Pyrazole Amide Derivatives

Abstract

The present invention relates to a compound represented by formula I or II: TIFF2024504788000072.tif64170[where, X 1 , R 1 , and R 2 is as described herein, as well as pharma- ceutically acceptable salts thereof. The invention further relates to the preparation of compounds of formula I, pharmaceutical compositions containing them, and their use as medicaments.

Description

[Technical field]

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

[0002] In particular, the present invention relates to compounds of formula I: TIFF2024504788000002.tif64170[In the formula, X 1 is N or CR 3 Either; R 1 teeth: one or more, in particular one to three, more in particular one or two, substituents R 1a (C3-C8)cycloalkyl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1b Heteroaryl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1c heterocycloalkyl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1d phenyl optionally substituted with R 1a , R 1b , R 1c , and R 1d are each independently selected from halogen, oxo, cyano, hydroxyl, (C-C)alkyl, (C-C)alkoxy, (C-C)cycloalkyl, (C-C)cycloalkyl-(C-C)alkyl, halo(C-C)alkyl, halo(C-C)alkoxy, hydroxy(C-C)alkyl, (C-C)alkoxy-(C-C)alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 2is (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, one or more, particularly one to three, more particularly one or two substituents R 2a (C3-C6)cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two, substituents R 2b or one or more, particularly one to three, more particularly one or two, substituents R 2c phenyl optionally substituted with R 2a , R 2b , and R 2c are each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 3 is hydrogen, halogen, or (C1-C6)alkyl; Or R 2 and R 3 together represent one or more, particularly one to three, more particularly one or two, substituents R 3f C which may be substituted with 2-7 Forming an alkylene R 3f are each independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl. and pharma- ceutically acceptable salts thereof.

[0003] 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 belongs. 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.

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

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

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

[0007] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substitutions, i.e., replacement of one hydrogen to replacement of all hydrogens by substituents, particularly "one or more" refers to one, two or three, and most particularly "one or more" refers to one or two.

[0008] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom of a parent molecule.

[0009] The term "substituted" indicates that the specified group bears one or more substituents. Any group can have multiple substituents, and when a variety of possible substituents are provided, 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 with 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 substitutions, i.e., from the replacement of one hydrogen by a substituent to the replacement of all hydrogens.

[0010] The term "amino" refers to a group of formula -NR'R'', where R' and R'' are independently hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, or (C3-C6)cycloalkyl, as described herein. Alternatively, R' and R'' can be taken together with the nitrogen to which they are attached to form a heterocycloalkyl. The term "primary amino group" refers to a group where R' and R'' are both hydrogen. The term "secondary amino" refers to a group where R' is hydrogen and R'' is a group other than hydrogen, particularly where R'' is (C1-C6)alkyl. The term "secondary amino" refers to a group where R' and R'' are both other than hydrogen, particularly where R' and R'' are both (C1-C6)alkyl. Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine, dipropylamine and diisopropylamine, and most particularly amino refers to ethylamine.

[0011] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo, especially chloro or fluoro.

[0012] "Hydroxy" refers to the group --OH.

[0013] "(C1-C6)alkyl" means a branched or straight hydrocarbon chain of 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl.

[0014] The term "(C1-C6)alkylene" refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. Examples of alkylene radicals include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene. Specific examples of alkylene are ethylene, propylene, and butylene.

[0015] "(C1-C6)alkoxy" refers to a group of the formula -OR a In the formula, R a is a (C1-C6)alkyl moiety as defined herein. Examples of (C1-C6)alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0016] The term "(C3-C8)cycloalkyl" denotes a monovalent saturated monocyclic hydrocarbon group having 3 to 6 ring carbon atoms. Examples of monocyclic (C3-C8)cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or cycloheptyl. A particular example of (C3-C6)cycloalkyl is cyclopropyl.

[0017] "(C3-C6)cycloalkyl-(C1-C6)alkyl" means a (C1-C6)alkyl as defined above substituted with one or more (C3-C6)cycloalkyl groups, in particular with one (C3-C6)cycloalkyl group. More particularly, "(C3-C6)cycloalkyl-(C1-C6)alkyl" means means TIFF2024504788000003.tif19170.

[0018] The term "perhalo(C1-C3)alkyl" refers to a (C1-C3)alkyl group as defined above, in which all hydrogen atoms are replaced by halogen atoms. In particular, "(C1-C3)perhaloalkyl" is a (C1-C3)perfluoroalkyl, most preferably trifluoromethyl.

[0019] "Halo(C1-C6)alkyl" means (C1-C6)alkyl as defined above substituted with one or more halogen atoms, in particular with 1 to 3 halogen atoms. More particularly, halo(C1-C6)alkyl is chloro-(C1-C6)alkyl and fluoro-(C1-C6)alkyl. In some particular embodiments, halo(C1-C6)alkyl means perhalo(C1-C3)alkyl as defined herein. Most particularly, halo(C1-C6)alkyl is trifluoromethyl, difluoromethyl, or fluoromethyl.

[0020] "Halo(C1-C6)alkoxy" refers to (C1-C6)alkoxy as defined above, substituted with one or more halogen atoms, in particular with 1 to 3 halogen atoms. In particular, halo(C1-C6)alkoxy is chloro-(C1-C6)alkoxy and fluoro-(C1-C6)alkoxy. In some particular embodiments, halo(C1-C6)alkoxy refers to perhalo(C1-C3)alkoxy, for example trifluoromethoxy or difluoromethoxy.

[0021] "Hydroxy(C1-C6)alkyl" means (C1-C6)alkyl as defined above substituted with one or more hydroxy groups, in particular with one hydroxy group. More particularly, hydroxy(C1-C6)alkyl means hydroxymethyl or hydroxyethyl.

[0022] "(C1-C6)alkoxy-(C1-C6)alkyl" means (C1-C6)alkyl as defined above substituted with one or more (C1-C6)alkoxy groups as defined herein, in particular with one (C1-C6)alkoxy group. More particularly, (C1-C6)alkoxy-(C1-C6)alkyl means -CH2-O-CH3 or -CH2CH2-O-CH3.

[0023] "Halo(C1-C6)alkoxy" means alkoxy as defined above substituted with one or more halogen atoms, in particular with 1 to 3 halogen atoms. More particularly, halo(C1-C6)alkoxy is chloro-(C1-C6)alkoxy and fluoro-(C1-C6)alkoxy.

[0024] "Heteroaryl" means a monovalent monocyclic or bicyclic moiety of 5 to 12 ring atoms having at least one aromatic ring containing 1, 2 or 3 ring heteroatoms each independently selected from N, O, or S (preferably N or O), the remaining ring atoms being C, and it is understood that the point of attachment of the heteroaryl moiety is on the aromatic ring. 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. In particular, "N-heteroaryl" refers to heteroaryl as defined above that contains at least one nitrogen atom. The point of attachment of N-heteroaryl to the rest of the molecule can be via a nitrogen atom or a carbon ring atom. Examples of N-heteroaryl are pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl.

[0025] The terms "heterocycloalkyl" or "heterocyclic" refer to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 9 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocycloalkyl are pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolane, 1,4-dioxepanyl, oxepanyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. More particularly, heterocycloalkyl means dihydrofuryl, 1,3-dioxolyl, dihydropyryl, dihydrothiophyl, dihydropyrazolyl, dihydroisoxazolyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazyl, 1,2,3,4-tetrahydropyrazyl.

[0026] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition or disorder, (ii) attenuates, alleviates, or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. A therapeutically effective amount will vary depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0027] "Optional" or "optionally" means that the event or circumstance described thereafter may or may not occur, and that the description includes situations where the event or circumstance occurs and situations where it does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl may be present, but does not have to be present, and that the description includes situations where the aryl group is substituted with an alkyl group and situations where the aryl group is not substituted with an alkyl group.

[0028] The term "individual" or "subject" refers to a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

[0029] The terms "compound of this invention" and "compound of the present invention" mean compounds disclosed herein, as well as their stereoisomers, tautomers, solvates, and salts (e.g., pharma- ceutically acceptable salts).

[0030] When the compounds of the invention are solids, those skilled in the art will understand that the compounds, as well as their solvates and salts, may exist in different solid forms, particularly different crystalline forms, all of which are included within the scope of the invention and the specified formula.

[0031] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0032] The term "pharmaceutically acceptable acid addition salts" refers to pharmaceutically acceptable salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid) and with organic acids of the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes (e.g., formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid).

[0033] The term "pharmacologically acceptable base addition salt" refers to a pharma-ceutically acceptable salt 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 pharma-ceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines including 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, piperidine, piperidine, N-ethylpiperidine, and polyamine resins.

[0034] The term "active pharmaceutical ingredient" (or "API") refers to a compound or molecule that has a specific biological activity in a pharmaceutical composition.

[0035] The terms "pharmaceutical composition" or "pharmaceutical formulation" (or "formulation") refer to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients, used interchangeably, and administered to a mammal, e.g., a human, in need thereof.

[0036] The terms "pharmaceutically acceptable additive", "pharmaceutically acceptable carrier" and "therapeutically inactive excipient" are used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition used in the preparation of a pharmaceutical product, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant, that has no therapeutic activity and is non-toxic to a subject to which it is administered.

[0037] The term "treating" or "treatment" of a condition includes suppressing the condition, i.e., arresting the development of the condition or its clinical symptoms, or alleviating the condition, i.e., the temporary or permanent regression of the condition or its clinical symptoms.

