants, binders, fillers, solvents, buffers, tonicity adjusting agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in the formulation of pharmaceutical products.

The terms "treatment" or "treatment" of a disease state include inhibition of the disease state, i.e., delaying the development of the disease state or its clinical symptoms, or alleviation of the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are non-superimposed mirror images of each other are called "enantiomers". When a compound has an asymmetric center, such as if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer may be characterized by the absolute configuration of its asymmetric center and described by the R- and S-sequence rules of Cahn, Ingold, and Prelog, or by the way the molecule rotates in the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). A chiral compound can exist either as a single enantiomer or as a mixture of both. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

Compounds of formula I may have one or more centers or axes of asymmetry. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both their individual enantiomers, atropisomers, and mixtures, racemic or otherwise, and individual epimers, atropisomers, and mixtures thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of Advanced Organic Chemistry, 4th edition J. March, John Wiley and Sons, New York, 1992).

Some compounds may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Prototropic tautomers are produced by migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate individual tautomers usually yield a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium depends on the chemical features of the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, whereas in phenols the enol form predominates. Common prototropic tautomers include the 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-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention encompasses all tautomeric forms of the compounds.

It has now been discovered that the compounds of formula I of the present invention are inhibitors of Mat2A and as such may have therapeutic use in the treatment of cancers including lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme and mesothelioma.

These compounds are potent inhibitors of human adenosylmethionine synthetase II alpha (MAT2A). MAT2A and MAT1A (methionine adenosyltransferase I alpha) are two genes that encode methionine adenosyltransferase activity, thereby producing S-adenosylmethionine (SAM), the major methyl donor in cells. MAT1A is a liver-specific SAM-producing enzyme, whereas MAT2A is expressed in many sites except the liver. MAT2A is found in a complex with MAT2B (methionine adenosyltransferase II beta), an allosteric regulator of MAT2A, and MAT2B acts as a rheostat for MAT2A enzymatic activity. When MAT2B binds to MAT2A, MAT2A undergoes a conformational change that increases its affinity for methionine and SAM. The net effect is that MAT2A, when bound to MAT2B, is more active at low methionine concentrations but is inhibited at high methionine concentrations.

Loss-of-function mutations in tumor suppressor genes are critical in the molecular pathogenesis of cancer, however, successful targeting of tumor suppressor genes has been elusive, primarily because mutant proteins cannot be directly inhibited for therapeutic benefit, and restoration of mutant function (such as restoration of mutant p53 function) has thus far been impossible. Recent clinical success with PARP inhibition in BRCA1/2-deficient patients has shown that targeting the associated synthetic lethality (ASL) that arises from loss-of-function mutations in tumor suppressor genes is a clinically viable approach for the treatment of cancer. The ASL relationship is not only valid for tumor suppressor genes, but can be extended to genes that reside in the same genetic region of a tumor suppressor gene and are lost when that region is deleted. Methylthioadenosine phosphorylase (MTAP) is one such gene that is located close to the CDKN2A tumor suppressor gene and is deleted in ~15% of all cancers. MTAP is deleted in, among others, ~53% of glioblastoma multiforme (GBM), ~25% of pancreatic adenocarcinoma (PAC), ~25% of melanoma, ~23% of lung squamous cell carcinoma, ~20% of head and neck squamous cell carcinoma, and ~15% of lung adenocarcinoma. Of course, this deletion occurs in a variety of indications, many of which are areas of high unmet medical need with limited effective therapies. In glioblastoma, where the median survival is 14 months, approval of newer therapies has not significantly improved overall survival (OS) and standard of care (SOC) has remained the same for more than a decade. The same is true for most patients with AKG, where OS is less than 1 year. MTAF deletion is a foundational event that occurs early in tumor evolution and will be maintained throughout tumor progression, including metastasis. Thus, its loss represents a change that is not affected by tumor heterogeneity, heredity, or resistance to any approved clinical treatment. The OSL relationship defined for MTAF deficiency will represent a true weakness for many tumor indications.

MTAP is located close to the tumor suppressor gene CDKN2A on chromosome 9. When CDKN2A is deleted, MTAP is often co-deleted. Its loss is considered a side effect and phenotypically neutral. MTAP is a cornerstone of the adenine and methionine waste disposal pathway in cells. The methionine waste disposal pathway feeds into the SAM pathway, and SAM levels are a master regulator of cancer cell growth that must be tightly regulated because large changes in SAM concentrations, either elevated or decreased, lead to cell cycle arrest. The importance of SAM levels in cancer growth lies in its central role for protein, DNA, and RNA methylation, acting as a checkpoint for cellular health, and can be read as hypomethylation when SAM is decreased, or hypermethylation when SAM is increased. Cells lacking MTAP accumulate methylthioadenosine (MTA) and decarboxylated SAM (dcSAM) without adversely affecting the levels of any waste products, including SAM. This accumulation creates a new stress on the cell, with MTA acting as a competitive inhibitor of SAM-dependent reactions due to their structural similarity. The loss of MTAP forces the cell to adapt to a new MTA/SAM paradigm without any loss of viability that the MTAP-containing cell would otherwise have to contend with, and this adaptation creates a persistent dependence on methionine adenosyltransferase II alpha 2 (MAT2A), one of the enzymes that produces SAM, in MTAP-deficient cells. This relationship between MTAF loss-induced synthetic lethality (MSL) and MAT2A dependence was identified in three large-scale shRNA studies (Marjon Cell Reports 2016, Kryukov Science 2016, and Mavrakis Science 2016).

Targeting MAT2A with small molecule inhibition will benefit a genetically defined patient population representing many areas of high unmet medical need.

The objects of the present invention are compounds of formula I, the use of such compounds for the production of medicaments for the treatment, prevention and/or delay of the progression of cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, esophageal carcinoma, glioblastoma multiforme and mesothelioma, more particularly for the treatment of cancer, including lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck, their production and medicaments based on the compound of formula I according to the present invention.

Further objects of the present invention are all forms of optically pure enantiomers, racemates or diastereoisomeric mixtures of the compounds of formula I.

In particular, the present invention relates to compounds of formula Ia

Where

X ¹ is either N or C;

X ³ is either N or CR ⁵ ,

the dotted line represents a double bond to ensure that six-membered rings are aromatic provided that when X ¹ is N and R ⁴ is oxo then the bond is a single bond;

R ¹ is -SO ₂ R ^1a or -SOR ^1b ;

R ^1a and R ^1b are independently selected from (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, 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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₆ )alkyl and the other is H or (C ₁ -C ₆ )alkyl; or

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'' represents 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'' represents 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 ;

R ^4a , R ^4b and R ^4c are independently selected from 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 selected from (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 ^4h and R ^4g are independently selected from 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 selected from 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 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 ;

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 , where one of R ^7'a and R ^7'b 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 ;

or its pharmaceutically acceptable salts.

In particular, the present invention relates to compounds of formula 1b

,

Where

X ³ is either N or CR ⁵ ,

R ¹ is -SO ₂ R ^1'a or -SOR ^1b ;

R ^1a and R ^1b are independently selected from (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, 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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₆ )alkyl and the other is H or (C ₁ -C ₆ )alkyl; or

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'' represents 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'' represents 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 ;

R ^4a , R ^4b and R ^4c are independently selected from 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 selected from (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 ^4h and R ^4g are independently selected from 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 selected from 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 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 ;

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 , where one of R ^7'a and R ^7'b 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 ;

or its pharmaceutically acceptable salts.

In another embodiment, the present invention relates to compounds of formula Ib

Where

R ¹ is -SO ₂ R ^1a or -SOR ^1b ;

R ^1a and R ^1b are independently selected from (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, 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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₆ )alkyl and the other is H or (C ₁ -C ₆ )alkyl; or

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'' represents 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'' represents 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 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 ;

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 , where one of R ^7'a and R ^7'b 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 ; and

its pharmaceutically acceptable salts.

In another embodiment, the present invention provides a compound of formula Ig

Where

R ¹ is -SO ₂ R ^1a or -SOR ^1b ;

R ^1a and R ^1b are independently selected from (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, 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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₆ )alkyl and the other is H or (C ₁ -C ₆ )alkyl; or

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'' represents 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'' represents 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 ;

R ^4a , R ^4b and R ^4c are independently selected from 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 selected from (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 ^4h and R ^4g are independently selected from 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 selected from 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 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 ;

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 , where one of R ^7'a and R ^7'b 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 ; and

its pharmaceutically acceptable salts.

In another embodiment, the present invention relates to compounds of formula Id

,

Where

R ¹ is -SO ₂ R ^1a or -SOR ^1b ;

R ^1a and R ^1b are independently selected from (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, 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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₆ )alkyl and the other is H or (C ₁ -C ₆ )alkyl; or

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'' represents 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'' represents 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 , -SR ^4f , -SO(NR ^4h )R ^4g or -SO ₂ (NR ⁴ⁱ )R ^4j ;

R ^4a , R ^4b and R ^4c are independently selected from 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 selected from (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 ^4h and R ^4g are independently selected from 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 selected from 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 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 ;

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 , where one of R ^7'a and R ^7'b 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 ; and

its pharmaceutically acceptable salts.

It should further be understood that each embodiment relating to a particular 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 , R7, R ^7'a and R ^7'b , as disclosed herein, can be combined with any other embodiment relating to other X ¹ , X ² , X ³ , 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 as disclosed herein.

A particular embodiment of the present invention relates to a compound of formula I wherein X ⁴ is N.

A particular embodiment of the present invention relates to a compound of formula I wherein X ¹ is N or C, X ² is N or CR ⁴ , and X ³ is N or CR ⁵ .

A particular embodiment of the present invention relates to a compound of formula I wherein X ¹ is C.

A particular embodiment of the present invention relates to a compound of formula I wherein X ² is CR ⁴ .

A particular embodiment of the present invention relates to a compound of formula I wherein X ³ is N.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Id, wherein R ¹ is -SO ₂ R ^1a .

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Id, wherein R ^1a and R ^1b are independently selected from (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, 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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₆ )alkyl and the other is H or (C ₁ -C ₆ )alkyl, in particular where R ^1a is selected from (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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₃ )alkyl and the other is H or (C ₁ -C ₃ )alkyl, more particularly wherein R ^1a is selected from methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, 1,2-difluoroethyl, 1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methylamino ( _-NHCH3 ), dimethylamino (-N( _CH3 ) ₂ ) and oxetanyl, more particularly where R ^1a is selected from ethyl, propyl, isopropyl, isobutyl, cyclopropyl, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, 1,2-difluoroethyl, 1,1,2-trifluoroethyl and 1,2,2-trifluoroethyl, most particularly where R ^1a is selected from methyl, ethyl, cyclopropyl and difluoromethyl.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Id, wherein R ^1b is (C ₁ -C ₆ )alkyl, more particularly is (C ₁ -C ₃ )alkyl, most particularly methyl.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Id, if R ^2' is other than hydrogen as defined herein, then R ^3' is hydrogen, R ^2'' is hydrogen, and R ^3'' is as defined herein, and conversely, if R ^2'' is other than hydrogen, then R ^3'' is hydrogen, R ^2' is hydrogen, and R ^3' is as defined herein.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Id, wherein one of R ^2' and R ^2" is hydrogen, halogen, -NH ₂ , (C ₁ -C ₂ )alkyl, (C ₁ -C ₂ )alkoxy or halo(C ₁ -C ₂ )alkyl while the other is hydrogen, in particular where R ^2' is hydrogen, halogen, -NH ₂ , methyl, ethyl, methoxy, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl or 1,2-difluoroethyl, and R ^2" is hydrogen, more in particular R ^2' is methyl, ethyl, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, 1,2-difluoroethyl, and R ^2" is hydrogen, most in particular R ^2' is methyl or difluoromethyl, and R ^2'' represents hydrogen.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Id, wherein one of R ^3' and R ^3" is hydrogen, halogen, -NH ₂ , (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy or halo(C ₁ -C ₃ )alkyl, while the other is hydrogen, more particularly R ^3" is hydrogen, halogen or (C ₁ -C ₃ )alkyl, and R ^3' is hydrogen, even more particularly R ^3" is hydrogen or fluoro, and R ^3' is hydrogen, most particularly both R ^3' and R ^3" are hydrogen.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ig or Id, wherein 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 , -SO(NR ^4h )R ^4g or -SO ₂ (NR ⁴ⁱ )R ^4j , in particular wherein 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 or -SO(NH)CH ₃ , in particular where R ⁴ is cyano, oxo, hydroxy, methoxy, -CF ₃ , -OCF ₃ , -methylmethoxy, cyclopropyl, -CO ₂ H, --CONR ^4b R ^4c , -SO ₂ R ^4d , -SOR ^4e or -SR ^4f , most particularly R ⁴ is cyano, oxo, -CONHR ^4c or -SO ₂ R ^4d .

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ig or Id, wherein R ^4a , R ^4b and R ^4c are independently selected from hydrogen, (C ₁ -C ₃ )alkyl, (C ₃ -C ₄ )cycloalkyl and oxetanyl, in particular wherein R ^4a , R ^4b and R ^4c are independently selected from hydrogen, (C ₁ -C ₃ )alkyl, cyclopropyl and oxetanyl, more particularly R ^4a , R ^4b and R ^4c are independently selected from hydrogen, (C ₁ -C ₃ )alkyl and cyclopropyl, most particularly R ^4a and R ^4b are hydrogen, R ^4c is hydrogen or methyl.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ig or Id, wherein R ^4d , R ^4e and R ^4f are independently selected from (C ₁ -C ₃ )alkyl, (C ₃ -C ₄ )cycloalkyl and oxetanyl, in particular wherein R ^4d , R ^4e and R ^4f are independently selected from (C ₁ -C ₃ )alkyl, cyclopropyl and oxetanyl, more particularly R ^4d , R ^4e and R ^4f are independently selected from (C ₁ -C ₃ )alkyl and cyclopropyl, most particularly R ^4d is methyl or cyclopropyl.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ig or Id, wherein R ^4h and R ^4g are independently selected from hydrogen and (C ₁ -C ₆ )alkyl, in particular hydrogen and (C ₁ -C ₃ )alkyl, more particularly wherein R ^4h is hydrogen and R ^4g is (C ₁ -C ₃ )alkyl, most particularly wherein R ^4h is hydrogen and R ^4g is methyl.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ig or Id, wherein R ⁴ⁱ and R ^4j are independently selected from hydrogen and (C ₁ -C ₆ )alkyl, in particular from hydrogen and (C ₁ -C ₃ )alkyl, more particularly wherein R ⁴ⁱ is hydrogen and R ^4j is (C ₁ -C ₃ )alkyl, most particularly wherein R ⁴ⁱ is hydrogen and R ^4j is methyl.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic or Id, wherein R ⁵ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or (C ₃ -C ₆ )cycloalkyl, in particular R ⁵ is hydrogen, halogen, (C ₁ -C ₂ )alkyl, (C ₁ -C ₂ )alkoxy or (C ₃ -C ₄ )cycloalkyl, more in particular R ⁵ is hydrogen, fluoro, chlorine, cyclopropyl, methyl or methoxy, most in particular R ⁵ is hydrogen.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Id, wherein 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 , wherein R ^6a is (C ₁ -C ₆ )alkyl, in particular R ⁶ is 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 , where R ^6a is (C ₁ -C ₆ )alkyl, in particular R ⁶ is halo(C ₁ -C ₃ )alkyl, halo(C ₁ -C ₃ )alkoxy or (C ₃ -C ₄ )cycloalkyl, more in particular R ⁶ is trifluoromethyl, trifluoromethoxy, difluoromethoxy or cyclopropyl.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Ig or Id, wherein R ^6a is (C ₁ -C ₆ )alkyl, more particularly R ^6a is methyl.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Ig or Id, wherein R ⁷ is hydrogen, halogen, hydroxy or (C ₁ -C ₆ )alkyl, in particular R ⁷ is hydrogen, halogen or hydroxy, more in particular R ⁷ is hydrogen.

A particular embodiment of the present invention relates to a compound of formula I, Ia, Ib, Ic, Id or Id, wherein one of R ^7'a and R ^7'b 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 , in particular wherein one of R ^7'a and R ^7'b is hydrogen and the other is hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy, more particularly where one of R ^7'a and R ^7'b is hydrogen and the other is hydrogen, (C ₁ -C ₃ )alkyl or (C ₁ -C ₃ )alkoxy.

Particular compounds of formula I of the present invention are those selected from the group consisting of:

3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-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-methylphenyl)-1H-pyrazolo[4,3-c]pyridine;

3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine;

3-cyclopropyl-4-(2,5-dimethyl-4-methylsulfonylphenyl)-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-methylsulfinylphenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride;

3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-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-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine;

3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-pyrazolo[4,3-c]pyridine;

4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine;

3-cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine;

3-(difluoromethoxy)-4-(4-ethylsulfonyl-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine;

4-(3-methyl-4-methylsulfonylphenyl)-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine;

4-[4-(cyclopropylmethylsulfonyl)-3-methylphenyl]-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine;

3-(difluoromethoxy)-4-(3-methyl-4-propylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine;

3-(difluoromethoxy)-4-[3-(difluoromethyl)-4-methylsulfonylphenyl]-1H-pyrazolo[4,3-c]pyridine;

3-(difluoromethoxy)-4-(4-isopropylsulfonyl-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine;

4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N,2-dimethylbenzenesulfonamide;

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-methylphenyl]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)sulfonylphenyl]-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-c1]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-methylphenyl]-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-methylsulfonylphenyl)-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-methylsulfonylphenyl)-1H-pyrazolo[4,3-b]pyridin-5-one;

3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-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-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile;

3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methylphenyl)-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-methylphenyl)-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-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile;

4-(3-methyl-4-methylsulfonylphenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one;

3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrrolo[3,2-b]pyridin-5-one;

4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-(difluoromethyl)-N,N-dimethylbenzenesulfonamide;

3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole;

3-cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-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-methylsulfonylphenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile;

3-(difluoromethoxy)-4-[5-(difluoromethyl)-2-methyl-4-methylsulfinylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile;

4-[3-(difluoromethyl)-4-methylsulfonylphenyl]-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-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-5-methylsulfonyl-1H-indazole;

3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-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-methylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole;

[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-iminomethyloxosulfane;

[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-methylmethyliminooxo-λ ⁶ -sulfane;

3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-sulfonamide;

3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-sulfonamide;

4-(4-cyclopropylsulfonyl-3-methylphenyl)-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-methylsulfonylphenyl)-1H-indazole;

3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-5-methylsulfonyl-1H-indazole, or

4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide,

or their pharmaceutically acceptable salts.

Particular compounds of formula I of the present invention are those selected from the group consisting of:

3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile;

3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-b]pyridin-5-one;

3-cyclopropyl-4-(4-ethylsulfonyl-3-methylphenyl)-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-methylphenyl]-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-methylsulfonylphenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile;

3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide;

3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; or

3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide,

or their pharmaceutically acceptable salts.

In another embodiment, the present invention provides a compound according to formula I, Ia, Ib, Ic, Id or Id, as described herein, for use as a therapeutically active substance.

In 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, more particularly for the treatment of cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme and head and neck squamous cell carcinoma.

In 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, more particularly for the treatment of cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme and head and neck squamous cell carcinoma.

In one aspect, the application provides a method of treating a Mat2A disorder in a subject having a Mat2A-related disorder, said method comprising administering to a subject in need thereof a therapeutically active amount of any of the above compounds.

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

In a particular embodiment, the present invention provides a method for treating, preventing and/or delaying the progression of, more particularly treating, cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme and head and neck squamous cell carcinoma, which comprises administering an effective amount of a compound according to formula I, Ia, Ib, Ic, Id or Ie, as described herein.

In particular, Mat2A disorders or Mat2A-related diseases are cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

In one aspect, the application provides a pharmaceutical composition comprising a compound according to any of the above embodiments, mixed with at least one pharmaceutically acceptable carrier, such as an excipient or diluent.

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

In another embodiment, the present invention provides medicinal products comprising a compound of formula I, Ia, Ib, Ic, Ig or Id, as defined herein, or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, are also an object of the present invention, as is a process for their preparation, which comprises bringing one or more compounds of formula I, Ia, Ib, Ic, Ig or Id and/or pharmaceutically acceptable acid addition salts and, if appropriate, one or more therapeutically valuable substances in galenic administration form together with one or more therapeutically inert carriers.

