Pyrazolamide derivatives

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to compounds of formula I:wherein X1 is N or CR3; R1 is (C3-C6)cycloalkyl optionally substituted with one R1a, pyridinyl optionally substituted with one R1b, pyrazinyl optionally substituted with one R1b, pyridazinyl optionally substituted with one R1b, thiazolyl optionally substituted with one R1b, 1,3-benzodioxolyl optionally substituted with one R1c, oxazolyl optionally substituted with one R1c, piperidinyl optionally substituted with one R1c, tetrahydrofuranyl optionally substituted with one R1c, tetrahydropyranyl optionally substituted with one R1c, or phenyl optionally substituted with one or two R1d; each of R1a, R1b, R1c and R1d is independently selected from halogen, oxo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(C1-C6)alkoxy; R2 is (C1-C3)alkyl, halo(C1-C3)alkyl, cyclopropyl optionally substituted with one or two substituents R2a, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, azetidinyl optionally substituted with one or two substituents R2b, dihydrofuranyl, dihydropyranyl, azabicyclo[2.2.1]heptanyl or phenyl; each of R2a and R2b is independently selected from halogen, (C1-C3)alkyl and halo(C1-C3)alkyl; R3 is hydrogen or halogen; or R2 and R3 together form C2-7-alkylene, optionally substituted with one or more, in particular one to three, more specifically one or two substituents R3f, and each R3f is independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, and pharmaceutically acceptable salts thereof, as well as to pharmaceutical compositions based thereon.EFFECT: novel compounds that may be useful for treating diseases associated with Mat2A.32 cl, 79 ex

Description

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

[0002] In particular, the present invention relates to compounds of formula I:

[0003]

[0004] where

[0005] X 1 represents either N or CR 3 ;

[0006] R 1 represents:

[0007] - (C3-C8)cycloalkyl, optionally substituted with one or more, in particular one to three, more particularly one or two R substituents 1a ,

[0008] - -heteroaryl, optionally substituted with one or more, in particular one to three, more in particular one or two R substituents 1b ,

[0009] - heterocycloalkyl, optionally substituted by one or more, in particular one to three, more particularly one or two R substituents1c ; or

[0010] - phenyl, optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1d ;

[0011] each of R 1a , R 1b , R 1c and R 1d independently selected from halogen, oxo, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl, heterocycloalkyl, and phenyl;

[0012] R 2 is (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, optionally substituted by one or more, in particular one to three, more in particular one or two substituents R 2a , heterocycloalkyl, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 2b, or phenyl, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 2c ;

[0013] each of R 2a , R 2b and R 2c independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy;

[0014] R 3 represents hydrogen, halogen or (C1-C6)alkyl;

[0015] or R 2 and R 3 together form C 2-7 -alkylene, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 3f , And

[0016] each R 3f independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl;

[0017] and their pharmaceutically acceptable salts.

[0018] Unless otherwise defined, 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.

[0019] All publications, patent applications, patents and other references mentioned in this document are incorporated by reference in their entirety.

[0020] The nomenclature used in this application is based on the IUPAC system nomenclature unless otherwise noted.

[0021] Any free valence occurring on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein indicates the presence of hydrogen unless otherwise noted.

[0022] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the maximum possible number of substitutions, i.e., replacement of one hydrogen atom to replacement of all hydrogen atoms by substituents, in particular, where "one or more" refers to one, two or three, in particular, "one or more" refers to one or two.

[0023] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom in a parent molecule.

[0024] The term "substituted" means that the specified group carries one or more substituents. Where any group is capable of carrying multiple substituents and a plurality of possible substituents is envisaged, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from the group of possible substituents. When indicating the number of substituents, the term "one or more" means from one substituent to the maximum possible number of substituents, i.e., from the replacement of one hydrogen atom to the replacement of all hydrogen atoms by substituents.

[0025] The term "amino" means a group of the formula -NR'R'', where R' and R'' independently represent hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, or (C3-C6)cycloalkyl, as described herein. Alternatively, R' and R'', together with the nitrogen atom to which they are attached, can form heterocycloalkyl. The term "primary amino" means a group in which both R' and R'' are hydrogen. The term "secondary amino" means a group in which R' is hydrogen and R'' is a group other than hydrogen, in particular, where R'' is (C1-C6)alkyl. The term "tertiary amino" denotes a group in which both R' and R'' are not hydrogen, particularly where both R' and R'' are (C1-C6)alkyl.Specific secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine, dipropylamine, and diisopropylamine, most specifically amino meaning ethylamine.

[0026] "Halo" or "halogen" means fluorine, chlorine, bromine or iodine, in particular chlorine or fluorine.

[0027] "Hydroxy" refers to the -OH group.

[0028] "(C1-C6)alkyl" refers to a branched or straight hydrocarbon chain of one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

[0029] The term “(C1-C6)alkylene” means a linear saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a divalent branched saturated hydrocarbon group of 3 to 6 carbon atoms. Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene. Specific examples of alkylene are ethylene, propylene, and butylene.

[0030] "(C1-C6)alkoxy" means a fragment of the formula -OR a , where R a is a (C1-C6)alkyl moiety as defined herein. Examples of (C1-C6)alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

[0031] The term "(C3-C8)cycloalkyl" means a saturated monovalent monocyclic hydrocarbon group with 3 to 6 ring carbon atoms. Examples of monocyclic (C3-C8)cycloalkyl include cyclopropyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, or cycloheptyl. One specific example of (C3-C6)cycloalkyl is cyclopropyl.

[0032] "(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

[0033] The term “perhalo(C1-C3)alkyl” means a (C1-C3)alkyl group as defined above, wherein all hydrogen atoms have been replaced by halogen atoms. More specifically, “(C1-C3)perhaloalkyl” is (C1-C3)perfluoroalkyl, most preferably trifluoromethyl.

[0034] “Halo-(C1-C6)alkyl” refers to (C1-C6)alkyl, as defined above, substituted with one or more halogen atoms, in particular one to three halogen atoms. More specifically, halo-(C1-C6)alkyl is chloro- and fluoro-(C1-C6)alkyl. In some specific embodiment, halo-(C1-C6)alkyl refers to perhalo-(C1-C3)alkyl, as defined herein. More specifically, halo-(C1-C6)alkyl is trifluoromethyl, difluoromethyl, or fluoromethyl.

[0035] "Halogeno-(C1-C6)alkoxy" refers to (C1-C6)alkoxy, as defined above, substituted by one or more halogen atoms, in particular one to three halogen atoms. More specifically, halo-(C1-C6)alkoxy is chloro- and fluoro-(C1-C6)alkoxy. In some specific embodiment, halo-(C1-C6)alkoxy refers to perhalogeno-(C1-C3)alkoxy, such as trifluoromethoxy or difluoromethoxy.

[0036] "Hydroxy-(C1-C6)alkyl" refers to (C1-C6)alkyl, as defined above, substituted by one or more hydroxy groups, in particular one hydroxy group. More specifically, hydroxy-(C1-C6)alkyl refers to methyl hydroxide or ethyl hydroxide.

[0037] "(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.

[0038] "Halogeno-(C1-C6)alkoxy" refers to an alkoxy group, as defined above, substituted by one or more halogen atoms, in particular by one to three halogen atoms. More specifically, halo-(C1-C6)alkoxy includes chloro- and fluoro-(C1-C6)alkoxy.

[0039] "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" refers in particular to a heteroaryl, as defined previously, containing at least one nitrogen atom. The point of attachment of an N-heteroaryl to the remainder of the molecule may be at the nitrogen atom or a ring carbon atom. Examples of N-heteroaryl include pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl.

[0040] The term "heterocycloalkyl" or "heterocyclic" means a monovalent saturated or partially unsaturated mono- or bicyclic ring 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, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolane, 1,4-dioxepanyl, oxepanyl, 1,1-dioxothiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl.More particularly, heterocycloalkyl refers to dihydrofuryl, 1,3-dioxolyl, dihydropyryl, dihydrothiophil, 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.

[0041] The term "therapeutically effective amount" means an amount of a compound or molecule according to 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.

[0042] "Optional" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, 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.

[0043] The terms "individual" or "subject" refer to a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human.

[0044] The terms “compound(s) of the present invention” and “compound(s) of this invention” refer to the compounds as disclosed herein and their stereoisomers, tautomers, solvates and salts (e.g., pharmaceutically acceptable salts).

[0045] While 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 formulas.

[0046] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0047] The term "pharmaceutically acceptable acid addition salt" means those pharmaceutically acceptable salts that are 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.,

[0048] The term "pharmaceutically acceptable base addition salt" refers to 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 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.

[0049] The term "active pharmaceutical ingredient" (or "API") means a compound or molecule in a pharmaceutical composition that has a specific biological activity.

[0050] 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.

[0051] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inert excipient" may be used interchangeably and refer to 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.

[0052] The terms "treat" or "treating" a disease state include inhibiting the disease state, i.e., delaying the development of the disease state or its clinical symptoms, or alleviating the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

[0053] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and those that are non-superpositional mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and 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 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."

[0054] Compounds of formula I may have one or more centers or axes of asymmetry. Unless otherwise indicated, the description or name 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).

[0055] Some compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible molecules. Prototropic tautomers are formed by the migration of a covalently bonded hydrogen atom between two atoms. Tautomers typically exist in equilibrium, and attempts to isolate individual tautomers typically yield a mixture whose chemical and physical properties are consistent with those of a mixture of compounds. The equilibrium position depends on the chemical elements in the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. Common prototropic tautomers include 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.

[0056] In this document, it was found that the compounds of formula I of the present invention are Mat2A inhibitors and thus may have therapeutic use for the treatment of cancer disorders including lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma.

[0057] These compounds are potent inhibitors of human methionine adenosyltransferase II alpha (MAT2A). MAT2A and MAT1A (methionine adenosyltransferase I alpha) are two genes that encode methionine adenosyltransferase activity, producing S-adenosylmethionine (SAM), the major methyl donor in cells. MAT1A is a liver-specific SAM-producing enzyme, while 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 MAT2 B 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 MAT2 B, is more active at low methionine concentrations but is inhibited at high methionine concentrations.

[0058] Loss-of-function mutations in tumor suppressor genes are critical to the molecular pathogenesis of cancer. However, successful targeting of tumor suppressor genes has been difficult to achieve, primarily because mutant proteins cannot be directly inhibited for therapeutic benefit, and restoration of mutant function (such as restoration of mutant p53 function) has been impossible until now. Recent clinical success with PARP inhibition in BRCA1 / 2-deficient patients has demonstrated that targeting the associated synthetic lethality (ASL) caused by loss-of-function mutations in tumor suppressor genes is a clinically viable approach for cancer treatment. The OSL relationship is not only valid for tumor suppressor genes, but can also be extended to genes that are 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, located near the CDKN2A tumor suppressor gene, and is deleted in 15% of all cancers. MTAP is deleted in, among other cases, ~53% of glioblastoma multiforme (GBM), ~25% of pancreatic adenocarcinoma (PAC), ~25% of melanoma, ~23% of squamous cell lung 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 represent areas of significant unmet medical need with limited effective treatment options. In glioblastoma, where the median survival is 14 months, approval of newer treatment options has not significantly improved overall survival (OS), and the standard of care (SOC) has remained the same for more than a decade. The same is true for most patients with ARVC, where OS is less than 1 year.MTAF deletion is a fundamental event that occurs early in tumor development and is maintained throughout tumor progression, including metastasis. Therefore, its loss represents a change unaffected by tumor heterogeneity, heredity, or resistance to any approved clinical treatment. The OSL relationship identified for MTAF deficiency will represent a true weakness for many tumor indications.