[0038] 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 one another are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when one carbon atom is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric center, described by the Cahn-Ingold-Prelog R / S rule, or by the way the molecule rotates the plane of polarized light, called dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing equal ratios of enantiomers is called a "racemic mixture".

[0039] The compound of formula I may have one or more asymmetric centers or axes.Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include individual epimers, atropisomers, and mixtures thereof, as well as individual enantiomers, atropisomers, and racemic or other mixtures thereof.Methods for identifying stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced, Organic Chemistry", 4th Edition, J. March, John Wiley and Sons, New York, 1992).

[0040] Certain compounds may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate individual tautomers usually produce mixtures whose chemical and physical properties match the mixture of compounds. The position of the equilibrium depends on the chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, whereas in phenols, the enol form predominates. Common protic tautomers include keto / enol (-C(=O)-CH-←→-C(-OH)=CH-), amide / imidic acid (-C(=O)-NH-←→-C(-OH)=N-), and amidine (-C(=NR)-NH-←→-C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings, and the invention encompasses all tautomeric forms of the compounds.

[0041] The present compounds of formula I have now been found to be inhibitors of Mat2A and may be of therapeutic interest for the treatment of cancer disorders including 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.

[0042] These compounds are potent inhibitors of human methionine adenosyltransferase II alpha (MAT2A). MAT2A and MAT1A (methionine adenosyltransferase I alpha) are two genes that encode methionine adenosyltransferase activity to produce S-adenosylmethionine (SAM), the principal methyl donor in cells. MAT1A is a liver-specific SAM-producing enzyme, whereas MAT2A is widely expressed except in the liver. MAT2A is found in a complex with MAT2B (methionine adenosyltransferase II beta), an allosteric regulator of MAT2A, which acts like a rheostat on MAT2A enzyme activity. Binding of MAT2B to MAT2A changes the conformation of MAT2A, increasing its affinity for methionine and SAM. The net effect is that when bound to MAT2B, MAT2A is more active at low concentrations of methionine but is inhibited at high concentrations of methionine.

[0043] Loss-of-function mutations in tumor suppressor genes are crucial in the molecular pathogenesis of cancer, yet effective targeting of tumor suppressors has been difficult to achieve, mainly because mutant proteins cannot be directly inhibited for therapeutic benefit and restoration of mutant function (e.g., of mutant p53) has not been possible so far. The recent clinical success of inhibiting PARP in patients with BRCA1 / 2 deficiency has demonstrated that targeting conditional synthetic lethality (CSL) resulting from loss-of-function mutations in tumor suppressors is a valid clinical approach for the treatment of cancer. The CSL relationship is not only valid for tumor suppressors, but can be extended to genes that reside in the same genetic region as the tumor suppressor and are lost when that region is deleted. Methylthioadenosine phosphorylase (MTAP) is one such gene, which is in close proximity to the tumor suppressor CDKN2A and is deleted in approximately 15% of all cancers. MTAP is deleted in, but not limited to, approximately 53% of glioblastoma multiforme (GBM), 25% of pancreatic adenocarcinoma (PDAC), 25% of melanoma, 23% of lung squamous cell carcinoma, 20% of head and neck squamous cell carcinoma, and 15% of lung adenocarcinoma. Indeed, this deletion occurs across multiple indications, many of which are areas of high unmet medical need with limited effective therapies. In glioblastoma, median survival is 14 months, recent approval of therapies has not significantly extended overall survival (OS), and standard of care (SoC) has remained the same for over a decade. The same is true for the majority of PDAC patients with OS less than 1 year. MTAP deletion is a truncal event that occurs early in tumor development and will be retained throughout all tumor progression, including metastasis. Its loss is therefore an alteration that is not influenced by tumor heterogeneity, genetic background, or resistance to any approved drug in clinical practice. The CSL relationships identified for MTAP deficiency may represent a real hotspot for multiple tumor indications.

[0044] MTAP is located near the tumor suppressor CDKN2A on chromosome 9. When CDKN2A is deleted, MTAP is frequently co-deleted. Its deletion is considered a bystander effect and phenotypically neutral. MTAP is the basis of the adenine and methionine salvage pathway in cells. The methionine salvage pathway feeds into the SAM production pathway, and SAM levels are key regulators of cancer cell growth that need to be tightly controlled, because large changes in SAM concentration, either up or down, lead to cell cycle arrest. The importance of SAM levels to cancerous growth lies in its central role for protein, DNA, and RNA methylation, which acts as a checkpoint for cell health, and can be read as hypomethylation when SAM is decreased, or hypermethylation when SAM is increased. Cells lacking MTAP accumulate methylthioadenosine (MTA) and decarboxylated SAM (dcSAM) without adversely affecting the levels of any salvage metabolites / products, including SAM. This accumulation imposes new stress on the cells where MTA acts as a competitive inhibitor of SAM-dependent reactions due to its structural similarity. Loss of MTAP forces cells to adapt to the new MTA / SAM paradigm without the loss of viability that MTAP-expressing cells do not have to deal with, and this adaptation creates a tight dependency on methionine adenosyltransferase II alpha 2 (MAT2A), one of the enzymes that produces SAM, in MTAP-deficient cells. This conditional synthetic lethality (CSL) relationship between MTAP loss and MAT2A dependency was identified in three large-scale shRNA screens (Marjon Cell Reports 2016, Kryukov Science 2016, and Mavrakis Science 2016).

[0045] Targeting MAT2A with small molecule inhibition may benefit genetically defined patient populations that represent many areas of high unmet medical need.

[0046] The object of the present invention is the use of compounds of formula I or II for preparing medicaments for the treatment, prevention and / or delay 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 manufacture as well as medicaments based on compounds of formula I according to the invention.

[0047] Further objects of the invention are the compounds of formula I in all forms of optically pure enantiomers, racemates or diastereomeric mixtures.

[0048] In particular, the present invention relates to compounds of formula I: TIFF2024504788000004.tif64170[In the formula, X 1 is N or CR 3 Either; R 1 teeth: one or more, in particular one to three, more in particular one or two, substituents R 1a (C3-C8)cycloalkyl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1b Heteroaryl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1c heterocycloalkyl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1d phenyl optionally substituted with R 1a , R 1b , R 1c , and R 1dare each independently selected from halogen, oxo, cyano, hydroxyl, (C-C)alkyl, (C-C)alkoxy, (C-C)cycloalkyl, (C-C)cycloalkyl-(C-C)alkyl, halo(C-C)alkyl, halo(C-C)alkoxy, hydroxy(C-C)alkyl, (C-C)alkoxy-(C-C)alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 2 is (C1-C6)alkyl, halo(C1-C6)alkyl, one or more, particularly one to three, more particularly one or two substituents R 2a (C3-C6)cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two, substituents R 2b or one or more, particularly one to three, more particularly one or two, substituents R 2c phenyl optionally substituted with R 2a , R 2b , and R 2c are each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 3 is hydrogen, halogen, or (C1-C6)alkyl; Or R 2 , and R 3 together represent one or more, particularly one to three, more particularly one or two, substituents R 3f C which may be substituted with 2-7 Forming an alkylene R 3f are each independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl. and pharma- ceutically acceptable salts thereof.

[0049] In certain embodiments, the present invention provides a compound of formula I': TIFF2024504788000005.tif64170[where, R 1 , R 2 , and R 3 is as defined herein], as well as pharma- ceutically acceptable salts thereof.

[0050] In addition, certain 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 Any of the embodiments of X may be used in combination with other X's described herein. 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 It should be understood that the present invention may be combined with any other embodiment described herein.

[0051] A particular embodiment of the present invention is 1 CR 3 The present invention relates to a compound of formula I,

[0052] A particular embodiment of the invention is a compound of formula I or I′, 1 is one substituent R 1a (C3-C8)cycloalkyl optionally substituted with one R 1b Heteroaryl optionally substituted with one or two R 1cor one or two R 1d phenyl, optionally substituted with R 1 is one R 1a (C3-C6)cycloalkyl optionally substituted with one R 1b 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 1c 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 or one or two R 1d and more particularly R 1 is one R 1a Cyclohexyl, even if substituted with one R 1b pyridinyl, optionally substituted with one R 1b pyrazinyl, optionally substituted with one R 1b pyridizanyl, 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 or two R 1d tetrahydropyranyl or phenyl, most particularly R 1 is one R 1b or one or two R 1dx and phenyl which may be substituted by.

[0053] A more particular embodiment of the present invention is a compound of formula I, I′ or I″, 1 is one R 1b or one or two R 1d and phenyl which may be substituted by.

[0054] A particular embodiment of the invention is a compound of formula I or I′, 1a , R 1b , R 1c , and R 1d are each independently selected from halogen, oxo, cyano, (C-C)alkyl, (C-C)alkoxy, halo(C-C)alkyl, and halo(C-C)alkoxy, particularly R 1a , R 1b , R 1c , and R 1d are each independently selected from halogen, oxo, cyano, (C-C)alkyl, (C-C)alkoxy, halo(C-C)alkyl, and halo(C-C)alkoxy, and more particularly, R 1a , R 1b , R 1c , and R 1d are each independently selected from halogen, oxo, cyano, (C-C)alkyl, (C-C)alkoxy, and halo(C-C)alkyl, and even more particularly, R 1a , R 1b , R 1c , and R 1d are each independently selected from chloro, fluoro, oxo, cyano, methyl, ethyl, methoxy, trifluoromethyl, and difluoromethyl, and most particularly, R 1a , R 1b , R 1c , and R 1d are each independently selected from chloro, fluoro, cyano, methyl, and methoxy.