Another embodiment provides pharmaceutical compositions or medicaments comprising the compounds of the present invention and a therapeutically inert carrier, diluent or pharmaceutically acceptable excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments.

The compositions are formulated, dosed and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the route of administration, the schedule of administration and other factors known to practitioners. Typically, such an amount may be below the amount that is toxic to normal cells or the mammal as a whole.

The compounds of the present invention may be administered by any suitable route, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural, and intranasal, and, where local treatment is desired, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

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

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

The dosage in which the compounds of the present invention can be administered can vary over a wide range and should, of course, be adjusted to the individual requirements in each specific case. In general, in the case of oral administration, a daily dosage of from about 0.01 to 1000 mg per person of a compound of formula I, Ia, Ib, Ic, Id or Ie should be administered, although the upper limit may also be exceeded if necessary.

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

An example of an aerosol formulation can be prepared by dissolving a compound, for example 10-100 mg, of the present invention in a suitable buffer solution, for example phosphate buffer, adding a tonicity regulator, i.e. a salt such as sodium chloride, if desired. The solution can be filtered, for example using a 0.2 μm filter, to remove impurities and contaminants.

An embodiment thus comprises a pharmaceutical composition comprising a compound of the present invention as described herein or a stereoisomer thereof. A further embodiment comprises a pharmaceutical composition comprising a compound of the present invention as described herein or a stereoisomer thereof together with a pharmaceutically acceptable carrier or excipient.

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

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

Another embodiment includes a pharmaceutical composition comprising a compound of the present invention as described herein for use in the treatment, prevention and/or delay of progression, more particularly in the treatment of Mat2A-related diseases. Another embodiment includes a pharmaceutical composition comprising a compound of the present invention as described herein for use in the treatment, prevention and/or delay of progression, more particularly in the treatment of Mat2A-related diseases.

In another embodiment, the present invention provides for the production of compounds of formula I, Ia, Ib, Ic, Id or Id as described herein.

The preparation of compounds of formula I, Ia, Ib, Ic, Id or Ie according to the present invention can be carried out by sequential or convergent synthetic routes. The synthetic methods according to the present invention are illustrated in the following general scheme. The skills necessary for carrying out the reaction and purifying the resulting products are known to those skilled in the art. In the case of a mixture of enantiomers or diastereoisomers obtained during the reaction, these enantiomers or diastereoisomers can be separated by methods described herein or known to those skilled in the art, such as, for example, chiral chromatography or crystallization.

In addition, the compounds of the present invention can be prepared from commercially available starting materials or by general synthetic techniques and procedures known to those skilled in the art. Reaction schemes suitable for preparing such compounds are noted below. Substituents and indices used in the following description of the processes have the meanings specified herein. Further illustration can be found in the specific examples detailed below.

General synthesis

In more detail, compounds of formula I, Ia, Ib, Ic, Ig or Id and their intermediate compounds can be prepared using scheme 1-2 and with the help of the description of specific examples.

A subgroup of compounds of formula I, Ia, Ib, Ic, Ig or Id, wherein X is halogen, X ¹ is C, X ⁴ is CH, R ^2″ and R ^3′ are H, and R ⁷ is H, and X ² , X ³ , R ^1a , R ^2′ , R ^3″ , R ⁴ , R ⁵ and R ⁶ are as previously defined, can be prepared as shown in Schemes 1-2 below.

Scheme 1

where X is halogen, R ^b is H or cyclized to a pinacol ester, and X ² , X ³ and R ⁶ are as previously defined.

Dihalide A was deprotonated with strong bases (e.g., H-BuLi, LDA, LiHDMS, TMPMgCl⋅LiCl) at low temperature (-78°C) in THF and then reacted either with aldehydes to give alcohol II (as described in Synthesis, 1988, pp. 803-805) or with the corresponding esters 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 ₂ , Dess-Martin periodinane, TEMPO/PhI(OAc) ₂ ) in dichloroethane. Ketone III can then be reacted with hydrazine (aqueous or monohydrate) at ambient or reduced temperatures in THF, dioxane, or ethanol to give pyrazoles IV (as described in Journal of Medicinal Chemistry, 2019 p. 531-551). Alternatively, ketone III can be coupled with a boronic ester or acids X in a Suzuki-Miura coupling in dioxane/water mixtures at _elevated temperatures (e.g. 80-120 °C) under palladium (e.g. Pd(dppf)) catalysis in the presence of _carbonate bases (e.g. _K2CO3 , _Cs2CO3 ) to give ketone VII, which likely cyclizes to pyrazole VIII with hydrazine. Alternatively, pyrazole IV can be N-protected (e.g., with SEM, THP, or trityl) under standard conditions, reacted similarly with boronic acid or esters X, and then deprotected with strong acids (e.g., 4 N HCl in dioxane or TFA) to give pyrazole VIII.

Scheme 2

where X is a halogen, R ^b is H or cyclized to a pinacol ester.

Alternatively, the pyrazole core III can be constructed from anilines A1 as described in the Journal of the American Chemical Society, 1954, 1176. Subsequent halogenation with halosuccinimides in polar solvents (e.g., DMF) gives halopyrazole IV. N-protection of pyrazole IV (e.g., with SEM, THP, or trityl) under standard conditions then allows subsequent halogen reaction (e.g., Suzuki coupling) to give pyrazole VI. Halogenation of VI can be accomplished with halosuccinimides as before to give pyrazole VII, which is then coupled with boronic esters or acids and deprotected as described in Scheme 1.

A subgroup of compounds of formula I or Ia wherein X is halogen, X ¹ is N, X ² is C=O, X ³ is CH, R ^2'' and R ^3' are H, and R ⁷ is H, and X ⁴ , R ^1a , R ^2' , R ^3'' , R ⁴ , R ⁵ and R ⁶ are as previously defined, can be prepared as outlined in Scheme 3 below.

Scheme 3

The pyridone structures are prepared by first protecting the nitrogen of the pyrazole or pyrrole A2 with suitable protecting groups (e.g. THP, SEM, trityl) under standard conditions to give II. Derivatization of the halogen X (e.g. by a Suzuki coupling) gives III, which can be converted to pyridone by treatment under strongly acidic conditions (e.g. hydrochloric acid in dioxane), which in some cases causes removal of the protecting group (CG), necessitating its reintroduction to give IV. Chan-Lam coupling of boronic acids V under copper(II) acetate catalysis with a mixture of pyridine and triethylamine gives derivative VI, which after standard deprotection (e.g. 4 N HCl in dioxane, TFA) gives the final compounds VII.

General procedures

Scheme 4

where X is halogen and X ² , X ³ and R ⁶ are as previously defined.

General Procedure A: Aryl/Heteroaryl Functionalization

To a solution of aryl or heteroaryl dihalide (equiv: 1) in anhydrous THF (0.1 M) cooled to -78 °C under Ar atmosphere was added lithium diisopropylamine or n-BuLi (equiv: 1.1-1.5). After stirring for an appropriate period of time (10 min to 1 h), the desired electrophile (aldehyde, ester or chloroformate equiv: 1.5-2) was added and the reaction mixture was stirred for an additional period of time (10 min to 1 h) at the same temperature. After this time, the reaction was quenched at -78 °C by addition of aqueous saturated ammonium chloride, the reaction was brought to room temperature, diluted with ethyl acetate, the organic material was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. The crude products can be used directly in the next step or purified by flash column chromatography.

Scheme 5

where X is halogen, and X ² , X ³ and R ⁶ are as previously defined.

General Procedure B1: Oxidation of Benzyl Alcohol with Dess-Martin Periodinane

To a solution of benzyl alcohol (equiv.: 1) in dichloromethane (0.1 M) was added Dess-Martin periodinane (equiv.: 1.3) and the reaction mixture was stirred until completion of the reaction (1 h). The reaction mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash column chromatography.

General Procedure B2: Oxidation of Benzyl Alcohol with TEMPO

To a solution of benzyl alcohol (equiv: 1) in dichloromethane (0.1 M) was added TEMPO (equiv: 0.1) followed by (diacetoxyiodo)benzene (equiv: 1.1) and the reaction mixture was stirred until completion of the reaction (3 h). The reaction mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash column chromatography.

Scheme 6

where X is halogen, and X ² , X ³ and R ⁶ are as previously defined.

General Procedure B: Cyclization of Pyrazole

To a solution of ketone or ester (equiv: 1) dissolved in THF, dioxane or ethanol (0.1 M) at ambient temperature or with cooling was added hydrazine (equiv: 2-5) in the presence/absence of additional base (Et ₃ N equiv 1.5) and the reaction mixture was stirred until completion of the reaction (1 h). The reaction mixture was diluted with ethyl acetate, washed with water, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash column chromatography.

General Procedure G: Suzuki Combination

To a solution of the halide (equiv: 1) dissolved in dioxane:water (0.1 M, 4:1-10:1) were added potassium carbonate (equiv: 3-6), the desired boronic acid or ester (equiv: 1-6) and the mixture was degassed ultrasonically while bubbling Ar through the mixture. The adduct of 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride and dichloromethane was added (equiv: typically 0.05, and for difficult cases 0.5) and the mixture was heated under Ar at 100-120 °C until the starting materials were consumed (0.5-16 h). The reaction mixture was diluted with ethyl acetate, washed with water, _dried ( _Na2SO4 ) and concentrated. Alternatively, the reaction mixture can be absorbed directly onto silica gel and concentrated. The residue is purified by flash column chromatography.

General procedure D1: SEM protection

To a solution of pyrazole (equiv: 1) dissolved in anhydrous DMF or THF (0.1 M) under Ar atmosphere was added sodium hydride (60% dispersion in mineral oil, equiv: 2), the reaction mixture was stirred for 15 min before adding SEM-Cl (equiv: 1.8) and the reaction mixture was stirred until the starting material was completely consumed (1 h). The reaction was then diluted with ethyl acetate, extracted with water, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash column chromatography.

General procedure D2: SEM protection

To a solution of pyrazole (equiv.: 1) dissolved in dichloromethane (0.1 M) under Ar atmosphere were added DIPEA (equiv.: 1.2) and SEM-C1 (equiv.: 1.2) and the reaction mixture was stirred until the starting material was completely consumed (1 h). The reaction mixture was then concentrated and the residue was purified by flash column chromatography.

Scheme 7

where X is halogen and R ¹ R ^2' , R ^2'' , R ^3' and R ^3'' are as previously defined.

General Procedure E: Conversion of Aryl Halides to Boronates

To a solution of the aryl halide (equiv: 1) dissolved in dioxane (0.1 M) were added bis(pinacolato)diboron (equiv: 1.1), potassium acetate (equiv: 3) and the mixture was degassed by bubbling Ar under sonication. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) adduct (equiv: 0.1) was added and the reaction mixture was heated (80-100°C) until the conversion was complete. The reaction mixture was then diluted with ethyl acetate, washed _with brine, dried ( _Na2SO4 ) and concentrated. The residue was purified by flash column chromatography.

General Procedure G: Oxidation of Sulfides

To an ice-cold solution of the sulfide (equiv.: 1) in dichloromethane (0.1 M) was added m-chloroperbenzoic acid (equiv.: 1-2.5, depending on whether the sulfoxide or sulfone was required), the ice bath was removed and the reaction was allowed to proceed at room temperature. Stirring was continued until complete conversion, after which the reaction mixture was diluted with dichloromethane, washed with 1 N NaOH, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash column chromatography.

General Procedure I: Removal of Trityl Protection

The trityl protected compound (equiv: 1) was dissolved in trifluoroacetic acid (0.1 M) and triethylsilane was added (equiv: 1.5) and the reaction was stirred at ambient temperature until completion. The mixture was then carefully poured into saturated aqueous sodium hydrogen carbonate, extracted with dichloromethane, the combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash column chromatography or reverse phase preparative HPLC.

General procedure K1: Removing the TNR protection

The protected THP compound (equiv: 1) was dissolved in dichloromethane (0.1 M), trifluoroacetic acid (equiv: 10) was added and the reaction was stirred at ambient temperature until completion. The mixture was then diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash column chromatography or reversed-phase preparative HPLC.

General procedure K2: Removing the TNR protection

The protected THP compound (equiv: 1) was dissolved in 4 N HCl in dioxane (0.1 M) and the reaction was stirred at ambient temperature until completion. The mixture was then diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash column chromatography or reversed-phase preparative HPLC.

General Procedure L: Removing SEM/MOM Protection

The SEM/MOM protected compound (equiv: 1) was dissolved in trifluoroacetic acid (0.1 M) and the reaction was stirred at ambient temperature until completion. Evaporation of trifluoroacetic acid followed by redissolution of the reaction mixture in dichloromethane or dioxane (0.1 M) and addition of ethylenediamine (equiv: 10) completed the deprotection. The mixture was then concentrated and purified by flash column chromatography or reversed-phase preparative HPLC.

General Procedure L2: Removing SEM Protection

The protected SEM compound (equiv: 1) was dissolved in 1 M TBAF in THF (equiv: 10) and the reaction was heated to 50 °C until completion. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash column chromatography or reversed-phase preparative HPLC.

A particular embodiment of the present invention relates to a process for the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof, as defined according to the present invention, comprising deprotecting a compound 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 are as defined herein, in particular in the presence of an organic acid (e.g. TFA) or an inorganic acid (e.g. aqueous HCl), as shown in Scheme 8.

Scheme 8

The compounds were tested according to the test described later in this document.

Determination of Mat2A activity

Mat2A inhibition was measured in a 384-well absorbance-based assay format.

Recombinant human Mat2a (12.5 nM) and serially diluted compounds in DMSO (concentration range from 10 μM to 508 pM) or controls (DMSO) were incubated for 15 min at room temperature (RT) in assay buffer containing 50 mM HEPES pH 7.5, 50 mM KCl, 50 mM _MgCl2 , 0.01% Tween 20, and 10 mM DTT. The reaction was started by adding combined ATP and methionine substrates, each at a final concentration of 100 μM. The final assay condition was 12.5 nM Mat2A, 100 μM ATP and methionine substrates, and 2% DMSO. After 120 min of incubation at rt, the reaction was stopped by adding Biomol Green. The absorbance signal was measured at λ=635 nm using a multiple plate reader (BMG Pherastar reader or equivalent) after 30 min of equilibration at rt.

The table below shows the data for the selected connections:

Experimental part

The following examples are provided to illustrate the invention. They should not be considered as limiting the scope of the invention, but only as illustrative.

General

Analytical methods

HPLC (fast gradient LCMS method)

Column: Agilent Zorbax Eclipse Plus C18, Rapid Resolution HT, 2.1×30 mm, 1.8 µm, Part No. 959731-902

Solvent A: Water 0.01% formic acid; Solvent B: Acetonitrile (MeCN)

Gradients:

Abbreviations

The following abbreviations were used in the experimental section: Ar=argon; n-BuLi=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; LDI=lithium diisopropylamide;

LiHMDS=lithium bis(trimethylsilyl)amide; mCBP=metachloroperbenzoic acid; mol=molecular; MOM=methoxymethyl; NMP=N-methyl-2-pyrrolidone; prep=drug; SEM=[2-(trimethylsilyl)ethoxy)methyl]acetal; TBTU=2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate; THF=tetrahydrofuran; TEMPO=2,2,6,6-tetramethylpiperidinyloxyl; TBAF=tetra-n-butylammonium fluoride; TLC=thin layer chromatography

Source materials

The main 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.

Intermediate connections

Intermediate 1: 4-chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine

The title compound ([M+H, Cl] ⁺ 194.1) was prepared as described in WO 2010/106333 A1.

Intermediate 2: 4-bromo-3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

Step 1: 3-iodo-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

3-iodo-5-methoxy-1H-pyrazolo[3,4-c]pyridine (76006-07-0: WO 2015/25025 A1) was converted to the title compound ([M+H] ⁺ 406.2) using General Procedure D1 (accompanied by 20% of the regioisomer).

Step 2: 3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

3-iodo-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (step 1) was reacted with cyclopropylboronic acid (6 equiv), potassium carbonate (3 equiv) under catalysis with 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride adduct and dichloromethane (0.1 equiv) for 4 h according to General Procedure D to afford the title compound ([M+H] ⁺ 320.3).

Step 3: 4-bromo-3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine

To a solution of 3-cyclopropyl-5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (step 2, 20 mg, 63 μmol) in DCM (1 mL) was added N-bromosuccinimide (12 mg, 70 μmol) and the reaction was stirred for 4 h. The reaction was then 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).

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

Step 1: 4-chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine

2,4-Dichloropyridine was deprotonated with H-BuLi (1.3 equiv) for 30 min and reacted with ethyl 2,2,2-trifluoroacetate (2 equiv) according to General Procedure A to give 1-(2,4-dichloropyridin-3-yl)-2,2,2-trifluoroethan-1-one, which was reacted directly with hydrazine hydrate (5 equiv) in THF initially at -40 °C and elevated to ambient temperature for 16 h according to General Procedure B to give the title compound ([M+H, Cl] ⁺ 220.0).

Step 2: 4-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine

The title compound ([M+H, Cl] ⁺ 352.2) was prepared from 4-chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine (step 1) using General Procedure D2.

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

Step 1: 3-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine

3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine was converted to the title compound ([M+H, Br, Cl] ⁺ 361.1) using General Procedure D1.

Step 2: 4-chloro-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine

3-Bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (step 1) was reacted with cyclopropylboronic acid (6 equiv), potassium carbonate (6 equiv), catalyzed by 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride adduct and dichloromethane (0.15 equiv) for 1 h at 100°C according to General Procedure D to afford the title compound ([M+H, Cl] ⁺ 323.2).

Intermediate 5: 4-bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

Step 1: 3-bromo-4-(cyclopropanecarbonyl)-5-fluoropicolinonitrile

3-Bromo-5-fluoropicolinonitrile was treated with DAL (2 equiv) for 10 min before adding cyclopropanecarbaldehyde according to General Procedure A to give crude 3-bromo-4-(cyclopropyl(hydroxy)methyl)-5-fluoropicolinonitrile, which was then oxidized to the title compound ([M-H, Br] ^- 265.3) using General Procedure D2.

Step 3: 4-bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

3-Bromo-4-(cyclopropanecarbonyl)-5-fluoropicolinonitrile (step 2) was reacted with hydrazine hydrate (2 eq) in EtOH initially at 0°C and raised to ambient temperature for 1 h according to general procedure B to give the title compound ([M+H, Br] ⁺ 263.1).

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

Step 1: 1-(2-chloro-4-fluoropyridin-3-yl)-2,2-difluoropropan-1-one

2-Chloro-4-fluoropyridine was deprotonated with H-BuLi (1.3 equiv) for 1 h and reacted with ethyl 2,2-difluoropropanoate (1.3 equiv) according to General Procedure A to give the title compound ([M+H, Cl] ⁺ 224.1).

Step 2: 4-chloro-3-(1,1-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine

1-(2-Chloro-4-fluoropyridin-3-yl)-2,2-difluoropropan-1-one (step 1) was reacted with hydrazine hydrate (5 equiv) in THF at ambient temperature for 15 min according to General Procedure B to give the title compound ([M+H, Cl] ⁺ 218.1).

Intermediate 7: 2-[[4-chloro-3-(difluoromethyl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyltrimethylsilane

Step 1: 1-(2-chloro-4-fluoropyridin-3-yl)-2,2-difluoroethane-1-one

2-Chloro-4-fluoropyridine was deprotonated with DAL (2 equiv) for 3 h and reacted with ethyl 2,2-difluoroacetate (1.3 equiv) for 3 h according to General Procedure A to give the title compound ([M-H, Cl] ^- 206.1).

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

Step 3: 4-chloro-3-(1,1-difluoroethyl)-1H-pyrazolo[4,3-c]pyridine

4-Chloro-3-(difluoromethyl)-1H-pyrazolo[4,3-c]pyridine (step 2) was converted to the title compound ([M+H, Cl] ⁺ 324.1) using General Procedure D2, accompanied by its regioisomer.