[0059] MTAP is located near the CDKN2A tumor suppressor gene 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 is input into the SAM production pathway, and SAM levels are a key regulator of cancer cell growth that must be tightly regulated, as strong changes in SAM concentrations, either increased or decreased, lead to cell cycle arrest. The importance of SAM levels in cancer growth lies in its central role in protein, DNA, and RNA methylation, serving 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 negatively affecting the levels of any metabolic 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 the new MTA / SAM paradigm without any loss of viability, which MTAP-containing cells would otherwise not have to contend with. This adaptation creates a persistent dependence on methionine adenosyltransferase II alpha2 (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).

[0060] Targeting MAT2A through small molecule inhibition will benefit a genetically defined patient population representing many areas of high unmet medical need.

[0061] 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 slowing down 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.

[0062] Additional objects of the present invention are all forms of optically pure enantiomers, racemates or diastereoisomeric mixtures of the compounds of formula I.

[0063] In particular, the present invention relates to compounds of formula I:

[0064]

[0065] where

[0066] X 1 represents either N or CR 3 ;

[0067] R 1 represents:

[0068] - (C3-C8)cycloalkyl, optionally substituted with one or more, in particular one to three, more particularly one or two R substituents 1a ,

[0069] - heteroaryl, optionally substituted with one or more, in particular one to three, more particularly one or two R substituents 1b ,

[0070] - heterocycloalkyl, optionally substituted by one or more, in particular one to three, more particularly one or two R substituents 1c ; or

[0071] - phenyl, optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1d ;

[0072] each of R 1a , R 1b , R 1c and R 1d independently selected from halogen, oxo, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl, heterocycloalkyl, and phenyl;

[0073] R 2 represents (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 2a , heterocycloalkyl, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 2b, or phenyl, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 2c ;

[0074] each of R 2a , R 2b and R 2c independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy;

[0075] R 3 represents hydrogen, halogen or (C1-C6)alkyl;

[0076] or R 2 and R 3 together form C 2-7 -alkylene, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 3f , And

[0077] every R 3f independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl;

[0078] and their pharmaceutically acceptable salts.

[0079] In a particular embodiment, the present invention relates to compounds of formula I':

[0080]

[0081] where R1 , R 2 and R 3 are as defined herein, as well as their pharmaceutically acceptable salts.

[0082] Furthermore, it should be understood that each embodiment relating to specific X 1 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , R 2b , R 2c , R 3 , R 3a , R 3b , R 3c , R 3d and R 3e , as described herein, may be in combination with any other embodiment relating to other X 1 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , R 2b , R 2c , R 3 , R 3a , R 3b , R 3c , R 3d and R 3e , as described in this document.

[0083] A specific embodiment of the present invention relates to a compound of formula I, wherein X 1 represents CR 3 .

[0084] A specific embodiment of the present invention relates to a compound of formula I or I', wherein R 1 is (C3-C8)cycloalkyl, optionally substituted with one substituent R 1a , heteroaryl, optionally substituted with one R 1b , heterocycloalkyl, optionally substituted with one or two R 1c , or phenyl optionally substituted with one or two R 1d ; in particular R 1 is (C3-C6)cycloalkyl, optionally substituted with one R 1a , pyridinyl, optionally substituted with one R 1b , pyrazinyl, optionally substituted with one R 1b , pyridizanyl, optionally substituted with one R 1b , thiazolyl optionally substituted with one R 1b , 1,3-benzodioxolyl, optionally substituted with one R 1c, oxazolyl, optionally substituted with one R 1c , piperidinyl, optionally substituted with one R 1c , tetrahydrofuranyl, optionally substituted with one R 1c , tetrahydropyranyl, optionally substituted with one R 1c , or phenyl optionally substituted with one or two R 1d , more specifically, where R 1 is cyclohexyl, optionally substituted with one R 1a , pyridinyl, optionally substituted with one R 1b , pyrazinyl, optionally substituted with one R 1b , pyridizanyl, optionally substituted with one R 1b , thiazolyl optionally substituted with one R 1b , 1,3-benzodioxolyl, oxazolyl, optionally substituted with one R 1c , piperidinyl, optionally substituted with one R 1c , tetrahydrofuranyl, optionally substituted with one R 1c , tetrahydropyranyl or phenyl optionally substituted with one or two R 1d , most specifically R 1is pyridinyl, optionally substituted with one R 1b , or phenyl optionally substituted with one or two R 1d .

[0085] A more specific embodiment of the present invention relates to a compound of formula I or I', wherein R 1 is heteroaryl optionally substituted with one R 1b , or phenyl optionally substituted with one or two R 1d .

[0086] A specific embodiment of the present invention relates to a compound of formula I or I', wherein each of R 1a , R 1b , R 1c and R 1d independently selected from halogen, oxo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(C1-C6)alkoxy, in particular, where each of R 1a , R 1b , R 1c and R 1d independently selected from halogen, oxo, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl and halo(C1-C3)alkoxy, more particularly, where each of R 1a , R1b , R 1c and R 1d independently selected from halogen, oxo, cyano, (C1-C3)alkyl, (C1-C3)alkoxy and halogen(C1-C3)alkyl, even more particularly, where each of R 1a , R 1b , R 1c and R 1d independently selected from chloro, fluoro, oxo, cyano, methyl, ethyl, methoxy, trifluoromethyl and difluoromethyl, most particularly, wherein each of R 1a , R 1b , R 1c and R 1d independently selected from chlorine, fluorine, cyano, methyl and methoxy.

[0087] A particular embodiment of the present invention relates to a compound of formula I or I', wherein each of R 1b and R 1d independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl and halo(C1-C3)alkoxy, in particular, where each R 1b independently selected from halogen, (C1-C3)alkyl, (C1-C3)alkoxy, and halo(C1-C3)alkyl, and where each R 1dindependently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl and halo(C1-C3)alkoxy, more particularly, where each R 1b independently selected from chlorine, methyl, and methoxy, and where each R 1d independently selected from fluoro, cyano, methyl and methoxy.

[0088] A specific embodiment of the present invention relates to a compound of formula I or I', wherein R 1is 2-methoxyphenyl, 2-chlorophenyl, 2-methylphenyl, 1,3-benzodioxol-4-yl, 3-fluoro-2-methylphenyl, 2,3-dimethylphenyl, cyclohexyl, 2-methoxycyclohexyl, 3-fluoro-2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 3-methyl-2-oxopiperidin-4-yl, 2-ethylphenyl, 2-(difluoromethoxy)phenyl, 5-methyl-1,3-oxazol-4-yl, 4-methyl-1,3-thiazol-5-yl, 2-methyloxolan-3-yl, 3-methyltetrahydrofuran-2-yl, 3-cyano-2-methylphenyl, oxan-4-yl, 2-methylpyridin-3-yl, 2-oxopiperidin-4-yl, 2-methoxy-3-methylphenyl, 3-chloro-2-methoxyphenyl, 3-cyano-2-methoxyphenyl, oxan-3-yl, 3-methylpyrazin-2-yl, 2-methoxypyridin-3-yl, 2-chloropyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 3-methylpyridazin-4-yl, 3-methyl-1,2-thiazol-4-yl or 3-methyltetrahydrofuran-2-yl, in particular, where R 1 is 2-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 2-methylpyridin-3-yl, 3-cyano-2-methoxyphenyl, 2-methoxypyridin-3-yl, 2-chloropyridin-3-yl or 2-methylphenyl.

[0089] Another embodiment of the present invention relates to a compound of formula I, I' or I'', wherein R 2 represents (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, optionally substituted with one or two substituents R 2a , heterocycloalkyl, optionally substituted with one or two substituents R 2a , or phenyl, in particular, where R 2 represents (C1-C3)alkyl, halo(C1-C3)alkyl, cyclopropyl, optionally substituted with one or two substituents R 2a , cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, azetidinyl, optionally substituted with one or two substituents R 2b , dihydrofuranyl, dihydropyranyl, azabicyclo[2.2.1]heptanyl, -azabicyclo[2.2.1]heptanyl, pyrrolidinyl, azetidinyl, optionally substituted with one or two R substituents 2b , or phenyl, more specifically, where R 2represents isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, optionally substituted with one or two substituents R 2a , cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, azetidinyl, optionally substituted with one or two substituents R 2b , 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl, even more particularly, where R 2is isobutyl, tert-butyl, trifluoromethyl, cyclopropyl optionally substituted with one or two substituents selected from fluorine, methyl or trifluoromethyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclohexen-1-yl, azetidinyl optionally substituted with two fluorine atoms, 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl, most particularly wherein R is trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenten-1-yl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2-(trifluoromethyl)cyclopropyl, 2,3-dimethylcyclopropyl, 1-methylcyclopropyl or 3,4-dihydropyran-6-yl.

[0090] A more specific embodiment of the present invention relates to a compound of formula I or I', wherein R is halo(C1-C6)alkyl, (C3-C6)cycloalkyl, optionally substituted with one or two R substituents. 2a, or heterocycloalkyl optionally substituted with one or two R substituents. 2b

[0091] Another embodiment of the present invention relates to a compound of formula I, I' or I'', wherein each of R 2a , R 2b and R 2c independently selected from halogen, (C1-C3)alkyl and halo(C1-C3)alkyl, in particular each of R 2a , R 2b and R 2c independently selected from fluoro, methyl and trifluoromethyl, more particularly, each R 2a independently selected from fluoro, methyl, and trifluoromethyl, each R 2b is fluorine.

[0092] A specific embodiment of the present invention relates to a compound of formula I or I', wherein R 2is phenyl, 2-methylpropyl, pyrrolidin-1-yl, cyclopropyl, cyclohexen-1-yl, 3,4-dihydro-2-pyran-6-yl, cyclopenten-1-yl, azetidin-1-yl, trifluoromethyl, 3,3-difluoroazetidin-1-yl, cyclopentyl, cyclobutyl, 2-methylcyclopropyl, 2,5-dihydrofuran-3-yl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2-(trifluoromethyl)cyclopropyl, 2,3-dimethylcyclopropyl, 1-methylcyclopropyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl or tert-butyl, in particular where R is cyclopropyl, cyclopenten-1-yl, trifluoromethyl or cyclobutyl, 2,5-dihydrofuran-3-yl.

[0093] In another embodiment, the present invention relates to a compound of formula I or I', wherein R 3 represents hydrogen or halogen, in particular, where R 3 represents hydrogen, chlorine, or fluorine, more specifically, where R 3 is hydrogen.