[0055] A particular embodiment of the invention is a compound of formula I or I′, 1b , and R1d are each independently selected from halogen, cyano, (C-C)alkyl, (C-C)alkoxy, halo(C-C)alkyl, and halo(C-C)alkoxy; in particular, R 1b are each independently selected from halogen, (C-C)alkyl, (C-C)alkoxy, and halo(C-C)alkyl; R 1d are each independently selected from halogen, cyano, (C-C)alkyl, (C-C)alkoxy, halo(C-C)alkyl, and halo(C-C)alkoxy, and more particularly, R 1b are each independently selected from chloro, methyl, and methoxy; R 1d are each independently selected from fluoro, cyano, methyl, and methoxy.

[0056] A particular embodiment of the invention is a compound of formula I or I′, 1 are 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-methyl-tetrahydrofuran-4-yl, 5-methyl-1,3-oxazol-4-yl, 4-methyl-1,3-thiazol-5-yl, 2-methyloxolan-3-yl, 3-methyl-tetrahydrofuran-4-yl, 5-methyl-1,3-oxazol-4-yl, 4-methyl-1,3-thiazol-5-yl, 5-methyl-1,3-oxazol-4-yl, 5-methyl-1,3-thiazol-5-yl, 5-methyl-1,3-thiaz ...4-yl, 5-methyl-1,3-thiazol-5-yl, 5-methyl R is 3-methyl-1,2-thiazol-4-yl, 3-methyl-2-pyrazine-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 1is 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.

[0057] Another embodiment of the present invention is a compound of formula I, I′, or I″, wherein R 2 is (C1-C6)alkyl, halo(C1-C6)alkyl, one or two substituents R 2a (C3-C6)cycloalkyl optionally substituted with one or two substituents R 2b or phenyl, particularly R 2 is (C1-C3)alkyl, halo(C1-C3)alkyl, one or two substituents R 2a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, optionally substituted with one or two substituents R 2b Azetidinyl, dihydrofuranyl, dihydropyranyl, azabicyclo[2.2.1]heptanyl, -azabicyclo[2.2.1]heptanyl, pyrrolidinyl, optionally substituted with one or two substituents R 2b or phenyl, more particularly R 2 is i-butyl, t-butyl, trifluoromethyl, one or two substituents R 2a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, optionally substituted with one or two substituents R 2b azetidinyl, 2,5-dihydrofuran-3-yl, 3,4-dihydro-pyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl, optionally substituted with R 2is cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclohexen-1-yl, azetidinyl optionally substituted with one or two substituents selected from i-butyl, t-butyl, trifluoromethyl, fluoro, methyl, or trifluoromethyl, 2,5-dihydrofuran-3-yl, 3,4-dihydro-pyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl, most particularly 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-dihydro-pyran-6-yl.

[0058] A more particular embodiment of the present invention is a compound of formula I or I', 2 is halo(C1-C6)alkyl, one or two substituents R 2a or one or two substituents R 2b and heterocycloalkyl optionally substituted with

[0059] Another embodiment of the present invention is a compound of formula I, I′, or I″, wherein R 2a , R 2b , and R 2c are each independently selected from halogen, (C1-C3)alkyl, and halo(C1-C3)alkyl, in particular R 2a , R 2b , and R 2c are each independently selected from fluoro, methyl, and trifluoromethyl, and more particularly, R 2a are each independently selected from fluoro, methyl, and trifluoromethyl; R 2bは each of which is fluoro.

[0060] A particular embodiment of the invention is a compound of formula I or I′, 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-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 t-butyl, in particular R 2は , cyclopropyl, cyclopenten-1-yl, trifluoromethyl, or cyclobutyl, 2,5-dihydrofuran-3-yl.

[0061] Yet another embodiment of the present invention is a compound of formula I or I', 3 is hydrogen or halogen, in particular R 3 is hydrogen, chloro or fluoro, more particularly R 3 is hydrogen.

[0062] Certain compounds of formula I of the present invention are 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-(cyclopentenyl)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)(2-methoxyphenyl)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]-(2-methoxyphenyl)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]pyridine-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]pyridine-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 [3-Amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone

[0063] Certain compounds of formula I of the present invention are 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-(cyclopentenyl)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]pyridine-1-carbonyl)-2-methoxybenzonitrile (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

[0064] In another embodiment, the present invention provides a compound according to Formula I or I' as described herein for use as a therapeutically active substance.

[0065] In yet another embodiment, the present invention provides a compound according to formula I, I', I'' or II as described herein for the treatment, prevention and / or delay of progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0066] In another embodiment, the present invention provides the use of a compound according to formula I or I' as described herein for the treatment, prevention and / or delay of progression of cancer, particularly 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.

[0067] In one aspect, the present application provides a method for treating a Mat2A disorder in a subject having a Mat2A-related disorder, comprising administering to a subject in need thereof a therapeutically effective amount of any of the above compounds.

[0068] In another embodiment, the present invention provides a method of treatment, prevention and / or delay of progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, comprising administering an effective amount of a compound according to Formula I, I', I'' or II as described herein.

[0069] In certain embodiments, the present invention provides a method of treatment, prevention and / or delay of progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, more particularly the treatment, comprising administering an effective amount of a compound according to Formula I, I', I'' or II as described herein.

[0070] In particular, the Mat2A disorder or Mat2A-related disease is cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0071] In one aspect, the application provides a pharmaceutical composition comprising a compound according to any one of the above embodiments in admixture with at least one pharma- ceutically acceptable carrier, such as an excipient or diluent.

[0072] 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 delay of progression of a disease associated with Mat2A, more particularly for the treatment.

[0073] In yet another embodiment, the present invention provides a medicament comprising a compound of formula I or I' as described herein or a pharma- ceutically acceptable salt thereof and a therapeutically inert carrier, as well as a process for their preparation which comprises bringing one or more compounds of formula I or I' and / or a pharma- ceutically acceptable salt thereof, and, if desired, one or more other therapeutically valuable substances, together with one or more therapeutically inert carriers, into a galenical dosage form, which is an object of the present invention.

[0074] Other embodiments provide pharmaceutical compositions or medicaments comprising a compound of the invention and a therapeutically inert carrier, diluent or pharma- ceutically acceptable excipient, as well as methods of preparing such compositions and medicaments using the compounds of the invention.

[0075] The composition is formulated, dosed, and administered in a manner consistent with medical practice standards.Factors to be considered in this regard include the specific disease to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disease, the site of delivery of the drug, the method of administration, the administration schedule, and other factors known to medical practitioners.For example, such amount may be below the amount that is toxic to normal cells or to the mammal as a whole.

[0076] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, if desired for localized treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0077] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, coated tablets, dragees, powders, capsules (hard and soft gelatin capsules), solutions (i.e., injectable solutions), dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, eye drops, ear drops, etc. Such compositions may contain ingredients conventional in pharmaceutical preparations, such as diluents, carriers, pH modifiers, sweeteners, fillers, and additional active agents.

[0078] A typical formulation is prepared by mixing the compound of the present invention with a pharma- ceutically acceptable carrier or excipient. Suitable pharma- ceutically acceptable carriers and excipients are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C., et al. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is generally a finely divided solid that is a mixture with the finely divided active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding capacity in an appropriate ratio and compressed into the desired shape and size. Powders and tablets preferably contain 1 percent to about 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, low melting wax, cocoa butter, and the like.

[0079] The dosage that the compounds of the present invention can be administered can vary within a wide range and, of course, will be adapted to the individual requirements in each particular case.Generally, in the case of oral administration, the daily dosage of the compound of formula I or I' per person should be appropriate to be about 0.01-1000mg, but can exceed the upper limit as necessary.

[0080] One example of a suitable oral dosage form is a tablet containing about 100 mg to 500 mg of the compound of the present invention, formulated with about 30 to 90 mg of anhydrous lactose, about 5 to 40 mg of croscarmellose sodium, about 5 to 30 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment.

[0081] An example of an aerosol formulation can be prepared by dissolving the compound of the present invention, for example 10 to 100 mg, in a suitable buffer solution, for example phosphate buffer, and adding a tonicifier, for example a salt such as sodium chloride, if necessary. To remove impurities and contaminants, the solution may be filtered, for example, using a 0.2 μm filter.

[0082] Thus, one embodiment includes a pharmaceutical composition comprising a compound according to the invention described herein, or a stereoisomer thereof. A further embodiment includes a pharmaceutical composition comprising a compound according to the invention described herein, or a stereoisomer thereof, together with a pharma- ceutically acceptable carrier or excipient.

[0083] The compounds of the present invention can be used, either alone or in combination with other drugs, for the treatment, prevention and / or delay of progression of Mat2A-related diseases, in particular cancer, specifically 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.

[0084] A particular embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula I or I' as described above or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients for use in the treatment, prevention and / or delay of progression of cognitive impairment associated with cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0085] Another embodiment includes a pharmaceutical composition comprising a compound according to the invention as described herein for use in the treatment, prevention and / or delay of progression, more particularly in the treatment, of a Mat2A related disease.Another embodiment includes a pharmaceutical composition comprising a compound according to the invention as described herein for use in the treatment, prevention and / or delay of progression, more particularly in the treatment, of a Mat2A related disease.