Intermediate 8: 4-chloro-3-(difluoromethoxy)-1-tritylpyrazolo[4,3-c]pyridine

Step 1: 4-chloro-1H-pyrazolo[4,3-c]pyridin-3-ol

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

Step 2: 4-chloro-1-tritylpyrazolo[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 atmosphere was added triethylamine (1.55 mL, 11.5 mmol) and the reaction was stirred at 30 °C for 4 h, after which it was diluted with water and re-extracted with ethyl acetate. The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:6-3:1) gave the title compound (620 mg, 41%) as a yellow solid 1H-NMR (400 MHz, CHLOROFORM-d) δ=7.77 (d, J=6.1 Hz, 1H), 7.33-7.27 (s, 15H), 6.13 (d, J=6.1 Hz, 1H).

Step 3: 4-chloro-3-(difluoromethoxy)-1-tritylpyrazolo[4,3-c]pyridine

A suspension of 4-chloro-1-tritylpyrazolo[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-difluoroacetyl)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 give the title compound (100 mg, 89%) as a yellow solid, which 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).

Intermediate 9: 4-chloro-3-(oxetan-3-yl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridine

Step 1: (2,4-dichloro-3-pyridyl)-(oxetan-3-yl)methanol

2,4-Dichloropyridine was deprotonated with DAL (1.2 equiv) for 0.5 h and reacted with oxetane-3-carbaldehyde (1.5 equiv) for 1 h according to General Procedure A to give the title compound ([M+H, Cl] ⁺ 233.8).

Step 2: (2,4-dichloro-3-pyridyl)-(oxetan-3-yl)methanone

(2,4-Dichloro-3-pyridyl)-(oxetan-3-yl)methanol (step 1) was oxidized by General Procedure B1 to give the title compound. ([M+H, Cl] ⁺ 231.7).

Step 3: 4-chloro-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine

(2,4-Dichloro-3-pyridyl)-(oxetan-3-yl)methanone (step 2) was reacted with hydrazine monohydrate (1.5 equiv) and triethylamine (1.5 equiv) in dioxane at 60°C for 1 h according to general procedure B to give the title compound ([M+H, Cl] ⁺ 209.8).

Step 4: 4-chloro-3-(oxetan-3-yl)-1-tetrahydropyran-2-ylpyrazolo[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 quenched by addition of triethylamine (0.2 mL) and concentrated to dryness. Purification by preparative TLC (n-heptane:ethyl acetate 1:1) gave 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).

Intermediate 10: 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine

Step 1: Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone

2,4,6-Trichloropyridine (300 mg, 1.64 mmol, equiv: 1) was deprotonated with DAL (0.9 equiv) for 1 h and reacted with cyclopropanecarbaldehyde (1.5 equiv) for 1.5 h according to General Procedure A to give crude cyclopropyl(2,4,6-trichloropyridin-3-yl)methanol, which was directly oxidized by General Procedure B1 to give the title compound ([M+H, 2Cl] ⁺ 250.1). Step 2: 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone (step 2) was reacted with hydrazine monohydrate (5 equiv.) in THF at 0°C for 2 h and then at ambient temperature for 2 h according to general procedure B to give the title compound ([M+H, 2Cl] ⁺ 228.1).

Intermediate 11: 4-bromo-5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine

Step 1: 3-iodo-5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine

3-Iodo-5-methoxy-1H-pyrazolo[3,4-c]pyridine (WO 2015/25025 A1) was converted to the title compound ([M+H] ⁺ 406.2) using General Procedure D1, accompanied by its regioisomer.

Step 2: 5-methoxy-3-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine

To a suspension of 3-iodo-5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[3,4-c]pyridine (step 1) (70 mg, 0.17 mmol), copper(I) iodide (164 mg, 0.86 mmol) and potassium fluoride (50 mg, 0.17 mmol) in NMP (1 mL) was added (trifluoromethyl)trimethylsilane (0.13 mL, 0.86 mmol) and the mixture was heated under Ar to 50 °C for 1 h. The reaction was then diluted with water, filtered through Celite®, extracted with ethyl acetate and the organic material was dried (Na ₂ SO ₄ ) 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).

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).

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

Step 1: 4-chloro-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine

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

Step 2: 4-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine

4-Chloro-3-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine was converted to the title compound ([M+H,Cl] ⁺ 351.2) using General Procedure D1.

Intermediate 13: 4-bromo-3-cyclopropyl-5-(methoxymethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine

Step 1: 4-bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

4-Bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 5) (500 mg, 1.9 mmol) was suspended in water (15 mL) and sodium hydroxide (380 mg, 9.5 mmol) was added and the reaction was heated to 100 °C for 15 h. The reaction was then acidified with conc. 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).

Step 2: Methyl 4-bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylate

4-Bromo-3-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 1) (300 mg, 1.1 mmol) was suspended in dichloromethane (2 mL) and 3,4-dihydro-2H-pyran (0.5 mL, 5.3 mol) and p-toluenesulfonic acid monohydrate (20 mg, 0.1 mmol) were added. The reaction was stirred for 4 h, after which it was diluted with ethyl acetate, washed with 1 N HCl, dried (Na ₂ SO ₄ ) 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 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 after which it was 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).

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 the reaction was stirred for 90 min before adding a second portion of diisobutylaluminum hydride (3.37 mL, 1 M in THF, 3.4 mmol) and the mixture was stirred for another 3 h. The reaction was quenched by adding more drops of water, acidified with 1 N HCl, extracted with ethyl acetate, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:7) gave the title compound (60 mg, 19%) as a light gray solid ([M+H, Br] ⁺ 354.2).

Step 4: 4-bromo-3-cyclopropyl-5-(methoxymethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine

(4-Bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)methanol (step 3) (60 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), triethylamine (49 μL, 0.3 mmol) was added followed by methanesulfonyl chloride (16 μL, 0.2 mmol) and the reaction was stirred for 30 min. 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 another 3 h. The reaction was concentrated to dryness, redissolved in DCM (1 mL) and sodium methoxide (2.0 g, 9.3 mmol) was added. After 1 h, the reaction was diluted with saturated aqueous sodium hydrogen carbonate, extracted with DCM and _the combined organics were dried ( _Na2SO4 ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:1) gave the title compound (40 mg, 64%) as a colourless solid ([M+H, Br] ⁺ 368.2).

Intermediate 14: 4-bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

Step 1: 1-(2-bromo-6-fluoro-3-(methylsulfonyl)phenyl)-2,2,2-trifluoroethan-1-one

(2-Bromo-4-fluorophenyl)(methyl)sulfane was deprotonated with DAL (1.3 equiv) for 30 min and reacted with ethyl 2,2,2-trifluoroacetate (2 equiv) according to General Procedure A to give crude 1-(2-bromo-6-fluoro-3-(methylthio)phenyl)-2,2,2-trifluoroethan-1-one, which was used directly.

Crude 1-(2-bromo-6-fluoro-3-(methylthio)phenyl)-2,2,2-trifluoroethan-1-one (1.8 g, 5.1 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0 °C. mCPBA (3.5 g, 11.2 mmol) was added to the mixture brought to ambient temperature and stirred for 3 h. The reaction was diluted with dichloromethane, washed repeatedly with 1 N NaOH, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 7:3) gave the title compound (1.0 g, 56%) as a yellow oil.

Step 2: 4-bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole

1-(2-Bromo-6-fluoro-3-(methylsulfonyl)phenyl)-2,2,2-trifluoroethan-1-one (step 1) was reacted with hydrazine monohydrate (5 equiv.) in THF for 1 h at ambient temperature according to General Procedure B to give the title compound ([M+H, Br] ⁺ 343.1).

Step 3: 4-bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

4-Bromo-5-(methylsulfonyl)-3-(trifluoromethyl)-1H-indazole (step 3) was converted to the title compound ([M+H, Cl] ⁺ 351.2) using General Procedure D2. ^1H NMR (CHLOROFORM-d, 300 MHz) δ 8.37 (d, 1H, 3=9.1 Hz), 7.83 (d, 1H, J=9.1 Hz), 5.85 (s, 2H), 3.5-3.7 (m, 2H), 3.41 (s, 3H), 0.8-1.0 (m, 2H), 0.00 (s, 8H).

Intermediate 15: 4-bromo-3-cyclopropyl-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

To a solution of 4-bromo-3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-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 and washed with water, dried (Na ₂ SO ₄ ) and concentrated. Reversed-phase preparative HPLC gave the title compound (1.6 g, 51%) as a white solid ([M+H, Br] ⁺ 296.0).

Intermediate 16: 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole

Step 1: Ethyl 2-bromo-6-fluoro-3-(methylthio)benzoate

(2-Bromo-4-fluorophenyl)(methyl)sulfane was deprotonated with DAL (1.1 equiv) for 30 min and reacted with ethyl chloroformate (1.2 equiv) according to General Procedure A to give the title compound ([M+H, Br] ⁺ 292.3).

Step 2: Ethyl 2-bromo-6-fluoro-3-(methylsulfonyl)benzoate

To a solution of ethyl 2-bromo-6-fluoro-3-(methylthio)benzoate (step 1) (100 mg, 0.3 mmol) in dichloromethane (3 mL) was added mCPBA (153 mg, 0.7 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction was then diluted with DCM, washed with 1 N NaOH, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (111 mg, quant.) as a light yellow oil ([M+H, Br] ⁺ 325.0).

Step 3: 4-bromo-5-(methylsulfonyl)-1,2-dihydro-3H-indazol-3-one

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

Step 4: 4-bromo-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol

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

Step 5: 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole

To a solution of 4-bromo-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol (step 4) (250 mg, 0.5 mmol) in DMF (7.5 mL) were added sodium chlorodifluoroacetate (143 mg, 0.9 mmol) and potassium carbonate (194 mg, 1.4 mmol) and the mixture was heated to 80 °C for 30 min. The reaction was then diluted with ethyl acetate, washed with water, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 5:95-1:0) gave the title compound (192 mg, 70%) as a light yellow solid. ([M+H-Tr, Br] ⁺ 339.1).

Intermediate 17: 4-bromo-3-(difluoromethoxy)-1-tritylpyrazolo[3,4-c]pyridine-5-carbonitrile

Step 1: Ethyl 3-bromo-2-cyano-5-fluoropyridine-4-carboxylate

3-Bromo-5-fluoropicolinonitrile was deprotonated with a solution of 2,2,6,6-tetramethylpiperidinyl magnesium chloride complex and lithium chloride (2.5 equiv.) in THF at -78 °C for 1 h and then reacted with ethyl cyanoformate according to General Procedure A to give the title compound. 1H-NMR (400 MHz, CHLOROFORM-d) δ = 8.6 (s, 1H), 4.60-4.44 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H).

Step 2: 4-bromo-3-oxo-1,2-dihydropyrazolo[3,4-c]pyridine-5-carbonitrile

To a solution of ethyl 3-bromo-2-cyano-5-fluoropyridine-4-carboxylate (step 1) (5.0 g, 18.3 mmol) in ethanol (50 mL) was added hydrazine monohydrate (1.9 mL, 36.6 mmol) and the reaction was heated to 70 °C for 2 h. The reaction was concentrated to dryness and the residue was purified by reversed-phase HPLC to give the title compound (3.5 g, 80%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 13.15 (s, 1H), 11.74 (s, 1H), 8.88 (s, 1H).

Step 3: 4-bromo-3-hydroxy-1-tritylpyrazolo[3,4-c]pyridine-5-carbonitrile

To a solution of 4-bromo-3-oxo-1,2-dihydropyrazolo[3,4-c]pyridine-5-carbonitrile (step 2) (3500 mg, 14.6 mmol) in DMF (200 mL) were 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 1:9-1:3) to give the title compound (400 mg, 6%) as a yellow solid. ([M-H, Br] ^- 533.3). ¹ H-NMR (400 MHz, DMSO-d6) δ=7.48 (s, 1H), 7.44 (t, 1H), 7.39-7.35 (m, 9H), 7.21-7.17 (m, 6H).

Step 4: 4-bromo-3-(difluoromethoxy)-1-tritylpyrazolo[3,4-c]pyridine-5-carbonitrile

To a solution of 4-bromo-3-hydroxy-1-tritylpyrazolo[3,4-c]pyridine-5-carbonitrile (step 3) (50 mg, 0.1 mmol) in acetonitrile (1.5 mL) were added (2-chloro-2,2-difluoroacetyl)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. 1H NMR (400 MHz, DMSO-d6) δ = 7.49 (s, 1H), 7.45-7.16 (m, 16H).

Intermediate 18: 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: (4-bromo-2-methylphenyl)(cyclopropyl)sulfane

4-Bromo-2-methylbenzenethiol (600 mg, 3.0 mmol) was dissolved in DMF (12 mL), the solution was bubbled with Ar while sonicating before adding potassium tert-butoxide (398 mg, 3.6 mmol) and cyclopropyl bromide (0.5 mL, 5.9 mmol) and the mixture was heated to 100 °C for 26 h. The reaction was diluted with ethyl acetate, washed repeatedly with water, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (737 mg, 59%) as a light brown oil. 1H-NMR (CHLOROFORM-d, 300 MHz) δ 7.4-7.4 (m, 1H), 7.3-7.3 (m, 1H), 7.2-7.3 (m, 1H), 2.2-2.2 (m, 3H), 2.0-2.1 (m, 1H), 1.1-1.1 (m, 2H), 0.6-0.7 (m, 2H)

Step 2: 4-bromo-1-(cyclopropylsulfonyl)-2-methylbenzene

(4-Bromo-2-methylphenyl)(cyclopropyl)sulfane (step 1) was converted to the title compound using General Procedure G. 1H NMR (CHLOROFORM-d, 300 MHz) δ 7.7-7.8 (m, 1H), 7.5-7.5 (m, 2H), 2.7-2.7 (m, 3H), 2.5-2.6 (m, 1H), 1.3-1.4 (m, 2H), 1.0-1.1 (m, 2H).

Step 3: 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-1-(cyclopropylsulfonyl)-2-methylbenzene (step 2) was converted to the title compound using General Procedure E. ([M+H] ⁺ 323.2).

Intermediate 19: 2-(4-(cyclopropylsulfonyl)-3-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-1-(cyclopropylsulfonyl)-2-methylbenzene (CAS: 1310947-51-3, US 2011/237791 A1) was converted to the title compound using General Procedure E. ([M+H] ⁺ 343.2).

Intermediate 20: 2-chloro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

Step 1: 4-bromo-2-chloro-N,N-dimethylbenzenesulfonamide

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 (Na ₂ SO ₄ ) and concentrated to give the title compound (4.3 g, 84%) as a light brown solid ([M+H, Br, Cl] ⁺ 299.9).

Step 2: 2-chloro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

4-Bromo-2-chloro-N,N-dimethylbenzenesulfonamide (step 1) was converted to the title compound using General Procedure E. ([M+H] ⁺ 346.1).

Intermediate 21: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: (2-(difluoromethyl)phenyl)(methyl)sulfane

To a degassed solution of bromo-2-(difluoromethyl)benzene (400 mg, 1.9 mmol) in DMF (6 ml) was added sodium thiomethoxide (271 mg, 3.9 mmol) and the mixture was heated to 100 °C for 3 h. It was then diluted with ethyl acetate, washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.22 g, 44%) as a yellow oil. ¹ 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)

Step 2: 4-bromo-2-(difluoromethyl)phenyl)(methyl)sulfane

To an ice-cold solution of 2-(difluoromethyl)phenyl)(methyl)sulfane (step 1, 224 mg, 1.3 mmol) in DCM (4.5 mL) was added bromine (93 µL, 1.8 mmol) and the reaction was warmed to ambient temperature and stirred for 4 days. The reaction was diluted with DCM, washed with aqueous sodium thiosulfate, brine, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (0.29 g, 67%) as a yellow oil. ¹ 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)

Step 3: 4-bromo-2-(difluoromethyl)-1-(methylsulfonyl)benzene

4-Bromo-2-(difluoromethyl)phenyl)(methyl)sulfane (step 2) was converted to the title compound using General Procedure G. ¹ H-NMR (CHLOROFORM-d, 300 MHz) δ 8.0-8.1 (m, 1H), 8.0-8.0 (m, 1H), 7.8-7.9 (m, 1H), 7.4-7.8 (m, 1H), 3.1-3.1 (m, 3H)

Step 4: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-2-(difluoromethyl)-1-(methylsulfonyl)benzene (step 3) was converted to the title compound using General Procedure E. ([M+HC ₆ H ₁₂ ] ⁺ 500.2).

Intermediate 22: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: 4-bromo-2-(fluoromethyl)-1-(methylsulfonyl)benzene

To a solution of (5-bromo-2-(methylsulfonyl)phenyl)methanol (CAS: 773134-43-3, WO 2011/138751 A2) (780 mg, 2.9 mmol) cooled to -78 °C was added diethylaminosulfur trifluoride (0.5 mL, 3.5 mmol) and the reaction was stirred for 1 h before raising the temperature to 0 °C for 2 h. The reaction was then washed with saturated aqueous sodium hydrogen carbonate, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:7) gave the title compound (400 mg, 6%) as a yellow solid. ([M-H, Br] ^- 533.3). to give the title compound (0.62 g, 75%) as a white solid. ¹ H-NMR (DMSO-d6, 300 MHz) δ 7.9-8.0 (m, 1H), 7.7-7.8 (m, 2H), 5.64 (s, 1H), 4.9-4.9 (m, 2H), 3.25 (s, 3H)

Step 2: 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-2-(fluoromethyl)-1-(methylsulfonyl)benzene (step 1) was converted to the title compound using General Procedure E. ¹ H-NMR (CHLOROFORM-d, 300 MHz) δ 7.90-8.10 (m, 3H), 5.70-6.00 (m, 2H), 3.14 (s, 3H), 1.37 (s, 12H)

Intermediate 23: 4,4,5,5-tetramethyl-2-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1,3,2-dioxaborolane

Step 1: 3-((4-bromo-2-methylphenyl)thio)oxetane

A degassed solution of 4-bromo-2-methylbenzenethiol (200 mg, 0.9 mmol) and oxetan-3-yl 4-methylbenzenesulfonate (CAS: 26272-83-3, WO 2012/138678 A1) (275 mg, 1.1 mmol) was heated to 85 °C for 1 h. The reaction was then diluted with ethyl acetate, washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:7) gave the title compound (185 mg, 71%) as a colorless oil ([M+H, Br] ⁺ 261.0).

Step 2: 3-((4-bromo-2-methylphenyl)sulfonyl)oxetane

3-((4-Bromo-2-methylphenyl)thio)oxetane (step 2) was converted to the title compound using the general procedure G. ([M+H+MeCN, Br] ⁺ 334.1).

Step 4: 4,4,5,5-tetrmethyl-2-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1,3,2-dioxaborolane

3-((4-Bromo-2-methylphenyl)sulfonyl)oxetane was converted to the title compound using General Procedure E. ([M+H+MeCN] ⁺ 380.3).

Intermediate 24: 2-(4-ethylsulfonyl-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: 4-bromo-1-ethylsulfanyl-2-methylbenzene

Bromine (40.0 g, 256.0 mmol) was added to a solution of 1-ethylsulfanyl-2-methylbenzene (CAS: 3695-36-1) (30.0 g, 197.0 mmol) in dichloromethane (300 mL) at 0 °C, and the reaction was then stirred at ambient temperature for 1 h. The reaction was concentrated to give the title compound (40.0 g, 87%) as a yellow oil. ¹ H-NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.34 Hz, 3H), 2.23 (s, 3H), 2.93 (q, J=7.34 Hz, 2H), 7.18 (d, J=8.31 Hz, 1H), 7.31-7.41 (m, 2H)

Step 2: 4-bromo-1-ethylsulfonyl-2-methylbenzene

4-Bromo-1-ethylsulfanyl-2-methylbenzene (step 1) was converted to the title compound using General Procedure G. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ=7.89-7.82 (m, 1H), 7.55-7.50 (m, 2H), 3.17-3.11 (m, 2H), 2.67 (s, 3H), 1.27 (t, 3H) step 3: 2-(4-ethylsulfonyl-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-1-ethylsulfonyl-2-methylbenzene (step 2) was converted to the title compound using General Procedure E. ([M+H] ⁺ 229.1)

Intermediate 25: 2-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: 1-bromo-2-fluoro-5-methyl-4-methylsulfonylbenzene

1-Bromo-2-fluoro-5-methyl-4-methylsulfonylbenzene (CAS: 1351167-83-3, WO 2011/146335 A1) was converted to the title compound using the general procedure G. ([M+H+MeCN, Br] ⁺ 267.0).