[0094] Specific compounds of formula I of the present invention are selected from the group consisting of:

[0095] (3-amino-6-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0096] (3-amino-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0097] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0098] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chlorophenyl)methanone;

[0099] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0100] [3-amino-6-(cyclohexen-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0101] (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methoxyphenyl)methanone-2,2,2-trifluoroacetic acid;

[0102] (3-amino-5-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0103] (3-amino-5-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0104] (3-amino-5-fluoro-6-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0105] (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0106] (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chlorophenyl)methanone;

[0107] (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0108] (3-amino-6-(3,3-difluoroazetidin-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0109] (3-amino-6-(tert-butyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0110] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-(1]pyrimidin-1-yl)(2-methoxyphenyl)methanone;

[0111] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-(1]pyrimidin-1-yl)(o-tolyl)methanone;

[0112] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-c1]pyrimidin-1-yl)(2-

[0113] chlorophenyl)methanone;

[0114] (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(1,3-benzodioxol-4-yl)methanone;

[0115] (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methylphenyl)methanone;

[0116] (3-amino-7,7-dimethyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-1-yl)(2-methoxyphenyl)methanone;

[0117] [3-amino-6-(3,4-dihydro-2H-pyran-6-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0118] [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0119] (3-amino-6-(azetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0120] (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0121] (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0122] (3-amino-6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0123] (3-amino-6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0124] (3-amino-6-cyclopentylpyrazolo[3,4-b]pyridin-1-yl)-(2-methylphenyl)methanone;

[0125] [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methylphenyl)methanone;

[0126] (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0127] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methylphenyl)methanone;

[0128] (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0129] (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0130] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2,3-dimethylphenyl)methanone;

[0131] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(cyclohexyl)methanone;

[0132] [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0133] [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0134] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxycyclohexyl)methanone;

[0135] (3-amino-7-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-1-yl)(2-methoxyphenyl)methanone;

[0136] (3-amino-6-((trans)-2-fluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0137] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methoxyphenyl)methanone;

[0138] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(4-fluoro-2-methoxyphenyl)methanone;

[0139] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0140] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0141] [3-amino-6-[rac-(1R,2R)-2-(trifluoromethyl)cyclopropyl]pyrazolo[3,4-b]pyridin-1-yl]-(o-tolyl)methanone;

[0142] (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0143] (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0144] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methoxyphenyl)methanone;

[0145] (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methoxyphenyl)methanone;

[0146] [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(3-fluoro-2-methoxyphenyl)methanone;

[0147] rac-(cis)-4-(3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-carbonyl)-3-methylpiperidin-2-one;

[0148] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-ethylphenyl)methanone;

[0149] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-(difluoromethoxy)phenyl)methanone;

[0150] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(5-methyloxazol-4-yl)methanone;

[0151] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(4-methylthiazol-5-yl)methanone;

[0152] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methyltetrahydrofuran-3-yl)methanone;

[0153] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)((2S,3R)-2-methyltetrahydrofuran-3-yl)methanone;

[0154] 3-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-carbonyl)-2-methylbenzonitrile;

[0155] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;

[0156] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone;

[0157] 4-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-carbonyl)piperidin-2-one;

[0158] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxy-3-methylphenyl)methanone;

[0159] (3-amino-6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0160] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone;

[0161] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methyltetrahydrofuran-3-yl)methanone;

[0162] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-chloro-2-methoxyphenyl)methanone;

[0163] 3-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-carbonyl)-2-methoxybenzonitrile;

[0164] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(tetrahydro-2H-pyran-3-yl)methanone;

[0165] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-methylpyrazin-2-yl)methanone;

[0166] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxypyridin-3-yl)methanone;

[0167] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chloropyridin-3-yl)methanone;

[0168] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-(trifluoromethyl)pyridin-3-yl)methanone;

[0169] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-methylpyridazin-4-yl)methanone;

[0170] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-methylisothiazol-4-yl)methanone;

[0171] [3-amino-6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0172] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)((2R,3S)-3-methyltetrahydrofuran-2-yl)methanone;

[0173] [3-amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone.

[0174] Specific compounds of formula I of the present invention are selected from the group consisting of:

[0175] (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methoxyphenyl)methanone-2,2,2-trifluoroacetic acid;

[0176] (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methylphenyl)methanone;

[0177] [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0178] (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0179] [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methylphenyl)methanone;

[0180] (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0181] (3-amino-6-((3RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0182] (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0183] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0184] (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0185] [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(3-fluoro-2-methoxyphenyl)methanone;

[0186] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone;

[0187] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone;

[0188] 3-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-carbonyl)-2-methoxybenzonitrile;

[0189] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxypyridin-3-yl)methanone;

[0190] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chloropyridin-3-yl)methanone.

[0191] In another embodiment, the present invention provides a compound of formula I or I' as described herein for use as a therapeutically active substance.

[0192] In another embodiment, the present invention provides a compound of formula I, I', I'' or II as described herein for the treatment, prevention and / or slowing 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.

[0193] In another embodiment, the present invention provides the use of a compound of formula I or I' as described herein for the preparation of a medicament for the treatment, prevention and / or slowing down of progression, more particularly for the treatment of cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, esophageal carcinoma, glioblastoma multiforme and mesothelioma, more particularly lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

[0194] In one aspect, the application provides a method for treating a Mat2A disorder in a subject having a Mat2A-related disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of any of the above compounds.

[0195] In another embodiment, the present invention provides a method for treating, preventing and / or slowing down 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 or I', as described herein.

[0196] In a specific embodiment, the present invention provides a method for treating, preventing and / or slowing down 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 or I', as described herein.

[0197] 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 specifically lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme and head and neck squamous cell carcinoma.

[0198] 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.

[0199] In another embodiment, the present invention provides the use of a compound of formula I or I' in the preparation of a medicament for the treatment, prevention and / or slowing of progression, more particularly for the treatment of diseases associated with Mat2A.

[0200] In another embodiment, the present invention provides medicaments comprising a compound of formula I or I', 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, comprising combining one or more compounds of formula I or I' and / or pharmaceutically acceptable acid addition salts and, if necessary, one or more other therapeutically valuable substances in a galenic form for administration together with one or more therapeutically inert carriers.

[0201] In another embodiment, pharmaceutical compositions or medicaments are provided 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.

[0202] 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 lower than the amount that is toxic to normal cells or the mammal as a whole.

[0203] The compound of the present invention can be administered by any suitable route, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, as well as, if local treatment is required, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0204] 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 may contain components common to pharmaceutical preparations, such as diluents, carriers, pH modifiers, sweeteners, fillers and additional active agents.

[0205] 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, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, sachets, suppositories and dispersible granules.A solid carrier can be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is typically a finely divided solid that is mixed with the finely divided active component. In tablets, the active component is typically 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.

[0206] The dosage at which the compounds of the present invention can be administered can vary widely and, of course, should be selected depending on the individual requirements in each specific case. Generally, in the case of oral administration, the daily dosage of a compound of Formula I or I' is from about 0.01 to 1000 mg per person, although the above upper limit may also be exceeded if necessary.

[0207] 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, from 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 PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into a tablet using conventional equipment.

[0208] An exemplary aerosol formulation can be prepared by dissolving a compound of the present invention, for example, 10-100 mg, in a suitable buffer solution, for example, a phosphate buffer, and 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.

[0209] An embodiment thus includes a pharmaceutical composition comprising a compound of the present invention described herein or a stereoisomer thereof. A further embodiment includes a pharmaceutical composition comprising a compound of the present invention described herein or a stereoisomer thereof together with a pharmaceutically acceptable carrier or excipient.

[0210] The compounds of the present invention can be used, either alone or in combination with other drugs, for the treatment, prevention and / or slowing down the progression of Mat2A-related diseases, in particular cancer, in particular lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, esophageal carcinoma, glioblastoma multiforme and mesothelioma, more particularly lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

[0211] A particular embodiment of the present invention relates to pharmaceutical compositions comprising compounds of formula I or I' or pharmaceutically acceptable salts thereof, as defined above, and one or more pharmaceutically acceptable excipients for use in the treatment, prevention and / or slowing the progression of cognitive impairment associated with 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 lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

[0212] Another embodiment includes a pharmaceutical composition comprising the compound of the present invention described herein for use in the treatment, prevention and / or slowing of progression, more particularly in the treatment of diseases associated with Mat2A. Another embodiment includes a pharmaceutical composition comprising the compound of the present invention described herein for use in the treatment, prevention and / or slowing of progression, more particularly in the treatment of diseases associated with Mat2A.

[0213] In another embodiment, the present invention provides the production of compounds of formula I or I' as described herein.

[0214] The preparation of compounds of formula I or I' according to this invention can be carried out by sequential or convergent synthesis. The syntheses according to this invention are illustrated in the following general schemes. 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.

[0215] Furthermore, the compounds of the present invention can be prepared from commercially available starting materials or using general synthetic techniques and procedures known to those skilled in the art. Reaction schemes suitable for the preparation of such compounds are shown 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.

[0216] General schemes

[0217] In more detail, the compounds of formula I or I' and their intermediates can be prepared using Schemes 1-2 and by describing specific examples.

[0218] A subgroup of compounds of formula I or I', where X 1 represents CR 3 , R 4 represents H, and R 1 , R 2 and R 3 defined above can be obtained as described in Scheme 1 below.

[0219]

[0220] Chloropyridines IIa react with excess hydrazine in polar solvents (e.g., ethanol, ethylene glycol) (Canadian Journal of Chemistry, 1988, 420) to form aminopyrazoles IIIa. These are then selectively coupled with carboxylic acids IVa using mild activators (e.g., 1,1'-carbonyldiimidazole) in polar solvents (e.g., DMF, DMA, NMP) at elevated temperatures (80-120°C). Alternatively, pyrazole IIIa can be protected as benzaldehyde imine (VIa) by reaction with benzaldehyde in ethanol at elevated temperatures and further reaction with carboxylic acid IVa activated with more reactive coupling agents (e.g., GATU, TBTU) under basic conditions (e.g., iPr2NEt, Et3N) in polar solvents (e.g., DMF, DMA) at ambient temperature or slightly warmed (50°C) to afford protected products VIIa. The imine can be readily hydrolyzed under mildly acidic conditions (e.g., formic acid or 1 N HCl).HCl) to obtain the final products IIIa.

[0221] Chloropyridine IIa can be synthesized from 2,6-dihalo-3-nitrylopyridine VIIa by reaction at the 6-position with a boronic acid or boronic ester in a Suzuki-Miyaura type reaction using a palladium catalyst such as Pd(dppf)2Cl2⋅CH2Cl2 and an excess base such as K2CO3 or Na2CO3 at elevated temperatures (80-100°C) in solvents such as dioxane and water, or alternatively with an amine in a SnAr type reaction at elevated temperatures (>70°C) in polar solvents (e.g., THF, EtOH, DMF, DMA, NMP) using an excess base (e.g., DIPEA, TEA, K2CO3).

[0222] Alternatively, pyridine IIa can be synthesized by cyclizing intermediate VIIIa with 2-cyanoacetamide using a base (e.g., NaOEt) in polar solvents such as DMF at elevated temperatures to yield the corresponding hydroxypyridine IXa. Hydroxypyridine IXa can be converted to pyridine Ia using a dehydrating reagent such as POCl3 at elevated temperatures.

[0223] General Procedures

[0224] General Procedure A: Suzuki-Miyaura Type Cross-Combination

[0225] To 2,6-dihalo-3-nitrylopyridine dissolved in dioxane / water mixture (4:1 ratio, 0.1-0.2 M) was added K2CO3 or Na2CO3 (3 equiv.), then boronic acid or ester (1.5 equiv.) and the resulting reaction mixture was degassed by bubbling argon through the mixture with sonication. Pd(dppf)2Cl2⋅CH2Cl2 or tetrakis(triphenylphosphine)palladium complex (0.05-0.2 equiv.) was added and the reaction mixture was heated to 100°C until LCMS showed complete consumption of the pyridine starting material (0.5-16 h). The reaction mixture was then diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product could be purified by flash chromatography on silica gel.

[0226] General Procedure B: SnAr-Type Reaction

[0227] To a solution of 2,6-dihalo-3-nitrylopyridine in THF or DMF (0.1-0.2 M) were added DIPEA or TEA (2 equiv) and a secondary amine (1.1 equiv). The reaction mixture was stirred at ambient or elevated temperature until LCMS showed complete consumption of the pyridine starting material (up to 24 h). The reaction mixture was then diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product can be purified by flash chromatography on silica gel.

[0228] General Procedure B: Cyclization of Hydrazine

[0229] Hydrazine (2 equiv.) was added to a solution / suspension of the desired chloropyridine in ethanol or ethylene glycol (0.1-0.2 M), and the reaction mixture was stirred at 70°-120°C until LCMS showed complete consumption of the chloropyridine (up to 16 h). The reaction mixture was concentrated, and the crude product was purified by flash chromatography on silica gel or simply suspended in water and isolated by filtration.