[0086] In another embodiment, the present invention provides for the preparation of a compound of formula I or I' as described herein.

[0087] The preparation of the compounds of formula I or I' of the present invention may be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. If a mixture of enantiomers or diastereoisomers is produced during the reaction, these enantiomers or diastereoisomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization.

[0088] Additionally, the compounds of the present invention can be prepared from commercially available starting materials or by general synthetic techniques and procedures known to those skilled in the art. Outlined below are reaction schemes suitable for the preparation of such compounds. The substituents and indices used in the following description of the methods have the meanings described herein. Further examples can be found in the specific examples detailed below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0089] General scheme More specifically, compounds of formula I or I' and intermediates thereof can be prepared according to Schemes 1 or 2 and as described in the specific examples.

[0090] A compound of formula I or I', 1 is CR 3 and R 4 is H and R 1 , R 2 , and R 3 The subgroup of [wherein x is as defined above] may be prepared as outlined in Scheme 1 below. Scheme 1 TIFF2024504788000006.tif93170

[0091] The chloropyridines IIa are reacted with excess hydrazine in a polar solvent (e.g., ethanol, ethylene glycol) (Canadian Journal of Chemistry, 1988, 420) to form the aminopyrazoles IIIa. These are then selectively coupled to carboxylic acids IVa using mild activating agents (e.g., 1,1'-carbonyldiimidazole) in polar solvents (e.g., DMF, DMA, NMP) at elevated temperatures (80-120°C). Alternatively, the pyrazoles IIIa can be protected as benzaldehyde imines (VIa) by reaction with benzaldehyde in ethanol at elevated temperatures, and then reacted with carboxylic acids IVa and activated with more reactive coupling agents (e.g., HATU, TBTU) under basic conditions (e.g., iPr2NEt, Et3N) in polar solvents (e.g., DMF, DMA) at ambient temperature or at mild warming (50°C) to give the protected products VIIa. The imine can be readily hydrolyzed under mild acidic conditions (eg, formic acid or 1N hydrochloric acid) to give the final product IIIa.

[0092] Chloropyridines IIa can be synthesized from 2,6-dihalo-3-nitrilepyridines VIIa by reaction with boronic acids or esters at the 6-position in a Suzuki-Miyaura type reaction using a palladium catalyst such as Pd(dppf)2Cl2·CH2Cl2 or excess base such as K2CO3 or Na2CO3 in a solvent such as dioxane or water at elevated temperatures (80-100 °C) or with amines in a polar solvent (e.g. THF, EtOH, DMF, DMA, NMP) using excess base (e.g. DIPEA, TEA, K2CO3) in a SnAr type reaction at elevated temperatures (>70 °C).

[0093] Alternatively, pyridine IIa can be synthesized by cyclization of intermediate VIIIa with 2-cyanoacetamide using a base (e.g., NaOEt) in a polar solvent such as DMF at elevated temperature to give the corresponding hydroxypyridine IXa, which can be converted to pyridine Ia using a dehydrating reagent such as POCl3 at elevated temperature.

[0094] General Procedure General Procedure A: Suzuki-Miyaura-type cross-coupling To 2,6-dihalo-3-nitrile pyridine dissolved in dioxane / water (4:1 ratio, 0.1-0.2 M), K2CO3 or Na2CO3 (3 equiv.) was added followed by the boronic acid or ester (1.5 equiv.), and the resulting reaction mixture was subjected to sonication and degassed by bubbling argon through. Pd(dppf)2Cl2·CH2Cl2 complex or palladium tetrakis(triphenylphosphine) (0.05-0.2 equiv.) was added and the reaction mixture was heated to 100 °C until LCMS indicated complete consumption of the pyridine starting material (0.5 h-16 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated. The crude product may be purified using flash silica gel chromatography.

[0095] General Procedure B: SnAr Reaction To a solution of 2,6-dihalo-3-nitrilepyridine in THF or DMF (0.1-0.2 M) was added DIPEA or TEA (2 eq.) and a secondary amine (1.1 eq.). The reaction was stirred at ambient or elevated temperature until LCMS indicated complete consumption of the pyridine starting material (up to 24 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated. The product may be purified using flash silica gel chromatography.

[0096] General Procedure C: Hydrazine Cyclization To a solution / suspension of the required chloropyridine in ethanol or ethylene glycol (0.1-0.2 M) hydrazine (2 equiv.) was added and the reaction was stirred at 70-120° C. until LCMS indicated complete consumption of the chloropyridine (up to 16 h). The reaction was concentrated and the crude product was purified using flash silica gel chromatography or simply suspended in water and isolated by filtration.

[0097] General Procedure D: Pyridone Synthesis To a crude solution of the appropriate ene-one VIII in DMF (0.2-0.4 M) (prepared with modifications according to the procedure in J. Med. Chem. 2011, 54, 7974-7985), 2-cyanoacetamide (3 equiv.) and NaOEt (3 equiv.) as a base were added. The resulting reaction mixture was heated to 100° C. until LCMS showed complete consumption of starting material VIII (approximately 16 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated. The product may be purified using flash silica gel chromatography.

[0098] General Procedure E: Pyridyl Chloride Synthesis The hydroxypyridine was dissolved in POCl3 (10-20 equiv.) and the resulting reaction mixture was heated to 100 °C until LCMS indicated complete reaction (approximately 16 h). The reaction mixture was then concentrated under reduced pressure, diluted with EtOAc, and filtered. The organic layer was 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 may be purified using flash silica gel chromatography.

[0099] General Procedure F1: Amide Coupling with CDI As described in Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, 1088. To a solution of the appropriate carboxylic acid (1.5 equiv.) in DMF (0.1-0.2 M) carbonyldiimidazole (1.5 equiv.) is added and the mixture is stirred at ambient temperature for 0.5-1 h, after which the required pyrazolo[3,4-b]pyridin-3-amine (1 equiv.) is added and the mixture is heated to 100°C-140°C until LCMS indicates complete reaction (24 h-48 h). The reaction is then concentrated to dryness and purified by reverse phase preparative HPLC.

[0100] General Procedure F2: Amide coupling with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) and benzimine deprotection To a solution of the appropriate carboxylic acid (1.1 equiv.) in DMF (0.1-0.2M) was added TBTU (1.1 equiv.) and triethylamine (2 equiv.), 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 indicated complete reaction (16h-48h) or heated to 50°C to facilitate the reaction. 1N hydrochloric acid (aqueous) was then added dropwise and the reaction was stirred at ambient temperature for 1 h. The reaction was then concentrated to dryness and purified by reverse phase preparative HPLC.

[0101] A particular embodiment of the present invention is a compound of formula (I') 1 , R 1 , and R 2 is as defined herein] as well as pharma- ceutically acceptable salts thereof as defined according to the present invention. The method comprises coupling a compound of formula (III) with a carboxylic acid IVa using a mild activating agent (e.g., 1,1'-carbonyldiimidazole) in a polar solvent (e.g., DMF, DMA, NMP) at elevated temperature (80-120°C) to obtain a compound of formula (I), as shown in Scheme 2. Scheme 2 TIFF2024504788000007.tif65170

[0102] These compounds were investigated according to the tests given below.

[0103] Identification of Mat2A activity Mat2A inhibition is measured using an absorbance-based assay in a 384-well format.

[0104] Recombinant human Mat2a (12.5 nM) is incubated with serially diluted compounds in DMSO (concentration range 10 μM to 508 pM) or control (DMSO) for 15 min at room temperature (RT) in assay buffer containing 50 mM HEPES (pH 7.5), 50 mM KCl, 50 mM MgCl2, 0.01% Tween 20, and 10 mM DTT. The reaction is initiated by addition of combined substrates, ATP and methionine, at a final concentration of 100 μM each. Final assay conditions are 12.5 nM Mat2A, 100 μM ATP and methionine (substrates), and 2% DMSO. After 120 min of incubation at RT, the reaction is stopped by addition of Biomol Green. The absorbance signal is measured at λ=635 nm after 30 min equilibration at RT using a multiplate reader (BMG Pherastar reader or equivalent). TIFF2024504788000008.tif251170TIFF2024504788000009.tif255170TIFF2024504788000010.tif255170TIFF2024504788000011.tif31170

[0105] Abbreviation The following abbreviations are used in the experimental section: Ar = argon; nBuLi = n-butyllithium; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMSO = dimethyl sulfoxide; DMF = dimethylformamide; EtOH = ethanol; EtOAc = ethyl acetate; HCl = hydrochloric acid; HPLC = high performance liquid chromatography; LDA = lithium diisopropylamide; LiHMDS = lithium bis(trimethylsilyl)amide; mCPBA = metachloroperbenzoic acid; MOM = methoxymethyl; NMP = N-methyl-2-pyrrolidone; SEM = [2-(trimethylsilyl)ethoxy)methyl]acetal; TBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate; THF = tetrahydrofuran; TEMPO = 2,2,6,6-tetramethylpiperidinyloxyl; TBAF = tetra-n-butylammonium fluoride; TLC = Thin Layer Chromatography

[0106] Starting materials Basic chemicals and solvents were purchased and used as is without further purification. Some intermediates are commercially available or can be synthesized using methods known in the art.

[0107] Intermediates Intermediate 1: 6-Phenyl-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, the title compound ([M+H] + 211.1) was prepared.