Step 2: 2-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-Bromo-2-fluoro-5-methyl-4-methylsulfonylbenzene (step 1) was converted to the title compound using General Procedure E at 70°C. ([M+HC ₆ H ₁₂ ] ⁺ 233.1).

Intermediate 26: 2-(2,5-dimethyl-4-methylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: 1-bromo-2,5-dimethyl-4-methylsulfonylbenzene

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) were added sodium hydroxide (0.2 g, 6.1 mmol) and sodium methanesulfinate (1.0 g, 9.9 mmol). The mixture was stirred at 120 °C for 20 h under nitrogen, after which it was diluted with water and re-extracted with ethyl acetate. The combined organic material was washed with brine, dried (Na ₂ SO ₄ ), and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:4) gave the title compound (627 mg, 13%) as a yellow solid ([M+H, Br] ⁺ 263.0).

Step 2: 2-(2,5-dimethyl-4-methylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-Bromo-2,5-dimethyl-4-methylsulfonylbenzene (step 1) was converted to the title compound using General Procedure E at 95°C. ([M+H] ⁺ 311.2).

Intermediate 27: 2-[4-(difluoromethylsulfonyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: 4-bromo-1-(difluoromethylsulfanyl)-2-methylbenzene

To a solution of 1-(difluoromethylsulfanyl)-2-methylbenzene (CAS: 1450743-54-0, Organic Letters, 2013, 5036-5039) (15.0 g, 86.1 mmol) in heptane (162 mL) was added bromine (15.1 g, 94.7 mmol) and the mixture was stirred at ambient temperature for 12 h, after which the reaction was diluted with ethyl acetate, washed with saturated sodium bisulfite, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (15.0 g, 69%) as a yellow liquid. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ=7.50 (d, J=1.9 Hz, 1H), 7.51-7.48 (m, 1H), 7.40-7.31 (m, 2H), 6.97-6.61 (m, 1H), 2.50 (s, 3H)

Step 2: 4-bromo-1-(difluoromethylsulfonyl)-2-methylbenzene

4-Bromo-1-(difluoromethylsulfanyl)-2-methylbenzene (step 1) was converted to the title compound using General Procedure G. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ=7.89 (d, J=9.0 Hz, 1H), 7.64-7.58 (m, 2H), 6.37-6.05 (m, 1H), 2.71 (s, 3H)

Step 3: 2-[4-(difluoromethylsulfonyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-1-(difluoromethylsulfonyl)-2-methylbenzene (step 1) was converted to the title compound using General Procedure E at 80°C. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ=7.99 (d, J=7.8 Hz, 1H), 7.86-7.79 (m, 2H), 6.38-5.97 (m, 1H), 2.71 (s, 3H), 1.36 (s, 12H)

Intermediate 28: 2-[4-(cyclopropylmethylsulfonyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: 1-(cyclopropylmethylsulfanyl)-2-methylbenzene

To a solution of o-thiocresol (2.0 g, 16.1 mmol) in acetonitrile (20 mL) were 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, quant.) 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)

Step 2: 4-bromo-1-(cyclopropylmethylsulfanyl)-2-methylbenzene

To a solution of 1-(cyclopropylmethylsulfanyl)-2-methylbenzene (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 (Na ₂ SO ₄ ) and concentrated to give the title compound (3.7 g, 86%) as a yellow liquid. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ ppm 0.01-0.07 (m, 2H) 0.34-0.42 (m, 2H) 0.76-0.90 (m, 1H) 2.14 (s, 3H) 2.16-2.19 (m, 1H) 2.17-2.18 (m, 1H) 2.59 (d, J=7.00 Hz, 2H) 2.62 (d, J=7.00 Hz, 1H) 6.93 (d, J=8.25 Hz, 1H) 6.91-6.94 (m, 1H) 7.03-7.06 (m, 1H) 7.08-7.10 (m, 1H) 7.09 (d, J=2.25 Hz, 1N)

Step 3: 4-bromo-1-(cyclopropylmethylsulfonyl)-2-methylbenzene

4-Bromo-1-(cyclopropylmethylsulfanyl)-2-methylbenzene (step 2) was converted to the title compound using General Procedure G. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.13-0.18 (m, 2H) 0.53-0.58 (m, 2H) 0.90-1.03 (m, 1H) 2.65 (s, 3H) 3.04 (d, J=7.25 Hz, 2H) 7.49-7.54 (m, 2H) 7.88 (d, J=8.25 Hz, 1H)

Step 4: 2-[4-(cyclopropylmethylsulfonyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-1-(cyclopropylmethylsulfonyl)-2-methylbenzene (step 3) was converted to the title compound using General Procedure E at 70°C. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ ppm 0.12 (q, J=5.13 Hz, 2H) 0.47-0.56 (m, 2H) 0.95 (quint, J=7.65, 7.65, 7.65, 7.65, 4.85, 4.85 Hz, 1H) 1.36 (s, 12H) 2.68 (s, 3H) 3.05 (d, J=7.13 Hz, 2H) 7.74 (s, 1H) 7.77 (d, J=7.88 Hz, 1H) 8.01 (d, J=7.88 Hz, 1H)

Intermediate 29: 4,4,5,5-tetramethyl-2-(3-methyl-4-propylsulfonylphenyl)-1,3,2-dioxaborolane

Step 1: 1-methyl-2-propylsulfanylbenzene

To a solution of o-thiocresol (2.0 g, 16.1 mmol) in acetonitrile (20 mL) were 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)

Step 2: 4-bromo-2-methyl-1-propylsulfanylbenzene

To a solution of 1-methyl-2-propylsulfanylbenzene (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 (Na ₂ SO ₄ ) 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, 2H) 0.34-0.42 (m, 2H) 0.76-0.90 (m, 1H) 2.14 (s, 3H) 2.16-2.19 (m, 1H) 2.17-2.18 (m, 1H) 2.59 (d, J=7.00 Hz, 2H) 2.62 (d, J=7.00 Hz, 1H) 6.93 (d, J=8.25 Hz, 1H) 6.91-6.94 (m, 1H) 7.03-7.06 (m, 1H) 7.08-7.10 (m, 1H) 7.09 (d, J=2.25 Hz, 1N)

Step 3: 4-bromo-2-methyl-1-propylsulfonylbenzene 4-bromo-2-methyl-1-propylsulfanylbenzene (step 2) was converted to the title compound using General Procedure G. 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)

Step 4: 4,4,5,5-tetramethyl-2-(3-methyl-4-propylsulfonylphenyl)-1,3,2-dioxaborolane-4-bromo-1-(cyclopropylmethylsulfonyl)-2-methylbenzene (step 3) was converted to the title compound using General Procedure E at 90°C. ([M+H] ⁺ 311.2).

Intermediate 30: 2-(4-isopropylsulfonyl-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: 1-isopropylsulfanyl-2-methylbenzene

To a solution of o-thiocresol (2.0 g, 16.1 mmol) in acetonitrile (20 mL) were 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)

Step 2: 4-bromo-2-methyl-1-propylsulfanylbenzene To a solution of 1-isopropylsulfanyl-2-methylbenzene (step 1) (2.5 g, 15.0 mmol) in dichloromethane (25 mL) was added bromine (2.6 g, 16.5 mmol) and the mixture was stirred at ambient temperature for 3 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (3.6 g, 98%) as a yellow liquid. ¹ H-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)

Step 3: 4-bromo-1-isopropylsulfonyl-2-methylbenzene

4-Bromo-2-methyl-1-propylsulfanylbenzene (step 2) was converted to the title compound using General Procedure G. 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)

Step 4: 2-(4-isopropylsulfonyl-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-4-bromo-1-(cyclopropylmethylsulfonyl)-2-methylbenzene (step 3) was converted to the title compound using General Procedure E at 90°C. ([M+H] ⁺ 325.1).

Intermediate 31: N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

Step 1: 4-bromo-N,2-dimethylbenzenesulfonamide

To a solution of methylamine hydrochloride (0.6 g, 8.9 mmol) in dichloromethane (30 mL) were 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 for 1 h at ambient temperature. The reaction was diluted with dichloromethane, washed with brine, dried (Na ₂ SO ₄ ) 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)

Step 2: N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide 4-bromo-N,2-dimethylbenzenesulfonamide (step 2) was converted to the title compound using General Procedure E at 90°C. ([M+H] ⁺ 312.1).

Intermediate 32: tert-butyldimethyl-[2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylethoxy]silane

Step 1: tert-butyldimethyl-[2-(o-tolylsulfanyl)ethoxy]silane

To a solution of o-thiocresol (2.0 g, 16.1 mmol) in acetonitrile (30 mL) were 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. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ=7.32 (d, J=7.6 Hz, 1H), 7.18-7.14 (m, 2H), 7.12-7.07 (m, 1H), 3.81 (t, J=7.2 Hz, 2H), 3.06 (t, J=7.2 Hz, 2H), 2.39 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H)

Step 2: 2-(4-bromo-2-methylphenyl)sulfanylate-tert-butyldimethylsilane To a solution of tert-butyldimethyl-[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 (Na ₂ SO ₄ ) and concentrated to give the title compound (9.0 g, 65%) as a yellow liquid, used directly in the next step.

Step 3: 2-(4-bromo-2-methylphenyl)sulfonylethoxy-tert-butyldimethylsilane

2-(4-Bromo-2-methylphenyl)sulfanylethoxy-tert-butyldimethylsilane (step 2) was converted to the title compound using the general procedure G. ([M+H] ⁺ 393.0).

Step 4: tert-butyldimethyl-[2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylethoxy]silane

2-(4-Bromo-2-methylphenyl)sulfonylethoxy-tert-butyldimethylsilane (step 3) was converted to the title compound using General Procedure E at 90°C. ([M+H] ⁺ 441.1).

Intermediate 33: 4,4,5,5-tetramethyl-2-[3-methyl-4-(1-methylcyclopropyl)sulfonylphenyl]-1,3,2-dioxaborolane

Step 1: 4-bromo-2-methyl-1-(1-methylcyclopropyl)sulfonylbenzene

To a solution of 4-bromo-1-cyclopropylsulfonyl-2-methylbenzene (intermediate 18, step 2) (500 mg, 1.8 mmol) in THF (23 mL) under nitrogen at -78 °C was added LiHMDS (2.18 mL, 1 M in THF, 2.18 mmol) and the mixture was stirred for 1 h before iodomethane (515 mg, 3.6 mmol) was added and the mixture was warmed to 20 °C and stirred for another 15 h. The mixture was diluted with ethyl acetate, washed with water, dried (Na ₂ SO ₄ ) and concentrated. Purification by preparative TLC (petroleum ether:ethyl acetate 5:1) gave the title compound (0.45 g, 86%) as a colourless gum. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ=7.84-7.80 (m, 1H), 7.51-7.47 (m, 2H), 3.48 (s, 1H), 2.66 (s, 3H), 1.63-1.60 (m, 2H), 1.29 (s, 3H), 0.88-0.84 (m, 2H)

Step 2: 4,4,5,5-tetramethyl-2-[3-methyl-4-(1-methylcyclopropyl)sulfonylphenyl]-1,3,2-dioxaborolane

4-Bromo-2-methyl-1-(1-methylcyclopropyl)sulfonylbenzene (step 2) was converted to the title compound using General Procedure E at 80°C. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 7.98 (d, J = 7.7 Hz, 1H), 7.81-7.76 (m, 2H), 2.72 (s, 3H), 1.66 (br d, J = 2.0 Hz, 2H), 1.42-1.37 (m, 15H), 0.89-0.84 (m, 2H)

Intermediate 34: 2-[4-(methoxymethylsulfonyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: 4-bromo-1-(methoxymethylsulfanyl)-2-methylbenzene

To a solution of chloromethyl methyl ether (0.28 ml, 3.7 mmol) in acetonitrile (3 ml) were added potassium carbonate (680 mg, 4.9 mmol) and 4-bromo-2-methylbenzenethiol (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 ₂ SO ₄ ) and concentrated. Flash column chromatography (n-heptane) gave the title compound (220 mg, 36%) as a light yellow oil. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ=7.34-7.30 (m, 1H), 7.25 (d, J=1.9 Hz, 1H), 7.22-7.18 (m, 1H), 4.87-4.83 (m, 2H), 3.35 (s, 3H), 2.29 (s, 3H)

Step 2: 4-bromo-1-(methoxymethylsulfonyl)-2-methylbenzene

4-Bromo-1-(methoxymethylsulfanyl)-2-methylbenzene (step 2) was converted to the title compound using General Procedure G. ¹ H-NMR (400 MHz, 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)

Step 3: 2-[4-(methoxymethylsulfonyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-1-(methoxymethylsulfonyl)-2-methylbenzene (step 3) was converted to the title compound using General Procedure E at 70°C and used crude in the next step.

Intermediate 35: 2-[5-(difluoromethyl)-2-methyl-4-methylsulfinylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: 2-bromo-1-(difluoromethyl)-4-methylbenzene

To a solution of 2-bromo-4-methylbenzaldehyde (5.0 g, 25.1 mmol) in dichloromethane (75 mL) was slowly added diethylaminosulfur trifluoride (6.1 g, 37.7 mmol) over 0.5 h and the reaction was stirred for 16 h. The reaction was diluted with dichloromethane, washed cautiously with saturated aqueous sodium hydrogen carbonate and concentrated. Flash column chromatography (n-heptane) gave the title compound (3.6 g, 65%) as a yellow liquid. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ=7.53 (d, J=7.9 Hz, 1H), 7.43 (s, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.04-6.72 (m, 1H), 2.47-2.29 (m, 3H)

Step 2: 1-(difluoromethyl)-4-methyl-2-methylsulfanylbenzene

To a cooled (-78°C) solution of 2-bromo-1-(difluoromethyl)-4-methylbenzene (step 1) (3.6 g, 16.3 mmol) in THF (67 mL) under nitrogen was added n-butyl lithium (7.2 mL, 2.5 M in hexanes, 18 mmol) and the mixture was stirred for 0.5 h before (methyldisulfanyl)methane (2.0 g, 21.5 mmol) was added and the mixture was stirred for a further 1 h. Saturated ammonium chloride was then added and the reaction was brought to ambient temperature and re-extracted with ethyl acetate. The combined organic material was concentrated to give the title compound (2.5 g, 82%) as a yellow liquid. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ=7.50 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.16-6.84 (m, 2H), 2.48 (s, 3H), 2.38 (s, 3H)

Step 3: 1-bromo-5-(difluoromethyl)-2-methyl-4-methylsulfanylbenzene

To a solution of 1-(difluoromethyl)-4-methyl-2-methylsulfanylbenzene (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 (Na ₂ SO ₄ ) and concentrated to give the title compound (90 mg, 63%) as a yellow liquid. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ = 7.75 (s, 1H), 7.25 (s, 1H), 7.11-6.77 (m, 1H), 2.47 (s, 3H), 2.42 (s, 3H)

Step 4: 1-bromo-5-(difluoromethyl)-2-methyl-4-methylsulfinylbenzene

To a solution of 1-bromo-5-(difluoromethyl)-2-methyl-4-methylsulfanylbenzene (step 3) (1.0 g, 3.7 mmol) in dichloromethane (20 mL) cooled to 0 °C was added 3-chlorobenzenecarboperoxoic acid (0.6 g, 3.0 mmol) and the mixture was stirred at 0 °C for 0.5 h, after which the reaction was diluted with dichloromethane, washed with saturated sodium bisulfite, saturated aqueous sodium hydrogen carbonate, brine, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:7) gave the title compound (800 mg, 57%) as a white solid ([M+H, Br] ⁺ 282.0).

Step 5: 2-[5-(difluoromethyl)-2-methyl-4-methylsulfinylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-Bromo-5-(difluoromethyl)-2-methyl-4-methylsulfinylbenzene (step 4)

was converted to the title compound using General Procedure E at 80°C. ([M+H] ⁺ 331.2).

Intermediate 36: 4-bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-tritylindazole

Step 1: Ethyl 2-bromo-6-fluoro-3-methylsulfanyl benzoate

2-Bromo-4-fluoro-1-methylsulfanylbenzene was deprotonated with DAL (1.2 equiv) for 0.5 h and reacted with ethyl chloroformate (1.5 equiv) for 1 h according to General Procedure A to give the title compound. 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)

Step 2: Ethyl 2-bromo-6-fluoro-3-methylsulfonyl benzoate

Ethyl 2-bromo-6-fluoro-3-methylsulfanyl benzoate was converted to the title compound using General Procedure G. ([M+H, Br] ⁺ 326.9).

Step 3: 4-bromo-5-methylsulfonyl-1,2-dihydroindazol-3-one

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

Step 4: 4-bromo-5-methylsulfonyl-1-tritylindazol-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) were added sodium hydride (41 mg, 60% dispersion in mineral oil, 1.0 mmol) and triphenylmethyl chloride (211 mg, 0.8 mmol) at 0 °C under nitrogen. The cooling bath was removed and the reaction was stirred for 2 h until ambient temperature was reached. The reaction was quenched by addition of saturated aqueous ammonium chloride, re-extracted with ethyl acetate, and the combined organic extracts were washed with brine and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:1) gave the title compound (150 mg, 41%) as a white solid. ([M+Na, Br] ⁺ 556.9).

Step 5: 4-bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-tritylindazole To a solution of 4-bromo-5-methylsulfonyl-1-tritylindazole-3-ol (step 4) (1.0 g, 1.9 mmol) in DMF (30 mL) were added sodium chlorodifluoroacetate (0.6 g, 3.8 mmol) and potassium carbonate (0.8 g, 5.6 mmol) and the reaction was heated to 80 °C for 30 min. The reaction was filtered and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:3) gave the title compound (0.9 g, 71%) as a white solid. ([M+Na, Br] ⁺ 605.0).

Intermediate 37: 4-Chloro-3-cyclopropyl-2-trimethylsilyl-1-(2-trimethylsilylethoxymethyl)indole-5-carbonitrile

Step 1: 4-bromo-3-chloro-2-iodoaniline was prepared as described in WO 2013/33228 A1.

Step 2: 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-indole

A mixture of 4-bromo-3-chloro-2-iodoaniline (step 1) (441 mg, 1.3 mmol), (cyclopropylethynyl)trimethylsilane (159 μL, 1.5 mmol), lithium chloride (56 mg, 1.33 mmol), and sodium carbonate (281 mg, 2.7 mmol) in DMF (5 mL) was bubbled with argon, then the adduct of [1,1'-1,1'-bis(diphenylphosphino)ferrocenepalladium(Ii) dichloride and dichloromethane (49 mg, 66 μmol) was added. The reaction was heated in a sealed tube to 100 °C for 16 h, after which the reaction was diluted with ethyl acetate, washed with aqueous sodium thiosulfate, brine, dried (Na ₂ SO ₄ ), and concentrated. Flash column chromatography (ethyl acetate: n-heptane 4:1) gave the title compound (185 mg, 39%) as a yellow solid. ([M+H, Cl, Br] ⁺ 342.2).

Step 3: 5-bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole

5-Bromo-4-chloro-3-cyclopropyl-2-(trimethylsilyl)-1H-indole was converted to the title compound using General Procedure D1 in THF. 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)

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 bubbled with argon and the reaction was heated in a microwave oven at 150 °C for 30 min. The reaction was diluted with water and re-extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate: n-heptane 4:1) gave the title compound (57 mg, 46%) as a yellow solid. ([M+H, Cl] ⁺ 301.2).

Intermediate 38: 2-(difluoromethyl)-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

Step 1: 1-benzylsulfanyl-4-bromo-2-(difluoromethyl)benzene

To an ice-cold solution of benzyl mercaptan (2.4 g, 19.4 mmol) in DMF (20 mL) was added sodium hydride (0.8 g, 60% dispersion in mineral oil, 20 mmol), after 0.5 h 4-bromo-2-(difluoromethyl)-1-fluorobenzene (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 0:1-5:95) gave the title compound (3.8 g, 83%) as a colorless oil. ¹ H-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)

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 the mixture was stirred for 1 h. The reaction was diluted with ethyl acetate, washed with water, brine and concentrated. Flash column chromatography (ethyl acetate:heptane 1:10) gave the title compound (150 mg, 65%) as a colorless oil. ¹ H-NMR (400 MHz, CHLOROFORM-d) δ=8.16-8.12 (m, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.93-7.86 (m, 1H), 7.67-7.38 (m, 1H)

Step 3: 4-bromo-2-(difluoromethyl)-N,N-dimethylbenzenesulfonamide

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 1 N HCl, brine and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:5) gave the title compound (1.6, 71%) as a white solid ([M+H, Br] ⁺ 315.9).