[0230] General Procedure D: Synthesis of Pyridone

[0231] To a crude solution of the appropriate enone VIII in DMF (0.2-0.4 M) (prepared according to a modification of the procedure from J. Med. Chem. 2011, 54, 7974) were added 2-cyanoacetamide (3 equiv.) and NaOEt (3 equiv.) as a base. The resulting reaction mixture was heated to 100°C until LCMS showed complete consumption of the starting material VIII (approximately 16 h). The reaction mixture was then diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product can be purified by flash chromatography on silica gel.

[0232] General Procedure D: Synthesis of Pyridyl Chloride

[0233] Hydroxypyridine was dissolved in POCl3 (10-20 equiv.) and the resulting reaction mixture was heated to 100°C until LCMS indicated the reaction was complete (approximately 16 h). The reaction mixture was then concentrated under reduced pressure, diluted with EtOAc, and filtered. The organic layers were diluted with water and extracted several times with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude chloropyridine product can be purified by flash chromatography on silica gel.

[0234] General Procedure E1: Amide Coupling with CDI

[0235] As described in Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, 1088. Carbonyldiimidazole (1.5 equiv) was added to a solution of the appropriate carboxylic acid (1.5 equiv) dissolved in DMF (0.1-0.2 M) and the mixture was stirred at ambient temperature for 0.5-1 h before the addition of the desired pyrazolo[3,4-b]pyridin-3-amine (1 equiv) and the mixture was heated to 100°C-140°C until LCMS showed the reaction to be complete (24-48 h). The reaction mixture was then concentrated to dryness and the product was purified by reverse-phase preparative HPLC.

[0236] General Procedure E2: Amide coupling with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) and benzimine deprotection

[0237] To a solution of the appropriate carboxylic acid (1.1 equiv.) dissolved in DMF (0.1-0.2 M), TBTU (1.1 equiv.) and triethylamine (2 equiv.) were added, followed by (E)-N-(6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-1-phenylmethanimine (1 equiv.), and the mixture was stirred at ambient temperature until LCMS showed the reaction to be complete (16-48 h), or heated to 50°C to accelerate the completion. Then, a drop of 1 N HCl (aqueous) was added, and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was then concentrated to dryness, and the product was purified by reverse-phase preparative HPLC.

[0238] A particular embodiment of the present invention relates to a method for preparing compounds of formula (I'), wherein X 1 , R 1 and R 2are as defined herein and their pharmaceutically acceptable salts as defined according to the present invention comprising coupling a compound of formula (III) with carboxylic acids IVa using mild activators (e.g. 1,1'-carbonyldiimidazole) in polar solvents (e.g. DMF, DMA, NMP) at elevated temperatures (80-120°C) to obtain a compound of formula (I) as shown in Scheme 2.

[0239]

[0240] The compounds were tested according to the test given later in this document.

[0241] Determination of Mat2A activity

[0242] Mat2A inhibition measurement was performed in a 384-well absorbance-based assay format.

[0243] 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 MgCh, 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.

[0244] The final assay condition was 12.5 nM Mat2A, 100 μM ATP and methionine substrates, and 2% DMSO. After 120 minutes 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 minutes of equilibration at RT.

[0245]

[0246]

[0247]

[0248] Abbreviations

[0249] The following abbreviations were used in the experimental section:

[0250] Ar = argon;

[0251] nBuLi = n-butyllithium;

[0252] DCM = dichloromethane;

[0253] DIPEA = diisopropylethylamine;

[0254] DMSO = dimethyl sulfoxide;

[0255] DMF = dimethylformamide;

[0256] EtOH = ethanol;

[0257] EtOAc = ethyl acetate;

[0258] HCl = hydrochloric acid;

[0259] HPLC=high performance liquid chromatography;

[0260] DAL = lithium diisopropylamide;

[0261] LiHMDS = lithium bis(trimethylsilyl)amide;

[0262] mCPBA = metachloroperbenzoic acid;

[0263] MOM = methoxymethyl;

[0264] NMP = N-methyl-2-pyrrolidone;

[0265] SEM = [2-(trimethylsilyl)ethoxy)methyl]acetal;

[0266] TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate;

[0267] THF = tetrahydrofuran;

[0268] TEMPO = 2,2,6,6-tetramethylpiperidinyloxyl;

[0269] TBAF = Tetra-n-butylammonium fluoride;

[0270] TLC = thin layer chromatography.

[0271] Source materials

[0272] 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.

[0273] Intermediate compounds

[0274] Intermediate 1: 6-phenyl-1H-pyrazolo[3,4-b]pyridin-3-amine

[0275]

[0276] Target compound ([M+H] + 211.1) was prepared from 2-chloro-6-phenylnicotinonitrile (CN 106146493 A) and hydrazine at 70°C according to general procedure B.

[0277] Intermediate 2: 6-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-amine

[0278]

[0279] Step 1: 2-chloro-6-isobutylnicotinonitrile

[0280] 2,6-Dichloronicotinonitrile (250 mg, 1.45 mmol) was dissolved in dioxane (5 mL), 2-methylpropylzinc bromide (3.47 mL, 0.5 M in THF, 1.73 mmol) was added, and argon was bubbled through the reaction mixture. Pd(dppf)2Cl2⋅CH2Cl2 complex (12 mg, 15 μmol) was added and the reaction mixture was heated to 90°C in a sealed tube for 18 h, after which a second portion of 2-methylpropylzinc bromide (3.47 mL, 0.5 M in THF, 1.73 mmol) and Pd(dppf)2Cl2⋅CH2Cl2 complex (12 mg, 15 μmol) were added and the reaction mixture was heated for another 2 h at 70°C. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel (ethyl acetate: n-heptane 0:1-1:0) to give the title compound (185 mg, 76%) as a colorless oil. ([M+H,Cl] + 195.1)

[0281] Step 2: 6-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-amine

[0282] Target compound ([M+H] +191.3) was prepared from 2-chloro-6-isobutylnicotinonitrile (step 1) and hydrazine at 70°C according to general procedure B.

[0283] Intermediate 3: 6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0284]

[0285] Step 1: 2-chloro-6-(pyrrolidin-1-yl)nicotinonitrile

[0286] Target compound ([M+H] + 208.1) was prepared from 2,6-dichloronicotinonitrile and pyrrolidine in THF and DIPEA as base according to the general procedure B.

[0287] Step 2: 6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0288] Target compound ([M+H] + 204.2) was prepared from 2-chloro-6-(pyrrolidin-1-yl)nicotinonitrile (step 1) and hydrazine at 100°C according to general procedure B and isolated by filtration from water.

[0289] Intermediate 4: 6-(cyclohexen-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0290]

[0291] Step 1: 2-chloro-6-(cyclohex-1-en-1-yl)nicotinonitrile

[0292] Target compound ([M+H, Cl] + 219.1) was prepared from 2,6-dichloronicotinonitrile and cyclohex-1-en-1-ylboronic acid under tetrakis(triphenylphosphine)palladium catalysis at 110°C according to the general procedure of A.

[0293] Step 2: 6-(cyclohexen-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0294] Target compound ([M+H] + 215.2) was prepared from 2-chloro-6-(cyclohex-1-en-1-yl)nicotinonitrile (step 1) and hydrazine at 100°C according to general procedure B.

[0295] Intermediate 5: cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-amine

[0296]

[0297] Target compound ([M+H] + 175.4) was prepared from 2-chloro-6-cyclopropylnicotinonitrile (38041-19-9) and hydrazine at 100°C according to the general procedure B.

[0298] Intermediate 6: 5-fluoro-6-phenyl-1H-pyrazolo[3,4-b]pyridin-3-amine

[0299]

[0300] Step 1: 2-chloro-5-fluoro-6-phenylnicotinonitrile

[0301] Target compound ([M+H+MeCN, Cl] + 275.1) was prepared from 2,6-dichloro-5-fluoronicotinonitrile and phenylboronic acid under catalysis using the complex Pd(dppf)2Cl2⋅CH2Cl2 at 90°C according to the general procedure A.

[0302] Step 2: 6-(cyclohexen-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0303] Target compound ([M+H] + 229.3) was prepared from 2-chloro-5-fluoro-6-phenylnicotinonitrile (step 1) and hydrazine at 75°C according to general procedure B.

[0304] Intermediate 7: 5-fluoro-6-pyrrolidin-1-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine

[0305]

[0306] To a solution of 2,6-dichloro-5-fluoro-3-pyridinecarbonitrile (200 mg, 1 mmol) in ethanol (2 mL) was added pyrrolidine (124 μL, 0.2 mmol), and the reaction mixture was heated to 95°C for 6 h. The reaction mixture was concentrated, and the residue was redissolved in ethylene glycol (2 mL), and hydrazine monohydrate (0.75 mL, 15.0 mmol) was added, and the reaction mixture was heated to 130°C for 3 h. The reaction mixture was absorbed onto silica gel and purified by flash column chromatography on silica gel (ethyl acetate: n-heptane 0:1-1:0) to give the title compound (149 mg, 68%) as a white solid ([M+H] + 222.1).

[0307] Intermediate 8: 6-(3,3-difluoroazetidin-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine

[0308]

[0309] Step 1: 2-chloro-6-(3,3-difluoroazetidin-1-yl)-5-fluoronicotinonitrile

[0310] The target compound was prepared from 2,6-dichloro-5-fluoronicotinonitrile and 3,3-difluoroazetidine hydrochloride in DMF using triethylamine as a base according to General Procedure B. 1 H NMR (DMSO-d6, 300 MHz) δ 8.18 (d, 1H, J=11.3 Hz), 4.70 (dt, 4H, J=1.8, 12.4 Hz)

[0311] Step 2: 6-(3,3-difluoroazetidin-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine

[0312] Target compound ([M+H] + 244.1) was prepared from 2-chloro-5-fluoro-6-phenylnicotinonitrile (step 1) and hydrazine in ethylene glycol at 120°C according to general procedure B.

[0313] Intermediate 9: 6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-amine

[0314]

[0315] Step 1: 4-chloro-2-(pyrrolidin-1-yl)pyrimidine-5-carbonitrile

[0316] Target compound ([M+H, Cl] +209.1) was prepared from 2,4-dichloropyrimidine-5-carbonitrile and pyrrolidine in THF and DIPEA as base according to General Procedure B.

[0317] Step 2: 6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-amine

[0318] Target compound ([M+H] + 205.2) was prepared from 4-chloro-2-(pyrrolidin-1-yl)pyrimidine-5-carbonitrile (step 1) and hydrazine in ethanol at 100°C according to general procedure B.

[0319] Intermediate 10: 6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-amine

[0320]

[0321] Target compound ([M+H] + 217.2) was prepared from 2-chloro-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile and hydrazine in ethanol at 100°C according to the general procedure of B.

[0322] Intermediate 11: 6-(3,4-dihydro-2H-pyran-6-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0323]

[0324] Step 1: 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)nicotinonitrile

[0325] Target compound ([M+H, Cl] + 221.1) was prepared from 2,6-dichloro-5-fluoronicotinonitrile and 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane under tetrakis(triphenylphosphine)palladium catalysis at 90°C according to the general procedure of A.

[0326] Step 2: 6-(3,4-dihydro-2H-pyran-6-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0327] Target compound ([M+H] + 217.1) was prepared from 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)nicotinonitrile (step 1) and hydrazine in ethanol at 100°C according to general procedure B.

[0328] Intermediate 12: 6-(cyclopenten-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0329]

[0330] Step 1: 2-chloro-6-(cyclopent-1-en-1-yl)nicotinonitrile

[0331] Target compound ([M+H, Cl] +205.1) was prepared from 2,6-dichloro-5-fluoronicotinonitrile and cyclopent-1-en-1-ylboronic acid under tetrakis(triphenylphosphine)palladium catalysis at 90°C according to the general procedure of A.