[0108] Intermediate 2: 6-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000013.tif36170Step 1: 2-Chloro-6-isobutylnicotinonitrile 2,6-Dichloronicotinonitrile (250 mg, 1.45 mmol) was dissolved in dioxane (5 ml) and 2-methylpropylzinc bromide (3.47 ml, 0.5 M in THF, 1.73 mmol) was added and the reaction mixture was sparged with argon. Pd(dppf)2Cl2·CH2Cl2 complex (12 mg, 15 μmol) was added and the reaction was heated to 90 °C for 18 h in a sealed tube. 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) was then added and the reaction was heated at 70 °C for an additional 2 h. The reaction was concentrated to dryness. The residue was purified by flash silica gel chromatography (ethyl acetate:n-heptane 0:1 to 1:0) to give the title compound (185 mg, 76%) as a colorless oil. ([M+H,Cl] + 195.1)

[0109] Step 2: 6-isobutyl-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, the title compound ([M+H] + 191.3) was prepared.

[0110] Intermediate 3: 6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000014.tif39170Step 1: 2-Chloro-6-(pyrrolidin-1-yl)nicotinonitrile According to general procedure B, the title compound ([M+H] + 208.1) was prepared.

[0111] Step 2: 6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, the title compound ([M+H] + 204.2) was prepared and isolated from water by filtration.

[0112] Intermediate 4: 6-(cyclohexen-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000015.tif39170Step 1: 2-Chloro-6-(cyclohex-1-en-1-yl)nicotinonitrile According to general procedure A, the title compound ([M+H,Cl]) was obtained from 2,6-dichloronicotinonitrile and cyclohex-1-en-1-ylboronic acid under tetrakis(triphenylphosphine)palladium catalysis at 110° C. + 219.1) was prepared.

[0113] Step 2: 6-(cyclohexen-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine According to general procedure C, the title compound ([M+H] + 215.2) was prepared.

[0114] Intermediate 5: Cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, the title compound ([M+H] + 175.4) was prepared.

[0115] Intermediate 6: 5-Fluoro-6-phenyl-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000017.tif43170Step 1: 2-Chloro-5-fluoro-6-phenylnicotinonitrile According to the general procedure A, the title compound ([M+H+MeCN,Cl]) was obtained from 2,6-dichloro-5-fluoronicotinonitrile and phenylboronic acid at 90 °C under the catalysis of Pd(dppf)2Cl2·CH2Cl2 complex. + 275.1) was prepared.

[0116] Step 2: 6-(cyclohexen-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 2-chloro-5-fluoro-6-phenylnicotinonitrile (step 1) and hydrazine were prepared at 75° C. to give the title compound ([M+H] + 229.3) was prepared.

[0117] Intermediate 7: 5-Fluoro-6-pyrrolidin-1-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine TIFF2024504788000018.tif33170To a solution of 2,6-dichloro-5-fluoro-3-pyridine-carbonitrile (200 mg, 1 mmol) in ethanol (2 ml), pyrrolidine (124 ul, 0.2 mmol) was added and the reaction heated at 95°C for 6 h. The reaction was concentrated, the residue redissolved in ethylene glycol (2 ml), hydrazine monohydrate (0.75 ml, 15.0 mmol) was added and the reaction mixture heated at 130°C for 3 h. The reaction was adsorbed onto silica gel and purified by flash silica gel column chromatography (ethyl acetate:n-heptane 0:1 to 1:0) to give the title compound (149 mg, 68%) as a white solid. ([M+H] + 222.1)

[0118] Intermediate 8: 6-(3,3-difluoroazetidin-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000019.tif43170Step 1: 2-Chloro-6-(3,3-difluoroazetidin-1-yl)-5-fluoronicotinonitrile Following general procedure B, the title compound was prepared from 2,6-dichloro-5-fluoronicotinonitrile and 3,3-difluoroazetidine hydrochloride in DMF using triethylamine as base. 1 H NMR(DMSO-d6,300MHz)δ8.18(d,1H,J=11.3Hz),4.70(dt,4H,J=1.8,12.4Hz)

[0119] Step 2: 6-(3,3-difluoroazetidin-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 2-chloro-5-fluoro-6-phenylnicotinonitrile (step 1) and hydrazine were prepared in ethylene glycol at 120° C. to give the title compound ([M+H] + 244.1) was prepared.

[0120] Intermediate 9: 6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-amine TIFF2024504788000020.tif43170Step 1: 4-Chloro-2-(pyrrolidin-1-yl)pyrimidine-5-carbonitrile Following general procedure B, the title compound ([M+H,Cl]) was obtained from 2,4-dichloropyrimidine-5-carbonitrile and pyrrolidine in THF using DIPEA as base. + 209.1) was prepared.

[0121] Step 2: 6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-amine The title compound ([M+H]) was obtained from 4-chloro-2-(pyrrolidin-1-yl)pyrimidine-5-carbonitrile (Step 1) and hydrazine according to General Procedure C. + 205.2) was prepared in ethanol at 100°C.

[0122] Intermediate 10: 6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-amine Following general procedure C, the title compound ([M+H] + 217.2) was prepared.

[0123] Intermediate 11: 6-(3,4-dihydro-2H-pyran-6-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000022.tif48170Step 1: 2-Chloro-6-(3,4-dihydro-2H-pyran-6-yl)nicotinonitrile According to general procedure A, 2,6-dichloro-5-fluoronicotinonitrile and 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane are reacted under tetrakis(triphenylphosphine)palladium catalysis at 90° C. to give the title compound ([M+H,Cl] + 221.1) was prepared.

[0124] Step 2: 6-(3,4-dihydro-2H-pyran-6-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)nicotinonitrile (step 1) and hydrazine were prepared in ethanol at 100° C. to give the title compound ([M+H] + 217.1) was prepared.

[0125] Intermediate 12: 6-(cyclopenten-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000023.tif48170Step 1: 2-Chloro-6-(cyclopent-1-en-1-yl)nicotinonitrile According to general procedure A, 2,6-dichloro-5-fluoronicotinonitrile and cyclopent-1-en-1-ylboronic acid are reacted with tetrakis(triphenylphosphine)palladium catalyst at 90° C. to give the title compound ([M+H,Cl] + 205.1) was prepared.

[0126] Step 2: 6-(cyclopenten-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 2-chloro-6-(cyclopent-1-en-1-yl)nicotinonitrile (step 1) and hydrazine were prepared in ethanol at 100° C. to give the title compound ([M+H] + 201.1) was prepared.

[0127] Intermediate 13: 6-(azetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000024.tif361706-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 in a sealed tube at 70° C. for 72 hours. The reaction mixture was poured into water, the resulting precipitate was filtered, and the filtrate was left for several days to crystallize. Purification by filtration gave the title compound (12 mg, 13%) as a white solid. ([M+H] + 190.1)

[0128] Intermediate 14: 6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000025.tif42170 Step 1: 4-Chloro-2-(pyrrolidin-1-yl)pyrimidine-5-carbonitrile According to general procedure B, the title compound ([M+H,Cl]) was obtained from 2,6-dichloronicotinonitrile and 3,3-difluoroazetidine hydrochloride in ethanol with DIPEA as base. + 230.0) was prepared.

[0129] Step 2: 6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 4-chloro-2-(pyrrolidin-1-yl)pyrimidine-5-carbonitrile (step 1) and hydrazine were prepared in ethanol at 80° C. to give the title compound ([M+H] + 205.2) was prepared.

[0130] Intermediate 15: 6-Cyclopentyl-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000026.tif381706-(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 at 50° C. under a hydrogen balloon atmosphere for 18 hours. The reaction mixture was cooled to ambient temperature, filtered through Dicalite® and concentrated to give the title compound (55 mg, 87%) as a yellow solid. ([M+H] + 203.1)

[0131] Intermediate 16: 6-Cyclobutyl-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000027.tif39170Step 1: 1-Cyclobutyl-3-(dimethylamino)prop-2-en-1-one To a solution of 1-cyclobutylethan-1-one (2.22 ml, 20.4 mmol) in DMF (5 ml) was 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, at which time a 1H-NMR aliquot of the solution showed complete conversion. The crude solution was used directly in the next step.

[0132] Step 2: 6-Cyclobutyl-2-hydroxynicotinonitrile The title compound ([M+H]) was obtained from 1-cyclobutyl-3-(dimethylamino)prop-2-en-1-one (step 2) and cyanoacetamide according to general procedure D. + 175.1) was prepared.

[0133] Step 3: 2-Chloro-6-cyclobutylnicotinonitrile The title compound ([M+H,Cl]+ 193.0) was prepared from 6-cyclobutyl-2-hydroxynicotinonitrile (step 2) and POCl3 following general procedure E.

[0134] Step 4: 6-(3,3-difluoroazetidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 2-chloro-6-cyclobutylnicotinonitrile (step 3) and hydrazine were prepared in ethanol at 75° C. to give the title compound ([M+H] + 189.1) was prepared.

[0135] Intermediate 17: 6-((1RS,2RS)-2-Methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000028.tif39170Step 1: 2-Hydroxy-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile The title compound ([M+H]) was obtained by reaction of (E)-3-(dimethylamino)-1-(2-methylcyclopropyl)prop-2-en-1-one (prepared from 1-(2-methylcyclopropyl)ethanone-CAS:930-56-3 by a modified procedure of J. Med. Chem. 2011, 54, 7974) and 2-cyanoacetamide using NaOMe as base. + 175.0) was prepared (General Procedure G).