Step 4: 2-(difluoromethyl)-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

4-Bromo-2-(difluoromethyl)-N,N-dimethylbenzenesulfonamide (step 3)

was converted to the title compound using General Procedure E at 80°C. ([M+H] ⁺ 362.2).

Examples

Example 56: 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

4-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (CAS: 1416713-66-0, US 2014/128374 A1) was reacted with (3-methyl-4-(methylsulfonyl)phenyl)boronic acid (1.1 equiv) at 100 °C using General Procedure D. ([M+H] ⁺ 372.2).

Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

4-(3-Methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (step 1) (40 mg, 0.1 mmol) was dissolved in dioxane/DCM (2.0/0.5 mL) and HCl (50 µL, 4 N in dioxane, 0.2 mmol) was added. The reaction was stirred for 16 h after which it was washed with saturated aqueous sodium hydrogen carbonate, water, brine, dried (Na ₂ SO ₄ ) and concentrated to give the title compound (23 mg, 67%) as a yellowish solid. ([M+H] ⁺ 288.1).

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 after which it was concentrated to dryness. Flash column chromatography (ethyl acetate:n-heptane 4:6-1:0) gave the title compound (185 mg, 71%) as a white solid ([M+H, Br] ⁺ 366.1).

Examples 57 and 58: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

Step 1: 4-chloro-1,2-dihydro-3H-pyrazolo[4,3-c]pyridin-3-one

Ethyl 2-chloro-4-fluoronicotinate was reacted with hydrazine hydrate (1 equiv.) and triethylamine (1 equiv.) in ethanol at 80°C according to General Procedure B to give the title compound. ([M+H, Cl] ⁺ 170.0).

Step 2: 4-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol

4-Chloro-1,2-dihydro-3H-pyrazolo[4,3-c]pyridin-3-one (20 mg, 0.1 mmol) in DMF (1 mL) was added sodium hydride (6 mg, 60% dispersion in mineral oil, 10 mmol) and triphenylmethyl chloride (33 mg, 0.1 mmol) at 0 °C under nitrogen. The cooling bath was removed and the reaction was stirred for 2 h until ambient temperature was reached. The reaction was quenched by addition of saturated aqueous ammonium chloride, re-extracted with ethyl acetate and the combined organic extracts were washed with brine and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:1) gave the title compound (19 mg, 37%) as a light yellow solid. ([M+H] ⁺ 412.3).

Step 3: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol

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

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

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

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

A mixture of 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (step 4) was deprotected using the general procedure to give the title compounds, separated by preparative reversed-phase HPLC. ([M+H] ⁺ 354.1 and 318.2).

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

Step 1: 3-cyclopropyl-4-(3-fluoro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

The title compound ([M+H] ⁺ 332.1) was prepared by Suzuki coupling of 4-chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (intermediate 1) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100°C according to the general procedure of G.

Step 2: 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline

To a pressure tube was added 3-cyclopropyl-4-(3-fluoro-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine (step 1) (30 mg, 0.1 mmol) and condensed with ammonia (approx. 3 mL) at -78 °C. The tube was then tightly capped and then allowed to warm to ambient temperature and stirred for 8 days. Evaporation of ammonia and flash column chromatography (ethyl acetate:n-heptane 1:1-1:0) gave the title compound (6 mg, 21%) as a white solid. ([M+H] ⁺ 329.1).

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

Step 1: 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

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

Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-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, 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 0:1-1:0) to give the title compound (40 mg, 42% yield) as a light yellow gum. ([M+H] ⁺ 418.1).

Step 3: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

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

Step 4: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine

4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (step 3) was deprotected using General Procedure I to give the title compound. ([M+H] ⁺ 366.0).

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

Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile

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

Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile

4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile (step 1) was deprotected using General Procedure I to give the title compound. ([M+H] ⁺ 313.1).

Example 62: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

3-Cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile (Example 16) (20 mg, 0.1 mmol) was suspended in aqueous sodium hydroxide (0.5 mL, 6 M, 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 reversed-phase preparative HPLC gave the title compound (8 mg, 36% yield) as a white solid. ([M+H] ⁺ 372.2).

Example 63: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile

Step 1: 2-bromo-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile

2-Bromo-4-fluorobenzonitrile was treated with DAL (1.3 equiv.) for 10 min before adding cyclopropanecarbaldehyde (1.4 equiv.) according to General Procedure A. 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)

Step 2: 2-bromo-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile

2-Bromo-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile was oxidized using General Procedure B1 to afford the title compound. 1H-MR (CHLOROFORM-d, 300 MHz) δ 7.7-7.8 (m, 1H), 7.2-7.3 (m, 1H), 2.24 (dtt, 1H, J=1.0, 4.5, 7.8 Hz), 1.4-1.5 (m, 2H), 1.2-1.3 (m, 2H)

Step 3: 3-(cyclopropanecarbonyl)-4-fluoro-2-(3-methyl-4-methylsulfonylphenyl)benzonitrile

The title compound ([M+H] ⁺ 358.2) was prepared by Suzuki coupling of 2-bromo-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 90°C according to the general procedure of G.

Step 4: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile

3-(Cyclopropanecarbonyl)-4-fluoro-2-(3-methyl-4-methylsulfonylphenyl)benzonitrile (step 3) was reacted with hydrazine hydrate (5 equiv) in THF at ambient temperature according to General Procedure B to give the title compound. ([M+H] ⁺ 352.3).

Example 64: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-ol

Step 1: 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine

A mixture of N-bromosuccinimide (109 mg, 0.6 mmol), 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-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 mixture was directly purified by preparative reversed-phase HPLC to give the title compound (30 mg, 24%) as a green solid ([M+H, Br] ⁺ 405.8).

Step 2: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-ol

In a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine (step 3) (60 mg, 0.2 mmol), potassium hydroxide (33 mg, 0.6 mmol), Pd2(dba)2 (5 mg, 0.03 mmol), tBuXPhos (4 mg, 0.01 mmol, 0.060 equiv) in dioxane (1.5 mL) and water (1 mL) and the mixture was stirred at 90 °C for 1 h under nitrogen. The reaction mixture was filtered and concentrated. Purification by preparative reversed-phase HPLC gave the title compound (6 mg, 10%) as a yellow solid. ([M+H] ⁺ 343.9)

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

Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine

3-Bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (intermediate 60, step 1) was reacted with thiophene-3-boronic acid using potassium carbonate as base at 90°C according to general procedure D. ([M+H] ⁺ 454.2).

Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine

4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-c]pyridine (step 1) was deprotected using General Procedure K2 to give the title compound. ([M+H] ⁺ 370.2).

Example 66: 3-ethoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine

Step 1: 3-ethoxy-4-(3-methyl-4-methylsulfonylphenyl)-1-tritylpyrazolo[4,3-c]pyridine

To a solution of 4-(3-methyl-4-methylsulfonylphenyl)-1-tritylpyrazolo[4,3- c ]pyridin-3-ol (Example 57, step 3) (100 mg, 0.2 mmol) in acetonitrile (2 mL) were 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) gave the title compound (60 mg, 54%) as a white solid. ([M+H] ⁺ 574.3).

Step 2: 3-ethoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine

3-Ethoxy-4-(3-methyl-4-methylsulfonylphenyl)-1-tritylpyrazolo[4,3-c]pyridine was deprotected using General Procedure I to give the title compound. ([M+H] ⁺ 332.1).

Example 67: 3-cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine

Step 1: 2-bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropylmethanol

2-Bromo-4-chloro-5-fluoropyridine was reacted with DAL (1.2 equiv) for 30 min before addition of cyclopropanecarbaldehyde (1.4 equiv) according to General Procedure A. ([M+H, Br] ⁺ 280.0)

Step 2: 2-bromo-4-chloro-5-fluoro-3-pyridyl)-cyclopropylmethanone

(2-Bromo-4-chloro-5-fluoro-3-pyridyl)cyclopropylmethanesulfonyl was oxidized using General Procedure B1 to give the title compound ([M+H, Br] ⁺ 278.0)

Step 3: [4-chloro-5-fluoro-2-(3-methyl-4-methylsulfonylphenyl)-3-pyridyl]-cyclopropylmethanone

The title compound ([M+H] ⁺ 368.1) was prepared by Suzuki coupling of 2-bromo-4-chloro-5-fluoro-3-pyridyl)cyclopropylmethanone (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100°C according to the general procedure of G.

Step 4: 3-cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine

4-Chloro-5-fluoro-2-(3-methyl-4-methylsulfonylphenyl)-3-pyridyl]cyclopropylmethanone (step 3) was reacted with hydrazine hydrate (5 equiv) in dioxane at 60 °C according to general procedure B to give the title compound. ([M+H] ⁺ 346.1).

Examples 68 and 69: 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile and 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile

Step 1: Ethyl 2-bromo-3-cyano-6-fluorobenzoate

2-Bromo-4-fluorobenzonitrile was deprotonated with DAL (1.2 equiv) for 0.5 h and reacted with ethyl chloroformate (1.2 equiv) for 0.5 h according to General Procedure A to give the title compound. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (dd, J=8.86, 5.64 Hz, 1H) 7.70 (t, J=8.76 Hz, 1H) 4.44 (q, J=7.05 Hz, 2H) 1.34 (t, J=7.05 Hz, 3H).

Step 2: 4-bromo-3-oxo-2,3-dihydro-1H-indazole-5-carbonitrile

Ethyl 2-bromo-3-cyano-6-fluorobenzoate (step 1) was reacted with hydrazine hydrate (1 equiv.) and triethylamine (1 equiv.) in ethanol at 80°C according to general procedure B to give the title compound ([M+H, Br] ⁺ 240.0).

Step 3: 4-bromo-3-hydroxy-1-trityl-1H-indazole-5-carbonitrile

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

Step 4: 3-hydroxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile

The title compound ([M-H] ^- 568.4) was prepared by Suzuki coupling of 4-bromo-3-hydroxy-1-trityl-1H-indazole-5-carbonitrile (step 3) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100 °C according to General Procedure D. Step 5: 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile and 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile

Methyl 2-chloro-2,2-difluoroacetate (20 μL, 0.2 mmol) was added 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). The reaction was stirred in a sealed tube at 80°C for 50 min. The reaction was diluted with ethyl acetate, washed with water, brine, dried (Na ₂ SO ₄ ) 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 used directly.

A mixture of 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile and 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-indazole-5-carbonitrile (step 4) was deprotected using General Procedure H to give the title compounds, separated by preparative reversed-phase HPLC ([M+H] ⁺ 342.2 and 378.2).

Example 70: 3-cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine

Step 1: Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone

2,4,6-Trichloropyridine was deprotonated with DAL (0.9 equiv) for 1 h and reacted with cyclopropanecarbaldehyde (1.2 equiv) for 1.5 h according to General Procedure A to give crude cyclopropyl(2,4,6-trichloropyridin-3-yl)methanol, which was directly oxidized using General Procedure B1 to give the title compound. ([M+H, Cl] ⁺ 250.1)

Step 2: 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine

Cyclopropyl(2,4,6-trichloropyridin-3-yl)methanone (step 1) was reacted with hydrazine hydrate (5 equiv) in ethanol at ambient temperature according to General Procedure B to give the title compound. ([M+H, Cl] ⁺ 228.1).

Step 3: 3-cyclopropyl-6-methoxy-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine

The title compound ([M+H, Cl] ⁺ 362.3) was prepared by Suzuki coupling of 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100°C according to the general procedure of G.

Step 4: 6-chloro-3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine

6-Chloro-3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3- c ]pyridine (step 3) (50 mg, 0.1 mmol) was SEM-protected using General Procedure D2. The crude product was dissolved in 2 M sodium methoxide in MeOH (2 mL) and the reaction was heated in the microwave to 130 °C for 30 min. The reaction mixture was concentrated, redissolved in trifluoroacetic acid (1 mL), ethylenediamine (0.1 mL, 1.4 mmol) was added and the mixture was stirred for 1 h. The reaction was concentrated and the residue was purified by reverse phase chromatography to afford the title compound (3 mg, 5%) as a white solid. ([M+H] ⁺ 358.2).

Example 71; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine

Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine

To a mixture of 4-(3-methyl-4-(methylsulfonyl)phenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-ol (Example 57, step 3) (45 mg, 0.1 mmol) and potassium carbonate (35 mg, 0.3 mmol) in DMF (0.8 mL) was added 1-(trifluoromethyl)-1λ3-benzo[d][1,2]iodooxol-3(1H)-one (40 mg, 0.3 mmol). The reaction was allowed to proceed at ambient temperature for 16 h, after which a second portion of potassium carbonate (35 mg, 0.3 mmol) and 1-(trifluoromethyl)-1λ3-benzo[d][1,2]iodooxol-3(1H)-one (40 mg, 0.3 mmol) were added and the mixture was stirred for another 16 h. The reaction was diluted with ethyl acetate, washed with water, brine, dried ( _Na2SO4 ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 0:1-1:4) gave the title compound (12 mg, 22%) as _a colourless gum. ([M+H] ⁺ 614.4).

Step 2: 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-c]pyridine

4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (step 1) was deprotected using General Procedure I to give the title compound. ([M+H] ⁺ 372.2).

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

Step 1: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

To a solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 62) (147 mg, 0.4 mmol) in dichloromethane (4 mL) were added 3,4-dihydro-2H-pyran (73 μL, 0.8 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.1 mmol) and the reaction was stirred for 7 h. Concentration of the reaction gave the crude title compound (181 mg, quant.) as a brown foam. ([M+H] ⁺ 456.3).

Step 2: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

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

Example 73: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

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

Example 74: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyridazine

Step 1: Methyl 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate

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

Step 2: (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol

To a solution of 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 Mb THF, 9.1 mmol) and the mixture was stirred at this temperature for 30 min before bringing to ambient temperature. The reaction was cooled again to -78 °C and water (0.3 mL) was added and the reaction was again brought to ambient temperature, Na ₂ SO ₄ was added, subsequent filtration and concentration gave the title compound (670 mg, 63%) as a white solid. ([M+H] ⁺ 223.2).

Step 3: 3-cyclopropyl-1-(tetrahydro-2H-pyran-2-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) were 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 mixture and flash column chromatography (heptane:ethyl acetate 1:1) gave the title compound (354 mg, 66%) as a light yellow oil. ([M+H] ⁺ 307.1).

Step 4: 3-cyclopropyl-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 (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:3) gave the title compound (400 mg, 68%) as a light yellow oil. ([M+H] ⁺ 433.1).

Step 5: (3-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol

To an ice-cold solution of 3-cyclopropyl-4-iodo-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole (step 4) (50 mg, 0.1 mmol) in THF (0.2 mL) under argon was added isopropylmagnesium chloride-lithium chloride complex (98 μL, 1.3 M in THF, 0.1 mmol). The reaction was warmed to ambient temperature for 5 min and then cooled again to 0 °C before quenching with a solution of 3-methyl-4-(methylsulfonyl)benzaldehyde (28 mg, 0.1 mmol) dissolved in THF (0.1 mL) and the reaction was then stirred at ambient temperature for 30 min. The reaction was diluted with ethyl acetate, washed with saturated ammonium chloride, water, brine, dried ( _Na2SO4 ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1: _9-4 :1) gave the title compound (40 mg, 62%) as an off-white solid. ([M+H] ⁺ 505.4).

Step 6: (3-cyclopropyl-5-(hydroxymethyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol

(3-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanol (step 5) (41 mg, 0.1 mmol) was dissolved in HCl (1.0 mL, 4 and in dioxane, 4.1 mmol) and water (15 μL, 0.1 mmol) was added. The reaction mixture was then stirred at 45 °C for 5 min, after which it was concentrated to give the crude title compound (40 mg, quant.) as a light yellow gum. ([M+H] ⁺ 337.2).

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 min. Hydrazine monohydrate (48 μL, 0.5 mmol) was then added and the reaction was stirred for another 16 h. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate, water, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (DCM:MeOH 1:0-1:9) gave the title compound (3 mg, 9%) as a light yellow solid. ([M+H] ⁺ 329.2).

Example 75: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole

Step 1: (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanol

(2-Bromo-4-fluorophenyl)(methyl)sulfane was reacted with DAL (1.1 equiv.) for 1 h before addition of cyclopropanecarbaldehyde (1.2 equiv.) according to General Procedure A. ¹ H NMR (300 MHz, DMS-6) δ ppm 6.98-7.11 (m, 1H), 6.91-6.98 (m, 1H), 5.25 (d, J=4.63 Hz, 1H), 4.15 (ddd, J=8.66, 4.53, 1.31 Hz, 1H), 2.24 (s, 3H), 1.16-1.35 (m, 1H), 0.11-0.49 (m, 4H)

Step 2: (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanone

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

Step 3: Cyclopropyl(3-fluoro-3'-methyl-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone

The title compound ([M+H] ⁺ 379.2) was prepared by Suzuki coupling of 4,6-dichloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100°C according to the general procedure of G.

Step 4: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylio)-1H-indazole

Cyclopropyl (3-fluoro-3'-methyl-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone (step 2) was reacted with hydrazine hydrate (15 equiv) in ethanol at 150°C (microwave treatment) according to General Procedure B to give the title compound. ([M+H] ⁺ 373.2).

Example 76: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfinyl)-1H-indazole

To an ice-cold solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole (Example 74) (23 mg, 0.1 mmol) in DCM (1 mL) was added a solution of m-chloroperbenzoic acid (124 µL, 0.5 M in DCM, 0.1 mmol) and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium hydrogen carbonate, water, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (DCM:MeOH 1:0-1:9) gave the title compound (15 mg, 59%) as a white solid. ([M+H] ⁺ 389.2).

Example 77: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole

To an ice-cold solution of 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylthio)-1H-indazole (Example 74) (26 mg, 0.1 mmol) in DCM (1 mL) was added a solution of m-chloroperbenzoic acid (263 µL, 0.5 M in DCM, 0.1 mmol) and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium hydrogen carbonate, water, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (DCM:MeOH 1:0-1:9) gave the title compound (18 mg, 61%) as a white solid. ([M+H] ⁺ 405.2).

Example 78: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-b]pyridin-5-one

Step 1: 3-iodo-5-methoxy-1-tritylpyrazolo[4,3-b]pyridine

To an ice-cold solution of 3-iodo-5-methoxy-1H-pyrazolo[4,3-b]pyridine (WO 2018/11628 A1) (1.0 g, 3.6 mmol) in DMF (20 mL) under argon atmosphere were added triphenylmethyl chloride (12.2 g, 4.4 mmol) and sodium hydride (175 mg, 60% dispersion in mineral oil, 4.4 mmol) and the reaction mixture was warmed to ambient temperature and stirred for 3 h. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, brine, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate: n-heptane 1:10) gave the title compound (0.9, 46%) as a white solid. ([M+Na] ⁺ 518.0).

Step 2: 5-methoxy-1-tritylpyrazolo[4,3-b]pyridin-3-ol

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

Step 3: 3-(difluoromethoxy)-5-methoxy-1-tritylpyrazolo[4,3-b]pyridine

A suspension of 5-methoxy-1-tritylpyrazolo[4,3-b]pyridin-3-ol (step 2) (400 mg, 1.0 mmol), sodium 2-chloro-2,2-difluoroacetate (224 mg, 1.5 mmol), cesium carbonate (640 mg, 2.0 mmol) in acetonitrile (20 mL) was stirred at 50 °C for 2 h. The reaction mixture was filtered and concentrated.