[0332] Step 2: 6-(cyclopenten-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0333] Target compound ([M+H] + 201.1) was prepared from 2-chloro-6-(cyclopent-1-en-1-yl)nicotinonitrile (step 1) and hydrazine in ethanol at 100°C according to the general procedure B.

[0334] Intermediate 13: 6-(azetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0335]

[0336] 6-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine (100 mg, 0.5 mmol) was dissolved in azetidine (0.5 mL, 12.5 mmol) and stirred at 70°C for 72 h in a sealed tube. The reaction mixture was poured onto water, the resulting precipitate was filtered off, and the filtrate was allowed to stand for several days, resulting in crystallization. Filtration gave the title compound (12 mg, 13%) as a white solid ([M+H] + 190.1).

[0337] Intermediate 14: 6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0338]

[0339] Step 1: 4-chloro-2-(pyrrolidin-1-yl)pyrimidine-5-carbonitrile

[0340] Target compound ([M+H, Cl] + 230.0) was prepared from 2,6-dichloronicotinonitrile and 3,3-difluoroazetidine hydrochloride in ethanol and DIPEA as base according to general procedure B.

[0341] Step 2: 6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0342] Target compound ([M+H] + 205.2) was prepared from 4-chloro-2-(pyrrolidin-1-yl)pyrimidine-5-carbonitrile (step 1) and hydrazine in ethanol at 80°C according to general procedure B.

[0343] Intermediate 15: 6-cyclopentyl-1H-pyrazolo[3,4-b]pyridin-3-amine

[0344]

[0345] 6-(cyclopent-1-en-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (intermediate 12, step 2) (61 mg, 0.3 mmol) was dissolved in ethanol (3 mL) and ethyl acetate (1 mL), and 10% palladium on carbon (6 mg, 6 μmol) was added. The reaction mixture was then stirred under a balloon hydrogen atmosphere at 50 °C for 18 h. The reaction mixture was allowed to cool to ambient temperature, then filtered through Dicalite® and concentrated to give the title compound (55 mg, 87%) as a yellow solid. ([M+H] + 203.1)

[0346] Intermediate 16: 6-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-3-amine

[0347]

[0348] Step 1: 1-cyclobutyl-3-(dimethylamino)prop-2-en-1-one

[0349] To a solution of 1-cyclobutylethan-1-one (2.22 mL, 20.4 mmol) in DMF (5 mL) were added 1,1-dimethoxy-N,N-dimethylmethanamine (5.43 mL, 40.8 mmol) and sodium methoxide (50 mg, 0.9 mmol), and the mixture was stirred at 100°C for 16 h, when 1H NMR of an aliquot of the solution showed complete conversion. The crude solution was directly used in the next step.

[0350] Step 2: 6-cyclobutyl-2-hydroxynicotinonitrile

[0351] Target compound ([M+H] + 175.1) was prepared from 1-cyclobutyl-3-(dimethylamino)prop-2-en-1-one (step 2) and cyanoacetamide according to the general procedure of G.

[0352] Step 3: 2-chloro-6-cyclobutylnicotinonitrile

[0353] Target compound ([M+H, Cl] +193.0) was prepared from 6-cyclobutyl-2-hydroxynicotinonitrile (step 2) and POCl3 according to the general procedure of D.

[0354] Step 4: 6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0355] Target compound ([M+H] + 189.1) was prepared from 2-chloro-6-cyclobutylnicotinonitrile (step 3) and hydrazine in ethanol at 75°C according to the general procedure B.

[0356] Intermediate 17: 6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0357]

[0358] Step 1: 2-hydroxy-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile

[0359] Target compound ([M+H] + 175.0) was prepared by the reaction of (E)-3-(dimethylamino)-1-(2-methylcyclopropyl)prop-2-en-1-one (prepared by a modification of the procedure from J. Med. Chem. 2011, 54, 7974 from 1-(2-methylcyclopropyl)ethanone-CAS No. 930-56-3) and 2-cyanoacetamide using NaOMe as the base (General Procedure G).

[0360] Step 2: 2-chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile

[0361] Target compound ([M+H, Cl] + 193.1) was prepared by the reaction of 2-hydroxy-6-(2-methylcyclopropyl)nicotinonitrile with POCl3 (General Procedure I).

[0362] Step 3: 6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0363] Target compound ([M+H] + 189.1) was prepared from 2-chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile (step 2) and hydrazine in ethanol at 75°C according to general procedure B.

[0364] Intermediate 18: 6-(2,5-dihydrofuran-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0365]

[0366] Target compound ([M+H] +203.1) was prepared from 6-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane under tetrakis(triphenylphosphine)palladium catalysis at 110°C according to the general procedure A.

[0367] Intermediate 19: 7-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-3-amine

[0368]

[0369] Target compound ([M+H] + 203.2) was prepared from 2-chloro-7-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile and hydrazine in ethanol at 75°C according to the general procedure of B.

[0370] Intermediate 20: 6-((1RS,2SR)-2-fluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0371]

[0372] Step 1: 6-((1RS,2SR)-2-fluorocyclopropyl)-2-hydroxynicotinonitrile

[0373] Target compound ([M+H] +179.0) was prepared by the reaction of 3-(dimethylamino)-1-((trans)-2-fluorocyclopropyl)prop-2-en-1-one (prepared using a modified procedure from J. Med. Chem. 2011, 54, 7974 from 1-(2-fluorocyclopropyl)ethanone (WO 2016 / 161960 A1, 2016)) and 2-cyanoacetamide using NaOMe as a base (General Procedure G).

[0374] Step 2: 2-chloro-6-((1RS,2SR)-2-fluorocyclopropyl)nicotinonitrile

[0375] Target connection ( 1 H NMR (CHLOROFORM-d, 300 MHz) δ 7.84 (d, 1H, J=7.9 Hz), 7.30 (d, 1H, J=7.9 Hz), 4.70-5.20 (m, 1H), 2.40-2.60 (m, 1H), 1.60-1.80 (m, 1H), 1.50-1.60 (m, 1H) was obtained by reaction of 6-((1RS,2SR)-2-fluorocyclopropyl)-2-hydroxynicotinonitrile (step 1) from POCl3 (general procedure I).

[0376] Step 3: 6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0377] Target compound ([M+H] +193.0) was prepared from 2-chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile (step 2) and hydrazine in ethanol at 75°C according to general procedure B.

[0378] Intermediate 21: 6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0379]

[0380] Step 1: 2-chloro-6-vinylnicotinonitrile

[0381] Target compound ([M+H, Cl] + 165.0) was prepared from 2,6-dichloronicotinonitrile and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane under catalysis with Pd(dppf)2Cl2⋅CH2Cl2 complex at 100°C according to the general procedure A.

[0382] Step 2: 2-chloro-6-(2,2-difluorocyclopropyl)nicotinonitrile

[0383] To a solution of 2-chloro-6-vinylnicotinonitrile (step 1) (50 mg, 0.30 mmol) in THF (2 mL), trimethyl(trifluoromethyl)silane (112 μL, 0.76 mmol) and NaI (9.2 mg, 0.06 mmol) were added. The reaction mixture was stirred in a sealed tube at 65 °C for 2 h. An additional portion of trimethyl(trifluoromethyl)silane (112 μL, 0.76 mmol) and NaI (9.2 mg, 0.06 mmol) were added and the reaction mixture was stirred for another hour at 65 °C before adding the last additional portion of trimethyl(trifluoromethyl)silane (112 μL, 0.76 mmol) and NaI (9.2 mg, 0.06 mmol) and the reaction mixture was stirred for another 3 h. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, brine, dried (Na2SO4), and concentrated. Flash chromatography on silica gel (ethyl acetate:n-heptane 0:1-1:1) gave the title compound (27 mg, 41%) as a yellow oil. ([M+H, Cl] + 215.1)

[0384] Step 3: 6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0385] Target compound ([M+H] + 211.1) was prepared from 2-chloro-6-(2,2-difluorocyclopropyl)nicotinonitrile (step 2) and hydrazine in ethanol at 100°C according to the general procedure B.

[0386] Intermediate 22: 6-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[3,4-b]pyridin-3-amine

[0387]

[0388] Step 1: 2-chloro-6-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]pyridine-3-carbonitrile

[0389] Target compound ([M+H, Cl] + 247.0) was prepared from 2,6-dichloronicotinonitrile and potassium trifluoro((1RS,2R8)-2-(trifluoromethyl)cyclopropyl)borate under butyldi-1-adamantylphosphine / palladium(II) acetate catalysis in a toluene / water mixture at 120°C according to General Procedure A. The desired product was inseparable from the 6-chloro-2-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]pyridine-3-carbonitrile isomer.

[0390] Step 3: 6-[(1RS,2118)-2-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[3,4-b]pyridin-3-amine

[0391] Target compound ([M+H] + 243.1) was prepared from 2-chloro-6-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]pyridine-3-carbonitrile (step 2) and hydrazine in ethanol at 100°C according to general procedure B.

[0392] Intermediate 23: 6-((1rs,2RS,3SR)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0393]

[0394] Step 1: 6-((1,rs,2RS,3SR)-2,3-dimethylcyclopropyl)-2-hydroxynicotinonitrile

[0395] Target compound ([M+H] + 189D) was prepared by the reaction of (E)-3-(dimethylamino)-1-((2RS,3SR)-2,3-dimethylcyclopropyl)prop-2-en-l-one (prepared by a modification of the procedure from J. Med. Chem. 2011, 54, 7974 from 1-[rac-(2R,3S)-2,3-dimethylcyclopropyl]ethanone (J. Org. Chem. 1978, 3422)) and 2-cyanoacetamide using NaOMe as the base (general procedure G).

[0396] Step 2: 2-chloro-6-((1rs8,2RS,3SR)-2,3-dimethylcyclopropyl)nicotinonitrile

[0397] Target compound ([M+H] + 207.1) was prepared by the reaction of 6-((1rs,2R,3S)-2,3-dimethylcyclopropyl)-2-hydroxynicotinonitrile (step 1) with POCl3 (General Procedure I).

[0398] Step 3: 6-((1rs,2RS,3SR)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0399] Target compound ([M+H] + 203.1) was prepared from 2-chloro-6-((1rs,2RS,3SR)-2,3-dimethylcyclopropyl)nicotinonitrile (step 2) and hydrazine in ethanol at 75°C according to general procedure B.

[0400] Intermediate 24: 6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0401]

[0402] Step 1: 2-hydroxy-6-(1-methylcyclopropyl)nicotinonitrile

[0403] Target compound ([M+H] +189.1) was prepared by the reaction of (E)-3-(dimethylamino)-1-(1-methylcyclopropyl)prop-2-en-1-one (prepared by a modification of the procedure from J. Med. Chem. 2011, 54, 7974 from 1-(1-methylcyclopropyl)ethan-1-one (Chem. Berichte, 1981, 3831) and 2-cyanoacetamide using NaOMe as base (general procedure G).

[0404] Step 2: 2-chloro-6-(1-methylcyclopropyl)nicotinonitrile

[0405] Target connection ( 1 H NMR (CHLOROFORM-d, 300 MHz) δ 7.80-7.90 (m, 1H), 7.30 (d, 1H, J=8.3 Hz), 1.51 (s, 3H), 1.40-1.43 (m, 2H), 0.90-1.0 (m, 2H)) was obtained by reacting 2-hydroxy-6-(1-methylcyclopropyl)nicotinonitrile (step 1) with POCl3 (general procedure I).