[0136] Step 2: 2-Chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile The reaction of 2-hydroxy-6-(2-methylcyclopropyl)nicotinonitrile with POCl3 gave the title compound ([M+H,Cl] + 193.1) was prepared (General Procedure H).

[0137] Step 3: 6-((1RS,2RS)-2-Methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 2-chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile (step 2) and hydrazine were prepared in ethanol at 75° C. to give the title compound ([M+H] + 189.1) was prepared.

[0138] Intermediate 18: 6-(2,5-dihydrofuran-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine According to general procedure A., the title compound ([M+H]) was obtained 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. + 203.1) was prepared.

[0139] Intermediate 19: 7-Methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-3-amine Following general procedure C, the title compound ([M+H] + 203.2) was prepared.

[0140] Intermediate 20: 6-((1RS,2SR)-2-fluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000031.tif33170Step 1: 6-((1RS,2SR)-2-fluorocyclopropyl)-2-hydroxynicotinonitrile The title compound ([M+H]+ 179.0) was prepared by the reaction of 3-(dimethylamino)-1-((trans)-2-fluorocyclopropyl)prop-2-en-1-one (prepared from 1-(2-fluorocyclopropyl)ethanone by a modified procedure from J. Med. Chem. 2011, 54, 7974 (WO2016 / 161960A1,2016)) and 2-cyanoacetamide using NaOMe as the base (General Procedure G).

[0141] Step 2: 2-Chloro-6-((1RS,2SR)-2-fluorocyclopropyl)nicotinonitrile Title compound ( 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 prepared by reaction of 6-((1RS,2SR)-2-fluorocyclopropyl)-2-hydroxynicotinonitrile (step 1) with POCl3 (general procedure H).

[0142] Step 3: 6-((1RS,2RS)-2-Methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 2-chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile (step 2) and hydrazine were prepared in ethanol at 75° C. to give the title compound ([M+H] + 193.0) was prepared.

[0143] Intermediate 21: 6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000032.tif33170Step 1: 2-Chloro-6-vinylnicotinonitrile According to general procedure A, the title compound ([M+H,Cl]) was obtained from 2,6-dichloronicotinonitrile and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane at 100 °C under the catalysis of Pd(dppf)2Cl2·CH2Cl2 complex. + 165.0) was prepared.

[0144] Step 2: 2-Chloro-6-(2,2-difluorocyclopropyl)nicotinonitrile To a solution of 2-chloro-6-vinylnicotinonitrile (step 1) (50 mg, 0.30 mmol) in THF (2 ml) was added trimethyl(trifluoromethyl)silane (112 μL, 0.76 mmol) and NaI (9.2 mg, 0.06 mmol). The reaction was stirred in a sealed tube at 65° C. for 2 h. An additional amount of trimethyl(trifluoromethyl)silane (112 μL, 0.76 mmol) and NaI (9.2 mg, 0.06 mmol) was added and the reaction was stirred at 65° C. for an additional hour, after which an additional amount of trimethyl(trifluoromethyl)silane (112 μL, 0.76 mmol) and NaI (9.2 mg, 0.06 mmol) was added and the reaction was stirred for an additional 3 h. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated. Flash silica gel chromatography (ethyl acetate:n-heptane 0:1 to 1:1) afforded the title compound (27 mg, 41%) as a yellow oil. ([M+H,Cl] + 215.1)

[0145] Step 3: 6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 2-chloro-6-(2,2-difluorocyclopropyl)nicotinonitrile (step 2) and hydrazine were prepared in ethanol at 100° C. to give the title compound ([M+H] + 211.1) was prepared.

[0146] Intermediate 22: 6-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000033.tif38170Step 1: 2-Chloro-6-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]pyridine-3-carbonitrile According to general procedure A., the title compound ([M+H,Cl]) was obtained from 2,6-dichloronicotinonitrile and potassium trifluoro((1RS,2RS)-2-(trifluoromethyl)cyclopropyl)borate in toluene / water at 120° C. under butyldi-1-adamantylphosphine / palladium(II) acetate catalysis. + 247.0) was prepared. The desired product was inseparable from the 6-chloro-2-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]pyridine-3-carbonitrile isomer.

[0147] Step 3: 6-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, the title compound ([M+H] + 243.1) was prepared.

[0148] Intermediate 23: 6-((1rs,2RS,3SR)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000034.tif41170Step 1: 6-((1,rs,2RS,3SR)-2,3-Dimethylcyclopropyl)-2-hydroxynicotinonitrile The title compound ([M+H]) was obtained by the reaction of (E)-3-(dimethylamino)-1-((2RS,3SR)-2,3-dimethylcyclopropyl)prop-2-en-1-one (prepared from 1-[rac-(2R,3S)-2,3-dimethylcyclopropyl]ethanone (J. Org. Chem. 1978, 3422) by a modified procedure from J. Med. Chem. 2011, 54, 7974) and 2-cyanoacetamide using NaOMe as a base. + 189.1) was prepared (General Procedure G).

[0149] Step 2: 2-Chloro-6-((1rs,2RS,3SR)-2,3-dimethylcyclopropyl)nicotinonitrile Title compound ([M+H] + 207.1) was prepared by reaction of 6-((1rs,2R,3S)-2,3-dimethylcyclopropyl)-2-hydroxynicotinonitrile (step 1) with POCl3 (general procedure H).

[0150] Step 3: 6-((1rs,2RS,3SR)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 2-chloro-6-((1rs,2RS,3SR)-2,3-dimethylcyclopropyl)nicotinonitrile (step 2) and hydrazine were prepared in ethanol at 75° C. to give the title compound ([M+H] + 203.1) was prepared.

[0151] Intermediate 24: 6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000035.tif51170Step 1: 2-Hydroxy-6-(1-methylcyclopropyl)nicotinonitrile The title compound ([M+H]) was obtained by the reaction of (E)-3-(dimethylamino)-1-(1-methylcyclopropyl)prop-2-en-1-one (prepared from 1-(1-methylcyclopropyl)ethan-1-one (Chem. Berichte, 1981, 3831) and 2-cyanoacetamide using NaOMe as the base with modifications of the procedure in J. Med. Chem. 2011, 54, 7974). + 189.1) was prepared (General Procedure G).

[0152] Step 2: 2-Chloro-6-(1-methylcyclopropyl)nicotinonitrile The title compound (1H 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 prepared by reaction of 2-hydroxy-6-(1-methylcyclopropyl)nicotinonitrile (step 1) with POCl3 (general procedure H).

[0153] Step 3: 6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine Following general procedure C, 2-chloro-6-(1-methylcyclopropyl)nicotinonitrile (step 2) and hydrazine were prepared in ethanol at 75° C. to give the title compound ([M+H] + 189.1) was prepared.

[0154] Intermediate 25: 6-(3-Azabicyclo[2.2.1]heptan-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF2024504788000036.tif43170 Step 1: 6-(3-Azabicyclo[2.2.1]heptan-3-yl)-2-chloro-pyridine-3-carbonitrile The title compound ( 1H 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 (br d, J = 9.6 Hz, 1H), 2.70-2.61 (m, 2H), 1.76-1.62 (m, 6H), 1.57-1.35 (m, 6H)) was prepared from 2,6-dichloronicotinonitrile and 3-azabicyclo[2.2.1]heptane in THF with TEA as base.

[0155] Step 2: 6-(3-Azabicyclo[2.2.1]heptan-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine According to general procedure C, 6-(3-azabicyclo[2.2.1]heptan-3-yl)-2-chloro-pyridine-3-carbonitrile (step 1) and hydrazine were prepared in ethanol at 80° C. to give the title compound ([M+H] + 205.2) was prepared.

[0156] Intermediate 26: [3-Amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone TIFF2024504788000037.tif45170Step 1: 6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-chloro-pyridine-3-carbonitrile The title compound ( 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) with DIPEA as base.

[0157] Step 2: [3-amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone The title compound ( 1 H 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-chloro-pyridine-3-carbonitrile (step 1) and hydrazine in ethanol at 80 °C.

[0158] Intermediate 27: (3RS,4RS)-3-Methyl-2-oxopiperidine-4-carboxylic acid TIFF2024504788000038.tif481703-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 stirred under an atmosphere of hydrogen (balloon) for 72 h. The reaction was filtered through Hyflo®, washed thoroughly with MeOH and concentrated to give the title compound (1.85 g, 84%) as a white solid. ([MH] - 156.0)

[0159] Intermediate 28: (E)-N-(6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-1-phenylmethanimine TIFF2024504788000039.tif541706-Cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-amine (Intermediate 5) (200 mg, 1.15 mmol) was added to a suspension of EtOH (4 ml) and the mixture was heated at 80° C. for 1 h. The reaction was cooled to ambient temperature and the title product was isolated by filtration (309 mg, quant.) as an off-white solid. ( 1 H NMR(CHLOROFORM-d,300MHz)δ13.28(s,1H),9.20(s,1H),8.28(d,1H,J=8.3Hz),8.00-8. 10(m,2H),7.5-7.6(m,3H),7.21(d,1H,J=8.3Hz),2.20-2.30(m,1H),1.00-1.10(m,4H)) EXAMPLES