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

Step 4: 3-(Difluoromethoxy)-1,3a,4,7a-tetrahydropyrazolo[4,3-b]pyridin-5-one 3-(Difluoromethoxy)-5-methoxy-1-tritylpyrazolo[4,3-b]pyridine (step 3) (300 mg, 0.7 mmol) was dissolved in HCl (15 mL, 4 N 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)

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), 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 gave the title compound (150 mg, 52%) as a white solid. ([M+H] ⁺ 286.0)

Step 6: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[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) were added (3-methyl-4-methylsulfonylphenyl)boronic acid (150 mg, 0.7 mmol), pyridine (0.06 mL, 0.7 mmol), triethylamine (0.1 mL, 0.7 mmol) and copper(II) acetate (128 mg, 0.7 mmol) and the reaction was stirred at ambient temperature in air. After 12 h, additional (3-methyl-4-methylsulfonylphenyl)boronic acid (150 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) were added and the mixture was stirred for a further 16 h before the reaction was diluted with ethyl acetate, washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. Preparative reversed-phase HPLC gave the title compound (70 mg, 44%) as a brown solid. ([M+H] ⁺ 454.1).

Step 5: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-b]pyridin-5-one

3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-one (step 4) was deprotected using General Procedure K1 to give the title compound. ([M+H] ⁺ 370.1).

Example 79: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine

Step 1: (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanone

3-Bromo-5-fluoro-2-(trifluoromethyl)pyridine was reacted with DAL (1.1 equiv) for 1 h before addition of cyclopropanecarbaldehyde (1.2 equiv) according to General Procedure A to give crude (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanol, which was directly oxidized using General Procedure B1 to give the title compound ([M+H, Br] ⁺ 312.1).

Step 2: Cyclopropyl(5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)pyridin-4-yl)methanone

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

Step 3: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridine

3-Cyclopropyl(5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)pyridin-4-yl)methanone (step 2) was reacted with hydrazine hydrate (5 equiv) in THF at ambient temperature according to General Procedure B to give the title compound. ([M+H] ⁺ 396.2).

Example 80: 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-b]pyridin-5-one

Step 1: 3-iodo-5-methoxy-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridine

To a solution of 3-iodo-5-methoxy-1H-pyrazolo[4,3-b]pyridine (WO 2018/11628 A1) (1.6 g, 5.8 mmol) in dichloromethane (40 mL) were 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 hydrogen carbonate, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (heptane:ethyl acetate 7:3) gave the title compound (1.8 g, 82%) as a brown viscous oil. ([M+H] ⁺ 359.9).

Step 2: 3-cyclopropyl-5-methoxy-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridine

The title compound ([M+H] ⁺ 274.0) was prepared by Suzuki coupling of 3-iodo-5-methoxy-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridine (step 1) and cyclopropylboronic acid (8 equiv.) with potassium carbonate (4 equiv.) at 100°C according to the general procedure of G.

Step 3: 3-cyclopropyl-1-tetrahydropyran-2-yl-4H-pyrazolo[4,3-b]pyridin-5-one

3-Cyclopropyl-5-methoxy-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridine (step 2) (270 mg, 1.0 mmol) was dissolved in HCl (30 mL, 4 nC and 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). 3,4-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 hydrogen carbonate, dried ( _Na2SO4 ) and concentrated. Flash column chromatography (ethyl acetate) gave the title compound (170 mg, 62%) as _a colourless viscous oil. ([M+H] ⁺ 260.3).

Step 4: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[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) were added (3-methyl-4-methylsulfonylphenyl)boronic acid (150 mg, 0.7 mmol), pyridine (0.06 mL, 0.7 mmol), triethylamine (0.1 mL, 0.7 mmol) and copper(II) acetate (128 mg, 0.7 mmol) and the reaction was stirred at ambient temperature in air. After 12 h, additional (3-methyl-4-methylsulfonylphenyl)boronic acid (150 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) were added and the mixture was stirred for another 16 h before additional (3-methyl-4-methylsulfonylphenyl)boronic acid (150 mg, 0.7 mmol) and triethylamine (0.1 mL, 0.7 mmol) were added and the mixture was stirred for another 16 h, the reaction was diluted with ethyl acetate, washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by preparative TLC (ethyl acetate) gave the title compound (90 mg, 50%) as a brown gum. ([M+H] ⁺ 428.1).

Step 5: 6-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-one

To a solution of 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-one (50 mg, 0.09 mmol) (step 4) in DMF (2.5 mL) was added N-bromosuccinimide (33 mg, 0.2 mmol). The reaction was stirred for 24 h, after which the reaction was diluted with ethyl acetate, washed with water, brine, dried (Na ₂ SO ₄ ), and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:1) gave the title compound (40 mg, 68%) as a white solid ([M+H, Br] ⁺ 506.0).

Step 6: 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-one

The title compound ([M+H]+ 422.1) was prepared by Suzuki coupling of 6-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-one (step 5) and trimethylboroxine with potassium carbonate at 100°C according to the general procedure of G.

Step 7: 3-cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-b]pyridin-5-one

3-Cyclopropyl-6-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-one (step 6) was deprotected using General Procedure K1 to give the title compound. ([M+H] ⁺ 358.1).

Example 81: 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-b]pyridin-5-one

Step 1: 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-one

The title compound ([M+H] ⁺ 468.1) was prepared by Suzuki coupling of 6-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-one (Example 81, step 5) and cyclopropylboronic acid (10 equiv.) with potassium carbonate (4 equiv.) at 100°C according to General Procedure G.

Step 2: 3-cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine

3,6-Dicyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-one was deprotected using General Procedure K1 to give the title compound. ([M+H] ⁺ 384.2).

Example 82: 3-cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine

Step 1: (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanol

3-Bromo-2-(difluoromethoxy)-5-fluoropyridine was reacted with DAL (1.2 equiv) for 1 h before addition of cyclopropanecarbaldehyde (3 equiv) according to General Procedure A to give the title compound ([M+H, Br] ⁺ 312.1).

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. ¹ H 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)

Step 3: Cyclopropyl(2-(difluoromethoxy)-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone

The title compound ([M+H] ⁺ 400.3) was prepared by Suzuki coupling of (3-bromo-2-(difluoromethoxy)-5-fluoropyridin-4-yl)(cyclopropyl)methanone (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 90°C according to the general procedure of G.

Step 4: 3-cyclopropyl-5-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine

Cyclopropyl (2-(difluoromethoxy)-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone (step 3) was reacted with hydrazine hydrate (5 equiv) in THF at ambient temperature according to General Procedure B to give the title compound. ([M+H] ⁺ 394.4).

Example 83: 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

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

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

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

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

Step 1: 3-chloro-2-cyclopropyl-5-fluoropyridine

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

Step 2: (3-chloro-2-cyclopropyl-5-fluoropyridin-4-yl)(cyclopropyl)methanone

3-Chloro-2-cyclopropyl-5-fluoropyridine was reacted with DAL (1.1 equiv) for 1 h before adding cyclopropanecarbaldehyde (1.2 equiv) according to General Procedure A to give crude (3-bromo-5-fluoro-2-(trifluoromethyl)pyridin-4-yl)(cyclopropyl)methanol, which was directly oxidized using General Procedure B1 to give the title compound. ([M+H, Cl] ⁺ 240.1)

Step 3: Cyclopropyl(2-cyclopropyl-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone

The title compound ([M+H] ⁺ 374.2) was prepared by Suzuki coupling of (3-bromo-2-(3-chloro-2-cyclopropyl-5-fluoropyridin-4-yl)(cyclopropyl)methanone (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 120°C according to the general procedure of G.

Step 4: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

Cyclopropyl (2-cyclopropyl-5-fluoro-3-(3-methyl-4-(methylsulfonyl)phenyl)pyridin-4-yl)methanone (step 3) was reacted with hydrazine hydrate (100 equiv) in THF at 170°C (microwave treatment) according to General Procedure B to give the title compound. ([M+H] ⁺ 368.2).

Example 86: N,3-dicyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

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

Example 87: 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide

Step 1: 6-chloro-2,4-difluoro-3-(triethylsilyl)benzonitrile

To a solution of 2-chloro-4,6-difluorobenzonitrile (100 mg, 0.6 mmol) dissolved in THF (2 mL) under Ar and cooled to -78 °C was added DAL (0.3 mL, 0.7 mmol) and the mixture was stirred for 5 min, after which chlorotrimethylsilane (0.1 mL, 0.6 mmol) was added and the reaction was stirred for another 30 min. The reaction was quenched by addition of saturated aqueous ammonium chloride, allowed to reach ambient temperature, extracted with ethyl acetate, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (heptane) gave the title compound (127 mg, 73%) as a colorless oil. 1H-NMR (CHLOROFORM-d, 300 MHz) δ 7.03 (dd, W, J=1.4, 8.1 Hz), 0.9-1.0 (m, 15H)

Step 2: 2-chloro-3-(cyclopropyl(hydroxy)methyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile

6-Chloro-2,4-difluoro-3-(triethylsilyl)benzonitrile (step 1) was reacted with DAL (1.2 equiv) for 0.25 h before adding cyclopropanecarbaldehyde (1.3 equiv) according to General Procedure A to give the title compound ([M+H, Cl] ⁺ 381.2).

Step 3: 2-chloro-3-(cyclopropanecarbonyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile

2-Chloro-3-(cyclopropyl(hydroxy)methyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile (step 2) was oxidized using General Procedure B1 to give the title compound. 1H NMR (CHLOROFORM-d, 300 MHz) δ 2.22 (dtt, 1H, J=1.3, 4.5, 7.8 Hz), 1.37 (t, 2H, J=3.9 Hz), 1.1-1.2 (m, 2H), 0.9-1.0 (t, 15H)

Step 4: 6-(cyclopropanecarbonyl)-3,5-difluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile

The title compound ([M+H] ⁺ 376.4) was prepared by Suzuki coupling of 2-chloro-3-(cyclopropanecarbonyl)-4,6-difluoro-5-(triethylsilyl)benzonitrile (step 3) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 120°C according to the general procedure of G.

Step 5: 3-cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide

6-(Cyclopropanecarbonyl)-3,5-difluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile (step 4) was reacted with hydrazine hydrate (2 equiv) in THF at ambient temperature according to General Procedure B to give the title compound. ([M+H] ⁺ 370.2).

Example 88 and 89: 3-cyclopropyl-6-fluoro-N-methyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carboxamide and 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

3-Cyclopropyl-6-fluoro-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile (Example 87) (20 mg, 54 μmol) was suspended in sodium hydroxide (3 mL, 3 M in water, 9 mmol) and heated to 150°C in a microwave oven for 4.5 h. The reaction was acidified with 6 N hydrochloric acid and extracted with ethyl acetate, the combined organic material was dried (Na ₂ SO ₄ ) and concentrated to give a crude mixture (1:1) of 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide and 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid. Reaction with methylamine hydrochloride, prepared in analogy to Example 72, followed by reversed-phase preparative HPLC gave the two title compounds ([M+H] ⁺ 402.3 and 388.2).

Example 90: 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile

Step 1: 2,6-dichloro-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile

2,6-Dichloro-4-fluorobenzonitrile was reacted with DAL (1.0 equiv) for 1 h before addition of cyclopropanecarbaldehyde (1.2 equiv) according to General Procedure A to give the title compound ([M- _H2O , 2Cl] ⁺ 242.1).

Step 2: 2,6-dichloro-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile

2,6-Dichloro-3-(cyclopropyl(hydroxy)methyl)-4-fluorobenzonitrile (step 1) was oxidized using General Procedure B1 to give the title compound. ([M+H, 2Cl] ⁺ 258.1).

Step 3: 3-chloro-6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile

The title compound ([M+H,Cl] ⁺ 392.2) was prepared by Suzuki coupling of 2,6-dichloro-3-(cyclopropanecarbonyl)-4-fluorobenzonitrile (step 2) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with cesium carbonate at 100°C according to the general procedure of G.

Step 4: 6-chloro-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-carbonitrile

3-Chloro-6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-carbonitrile (step 3) was reacted with hydrazine hydrate (15 equiv) in THF at ambient temperature according to General Procedure B to give the title compound. ([M+H,Cl] ⁺ 386.2).

Example 91: 4-(3-methyl-4-methylsulfonylphenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one

Step 1: 5-methoxy-3-(trifluoromethoxy)-1-tritylpyrazolo[4,3-b]pyridine

To a solution of 5-methoxy-1-tritylpyrazolo[4,3-b]pyridin-3-ol (Example 78, step 2) (430 mg, 1.1 mmol) in DMF (16 mL) were added potassium carbonate (438 mg, 3.2 mmol) and 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (1001 mg, 3.2 mmol). The mixture was stirred at 25 °C for 16 h, after which 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) were added and the reaction was stirred for another 12 h. The reaction was diluted with water and re-extracted with ethyl acetate. The combined organic material was washed with brine, dried ( _Na2SO4 ) and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:10) gave the title compound (110 mg, 21%) as _a white solid. ([M+H] ⁺ 476.1).

Step 2: 3-(trifluoromethoxy)-1-trityl-4H-pyrazolo[4,3-b]pyridin-5-one

A solution of 5-methoxy-3-(trifluoromethoxy)-1-tritylpyrazolo[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) gave the title compound (60 mg, 53%) as a white solid. ([M+H] ⁺ 462.1).

Step 3: 4-(3-methyl-4-methylsulfonylphenyl)-3-(trifluoromethoxy)-1-tritylpyrazolo[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) were added (3-methyl-4-methylsulfonylphenyl)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 oxygen (balloon). After 12 h, additional (3-methyl-4-methylsulfonylphenyl)boronic acid (51 mg, 0.2 mmol), pyridine (0.02 mL, 0.2 mmol), triethylamine (0.03 mL, 0.2 mmol) were added and the mixture was stirred for a further 12 h before diluting the reaction with ethyl acetate and filtering. Purification by preparative TLC gave the title compound (90 mg, 63%) as a white solid. ([M+H] ⁺ 630.1).

Step 4: 4-(3-methyl-4-methylsulfonylphenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one

4-(3-Methyl-4-methylsulfonylphenyl)-3-(trifluoromethoxy)-1-tritylpyrazolo[4,3-b]pyridin-5-one was deprotected using General Procedure K1 to give the title compound. ([M+H] ⁺ 388.1).

Example 92: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrrolo[3,2-b]pyridin-5-one

Step 1: 3-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridine

To a solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (1.0 g, 6.75 mmol, 1 equiv.) in DMF (20 mL) was added N-bromosuccinimide (1.4 g, 7.1 mmol) at 25 °C and the reaction mixture was stirred at ambient temperature for 16 h. The reaction was diluted with water and re-extracted with ethyl acetate. The combined organic material was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane = 0:1-1:8) gave the title compound (1.2, 76%) as a white solid ([M+H, Br] ⁺ 227.0).

Step 2: 2-[(3-bromo-5-methoxypyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyltrimethylsilane

3-bromo-5-methoxy-1H-pyrrolo[3,2-b]pyridine (step 1) was converted to the title compound using General Procedure D1 in THF ([M+H, Br] ⁺ 357.1).

Step 3: 2-[(3-cyclopropyl-5-methoxypyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyltrimethylsilane

The title compound ([M+H1] ⁺ 319.2) was prepared by Suzuki coupling of 2-[(3-bromo-5-methoxypyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyltrimethylsilane (step 2) and cyclopropylboronic acid (10 equiv.) with potassium carbonate (8 equiv.) at 100°C according to the general procedure of G.

Step 4: 3-cyclopropyl-1-(methoxymethyl)-4H-pyrrolo[3,2-b]pyridin-5-one

A solution of 2-[(3-cyclopropyl-5-methoxypyrrolo[3,2-b]pyridin-1-yl)methoxy]ethyltrimethylsilane (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) gave the title compound (140 mg, 58%) as a yellowish solid. ([M+H] ⁺ 219.1).

Step 5: 3-cyclopropyl-1-(methoxymethyl)-4-(3-methyl-4-methylsulfonylphenyl)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) were added (3-methyl-4-methylsulfonylphenyl)boronic acid (250 mg, 1.2 mmol), pyridine (0.09 mL, 1.2 mmol), triethylamine (0.16 mL, 1.2 mmol) and copper(II) acetate (212 mg, 1.2 mmol) and the reaction was stirred at ambient temperature under an oxygen atmosphere (balloon). After 2 h, an additional portion of (3-methyl-4-methylsulfonylphenyl)boronic acid (250 mg, 1.2 mmol) and triethylamine (0.16 mL, 1.2 mmol) were added and the mixture was stirred for a further 2 h before a third identical repeat addition of the boronic acid and triethylamine and the reaction was stirred for a further 12 h. The reaction was then filtered and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:1) gave the title compound (170 mg, 68%) as a yellow solid. ([M+H] ⁺ 387.1).

Step 6: 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrrolo[3,2-b]pyridin-5-one

3-Cyclopropyl-1-(methoxymethyl)-4-(3-methyl-4-methylsulfonylphenyl)pyrrolo[3,2-b]pyridin-5-one (step 5) was deprotected using General Procedure A to give the title compound. ([M+H] ⁺ 343.2).

Example 93; 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole

Step 1: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol

The title compound ([M-H] ⁼ 621.5) was prepared by Suzuki coupling of 4-bromo-5-(methylsulfonyl)-1-trityl-1H-indazol-3-ol (intermediate 16, step 4) and (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate at 100°C according to the general procedure of G.

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) were added potassium carbonate (137 mg, 1.0 mmol) and 1-(trifluoromethyl)-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one (165 mg, 0.5 mmol) and the mixture was stirred for 18 h at ambient temperature. The reaction was concentrated to dryness, suspended in ethyl acetate, washed with water, dried (Na ₂ SO ₄ ), and concentrated. Flash column chromatography (heptane:ethyl acetate 1:9-0:1) gave the title compound (46 mg, 20%) as a white solid. ([M+NH ₄ ⁺ ] ⁺ 708.5)

Step 3: 4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1H-indazole

4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-3-(trifluoromethoxy)-1-trityl-1H-indazole (step 2) was deprotected using General Procedure K1 to give the title compound. ([M+H] ⁺ 449.2).

Example 94: 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole

Step 1: Cyclopropyl(3'-(difluoromethyl)-3-fluoro-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone

The title compound ([M+H] ⁺ 415.2) was prepared by Suzuki coupling of (2-bromo-6-fluoro-3-(methylthio)phenyl)(cyclopropyl)methanone (Example 75, step 2) and 2-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 21) with potassium carbonate at 100°C according to General Procedure D. Step 2: cyclopropyl(3'-(difluoromethyl)-3-fluoro-4',6-bis(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methanone

Cyclopropyl(3'-(difluoromethyl)-3-fluoro-4'-(methylsulfonyl)-6-(methylthio)-[1,1'-biphenyl]-2-yl)methanone (step 1) was converted to the title compound using General Procedure G. ([M+H] ⁺ 447.3).

Step 3: 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole

Cyclopropyl(3'-(difluoromethyl)-3-fluoro-4',6-bis(methylsulfonyl)-[1,1'-biphenyl]-2-yl)methanone (step 2) was reacted with hydrazine hydrate (2 eq.) in THF at ambient temperature according to General Procedure B to give the title compound. ([M+H] ⁺ 441.2).

Example 95: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

Step 1: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

To a solution of 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-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 and acidified with concentrated aqueous HCl, re-extracted with ethyl acetate, and the combined organic material was dried (Na ₂ SO ₄ ) and concentrated to give the title compound.

(100 mg, 95%) as a yellow solid. ([M+H] ⁺ 398.0)

Step 2: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

The title compound ([M+H] ⁺ 411.1) was prepared in analogy to Example 72 from 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 4) and methylamine hydrochloride.

Example 96: 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

Step 1: 1-bromo-4-cyclopropylsulfanyl-2-fluoro-5-methylbenzene

To a stirred suspension of potassium tert-butoxide (61 mg, 0.5 mmol) in DMSO (1 mL) was added 4-bromo-5-fluoro-2-methylbenzenethiol (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 re-extracted with ethyl acetate and the combined organic material was dried (Na ₂ SO ₄ ) and concentrated. Purification by preparative TLC (heptane) gave the title compound (60 mg, 51%) as a colourless oil. 1H-NMR (400 MHz, CHLOROFORM-d) δ = 7.29 (d, J = 9.5 Hz, 1H), 7.27-7.24 (m, 1H), 2.18 (s, 3H), 2.13-2.06 (m, 1H), 1.19-1.13 (m, 2H), 0.75-0.67 (m, 2H)

Step 2: 1-bromo-4-cyclopropylsulfonyl-2-fluoro-5-methylbenzene

1-Bromo-4-cyclopropylsulfanyl-2-fluoro-5-methylbenzene (step 1) was converted to the title compound using General Procedure G. ([M+H] ⁺ 293.0).