[0406] Step 3: 6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0407] Target compound ([M+H] + 189.1) was prepared from 2-chloro-6-(1-methylcyclopropyl)nicotinonitrile (step 2) and hydrazine in ethanol at 75°C according to the general procedure B.

[0408] Intermediate 25: 6-(3-azabicyclo[2.2.1]heptan-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0409]

[0410] Step 1: 6-(3-azabicyclo[2.2.1]heptan-3-yl)-2-chloropyridine-3-carbonitrile

[0411] Target connection ( 1 H NMR (400 MHz, DMSO-d6) δ = 7.93 - 7.71 (m, 2H), 6.72 (br d, J=8.8 Hz, 1H), 6.37 (br d, J=8.8 Hz, 1H), 4.79 - 4.62 (m, 1H), 4.57 -4.40 (m, 1H), 3.42 - 3.35 (m, 2H), 3.21 - 3.12 (m, 1H), 3.02 (width, J=9.6 Hz, 1H), 2.70 - 2.61 (m, 2H), 1.76 - 1.62 (m, 6H), 1.57 - 1.35 (m, 6H)) were obtained from 2,6-dichloronicotinonitrile and 3-azabicyclo[2.2.1]heptane in THF and TEA as base according to General Procedure B.

[0412] Step 2: 6-(3-azabicyclo[2.2.1]heptan-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0413] Target compound ([M+H] +205.2) was prepared from 6-(3-azabicyclo[2.2.1]heptan-3-yl)-2-chloropyridine-3-carbonitrile (step 1) and hydrazine in ethanol at 80°C according to general procedure B.

[0414] Intermediate 26: [3-amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone

[0415]

[0416] Step 1: 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-chloropyridine-3-carbonitrile

[0417] Target connection ( 1 H NMR (400 MHz, DMSO-d6) δ = 8.01 (d, J=1.3 Hz, 1H), 6.99 - 6.84 (m, 1H), 4.74 - 4.48 (m, 2H), 1.73 - 1.64 (m, 4H), 1.57 - 1.46 (m, 4H)) was prepared from 2,6-dichloronicotinonitrile and 7-azabicyclo[2.2.1]heptane hydrochloride in THF / acetonitrile (1:1) and DIPEA as base according to general procedure B.

[0418] Step 2: [3-amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone

[0419] Target connection ( 1H NMR (400 MHz, DMSO-d6) δ = 11.47 - 11.24 (m, 1H), 7.84 - 7.68 (m, 1H), 6.52 (d, J = 8.8 Hz, 1H), 5.26 - 5.08 (s, 2H), 4.61 - 4.35 (s, 2H), 1.71 - 1.60 (m, 4H), 1.50 - 1.37 (m, 4H)) was prepared from 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-chloropyridine-3-carbonitrile (step 1) and hydrazine in ethanol at 80°C according to general procedure B.

[0420] Intermediate 27: (3RS,4RS)-3-methyl-2-oxopiperidine-4-carboxylic acid

[0421]

[0422] 3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (Tetrahedron, 1989, 7469) (1.82 g, 11.9 mmol) was suspended in methanol (5 mL) and 10% Pd-C (632 mg, 0.5 mmol) was added and the reaction mixture was stirred under hydrogen atmosphere (balloon) for 72 h. The reaction mixture was filtered through Hyflo®, washing extensively with MeOH, and concentrated to give the title compound (1.85 g, 84%) as a white solid ([M-H] - 156.0).

[0423] Intermediate 28: (E)-N-(6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-1-phenylmethanimine

[0424]

[0425] To a suspension of 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-amine (intermediate 5) (200 mg, 1.15 mmol) in EtOH (4 mL) was added benzaldehyde (0.13 mL, 1.26 mmol), and the mixture was heated to 80°C for 1 h. The reaction mixture was cooled to ambient temperature, and the desired product (309 mg, quant.) was isolated by filtration as an off-white solid. ( 1 H NMR (CHLOROFORM-d, 300 MHz) δ 13.28 (s, 1H), 9.20 (s, 1H), 8.28 (d, 1H, J=8.3 Hz), 8.00-8.10 (m, 2H), 7.5-7.6 (m, 3H), 7.21 (d, 1H, J=8.3 Hz), 2.20-2.30 (m, 1H), 1.00-1.10 (m, 4H))

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457] Aspects of the present invention:

[0458] 1. Compound of formula I:

[0459]

[0460] where

[0461] X 1 represents either N or CR 3 ;

[0462] R 1 represents:

[0463] - (C3-C8)cycloalkyl, optionally substituted with one or more, in particular one to three, more particularly one or two R substituents 1a ,

[0464] - heteroaryl, optionally substituted with one or more, in particular one to three, more particularly one or two R substituents 1b ,

[0465] - heterocycloalkyl, optionally substituted by one or more, in particular one to three, more particularly one or two R substituents 1c ; or

[0466] - phenyl, optionally substituted with one or more, in particular one to three, more particularly one or two substituents R 1d ;

[0467] each of R 1a , R 1b , R 1c and R 1dindependently selected from halogen, oxo, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl, heterocycloalkyl, and phenyl;

[0468] R 2 is (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C6)cycloalkyl, optionally substituted by one or more, in particular one to three, more in particular one or two substituents R 2a , heterocycloalkyl, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 2b , or phenyl, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 2c ;

[0469] each of R 2a , R 2b and R 2cindependently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy;

[0470] R represents hydrogen, halogen or (C1-C6)alkyl;

[0471] or R 2 and R 3 together form C 2-7 -alkylene, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 3f , And

[0472] every R 3f independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl;

[0473] and its pharmaceutically acceptable salts.

[0474] 2. The compound according to aspect 1, wherein the compound has formula I':

[0475]

[0476] R 1 represents:

[0477] - (C3-C8)cycloalkyl, optionally substituted with one or more, in particular one to three, more particularly one or two R substituents 1a ,

[0478] - heteroaryl, optionally substituted with one or more, in particular one to three, more particularly one or two R substituents 1b ,

[0479] - heterocycloalkyl, optionally substituted by one or more, in particular one to three, more particularly one or two R substituents 1c ; or

[0480] - phenyl, optionally substituted with one or more, in particular one to three, more particularly one or two R substituents 1d ;

[0481] each of R 1a , R 1b , R 1c and R 1d independently selected from halogen, oxo, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl, heterocycloalkyl, and phenyl;

[0482] R 2represents (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 2a , heterocycloalkyl, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 2b , or phenyl, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 2c ;

[0483] each of R 2a , R 2b and R 2c independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy;

[0484] R 3 represents hydrogen, halogen or (C1-C6)alkyl;

[0485] or R 2 and R 3 together form C 2-7 -alkylene, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 3f , And

[0486] every R 3f independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl;

[0487] and its pharmaceutically acceptable salts.

[0488] 3. Connection according to aspect 1, where X 1 represents CR 3 .

[0489] 4. Connection according to any of the aspects 1-3, where R 1 is (C3-C8)cycloalkyl, optionally substituted with one substituent R 1a , heteroaryl, optionally substituted with one R 1b , heterocycloalkyl, optionally substituted with one or two R 1c , or phenyl optionally substituted with one or two R 1d .

[0490] 5. Connection according to any of the aspects 1-4, where R 1 is (C3-C6)cycloalkyl, optionally substituted with one R 1a , pyridinyl, optionally substituted with one R 1b , pyrazinyl, optionally substituted with one R 1b , pyridizanyl, optionally substituted with one R1b , thiazolyl optionally substituted with one R 1b , 1,3-benzodioxolyl, optionally substituted with one R 1c , oxazolyl, optionally substituted with one R 1c , piperidinyl, optionally substituted with one R 1c , tetrahydrofuranyl, optionally substituted with one R 1c , tetrahydropyranyl, optionally substituted with one R 1c , or phenyl optionally substituted with one or two R 1d .

[0491] 6. Connection according to any of the aspects 1-5, where R 1 is cyclohexyl, optionally substituted with one R 1a , pyridinyl, optionally substituted with one R 1b , pyrazinyl, optionally substituted with one R 1b , pyridizanyl, optionally substituted with one R 1b , thiazolyl optionally substituted with one R 1b , 1,3-benzodioxolyl, oxazolyl, optionally substituted with one R 1c , piperidinyl, optionally substituted with one R 1c, tetrahydrofuranyl, optionally substituted with one R 1c , tetrahydropyranyl or phenyl optionally substituted with one or two R 1d .

[0492] 7. Connection according to any of the aspects 1-6, where R 1 , most specifically, R 1 is pyridinyl, optionally substituted with one R 1b , or phenyl optionally substituted with one or two R 1d .

[0493] 8. Connection according to any of the aspects 1-4, where R 1 is heteroaryl optionally substituted with one R 1b , or phenyl optionally substituted with one or two R 1d .

[0494] 9. Connection according to any of the aspects 1-8, where each of R 1a , R 1b , R 1c and R 1d independently selected from halogen, oxo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy.

[0495] 10. Connection according to any of the aspects 1-9, where each of R 1a , R 1b , R 1c and R 1d independently selected from halogen, oxo, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl and halo(C1-C3)alkoxy.

[0496] 11. Connection according to any of the aspects 1-10, where each of R 1a , R 1b , R 1c and R 1d independently selected from chloro, fluoro, oxo, cyano, methyl, ethyl, methoxy, trifluoromethyl, and difluoromethyl.

[0497] 12. Connection according to any of the aspects 1-11, where each of R 1a , R 1b , R 1c and R 1d independently selected from chlorine, fluorine, cyano, methyl and methoxy.

[0498] 13. Connection according to any of the aspects 1-10, where each of R 1b and R 1d independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy.

[0499] 14. Connection according to any of the aspects 1-10, where each R 1b independently selected from halogen, (C1-C3)alkyl, (C1-C3)alkoxy, and halo(C1-C3)alkyl, and where each R 1d independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy.

[0500] 15. Connection according to any of the aspects 1-10, where each R 1b independently selected from chlorine, methyl, and methoxy, and where each R 1d independently selected from fluoro, cyano, methyl and methoxy.

[0501] 16. Connection in accordance with any of the aspects 1-15, while R 1is 2-methoxyphenyl, 2-chlorophenyl, 2-methylphenyl, 1,3-benzodioxol-4-yl, 3-fluoro-2-methylphenyl, 2,3-dimethylphenyl, cyclohexyl, 2-methoxycyclohexyl, 3-fluoro-2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 3-methyl-2-oxopiperidin-4-yl, 2-ethylphenyl, 2-(difluoromethoxy)phenyl, 5-methyl-1,3-oxazol-4-yl, 4-methyl-1,3-thiazol-5-yl, 2-methyloxolan-3-yl, 3-methyltetrahydrofuran-2-yl, 3-cyano-2-methylphenyl, oxan-4-yl, 2-methylpyridin-3-yl, 2-oxopiperidin-4-yl, 2-methoxy-3-methylphenyl, 3-chloro-2-methoxyphenyl, 3-cyano-2-methoxyphenyl, oxan-3-yl, 3-methylpyrazin-2-yl, 2-methoxypyridin-3-yl, 2-chloropyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 3-methylpyridazin-4-yl, 3-methyl-1,2-thiazol-4-yl or 3-methyltetrahydrofuran-2-yl.

[0502] 17. Connection in accordance with any of the aspects 1-16, where R 1 is 2-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 2-methylpyridin-3-yl, 3-cyano-2-methoxyphenyl, 2-methoxypyridin-3-yl, 2-chloropyridin-3-yl or 2-methylphenyl.

[0503] 18. Connection in accordance with any of the aspects 1-17, where R 2 represents (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, optionally substituted with one or two substituents R 2a , heterocycloalkyl, optionally substituted with one or two substituents R 2b , or phenyl.