[0160] Working Example TIFF2024504788000040.tif220170TIFF2024504788000041.tif208170TIFF2024504788000042.tif230170TIFF20245047880 00043.tif223170TIFF2024504788000044.tif250170TIFF2024504788000045.tif247170TIFF2024504788000046.tif215170 TIFF2024504788000047.tif215170TIFF2024504788000048.tif238170TIFF2024504788000049.tif252170TIFF20245047880 00050.tif240170TIFF2024504788000051.tif245170TIFF2024504788000052.tif238170TIFF2024504788000053.tif245170 TIFF2024504788000054.tif243170TIFF2024504788000055.tif238170TIFF2024504788000056.tif252170TIFF20245047880 00057.tif247170TIFF2024504788000058.tif252170TIFF2024504788000059.tif230170TIFF2024504788000060.tif252170 TIFF2024504788000061.tif215170TIFF2024504788000062.tif252170TIFF2024504788000063.tif223170TIFF20245047880 00064.tif252170TIFF2024504788000065.tif208170TIFF2024504788000066.tif250170TIFF2024504788000067.tif223170

[0161] Aspects of the present invention: 1. Compounds of Formula I: TIFF2024504788000068.tif64170[In the formula, X 1 is N or CR3 Either; R 1 teeth: one or more, in particular one to three, more in particular one or two, substituents R 1a (C3-C8)cycloalkyl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1b Heteroaryl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1c heterocycloalkyl, optionally substituted with; or one or more, in particular one to three, more in particular one or two, substituents R 1d phenyl optionally substituted with R 1a , R 1b , R 1c , and R 1d are each independently selected from halogen, oxo, cyano, hydroxyl, (C-C)alkyl, (C-C)alkoxy, (C-C)cycloalkyl, (C-C)cycloalkyl-(C-C)alkyl, halo(C-C)alkyl, halo(C-C)alkoxy, hydroxy(C-C)alkyl, (C-C)alkoxy-(C-C)alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 2 is (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, one or more, particularly one to three, more particularly one or two substituents R 2a (C3-C6)cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two, substituents R 2b or one or more, particularly one to three, more particularly one or two, substituents R 2c phenyl optionally substituted with R 2a , R2b , and R 2c are each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 3 is hydrogen, halogen, or (C1-C6)alkyl; Or R 2 , and R 3 together represent one or more, particularly one to three, more particularly one or two, substituents R 3f C which may be substituted with 2-7 Forming an alkylene R 3f are each independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl. and pharma- ceutically acceptable salts thereof.

[0162] 2. Compound of formula I': TIFF2024504788000069.tif64170[where, R 1 teeth: one or more, in particular one to three, more in particular one or two, substituents R 1a (C3-C8)cycloalkyl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1b Heteroaryl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1c heterocycloalkyl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R 1d phenyl optionally substituted with R 1a , R 1b , R 1c , and R 1dare each independently selected from halogen, oxo, cyano, hydroxyl, (C-C)alkyl, (C-C)alkoxy, (C-C)cycloalkyl, (C-C)cycloalkyl-(C-C)alkyl, halo(C-C)alkyl, halo(C-C)alkoxy, hydroxy(C-C)alkyl, (C-C)alkoxy-(C-C)alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 2 is (C1-C6)alkyl, halo(C1-C6)alkyl, one or more, particularly one to three, more particularly one or two substituents R 2a (C3-C6)cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two, substituents R 2b or one or more, particularly one to three, more particularly one or two, substituents R 2c phenyl optionally substituted with R 2a , R 2b , and R 2c are each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R 3 is hydrogen, halogen, or (C1-C6)alkyl; Or R 2 , and R 3 together represent one or more, particularly one to three, more particularly one or two, substituents R 3f C which may be substituted with 2-7 Forming an alkylene R 3f are each independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl. and pharma- ceutically acceptable salts thereof.

[0163] 3. X 1 CR3 2. The compound according to embodiment 1, wherein

[0164] 4. R 1 However, one substituent R 1a (C3-C8)cycloalkyl optionally substituted with one R 1b Heteroaryl optionally substituted with one or two R 1c or one or two R 1d A compound according to any one of aspects 1 to 3, wherein R is phenyl optionally substituted with R.

[0165] 5. R 1 But one R 1a (C3-C6)cycloalkyl optionally substituted with one R 1b 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 1c 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 or one or two R 1d The compound according to any one of aspects 1 to 4, wherein R is phenyl optionally substituted with

[0166] 6. R 1 But one R 1a Cyclohexyl, even if substituted with one R 1b pyridinyl, optionally substituted with one R 1b pyrazinyl, optionally substituted with one R 1b pyridizanyl, optionally substituted with one R1b 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 or two R 1d A compound according to any one of aspects 1 to 5, wherein R is tetrahydropyranyl or phenyl, optionally substituted with R.

[0167] 7. Most specifically, R 1 But one R 1b or one or two R 1d A compound according to any one of aspects 1 to 6, wherein R is phenyl optionally substituted with R.

[0168] 8. R 1 But one R 1b or one or two R 1d A compound according to any one of aspects 1 to 4, wherein R is phenyl optionally substituted with R.

[0169] 9. R 1a , R 1b , R 1c , and R 1d are each independently selected from halogen, oxo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy.

[0170] 10. R 1a , R 1b , R 1c , and R 1dare each independently selected from halogen, oxo, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy.

[0171] 11. R 1a , R 1b , R 1c , and R 1d is independently selected from chloro, fluoro, oxo, cyano, methyl, ethyl, methoxy, trifluoromethyl, and difluoromethyl.

[0172] 12. R 1a , R 1b , R 1c , and R 1d is independently selected from chloro, fluoro, cyano, methyl, and methoxy.

[0173] 13. R 1b , and R 1d are each independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy.

[0174] 14. R 1b are each independently selected from halogen, (C-C)alkyl, (C-C)alkoxy, and halo(C-C)alkyl; R 1d are each independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy.

[0175] 15. R 1bare each independently selected from chloro, methyl, and methoxy; R 1d is each independently selected from fluoro, cyano, methyl, and methoxy.

[0176] 16. R 1 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-methyl-tetrahydrofuran-2-yl, 16. The compound according to any one of aspects 1 to 15, which is 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.

[0177] 17. 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.

[0178] 18. R 2is (C1-C6)alkyl, halo(C1-C6)alkyl, one or two substituents R 2a (C3-C6)cycloalkyl optionally substituted with one or two substituents R 2b 18. The compound according to any one of the aspects 1 to 17, wherein R is heterocycloalkyl optionally substituted with R, or phenyl.

[0179] 19. R 2 is (C1-C3)alkyl, halo(C1-C3)alkyl, one or two substituents R 2a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, optionally substituted with one or two substituents R 2b Azetidinyl, dihydrofuranyl, dihydropyranyl, azabicyclo[2.2.1]heptanyl, -azabicyclo[2.2.1]heptanyl, pyrrolidinyl, optionally substituted with one or two substituents R 2b 19. The compound according to any one of aspects 1 to 18, wherein R is azetidinyl, optionally substituted with R, or phenyl.

[0180] 20. R 2 is i-butyl, t-butyl, trifluoromethyl, one or two substituents R 2a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, optionally substituted with one or two substituents R 2b 20. The compound according to any one of aspects 1 to 19, wherein R is azetidinyl, 2,5-dihydrofuran-3-yl, 3,4-dihydro-pyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl, optionally substituted with R.

[0181] twenty one. R 2 is halo(C1-C6)alkyl, one or two substituents R 2a or one or two substituents R 2bA compound according to any one of the preceding aspects, wherein R is heterocycloalkyl optionally substituted with R.

[0182] twenty two. R 2a , R 2b , and R 2c is each independently selected from halogen, (C1-C3)alkyl, and halo(C1-C3)alkyl.

[0183] twenty three. R 2a , R 2b , and R 2c is independently selected from fluoro, methyl, and trifluoromethyl.

[0184] twenty four. R 2a are each independently selected from fluoro, methyl, and trifluoromethyl; R 2b The compound according to any one of embodiments 1-23, wherein each is fluoro.

[0185] twenty five. R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclohexen-1-yl, optionally substituted with one or two substituents selected from i-butyl, t-butyl, trifluoromethyl, fluoro, methyl, or trifluoromethyl, azetidinyl optionally substituted with two fluoro, 2,5-dihydrofuran-3-yl, 3,4-dihydro-pyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl.

[0186] 26. R 2is trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenten-1-yl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2-(trifluoromethyl)cyclopropyl, 2,3-dimethylcyclopropyl, 1-methylcyclopropyl, or 3,4-dihydro-pyran-6-yl.

[0187] 27. 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-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 t-butyl.

[0188] 28. R 2 The compound according to any one of aspects 1 to 26, wherein is cyclopropyl, cyclopenten-1-yl, trifluoromethyl, or cyclobutyl, 2,5-dihydrofuran-3-yl.

[0189] 29. R 3 The compound according to any one of aspects 1-28, wherein is hydrogen or halogen.

[0190] 30. R 3 The compound according to any one of the preceding aspects, wherein is hydrogen, chloro, or fluoro.

[0191] 31. R 3The compound according to any one of aspects 1-30, wherein is hydrogen.

[0192] 32. below: (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-(cyclopentenyl)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)(2-methoxyphenyl)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]-(2-methoxyphenyl)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]pyridine-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]pyridine-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 [3-Amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridin-1-yl]-(2-methoxyphenyl)methanone 31. The compound according to any one of aspects 1 to 30, selected from the group consisting of:

[0193] 33. below: (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-(cyclopentenyl)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]pyridine-1-carbonyl)-2-methoxybenzonitrile (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 31. The compound according to any one of aspects 1 to 30, selected from the group consisting of:

[0194] 34. A compound according to any one of aspects 1 to 33 for use as a therapeutically active substance.