Step 3: 2-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-Bromo-4-cyclopropylsulfonyl-2-fluoro-5-methylbenzene (step 2) was converted to the title compound using General Procedure E. ([M+H] ⁺ 258.9).

Step 4: 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

The title compound ([M+H] ⁺ 397.2) was prepared by Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-tritylpyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 17), 2-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (step 4) with potassium carbonate and the adduct of 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride and dichloromethane (0.5 equiv.) at 120°C according to General Procedure G.

Step 5: 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

To a solution of 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-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, 6 N, 0.3 mmol) and the reaction was heated to 100 °C for 38 h. The reaction mixture was cooled to 0 °C and acidified with concentrated aqueous HCl, re-extracted with ethyl acetate, and the combined organic material was dried (Na ₂ SO ₄ ) and concentrated to give the title compound (20 mg, 95%). ([M+H] ⁺ 416.1)

Step 6: 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

The title compound ([M+H] ⁺ 429.1) was prepared in analogy to Example 72 from 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 5) and methylamine hydrochloride.

Example 97: 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

Step 1: 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

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

Step 2: 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

The title compound ([M+H] ⁺ 403.1) was prepared in analogy to Example 72 from 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 1) and methylamine hydrochloride.

Example 98: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

To a solution of 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-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, 6 N, 0.3 mmol) and the reaction was heated to 100 °C for 12 h. The reaction mixture was concentrated and the residue was purified by reverse-phase preparative HPLC to give the title compound (28 mg, 26%) as a white solid. ([M+H] ⁺ 397.1)

Example 99: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide; formate salt

Step 1: 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridine

To a solution of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine (Example 64, step 1) (100 mg, 0.3 mmol) in THF (1 mL) were added p-toluenesulfonic acid monohydrate (13 mg, 0.1 mmol) and dihydropyran (0.07 mL, 0.7 mmol), and the reaction solution was stirred at 60 °C for 12 h. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and the combined organics were dried (Na ₂ SO ₄ ) and concentrated. Purification by preparative TLC (heptane:ethyl acetate 1:1) gave the title compound (60 mg, 50%) as a yellow oil ([M+H, Br] ⁺ 490.0).

Step 2: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide

To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[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) ₂ (4.6 mg, 0.02 mmol) and stirred at 80 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed-phase preparative HPLC gave the title compound (40 mg, 34%) as a yellow solid. ([M+H] ⁺ 556.2)

Step 3: N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide; formate salt

N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]acetamide (step 2) was deprotected using General Procedure K1 to give the title compound ([M+H] ⁺ 472.3).

Example 100: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide; formate salt

Step 1: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide

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

Step 2: N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide; formate salt

N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]propyl]acetamide (step 1) was deprotected using General Procedure K1 to afford the title compound. ([M+H] ⁺ 441.9).

Example 101: N-[2-(2-aminoethoxy)ethyl]-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-amine; formate salt

Step 1: tert-Butyl N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]carbamate

To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridine (Example 99, step 1) (120 mg, 0.2 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (399 mg, 1.2 mmol), N-Boc-2-(2-aminoethoxy)ethylamine (150 mg, 0.7 mmol), xantphos (17 mg, 0.03 mmol) and Pd(OAc) ₂ (5 mg, 0.02 mmol) and stirred at 80 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed-phase preparative HPLC gave the title compound (98 mg, 62%) as a yellow solid. ([M+H] ⁺ 614.2)

Step 2: N-[2-(2-aminoethoxy)ethyl]-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-amine; formate salt

Tert-butyl N-[2-[2-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]ethoxy]ethyl]carbamate (step 1) was deprotected using General Procedure K1 to afford the title compound. ([M+H] ⁺ 430.1).

Example 102: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]butane-1,4-diamine

Step 1: tert-Butyl N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]butyl]carbamate

To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridine (Example 99, step 1) (130 mg, 0.3 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (432 mg, 1.3 mmol), N-Boc-1,4-diaminobutane (150 mg, 0.8 mmol), Xantphos (18 mg, 0.03 mmol) and Pd(OAc) ₂ (6 mg, 0.03 mmol) and stirred at 80 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed-phase preparative HPLC gave the title compound (90 mg, 56%) as a yellow solid. ([M+H] ⁺ 598.2)

Step 2: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]butane-1,4-diamine

Tert-butyl N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]butyl]carbamate (step 1) was deprotected using General Procedure K1 to give the title compound. ([M+H] ⁺ 414.1).

Example 103: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide

Step 1: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide

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

Step 2: N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide

N-[4-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]butyl]acetamide (step 1) was deprotected using General Procedure K1 to afford the title compound. ([M+H] ⁺ 499.9).

Example 104: N'-[3-cyclopropyl-4-(3-methyl-4-methylsutphonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]propan-1,3-diamine

Step 1: tert-Butyl N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]propyl]carbamate

To a mixture of 7-bromo-3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridine (Example 99, step 1) (100 mg, 0.2 mmol) in 1,4-dioxane (4 mL) was added cesium carbonate (332 mg, 1.0 mmol), N-Boc-1,3-diaminopropane (107 mg, 0.6 mmol), Xantphos (14 mg, 0.02 mmol) and Pd(OAc) ₂ (5 mg, 0.02 mmol) and stirred at 80 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated. Purification by reversed-phase preparative HPLC gave the title compound (50 mg, 42%) as a brown oil. ([M+H] ⁺ 584.4)

Step 2: N'-[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridin-7-yl]propan-1,3-diamine

Tert-butyl N-[3-[[3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-7-yl]amino]propyl]carbamate (step 1) was deprotected using General Procedure K1 to give the title compound. ([M+H] ⁺ 399.9).

Example 105: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

Step 1: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

The title compound ([M+formate] ⁼ 701.3) was prepared by Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-tritylpyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 17), 2-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (step 4) with potassium carbonate and the adduct of 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride and dichloromethane (0.05 equiv.) at 100°C according to General Procedure G.

Step 2: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile was deprotected using General Procedure I to afford the title compound ([M+H] ⁺ 415.2) after flash column chromatography.

Example 106: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

Step 1: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1-tritylpyrazolo[3,4-c]pyridine-5-carboxamide

To a solution of 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1-tritylpyrazolo[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 mL, 10.23 mmol). The reaction was stirred for 16 h, after which it was diluted with water, resulting in the precipitation of the product. The suspension was aged, filtered, and the filter cake was washed with water and dried to afford the title product compound (325 mg, quant.) as a yellowish powder. ([M+N] ⁺ 675.3)

Step 2: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1-tritylpyrazolo[3,4-c]pyridine-5-carboxamide was deprotected using General Procedure I to afford the title compound ([M+H] ⁺ 433.2) after flash column chromatography.

Example 107: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

Step 1: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonic acid

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

Step 2: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

The title compound ([M+H] ⁺ 489.2) was prepared in analogy to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 1) and oxetan-3-ylamine.

Example 108: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

The title compound ([M+H] ⁺ 447.1) was prepared in analogy to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 107, step 1) and methylamine hydrochloride.

Example 109: 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-N-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

The title compound ([M+H] ⁺ 447.1) was prepared in analogy to Example 72 from 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (Example 107, step 1) and 2-methoxyethylamine.

Example 110: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

Step 1: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid

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

Step 2: 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

The title compound ([M+H] ⁺ 411.3) was prepared in analogy to Example 72 from 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid (step 1) and methylamine hydrochloride.

Example 111: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole

Step 1: 3-(2-bromo-4-fluorophenyl)sulfanyloxyetane

To a stirred suspension of 3-iodoxetane (10.4 g, 56.5 mmol) in DMF (30 mL) were 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 (Na ₂ SO ₄ ), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:10-1:3) gave the title compound (4.1 g, 83%) as a yellow oil. 1H-NMR (400 MHz, CHLOROFORM-d) δ = 7.37 (dd, J=2.7, 8.1 Hz, 1H), 7.12-7.07 (m, 1H), 7.05-6.98 m, 1H), 5.06 (t, J=7.1 Hz, 2H), 4.68 (t, J=6.6 Hz, 2H), 4.49-4.41 (m, 1H)

Step 2: Ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfanyl)benzoate

3-(2-Bromo-4-fluorophenyl)sulfanyloxetane (step 1) was deprotonated with DAL (1.1 equiv) for 30 min and reacted with ethyl chloroformate (1.2 equiv) according to General Procedure A to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.12-7.05 (m, 2H), 5.07 (t, J=7.1 Hz, 2H), 4.67 (t, J=6.6 Hz, 2H), 4.50-4.42 (m, 3H), 1.42 (t, J=7.1 Hz, 3H)

Step 3: Ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfonyl)benzoate

To a solution of ethyl 2-bromo-6-fluoro-3-(oxetan-3-ylsulfanyl)benzoate (step 2) (4.1 g, 12.2 mmol) in dichloromethane (100 mL) was added mCPBA (6.2 g, 30.6 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction was then diluted with DCM, washed with 1 aq. saturated sodium hydrogen carbonate solution, dried (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 3:1-1:1) gave the title compound (4.6 g, 87%) as a yellow solid. 1H-NMR (400 MHz, CHLOROFORM-d) δ = 8.31 (dd, J=5.6, 8.9 Hz, 1H), 7.33 (dd, J=7.6, 8.9 Hz, 1H), 5.03-4.96 (m, 3H), 4.89-4.83 (m, 2H), 4.49 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H)

Step 4: 4-bromo-5-(oxetan-3-ylsulfonyl)-1,2-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 brought to ambient temperature. It was heated to 80 °C for 2 h, after which the reaction was concentrated to dryness. Reversed-phase preparative HPLC gave the title compound (2.8 g, 67%), which was obtained as a light yellow solid ([M+H, Br] ⁺ 335.0).

Step 5: 4-bromo-5-(oxetan-3-ylsulfonyl)-1-tritylindazol-3-ol

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

Step 6: 4-bromo-3-(difluoromethoxy)-5-(oxetan-3-ylsulfonyl)-1-trityl lindazole

A mixture of 4-bromo-5-(oxetan-3-ylsulfonyl)-1-tritylindazol-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 (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:3-1:0) gave the title compound (2.8 g, 86%) as a white solid. ([M+Na] ⁺ 649.1).

Step 7: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-5-(oxetan-3-ylsulfonyl)-1-tritylindazole

The title compound ([M+Na ⁺ ] ⁺ 737.4) was prepared by Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-(oxetan-3-ylsulfonyl)-1-tritylindazole (step 6), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and the adduct of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride and dichloromethane (0.1 equiv.) at 100°C according to General Procedure G.

Step 8: 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole

3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-5-(oxetan-3-ylsulfonyl)-1-tritylindazole (step 7) was deprotected using General Procedure I to give the title compound ([M+H] ⁺ 495.2) after flash column chromatography.

Example 112; [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-iminomethyloxosulfan

Step 1: (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(imino)(methyl)-λ6-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) were 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 (Na ₂ SO ₄ ), and concentrated. Flash column chromatography (dichloromethane:MeOH 1:0-9:1) gave the title compound (199 mg, 72%) as a white solid. ([M+H] ⁺ 410.2).

Step 2: [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-iminomethyloxosulfan

To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(imino)(methyl)-λ6-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) gave the title compound (10 mg, 67%) as a white solid. ([M+H] ⁺ 404.1).

Example 113: [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-methylmethyliminooxo-λ ⁶ -sulfan

Step 1: (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(methyl)(methylimino)-λ6-sulfanone

To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(imino)(methyl)-λ6-sulfanone (50 mg, 122 μmol) in DMF (1 mL) were 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 (Na ₂ SO ₄ ) and concentrated. Reversed-phase preparative HPLC gave the title compound (22 mg, 37%) as a white solid. ([M+H] ⁺ 424.2).

Step 2: [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-methylmethyliminooxo-λ ⁶ -sulfan

To a solution of (6-(cyclopropanecarbonyl)-5-fluoro-3'-methyl-4'-(methylsulfonyl)-[1,1'-biphenyl]-2-yl)(methyl)(methylimino)-λ6-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) and the reaction was stirred at ambient temperature for 16 h, after which the reaction was concentrated to dryness. Flash column chromatography (dichloromethane:MeOH 9:1) gave the title compound (19 mg, 85%) as a white solid. ([M+H] ⁺ 418.2).

Example 114: 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-sulfonamide

Step 1: 2-bromo-4-fluoro-N,N-dimethylbenzenesulfonamide

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 for 2 h at ambient temperature. The reaction was diluted with ethyl acetate, washed with 1 M HCl and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:10-3:1) gave the title compound (1.8 g, 83%) as a white solid ([M+H, Br] ⁺ 282.0).

Step 2: 2-bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethylbenzenesulfonamide

2-Bromo-4-fluoro-N,N-dimethylbenzenesulfonamide (step 1) was deprotonated with DAL (1.2 equiv) for 0.5 h and reacted with cyclopropanecarboxaldehyde (1.5 equiv) for 1 h according to General Procedure A to give the title compound ([M+H(-OH), Br] ⁺ 334.0.

Step 3: 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N,N-dimethylbenzenesulfonamide

2-Bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethylbenzenesulfonamide (step 2) was oxidized using General Procedure B2 to give the title compound ([M+H, Br] ⁺ 350.0.

Step 4: 4-bromo-3-cyclopropyl-N,N-dimethyl-1H-indazole-5-sulfonamide

To a solution of 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N,N-dimethylbenzenesulfonamide (step 3) (60 mg, 170 μmol) in ethanol (2 mL) was added hydrazine monohydrate (170 μL, 316 μmol) followed by triethylamine (30 μL, 210 μmol) and the reaction was heated to 80 °C for 16 h, after which the reaction was concentrated to dryness. Reversed-phase preparative HPLC gave the title compound (40 mg, 67%) as a light yellow solid ([M+H, Br] ⁺ 346.1).

Step 5: 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-sulfonamide

The title compound ([M+Na ⁺ ] ⁺ 434.2) was prepared by Suzuki coupling of 4-bromo-3-cyclopropyl-N,N-dimethyl-1H-indazole-5-sulfonamide (step 4), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and the adduct of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride and dichloromethane (0.1 equiv.) at 100°C according to the general procedure of G.

Example 115: 3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-sulfonamide

Step 1: 2-bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide

To a solution of 2-bromo-4-fluorobenzenesulfonyl chloride (2.0 g, 7.31 mmol) in dichloromethane (20 mL) were added diisopropylethylamine (1.6 mL, 14.6 mmol) and 4-methoxy-N-methylbenzylamine (1.7 g, 11.0 mmol) and the reaction mixture was stirred for 2 h at ambient temperature. 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).

Step 2: 2-bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide

2-Bromo-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide (step 1) was deprotonated with DAL (1.2 equiv) for 0.5 h and reacted with cyclopropanecarboxaldehyde (1.5 equiv) for 1 h according to general procedure A to give the title compound ([M+Na, Br] ⁺ 482.1).

Step 3: 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide

2-Bromo-3-[cyclopropyl(hydroxy)methyl]-4-fluoro-N,N-dimethylbenzenesulfonamide (step 2) was oxidized using General Procedure B2 to give the title compound ([M+H, Br] ⁺ 480.2).

Step 4: 4-bromo-3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-1H-indazole-5-sulfonamide

To a solution of 2-bromo-3-(cyclopropanecarbonyl)-4-fluoro-N-[(4-methoxyphenyl)methyl]-N-methylbenzenesulfonamide (step 3) (200 mg, 440 μmol) in ethanol (4 mL) was added hydrazine monohydrate (44 μL, 880 μmol) followed by triethylamine (70 μL, 530 μmol) and the reaction was heated to 80 °C for 2 h, after which the reaction was concentrated to dryness. Reversed-phase preparative HPLC gave the title compound (200 mg, quant.) as a white solid ([M+H, Br] ⁺ 450.0).

Step 5: 3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-4-(3-methyl-4-methylsulfonyl-phenyl)-1H-indazole-5-sulfonamide

The title compound ([M+Na ⁺ ] ⁺ 540.2) was prepared by Suzuki coupling of 4-bromo-3-cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-1H-indazole-5-sulfonamide (step 4), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and the adduct of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride and dichloromethane (0.1 equiv.) at 100°C according to the general procedure of G.

Step 6: 3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-sulfonamide

3-Cyclopropyl-N-[(4-methoxyphenyl)methyl]-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-sulfonamide (step 5) was deprotected using General Procedure I to give the title compound ([M+H]+ 420.0) after flash column chromatography.

Example 116: 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

Step 1: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile

The title compound ([M+Na] ⁺ 669.3) was prepared by Suzuki coupling of 4-bromo-3-(difluoromethoxy)-1-tritylpyrazolo[3,4-c]pyridine-5-carbonitrile (intermediate 17) and 2-(4-(cyclopropylsulfonyl)-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 8) with potassium carbonate and the adduct of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride and dichloromethane (0.05 equiv.) at 100°C according to General Procedure G.

Step 2: 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1-tritylpyrazolo[3,4-c]pyridine-5-carboxamide

To a solution of 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1-tritylpyrazolo[3,4-c]pyridine-5-carbonitrile (step 1) (220.0 mg, 0.34 mmol) in ethanol (5 mL) was added 2 N aq. NaOH (0.85 mL, 1.7 mmol) and the reaction was heated to 100 °C for 6 h. The reaction was acidified by adding 1 N HCl, extracted with ethyl acetate and concentrated. Preparative TLC (ethyl acetate:n-heptane 1:2) gave the title compound (150 mg, 66%) as a yellow solid.

Step 3: 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

4-(4-Cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1-tritylpyrazolo[3,4-c]pyridine-5-carboxamide (step 2) was deprotected using General Procedure I to afford the title compound ([M+H]+ 423.2) after flash column chromatography.

Example 117: 3-(difluoromethoxy)-4-(4-((difluoromethyl)sulfonyl)-3-methylphenyl)-5-(methylsulfonyl)-1H-indazole

The title compound ([M+Na] ⁺ 465.1) can be prepared in analogy to Example 49 by a Suzuki coupling from 4-bromo-3-(difluoromethoxy)-5-(methylsulfonyl)-1-trityl-1H-indazole (intermediate 6) and 2-[4-(difluoromethylsulfonyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 27) followed by deprotection using the general procedure I.

Example 118: 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole

Step 1: 2-bromo-1-cyclopropylsulfanyl-4-fluorobenzene

To a stirred suspension of cyclopropyl bromide (6.1 g, 50.71 mmol) in DMF (50 mL) were 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 (Na ₂ SO ₄ ), and concentrated. Flash column chromatography (n-heptane) gave the title compound (1.7 g, 41%) as a colorless oil. 1H-NMR (400 MHz, CHLOROFORM-d) δ = 7.50 (dd, J=5.6, 8.4 Hz, 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)

Step 2: Ethyl 2-bromo-3-cyclopropylsulfanyl 6-fluorobenzoate

2-Bromo-1-cyclopropylsulfanyl-4-fluorobenzene (step 1) was deprotonated with DAL (1.1 equiv) for 30 min and reacted with ethyl chloroformate (1.2 equiv) according to General Procedure A 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)

Step 3: Ethyl 2-bromo-3-cyclopropylsulfanyl 6-fluorobenzoate To a solution of ethyl 2-bromo-3-cyclopropylsulfanyl 6-fluorobenzoate (step 2) (1.9 g, 5.95 mmol) in dichloromethane (40 mL) was added mCPBA (3.6 g, 17.9 mmol) and the reaction was stirred at ambient temperature for 12 h. The reaction was then diluted with DCM, washed with 1 aq. sat. sodium hydrogen carbonate solution, dried (Na ₂ SO ₄ ), and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:5-1:3) gave the title compound (2.0 g, 84%) as a white solid ([M+H, Br] ⁺ 353.0).

Step 4: 4-bromo-5-cyclopropylsulfonyl-1,2-dihydroindazol-3-one

To an ice-cold solution of ethyl 2-bromo-3-cyclopropylsulfonyl 6-fluorobenzoate (step 3) (2.0 g, 5.69 mmol) in ethanol (20 mL) was added hydrazine monohydrate (ISO 22.6 µL, 22.6 mmol) followed by triethylamine (0.79 mL, 5.69 mmol) and the reaction was brought to ambient temperature. It was heated to 80 °C for 2 h, after which the reaction was concentrated to dryness. Reversed-phase preparative HPLC gave the title compound (1.1 g, 58%), which was obtained as an off-white solid ([M+H, Br] ⁺ 316.8).