[0504] 19. The compound according to any one of aspects 1 to 18, wherein R is (C1-C3)alkyl, halo(C1-C3)alkyl, cyclopropyl, optionally substituted with one or two R substituents 2a , cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, azetidinyl, optionally substituted with one or two substituents R 2b , dihydrofuranyl, dihydropyranyl, azabicyclo[2.2.1]heptanyl, azabicyclo[2.2.1]heptanyl, pyrrolidinyl, azetidinyl, optionally substituted with one or two R substituents 2b , or phenyl.

[0505] 20. The compound according to any one of aspects 1-19, wherein R is isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, optionally substituted with one or two R substituents 2a , cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, azetidinyl, optionally substituted with one or two substituents R 2b , 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl or phenyl.

[0506] 21. Connection in accordance with any of the aspects 1-17, where R 2 is halogen (C1-C6)alkyl, (C3-C6)cycloalkyl, optionally substituted with one or two substituents R 2a , or heterocycloalkyl optionally substituted with one or two substituents R 2b .

[0507] 22. Connection according to any of the aspects 1-21, where each of R 2a , R 2b and R 2c independently selected from halogen, (C1-C3)alkyl, and halo(C1-C3)alkyl.

[0508] 23. Connection according to any of the aspects 1-22, where each of R 2a , R 2b and R 2c independently selected from fluoro, methyl, and trifluoromethyl.

[0509] 24. Connection according to any of the aspects 1-23, where each R 2a independently selected from fluoro, methyl, and trifluoromethyl, each R 2b is fluorine.

[0510] 25. Connection in accordance with any of the aspects 1-24, where R 2 represents isobutyl, tert-butyl, trifluoromethyl, cyclopropyl optionally substituted with one or two substituents selected from fluorine, methyl or trifluoromethyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclohexen-1-yl, azetidinyl optionally substituted with two fluorine atoms, 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl or phenyl.

[0511] 26. Connection in accordance with any of the aspects 1-25, where R 2is trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenten-1-yl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2-(trifluoromethyl)cyclopropyl, 2,3-dimethylcyclopropyl, 1-methylcyclopropyl or 3,4-dihydropyran-6-yl.

[0512] 27. Connection in accordance with any of the aspects 1-26, where R 2 is phenyl, 2-methylpropyl, pyrrolidin-1-yl, cyclopropyl, cyclohexen-1-yl, 3,4-dihydro-2-pyran-6-yl, cyclopenten-1-yl, azetidin-1-yl, trifluoromethyl, 3,3-difluorazetidin-1-yl, cyclopentyl, cyclobutyl, 2-methylcyclopropyl, 2,5-dihydrofuran-3-yl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2-(trifluoromethyl)cyclopropyl, 2,3-dimethylcyclopropyl, 1-methylcyclopropyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl or tert-butyl.

[0513] 28. Connection in accordance with any of the aspects 1-26, where R 2 is cyclopropyl, cyclopenten-1-yl, trifluoromethyl or cyclobutyl, 2,5-dihydrofuran-3-yl.

[0514] 29. Connection in accordance with any of the aspects 1-28, where R 3 is hydrogen or halogen.

[0515] 30. Connection in accordance with any of the aspects 1-29, where R 3 is hydrogen, chlorine or fluorine.

[0516] 31. Connection in accordance with any of the aspects 1-30, where R 3 is hydrogen.

[0517] 32. A compound according to any one of aspects 1-30, selected from the group consisting of:

[0518] (3-amino-6-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0519] (3-amino-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0520] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0521] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chlorophenyl)methanone;

[0522] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0523] [3-amino-6-(cyclohexen-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0524] (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methoxyphenyl)methanone-2,2,2-trifluoroacetic acid;

[0525] (3-amino-5-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0526] (3-amino-5-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0527] (3-amino-5-fluoro-6-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0528] (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0529] (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chlorophenyl)methanone;

[0530] (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0531] (3-amino-6-(3,3-difluoroazetidin-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0532] (3-amino-6-(tert-butyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0533] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-c1]pyrimidin-1-yl)(2-methoxyphenyl)methanone;

[0534] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-c1]pyrimidin-1-yl)(o-tolyl)methanone;

[0535] (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-c1]pyrimidin-1-yl)(2-chlorophenyl)methanone;

[0536] (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(1,3-benzodioxol-4-yl)methanone;

[0537] (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methylphenyl)methanone;

[0538] (3-amino-7,7-dimethyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-1-yl)(2-methoxyphenyl)methanone;

[0539] [3-amino-6-(3,4-dihydro-2H-pyran-6-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0540] [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0541] (3-amino-6-(azetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0542] (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0543] (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0544] (3-amino-6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0545] (3-amino-6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0546] (3-amino-6-cyclopentylpyrazolo[3,4-b]pyridin-1-yl)-(2-methylphenyl)methanone;

[0547] [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methylphenyl)methanone;

[0548] (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0549] (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0550] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methylphenyl)methanone;

[0551] (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0552] (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0553] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2,3-dimethylphenyl)methanone;

[0554] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(cyclohexyl)methanone;

[0555] [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0556] [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0557] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxycyclohexyl)methanone;

[0558] (3-amino-7-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-1-yl)(2-methoxyphenyl)methanone;

[0559] (3-amino-6-((trans)-2-fluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0560] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methoxyphenyl)methanone;

[0561] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(4-fluoro-2-methoxyphenyl)methanone;

[0562] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0563] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0564] [3-amino-6-[rac-(1R,2R)-2-(trifluoromethyl)cyclopropyl]pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0565] (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0566] (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0567] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methoxyphenyl)methanone;

[0568] (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methoxyphenyl)methanone;

[0569] [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(3-fluoro-2-methoxyphenyl)methanone;

[0570] rac-(cis)-4-(3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-carbonyl)-3-methylpiperidin-2-one;

[0571] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-ethylphenyl)methanone;

[0572] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-(difluoromethoxy)phenyl)methanone;

[0573] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(5-methyloxazol-4-yl)methanone;

[0574] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(4-methylthiazol-5-yl)methanone;

[0575] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methyltetrahydrofuran-3-yl)methanone;

[0576] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)((2R,3R)-2-methyltetrahydrofuran-3-yl)methanone;

[0577] 3-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-carbonyl)-2-methylbenzonitrile;

[0578] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;

[0579] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone;

[0580] 4-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-carbonyl)piperidin-2-one;

[0581] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxy-3-methylphenyl)methanone;

[0582] (3-amino-6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0583] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone;

[0584] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methyltetrahydrofuran-3-yl)methanone;

[0585] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-chloro-2-methoxyphenyl)methanone;

[0586] 3-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-carbonyl)-2-methoxybenzonitrile;

[0587] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(tetrahydro-2H-pyran-3-yl)methanone;

[0588] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-methylpyrazin-2-yl)methanone;

[0589] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxypyridin-3-yl)methanone;

[0590] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chloropyridin-3-yl)methanone;

[0591] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-(trifluoromethyl)pyridin-3-yl)methanone;

[0592] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-methylpyridazin-4-yl)methanone;

[0593] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-methylisothiazol-4-yl)methanone;

[0594] [3-amino-6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0595] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)((2R,3S)-3-methyltetrahydrofuran-2-yl)methanone;

[0596] [3-amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone.

[0597] 33. A compound according to any one of aspects 1-30, selected from the group consisting of:

[0598] (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methoxyphenyl)methanone-2,2,2-trifluoroacetic acid;

[0599] (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methylphenyl)methanone;

[0600] [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone;

[0601] (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0602] [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methylphenyl)methanone;

[0603] (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0604] (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone;

[0605] (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0606] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0607] (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone;

[0608] [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(3-fluoro-2-methoxyphenyl)methanone;

[0609] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone;

[0610] (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone;

[0611] 3-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-carbonyl)-2-methoxybenzonitrile;

[0612] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxypyridin-3-yl)methanone;

[0613] (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chloropyridin-3-yl)methanone.

[0614] 34. The compound according to any one of aspects 1 to 33 for use as a therapeutically active substance.

[0615] 35. Pharmaceutical compositions comprising compounds of formula I or I' according to any of aspects 1-33 or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

[0616] 36. Compounds of formula I or I' according to any of aspects 1 to 33, or pharmaceutically acceptable salts thereof, as defined above, for use as therapeutically active substances.

[0617] 37. Compounds of formula I or I' according to any of aspects 1-33 or pharmaceutically acceptable salts thereof for use in the treatment, prevention and / or slowing down the progression of 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.

[0618] 38. Compounds according to aspect 37 for use in the treatment, prevention and / or slowing down the progression of lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

[0619] 39. A method for treating or preventing lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme and mesothelioma, wherein the method comprises administering to the subject compounds of formula I according to any one of aspects 1-33 or pharmaceutically acceptable salts thereof, as defined above.

[0620] 40. The method according to aspect 40 for treating or preventing lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

[0621] 41. Use of compounds of formula I according to any of aspects 1-33 or pharmaceutically acceptable salts thereof for the treatment, prevention and / or slowing down the progression of 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.

[0622] 42. Use of compounds according to aspect 41 for the treatment, prevention and / or slowing down the progression of lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

[0623] 43. Use of compounds of formula I according to any of aspects 1-33 or pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment or prevention of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, esophageal carcinoma, glioblastoma multiforme and mesothelioma.

[0624] 44. Use of compounds according to aspect 43 for the treatment, prevention and / or slowing down the progression of lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

Claims

1. Compound of formula I: Where X 1 represents either N or CR 3 ; R 1 is (C3-C6)cycloalkyl, optionally substituted with one R 1a , pyridinyl, optionally substituted with one R 1b , pyrazinyl, optionally substituted with one R 1b , pyridazinyl, optionally substituted with one R 1b , thiazolyl optionally substituted with one R 1b , 1,3-benzodioxolyl, optionally substituted with one R 1c , oxazolyl, optionally substituted with one R 1с , piperidinyl, optionally substituted with one R 1с , tetrahydrofuranyl, optionally substituted with one R 1c , tetrahydropyranyl, optionally substituted with one R 1с , or phenyl optionally substituted with one or two R 1d ; each of R 1a , R 1b , R 1c and R 1dindependently selected from halogen, oxo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, halogen (C1-C6)alkyl, and halogen (C1-C6)alkoxy; R 2 represents (C1-C3)alkyl, halogen (C1-C3)alkyl, cyclopropyl, optionally substituted with one or two substituents R 2a , cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, azetidinyl, optionally substituted with one or two substituents R 2b , dihydrofuranyl, dihydropyranyl, azabicyclo[2.2.1]heptanyl, pyrrolidinyl or phenyl; each of R 2a and R 2b independently selected from halogen, (C1-C3)alkyl, and halo(C1-C3)alkyl; R 3 is hydrogen or halogen; or R 2 and R 3 together form C 2-7 -alkylene, optionally substituted by one or more, in particular one to three, more particularly one or two substituents R 3f , And each R 3findependently selected from halogen, (C1-C6) alkyl, halogen(C1-C6) alkyl; and its pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein said compound has formula I': R 1 is (C3-C6) cycloalkyl, optionally substituted with one R 1a , pyridinyl, optionally substituted with one R 1b , pyrazinyl, optionally substituted with one R 1b , pyridazinyl, optionally substituted with one R 1b , thiazolyl optionally substituted with one R 1b , 1,3-benzodioxolyl, optionally substituted with one R 1c , oxazolyl, optionally substituted with one R 1c , piperidinyl, optionally substituted with one R 1c , tetrahydrofuranyl, optionally substituted with one R 1c , tetrahydropyranyl, optionally substituted with one R 1c , or phenyl optionally substituted with one or two R 1d ; each of R 1a , R 1b , R 1c and R 1d independently selected from halogen, oxo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 2 represents (C1-C3)alkyl, halo(C1-C3)alkyl, cyclopropyl, optionally substituted with one or two substituents R 2a , cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, azetidinyl, optionally substituted with one or two substituents R 2b , dihydrofuranyl, dihydropyranyl, azabicyclo[2.2.1]heptanyl, pyrrolidinyl or phenyl; each of R 2a and R 2b independently selected from halogen, (C1-C3)alkyl, and halo(C1-C6)alkyl; R 3 is hydrogen or halogen; or R 2 and R 3 together form C 2-7 -alkylene, optionally substituted with one or two substituents R 3f , And each R 3f independently selected from (C1-C6)alkyl; and its pharmaceutically acceptable salts.