[0195] 35. A pharmaceutical composition comprising a compound of formula I or I' as defined in any one of aspects 1 to 33 or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

[0196] 36. A compound of formula I or I' or a pharma- ceutically acceptable salt thereof according to any one of the aspects 1 to 33 for use as a therapeutically active substance.

[0197] 37. A compound of formula I or I' or a pharma- ceutically acceptable salt thereof, as defined in any one of aspects 1 to 33, for use in the treatment, prevention and / or delay of progression of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, esophageal carcinoma, glioblastoma multiforme, and mesothelioma.

[0198] 38. A compound according to embodiment 37 for use in the treatment, prevention and / or delay of progression of lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0199] 39. A method for the treatment or prevention of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, esophageal carcinoma, glioblastoma multiforme, and mesothelioma, comprising administering to a subject a compound of formula I, or a pharma- ceutically acceptable salt thereof, as defined above, according to any one of aspects 1 to 33.

[0200] 40. The method according to embodiment 40, for the treatment or prevention of lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0201] 41. The use of a compound of formula I, or a pharma- ceutically acceptable salt thereof, according to any one of aspects 1 to 33, for the treatment, prevention and / or delay of progression of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, esophageal carcinoma, glioblastoma multiforme, and mesothelioma.

[0202] 42. 42. Use of a compound according to embodiment 41 for the treatment, prevention and / or delay of progression of lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0203] 43. Use of a compound of formula I or a pharma- ceutically acceptable salt thereof, according to any one of aspects 1 to 33, for the preparation of a medicament for the treatment or prevention of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma.

[0204] 44. 44. Use of a compound according to embodiment 43 for the treatment, prevention and / or delay of progression of lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

Claims

1. Compounds of Formula I: [In the formula, X １ is N or CR ３ either R １ teeth: one or more, in particular one to three, more in particular one or two, substituents R １ａ (C ３ -C ８ ) cycloalkyl, one or more, in particular one to three, more in particular one or two, substituents R １ｂ Heteroaryl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R １ｃ or one or more, in particular one to three, more in particular one or two, substituents R １ｄ phenyl optionally substituted with R １ａ , R １ｂ , R １ｃ , and R １ｄ are each independently halogen, oxo, cyano, hydroxyl, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C ３ -C ６ ) cycloalkyl, (C ３ -C ６ ) cycloalkyl-(C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkoxy, hydroxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C １ -C ６ ) selected from alkyl, heteroaryl, heterocycloalkyl, and phenyl; R ２ (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halo (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkoxy, one or more, particularly one to three, more particularly one or two, substituents R ２ａ (C ３ -C ６ ) cycloalkyl, one or more, particularly one to three, more particularly one or two, substituents R ２ｂ or one or more, particularly one to three, more particularly one or two, substituents R ２ｃ phenyl optionally substituted with R ２ａ , R ２ｂ , and R ２ｃ Each independently represents a halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halo (C １ -C ６ ) alkyl, and halo(C １ -C ６ ) alkoxy; R ３ is hydrogen, halogen, or (C １ -C ６ ) alkyl; Or, R ２ , and R ３ together represent one or more, particularly one to three, more particularly one or two, substituents R ３ｆ C optionally substituted with ２－７ Forming an alkylene R ３ｆ Each independently represents a halogen, (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl. or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is a compound of formula I': [In the formula, R １ teeth: one or more, in particular one to three, more in particular one or two, substituents R １ａ (C ３ -C ８ ) cycloalkyl, one or more, in particular one to three, more in particular one or two, substituents R １ｂ Heteroaryl optionally substituted with one or more, in particular one to three, more in particular one or two, substituents R １ｃ or one or more, in particular one to three, more in particular one or two, substituents R １ｄ phenyl optionally substituted with R １ａ , R １ｂ , R １ｃ , and R １ｄ are each independently halogen, oxo, cyano, hydroxyl, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C ３ -C ６ ) cycloalkyl, (C ３ -C ６ ) cycloalkyl-(C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkoxy, hydroxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C １ -C ６ ) selected from alkyl, heteroaryl, heterocycloalkyl, and phenyl; R ２ (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, one or more, particularly one to three, more particularly one or two, substituents R ２ａ (C ３ -C ６ ) cycloalkyl, one or more, particularly one to three, more particularly one or two, substituents R ２ｂ or one or more, particularly one to three, more particularly one or two, substituents R ２ｃ phenyl optionally substituted with R ２ａ , R ２ｂ , and R ２ｃ Each independently represents a halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halo (C １ -C ６ ) alkyl, and halo(C １ -C ６ ) alkoxy; R ３ is hydrogen, halogen, or (C １ -C ６ ) alkyl; Or, R ２ , and R ３ together represent one or more, particularly one to three, more particularly one or two, substituents R ３ｆ C optionally substituted with ２－７ Forming an alkylene R ３ｆ Each independently represents a halogen, (C １ -C ６ ) alkyl, and halo(C １ -C ６ ) alkyl.

2. The compound of claim 1, wherein:

3. X １ is CR ３ 2. The compound of claim 1, wherein:

4. R １ But one R １ａ cyclohexyl optionally substituted with one R １ｂ pyridinyl optionally substituted with one R １ｂ pyrazinyl optionally substituted with one R １ｂ pyridizanyl optionally substituted with one R １ｂ 1,3-benzodioxolyl, thiazolyl 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 or two R １ｄ 4. The compound according to claim 1, wherein R is tetrahydropyranyl or phenyl, optionally substituted by R, or a pharma- ceutically acceptable salt thereof.

5. R １ａ , R １ｂ , R １ｃ , and R １ｄ or a pharma- ceutically acceptable salt thereof.

5. The compound of claim 1, wherein each is independently selected from chloro, fluoro, cyano, methyl, and methoxy; or a pharma- ceutically acceptable salt thereof.

6. R １ｂ , and R １ｄ each independently represents a halogen, a cyano, １ -C ３ ) alkyl, (C １ -C ３ ) alkoxy, halo (C １ -C ３ ) alkyl, and halo(C １ -C ３ 5. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

7. R １ｂ each independently represents a halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) alkoxy, and halo (C １ -C ３ ) alkyl; R １ｄ each independently represents a halogen, a cyano, １ -C ３ ) alkyl, (C １ -C ３ ) alkoxy, halo (C １ -C ３ ) alkyl, and halo(C １ -C ３ 7. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R is 0, R is 1, R is 2, R is 3, R is 4, R is 5, R is 6, R is 7, R is 8, R is 9, R is 10, R is 11, R is 12, R is 13, R is 14, R is 15, R is 16, R is 17, R is

8. R １ｂ are each independently selected from chloro, methyl, and methoxy; R １ｄ or a pharma- ceutically acceptable salt thereof.

5. The compound of claim 1, wherein each is independently selected from fluoro, cyano, methyl, and methoxy; or a pharma- ceutically acceptable salt thereof.

9. R １ 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-methyl-tetrahydrofuran-2-yl, 3-cyano-2- 9. The compound according to any one of claims 1 to 8, which is 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, or a pharma- ceutically acceptable salt thereof.

10. 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; or a pharma- ceutically acceptable salt thereof.

11. R ２ But, Halo (C １ -C ６ ) alkyl, one or two substituents R ２ａ (C ３ -C ６ ) cycloalkyl or one or two substituents R ２ｂ 11. The compound of claim 1, wherein R is an optionally substituted heterocycloalkyl group, or a pharma- ceutically acceptable salt thereof.

12. R ２ａ are each independently selected from fluoro, methyl, and trifluoromethyl; R ２ｂ or a pharma- ceutically acceptable salt thereof.

13. The compound of claim 1, wherein each is fluoro;

13. R ２ is i-butyl, t-butyl, trifluoromethyl; cyclopropyl optionally substituted with one or two substituents selected from fluoro, methyl, or trifluoromethyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclohexen-1-yl, azetidinyl optionally substituted with two fluoro, 2,5-dihydrofuran-3-yl, 3,4-dihydro-pyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl, or a pharma- ceutically acceptable salt thereof.

14. 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-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 t-butyl. The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof.

15. R ２ The compound according to any one of claims 1 to 13, wherein is cyclopropyl, cyclopenten-1-yl, trifluoromethyl, or cyclobutyl, 2,5-dihydrofuran-3-yl, or a pharma- ceutically acceptable salt thereof.

16. R ３ 16. The compound of any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

17. The compound of claim 1 (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)(2-methoxyphenyl)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]-(2-methoxyphenyl)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]pyridine-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]pyridine-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 17. The compound of any one of claims 1 to 16, selected from the group consisting of:

18. The compound comprising: (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]pyridine-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 18. The compound of any one of claims 1 to 17, selected from the group consisting of:

19. 20. A compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

21. 20. A compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt thereof for use as a therapeutically active substance.

22. 20. A compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt thereof for use in the treatment, prevention and / or delay of progression of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, esophageal carcinoma, glioblastoma multiforme, and mesothelioma.

23. 23. The compound of claim 22 or a pharma- ceutically acceptable salt thereof for use in the treatment, prevention and / or delay of progression of lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

24. 20. Use of a compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the treatment, prevention and / or delay of progression of lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal carcinoma, glioblastoma multiforme, and mesothelioma.

25. 25. The use according to claim 24 for the preparation of a medicament for the treatment, prevention and / or delay of progression of lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

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