Step 5: 4-bromo-5-cyclopropylsulfonyl-1-tritylindazol-3-ol

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

Step 6: 4-bromo-5-cyclopropylsulfonyl-3-(difluoromethoxy)-1-tritylindazole

A mixture of 4-bromo-5-cyclopropylsulfonyl-1-tritylindazol-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 (Na ₂ SO ₄ ) and concentrated. Flash column chromatography (ethyl acetate:n-heptane 1:5-1:3) gave the title compound (1.1 g, 83%) as a light yellow solid. ([M+Na] ⁺ 633.0).

Step 7: 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1-tritylindazole

The title compound ([M+Na ⁺ ] ⁺ 721.1) was prepared by Suzuki coupling of 4-bromo-5-cyclopropylsulfonyl-3-(difluoromethoxy)-1-tritylindazole (step 6), (3-methyl-4-(methylsulfonyl)phenyl)boronic acid with potassium carbonate and the adduct of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride and dichloromethane (0.1 equiv.) at 100°C according to the general procedure of G.

Step 8: 5-cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole

5-Cyclopropylsulfonyl-3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1-tritylindazole (step 7) was deprotected using General Procedure I to give the title compound ([M+H]+ 457.2) after flash column chromatography.

Example 119: 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-5-methylsulfonyl-1H-indazole

Step 1: 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-5-methylsulfonyl-1-tritylindazole

The title compound ([M+Na+] ⁺ 713.2) was prepared by Suzuki coupling of 4-bromo-3-(difluoromethoxy)-5-methylsulfonyl-1-tritylindazole (intermediate 36), (2-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 25) with potassium carbonate and SPhosPd G3 (0.1 equiv.) at 100°C according to the general procedure of G.

Step 2: 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-5-methylsulfonyl-1H-indazole

3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-5-methylsulfonyl-1-tritylindazole (step 1) was deprotected using General Procedure I to give the title compound ([M+H]+ 448.0) after flash column chromatography.

Example 120: 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide

Step 1: 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1-tritylpyrazolo[3,4-c]pyridine-5-carboxamide

To a solution of 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1-tritylpyrazolo[3,4-c]pyridine-5-carboxamide (Example 116, step 2) (150.0 mg, 0.23 mmol) in DMF (1 mL) was added NaH (5.4 mg, 0.23 mmol) at 0 °C and the reaction was allowed to reach ambient temperature, after which 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 (Na ₂ SO ₄ ) and concentrated. Preparative TLC (ethyl acetate:n-heptane 1:3) gave the title compound (110 mg, 73%) as a white solid. ([M+H] ⁺ 679.2).

Claims (290)

1. Compound of formula I Where X ¹ is either N or C, X ² is either N or CR ⁴ , X ³ is either N or CR ⁵ , X ⁴ is either N or CH, provided that no more than two of X ¹ , X ² , and X ³ represent N; the dotted lines represent a single or double bond to ensure that six-membered rings are aromatic, provided that when X ¹ is N and X ² is C=O, then the bond between X ¹ and X ² , the bond between X ² and X ³ , bonds a and c are single bonds, and the bond between X ³ and CR ⁷ and b are double bonds; and provided that when X ¹ is N and X ² is not C=O, then the bond between X ¹ and X ² , the bond between X ³ and CR ⁷ , bonds b and c are single bonds, and the bond between X ² and X ³ and bond a are double bonds; R ¹ is -SO ₂ R ^1a or -SOR ^1b ; R ^1a is selected from (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, wherein at least one of R ^1'a and R ^{1 ' b} is (C ₁ -C ₃ )alkyl and the other is H or (C ₁ -C ₃ )alkyl; R ^1b is (C ₁ -C ₆ )alkyl; R ^2' is hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^2'' represents hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^3' is hydrogen; R ^3'' represents hydrogen, halogen or (C ₁ -C ₃ )alkyl; 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 ; R ^4a , R ^4b and R ^4c are independently selected from 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 selected from (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 ^4h and R ^4g are independently selected from 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 or (C ₁ -C ₆ )alkoxy; 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, oxetanyl or thiophenyl, or -SO ₂ R ^6a ; R ^6a is (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl or halo(C ₁ -C ₆ )alkyl; R ⁷ represents hydrogen, halogen or hydroxy; or its pharmaceutically acceptable salts. 2. The compound according to claim 1, wherein said compound has the formula Ia Where X ¹ is either N or C; X ³ is either N or CR ⁵ , the dotted line represents a double bond to ensure that six-membered rings are aromatic provided that when X ¹ is N and R ⁴ is oxo then the bond is a single bond; R ¹ is -SO ₂ R ^1a or -SOR ^1b ; R ^1a is selected from (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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₃ )alkyl and the other is H or (C ₁ -C ₃ )alkyl; R ^1b is (C ₁ -C ₆ )alkyl; R ^2' is hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^2'' represents hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^3' is hydrogen; R ^3'' represents hydrogen, halogen or (C ₁ -C ₆ )alkyl; 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 ; R ^4a , R ^4b and R ^4c are independently selected from 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 selected from (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 ^4h and R ^4g are independently selected from 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 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 ; R ^6a is (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl or halo(C ₁ -C ₆ )alkyl; R ⁷ represents hydrogen, halogen or hydroxy; and its pharmaceutically acceptable salts. 3. The compound according to claim 1, wherein said compound has the formula Ib Where X ³ is either N or CR ⁵ , R ¹ is -SO ₂ R ^1a or -SOR ^1b ; R ^1a is selected from (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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₃ )alkyl and the other is H or (C ₁ -C ₃ )alkyl; R ^1b is (C ₁ -C ₆ )alkyl; R ^2' is hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^2'' represents hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^3' is hydrogen; R ^3'' represents hydrogen, halogen or (C ₁ -C ₃ )alkyl; 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 ; R ^4a , R ^4b and R ^4c are independently selected from 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 selected from (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 ^4h and R ^4g are independently selected from hydrogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, (C ₁ -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 or (C ₁ -C ₆ )alkoxy; 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, oxetanyl or thiophenyl, or -SO ₂ R ^6a ; R ^6a is (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl or halo(C ₁ -C ₆ )alkyl; R ⁷ represents hydrogen, halogen or hydroxy; and its pharmaceutically acceptable salts. 4. The compound according to claim 1, wherein said compound has the formula Iв Where R ¹ is -SO ₂ R ^1a or -SOR ^1b ; R ^1a is selected from (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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₃ )alkyl and the other is H or (C ₁ -C ₃ )alkyl; R ^1b is (C ₁ -C ₆ )alkyl; R ^2' is hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^2'' represents hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^3' is hydrogen; R ^3'' represents hydrogen, halogen or (C ₁ -C ₃ )alkyl; R ⁵ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl or (C ₁ -C ₆ )alkoxy; 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, oxetanyl or thiophenyl, or -SO ₂ R ^6a ; R ^6a is (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl or halo(C ₁ -C ₆ )alkyl; R ⁷ represents hydrogen, halogen or hydroxy; and its pharmaceutically acceptable salts. 5. The compound of claim 1, wherein said compound is a compound of formula Ig , Where R ¹ is -SO ₂ R ^1a or -SOR ^1b ; R ^1a is selected from (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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₃ )alkyl and the other is H or (C ₁ -C ₃ )alkyl; R ^1b is (C ₁ -C ₆ )alkyl; R ^2' is hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^2'' represents hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^3' is hydrogen; R ^3'' represents hydrogen, halogen or (C ₁ -C ₃ )alkyl; 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 ; R ^4a , R ^4b and R ^4c are independently selected from 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 selected from (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, (C ₃ -C ₆ )cycloalkyl-(C ₁ -C ₈ )alkyl, halo(C ₁ -C ₆ )alkyl and oxetanyl; R ^4h and R ^4g are independently selected from 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 or (C ₁ -C ₆ )alkoxy; R ⁶ is halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, halo(C ₁ -C ₈ )alkyl, halo(C ₁ -C ₆ )alkoxy, (C ₃ -C ₆ )cycloalkyl, oxetanyl or thiophenyl, or -SO ₂ R ^6a ; R ^6a is (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl or halo(C ₁ -C ₈ )alkyl; R ⁷ represents hydrogen, halogen or hydroxy; and its pharmaceutically acceptable salts. 6. The compound of claim 1, wherein said compound is a compound of formula Id Where R ¹ is -SO ₂ R ^1a or -SOR ^1b ; R ^1a is selected from (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, wherein at least one of R ^1'a and R ^1'b is (C ₁ -C ₃ )alkyl and the other is H or (C ₁ -C ₃ )alkyl; R ^1b is (C ₁ -C ₆ )alkyl; R ^2' is hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^2'' represents hydrogen, halogen, -NH ₂ , (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or halogen(C ₁ -C ₆ )alkyl; R ^3' is hydrogen; R ^3'' represents hydrogen, halogen or (C ₁ -C ₃ )alkyl; 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 ; R ^4a , R ^4b and R ^4c are independently selected from 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 selected from (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 ^4h and R ^4g are independently selected from 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 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 ; R ^6a is (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl or halo(C ₁ -C ₆ )alkyl; R ⁷ represents hydrogen, halogen or hydroxy; and its pharmaceutically acceptable salts. 7. The compound according to claim 1, wherein X ⁴ is N. 8. The compound of claim 1, wherein X ¹ is N or C, X ² is N or CR ⁴ and X ³ is N or CR ⁵ . 9. A compound according to any one of claims 1 to 8, wherein R ¹ is -SO ₂ R ^1a . 10. A compound according to any one of claims 1 to 9, wherein R ^1a is selected from methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, 1,2-difluoroethyl, 1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methylaminyl (-NHCH ₃ ), dimethylaminyl (-N(CH ₃ ) ₂ ) and oxetanyl. 11. A compound according to any one of claims 1 to 10, wherein R ^1a is selected from ethyl, propyl, isopropyl, isobutyl, cyclopropyl, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, 1,2-difluoroethyl, 1,1,2-trifluoroethyl and 1,2,2-trifluoroethyl. 12. A compound according to any one of claims 1-11, wherein R ^1a is selected from methyl, ethyl, cyclopropyl and difluoromethyl. 13. A compound according to any one of claims 1 to 12, wherein R ^1b is (C ₁ -C ₃ )alkyl, more particularly methyl. 14. A compound according to any one of claims 1-12, wherein if R ^2' is other than hydrogen as defined in any one of claims 1-6, then R ^3' is hydrogen, R ^2'' is hydrogen and R ^3'' is as defined in any one of claims 1-6. 15. A compound according to any one of claims 1 to 13, wherein one of R ^2' and R ^2'' is hydrogen, halogen, -NH ₂ , (C ₁ -C ₂ )alkyl, (C ₁ -C ₂ )alkoxy or halogen(C ₁ -C ₂ )alkyl, while the other is hydrogen. 16. A compound according to any one of claims 1 to 15, wherein R ^2' is hydrogen, halogen, -NH ₂ , methyl, ethyl, methoxy, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl or 1,2-difluoroethyl and R ^2'' is hydrogen. 17. A compound according to any one of claims 1 to 16, wherein R ^2' is methyl, ethyl, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, 1,2-difluoroethyl and R ^2'' is hydrogen. 18. A compound according to any one of claims 1 to 17, wherein R ^2' is methyl or difluoromethyl and R ^2'' is hydrogen. 19. A compound according to any one of claims 1 to 18, wherein R ^3'' is hydrogen or fluorine and R ^3' is hydrogen. 20. A compound according to any one of claims 1 to 19, wherein both R ^3' and R ^3'' are hydrogen. 21. A compound according to any one of claims 1 to 20, wherein 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 . 22. A compound according to any one of claims 1 to 21, wherein R ⁴ is cyano, oxo, hydroxy, methoxy, -CF ₃ , -OCF ₃ , methylmethoxy, cyclopropyl, -CO ₂ H, -CONR ^4b R ^4c , -SO ₂ R ^4d , -SOR ^4e or -SR ^4f . 23. A compound according to any one of claims 1 to 22, wherein R ⁴ is cyano, oxo, -CONHR ^4c or -SO ₂ R ^4d . 24. A compound according to any one of claims 1 to 23, wherein R ^4a , R ^4b and R ^4c are independently selected from hydrogen, (C ₁ -C ₃ )alkyl, (C ₃ -C ₄ )cycloalkyl and oxetanyl. 25. A compound according to any one of claims 1 to 24, wherein R ^4a , R ^4b and R ^4c are independently selected from hydrogen, (C ₁ -C ₃ )alkyl, cyclopropyl and oxetanyl. 26. A compound according to any one of claims 1-25, wherein R ^4a , R ^4b and R ^4c are independently selected from hydrogen, (C ₁ -C ₃ )alkyl and cyclopropyl. 27. A compound according to any one of claims 1 to 26, wherein R ^4a is hydrogen. 28. A compound according to any one of claims 1 to 27, wherein R ^4b is hydrogen and R ^4c is hydrogen or methyl. 29. A compound according to any one of claims 1 to 23, wherein R ^4d , R ^4e and R ^4f are independently selected from (C ₁ -C ₃ )alkyl, (C ₃ -C ₄ )cycloalkyl and oxetanyl. 30. A compound according to any one of claims 1-23, wherein R ^4d , R ^4e and R ^4f are independently selected from (C ₁ -C ₃ )alkyl, cyclopropyl and oxetanyl. 31. A compound according to any one of claims 1 to 23, wherein R ^4d , R ^4e and R ^4f are independently selected from (C ₁ -C ₃ )alkyl and cyclopropyl, most particularly R ^4d is methyl or cyclopropyl. 32. A compound according to any one of claims 1 to 23, wherein R ^4d is methyl or cyclopropyl. 33. A compound according to any one of claims 1 to 32, wherein R ^4d is methyl. 34. A compound according to any one of claims 1-20, wherein R ^4h and R ^4g are independently selected from hydrogen and (C ₁ -C ₆ )alkyl. 35. A compound according to any one of claims 1-20, wherein R ^4h and R ^4g are independently selected from hydrogen and (C ₁ -C ₃ )alkyl. 36. A compound according to any one of claims 1 to 20, wherein R ^4h is hydrogen and R ^4g is (C ₁ -C ₃ )alkyl. 37. A compound according to any one of claims 1 to 20, wherein R ^4h is hydrogen and R ^4g is methyl. 38. A compound according to any one of claims 1 to 37, wherein R ⁵ is hydrogen, halogen, (C ₁ -C ₂ )alkyl, (C ₁ -C ₂ )alkoxy or (C ₃ -C ₄ )cycloalkyl. 39. A compound according to any one of claims 1 to 38, wherein R ⁵ is hydrogen, fluorine, chlorine, cyclopropyl, methyl or methoxy. 40. A compound according to any one of claims 1 to 39, wherein R ⁵ is hydrogen. 41. A compound according to any one of claims 1 to 40, wherein 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 . 42. A compound according to any one of claims 1 to 41, wherein R ⁶ is bromine, (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 . 43. A compound according to any one of claims 1 to 42, wherein R ⁶ is halo(C ₁ -C ₃ )alkyl, halo(C ₁ -C ₃ )alkoxy or (C ₃ -C ₄ )cycloalkyl. 44. A compound according to any one of claims 1 to 42, wherein R ⁶ is trifluoromethyl, trifluoromethoxy, difluoromethoxy or cyclopropyl. 45. A compound according to any one of claims 1 to 44, wherein R ^6a is (C ₁ -C ₆ )alkyl. 46. A compound according to any one of claims 1 to 45, wherein R ^6a is methyl. 47. A compound according to any one of claims 1 to 46, wherein R ⁷ is hydrogen. 48. A compound of formula I selected from the group consisting of: 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methoxy-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(methylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(4-(methylsulfonyl)-3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N,2-trimethylbenzenesulfonamide; 3-cyclopropyl-5-methoxy-4-(4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine; 3-cyclopropyl-4-(4-(cyclopropylsulfonyl)-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-chloro-4-(cyclopropylsulfonyl)phenyl)-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine; 2-chloro-4-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N-dimethylbenzenesulfonamide; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine; 4-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-(difluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-(fluoromethyl)-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-bromo-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrrolo[3,2-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(oxetan-3-ylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-methoxy-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 5-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)-2-(methylsulfonyl)aniline; 4-(3-methyl-4-(methylsulfonyl)phenyl)-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(1,1-difluoroethyl)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-carbonitrile; 3-(difluoromethyl)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-isopropyl-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-4-(2,5-dimethyl-4-methylsulfonylphenyl)-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-methylsulfinylphenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride; 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-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-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-pyrazolo[4,3-c]pyridine; 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-cyclopropyl-7-fluoro-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(4-ethylsulfonyl-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine; 4-(3-methyl-4-methylsulfonylphenyl)-3-(oxetan-3-yl)-1H-pyrazolo[4,3-c]pyridine; 4-[4-(cyclopropylmethylsulfonyl)-3-methylphenyl]-3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(3-methyl-4-propylsulfonylphenyl)-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-[3-(difluoromethyl)-4-methylsulfonylphenyl]-1H-pyrazolo[4,3-c]pyridine; 3-(difluoromethoxy)-4-(4-isopropylsulfonyl-3-methylphenyl)-1H-pyrazolo[4,3-c]pyridine; 4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-N,2-dimethylbenzenesulfonamide; 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-methylphenyl]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)sulfonylphenyl]-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-methylphenyl]-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-methylsulfonylphenyl)-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-methylsulfonylphenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3,6-dicyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-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-methylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-cyclopropyl-4-(4-cyclopropylsulfonyl-3-methylphenyl)-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-methylphenyl)-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-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-(3-methyl-4-methylsulfonylphenyl)-3-(trifluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrrolo[3,2-b]pyridin-5-one; 4-[3-(difluoromethoxy)-1H-pyrazolo[4,3-c]pyridin-4-yl]-2-(difluoromethyl)-N,N-dimethylbenzenesulfonamide; 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-5-(methylsulfonyl)-1H-indazole; 3-cyclopropyl-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-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-methylsulfonylphenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(difluoromethoxy)-4-[5-(difluoromethyl)-2-methyl-4-methylsulfinylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 4-[3-(difluoromethyl)-4-methylsulfonylphenyl]-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-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-cyclopropyl-4-(4-cyclopropylsulfonyl-2-fluoro-5-methylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-5-methylsulfonyl-1H-indazole; 3-cyclopropyl-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-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-methylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-N-(oxetan-3-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-N-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-5-(oxetan-3-ylsulfonyl)-1H-indazole; [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-iminomethyloxosulfane; [3-cyclopropyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazol-5-yl]-methylmethyliminooxo-λ ⁶ -sulfane; 3-cyclopropyl-N,N-dimethyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-sulfonamide; 3-cyclopropyl-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-indazole-5-sulfonamide; 4-(4-cyclopropylsulfonyl-3-methylphenyl)-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-methylsulfonylphenyl)-1H-indazole; 3-(difluoromethoxy)-4-(2-fluoro-5-methyl-4-methylsulfonylphenyl)-5-methylsulfonyl-1H-indazole or 4-(4-cyclopropylsulfonyl-3-methylphenyl)-3-(difluoromethoxy)-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide, and its pharmaceutically acceptable salts. 49. A compound according to any one of paragraphs 1-48, selected from the group consisting of: 3-(difluoromethoxy)-4-(3-methyl-4-(methylsulfonyl)phenyl)-1H-indazole-5-carbonitrile; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[4,3-b]pyridin-5-one; 3-cyclopropyl-4-(4-ethylsulfonyl-3-methylphenyl)-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-methylphenyl]-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-methylsulfonylphenyl]-N-methyl-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile; 3-(difluoromethoxy)-N-methyl-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide; 3-(difluoromethoxy)-4-(3-methyl-4-methylsulfonylphenyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxamide or 3-(difluoromethoxy)-4-[4-(difluoromethylsulfonyl)-3-methylphenyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxamide, and its pharmaceutically acceptable salts. 50. A pharmaceutical composition having inhibitory activity against methionine adenosyltransferase 2A (Mat2A), containing an effective amount of a compound of formula I according to any one of claims 1-49 or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.