3. The compound according to item 1, where X 1 represents CR 3 .

4. The connection according to any one of paragraphs 1-3, where R 1 is (C3-C6)cycloalkyl, optionally substituted with one R 1a , pyridinyl, optionally substituted with one R 1b , pyrazinyl, optionally substituted with one R 1b , pyridizanyl, optionally substituted with one R 1b , thiazolyl optionally substituted with one R 1b , 1,3-benzodioxolyl, optionally substituted with one R 1c , oxazolyl, optionally substituted with one R 1c , piperidinyl, optionally substituted with one R 1c , tetrahydrofuranyl, optionally substituted with one R 1c , tetrahydropyranyl, optionally substituted with one R 1c , or phenyl optionally substituted with one or two R 1d .

5. The connection according to any one of paragraphs 1-4, where R 1is cyclohexyl, optionally substituted with one R 1a , pyridinyl, optionally substituted with one R 1b , pyrazinyl, optionally substituted with one R 1b , pyridizanyl, optionally substituted with one R 1b , thiazolyl optionally substituted with one R 1b , 1,3-benzodioxolyl, oxazolyl, optionally substituted with one R 1c , piperidinyl, optionally substituted with one R 1c , tetrahydrofuranyl, optionally substituted with one R 1c , tetrahydropyranyl or phenyl optionally substituted with one or two R 1d .

6. A connection according to any one of paragraphs 1-5, where R 1 is pyridinyl, optionally substituted with one R 1b , or phenyl optionally substituted with one or two R 1d .

7. A connection according to any one of paragraphs 1-3, where R 1 is heteroaryl optionally substituted with one R 1b, or phenyl optionally substituted with one or two R 1d .

8. A compound according to any one of paragraphs 1-7, where each of R 1a , R 1b , R 1c and R 1d independently selected from halogen, oxo, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl and halo(C1-C3)alkoxy.

9. A compound according to any one of paragraphs 1-8, where each of R 1a , R 1b , R 1c and R 1d independently selected from chloro, fluoro, oxo, cyano, methyl, ethyl, methoxy, trifluoromethyl, and difluoromethyl.

10. The compound according to any one of paragraphs 1-6, where each of R 1a , R 1b , R 1c and R 1d independently selected from chlorine, fluorine, cyano, methyl and methoxy.

11. The compound according to any one of paragraphs 1-8, where each of R 1b and R 1d independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy.

12. The compound according to any one of paragraphs 1-8 or paragraph 11, where each R 1b independently selected from halogen, (C1-C3)alkyl, (C1-C3)alkoxy, and halo(C1-C3)alkyl, and where each R 1d independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy.

13. The compound according to any one of paragraphs 1-12, where each R 1b independently selected from chlorine, methyl, and methoxy, and where each R 1d independently selected from fluoro, cyano, methyl and methoxy.

14. The connection according to any one of paragraphs 1-13, where R 1is 2-methoxyphenyl, 2-chlorophenyl, 2-methylphenyl, 1,3-benzodioxol-4-yl, 3-fluoro-2-methylphenyl, 2,3-dimethylphenyl, cyclohexyl, 2-methoxycyclohexyl, 3-fluoro-2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 3-methyl-2-oxopiperidin-4-yl, 2-ethylphenyl, 2-(difluoromethoxy)phenyl, 5-methyl-1,3-oxazol-4-yl, 4-methyl-1,3-thiazol-5-yl, 2-methyloxolan-3-yl, 3-methyltetrahydrofuran-2-yl, 3-cyano-2-methylphenyl, oxan-4-yl, 2-methylpyridin-3-yl, 2-oxopiperidin-4-yl, 2-methoxy-3-methylphenyl, 3-chloro-2-methoxyphenyl, 3-cyano-2-methoxyphenyl, oxan-3-yl, 3-methylpyrazin-2-yl, 2-methoxypyridin-3-yl, 2-chloropyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 3-methylpyridazin-4-yl, 3-methyl-1,2-thiazol-4-yl or 3-methyltetrahydrofuran-2-yl.

15. The connection according to any one of paragraphs 1-14, where R 1 is 2-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 2-methylpyridin-3-yl, 3-cyano-2-methoxyphenyl, 2-methoxypyridin-3-yl, 2-chloropyridin-3-yl or 2-methylphenyl.

16. A connection according to any one of paragraphs 1-15, where R2 represents isobutyl, tert-butyl, trifluoromethyl, cyclopropyl, optionally substituted with one or two substituents R 2a , cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, azetidinyl, optionally substituted with one or two substituents R 2b , 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl or phenyl.

17. A connection according to any one of paragraphs 1-16, where R 2 is halogen (C1-C6)alkyl, (C3-C6)cycloalkyl, optionally substituted with one or two substituents R 2a , or heterocycloalkyl optionally substituted with one or two substituents R 2b .

18. The compound according to any one of paragraphs 1-17, where each of R 2a , R 2b and R 2c independently selected from fluoro, methyl, and trifluoromethyl.

19. The compound according to any one of paragraphs 1-18, where each R 2aindependently selected from fluoro, methyl, and trifluoromethyl, each R 2b is fluorine.

20. The connection according to any one of paragraphs 1-19, where R 2 represents isobutyl, tert-butyl, trifluoromethyl, cyclopropyl optionally substituted with one or two substituents selected from fluorine, methyl or trifluoromethyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclohexen-1-yl, azetidinyl optionally substituted with two fluorine atoms, 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl or phenyl.

21. The connection according to any one of paragraphs 1-20, where R 2 is trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenten-1-yl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2-(trifluoromethyl)cyclopropyl, 2,3-dimethylcyclopropyl, 1-methylcyclopropyl or 3,4-dihydropyran-6-yl.

22. The connection according to any one of paragraphs 1-21, where R 2is phenyl, 2-methylpropyl, pyrrolidin-1-yl, cyclopropyl, cyclohexen-1-yl, 3.4-dihydro-2-pyran-6-yl, cyclopenten-1-yl, azetidin-1-yl, trifluoromethyl, 3,3-difluorazetidin-1-yl, cyclopentyl, cyclobutyl, 2-methylcyclopropyl, 2.5-dihydrofuran-3-yl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2-(trifluoromethyl)cyclopropyl, 2,3-dimethylcyclopropyl, 1-methylcyclopropyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl or tert-butyl.

23. The connection according to any one of paragraphs 1-22, where R 2 is cyclopropyl, cyclopenten-1-yl, trifluoromethyl or cyclobutyl, 2,5-dihydrofuran-3-yl.

24. The connection according to any one of paragraphs 1-23, where R 3 is hydrogen, chlorine or fluorine.

25. The connection according to any one of paragraphs 1-24, where R 3 is hydrogen.

26. A compound selected from the group consisting of: (3-amino-6-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-isobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chlorophenyl)methanone; (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; [3-amino-6-(cyclohexen-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone; (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methoxyphenyl)methanone-2,2,2-trifluoroacetic acid; (3-amino-5-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-5-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; (3-amino-5-fluoro-6-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chlorophenyl)methanone; (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; (3-amino-6-(3,3-difluoroazetidin-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-(tert-butyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)(o-tolyl)methanone; (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)(2-chlorophenyl)methanone; (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(1,3-benzodioxol-4-yl)methanone; (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methylphenyl)methanone; (3-amino-7,7-dimethyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-1-yl)(2-methoxyphenyl)methanone; [3-amino-6-(3,4-dihydro-2H-pyran-6-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone; [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone; (3-amino-6-(azetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; (3-amino-6-cyclopentylpyrazolo[3,4-b]pyridin-1-yl)-(2-methylphenyl)methanone; [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methylphenyl)methanone; (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methylphenyl)methanone; (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2,3-dimethylphenyl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(cyclohexyl)methanone; [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone; [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxycyclohexyl)methanone; (3-amino-7-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-((trans)-2-fluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methoxyphenyl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(4-fluoro-2-methoxyphenyl)methanone; (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; [3-amino-6-[rac-(1R,2R)-2-(trifluoromethyl)cyclopropyl]pyrazolo[3,4-b]pyridin-1-yl]-(o-tolyl)methanone; (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone; (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methoxyphenyl)methanone; (3-amino-5-fluoro-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-fluoro-2-methoxyphenyl)methanone; [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(3-fluoro-2-methoxyphenyl)methanone; rac-(cis)-4-(3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-carbonyl)-3-methylpiperidin-2-one; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-ethylphenyl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-(difluoromethoxy)phenyl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(5-methyloxazol-4-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(4-methylthiazol-5-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methyltetrahydrofuran-3-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)((2S,3R)-2-methyltetrahydrofuran-3-yl)methanone; 3-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-carbonyl)-2-methylbenzonitrile; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone; 4-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-carbonyl)piperidin-2-one; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxy-3-methylphenyl)methanone; (3-amino-6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone; (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone; (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methyltetrahydrofuran-3-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-chloro-2-methoxyphenyl)methanone; 3-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-carbonyl)-2-methoxybenzonitrile; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(tetrahydro-2H-pyran-3-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-methylpyrazin-2-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxypyridin-3-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chloropyridin-3-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-(trifluoromethyl)pyridin-3-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-methylpyridazin-4-yl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(3-methylisothiazol-4-yl)methanone; [3-amino-6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone; (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl(2R,3S)-3-methyltetrahydrofuran-2-yl)methanone and [3-amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone.

27. A compound according to any one of paragraphs 1-26, selected from the group consisting of: (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methoxyphenyl)methanone-2,2,2-trifluoroacetic acid, (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridin-1-yl)-(2-methylphenyl)methanone, [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone, (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone, [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methylphenyl)methanone, (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone, (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(o-tolyl)methanone, (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone, (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone, (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone, [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-(3-fluoro-2-methoxyphenyl)methanone, (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone, (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methylpyridin-3-yl)methanone, 3-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-carbonyl)-2-methoxybenzonitrile, (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxypyridin-3-yl)methanone and (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-chloropyridin-3-yl)methanone.

28. A compound according to any one of claims 1-27 for use as a therapeutically active substance inhibiting human methionine adenosyltransferase II alpha (Mat2A).

29. Pharmaceutical compositions for the treatment of diseases associated with Mat2A, containing an effective amount of compounds of formula I or I' according to any of claims 1-27 or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

30. Compounds of formula I or I' according to any one of claims 1 to 27 or pharmaceutically acceptable salts thereof for use as therapeutically active substances inhibiting human methionine adenosyltransferase II alpha (Mat2A).

31. Compounds of formula I or I' according to any one of claims 1 to 27, or pharmaceutically acceptable salts thereof, for use in the treatment, prevention and / or slowing of the progression of 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.

32. Compounds according to claim 31 for use in the treatment, prevention and / or slowing the progression of lung adenocarcinoma, squamous cell carcinoma of the lung, pancreatic adenocarcinoma, glioblastoma multiforme and squamous cell carcinoma of the head and neck.

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