Pyrazoleamide 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 a compound that is an inhibitor of human methionine adenosyltransferase 2A (Mat2A) for use in the treatment, prevention and / or delay of progression of cancer.

Summary of the Invention

[0002] In particular, the present invention relates to a compound of formula I: TIFF0007862408000001.tif64170[where, X 1 is either N or CR 3 ; R 1 is: - (C3-C8) cycloalkyl optionally substituted with one or more, specifically 1 to 3, more specifically 1 or 2 substituents R 1a ; - heteroaryl optionally substituted with one or more, specifically 1 to 3, more specifically 1 or 2 substituents R 1b ; - heterocycloalkyl optionally substituted with one or more, specifically 1 to 3, more specifically 1 or 2 substituents R 1c ; or - phenyl optionally substituted with one or more, specifically 1 to 3, more specifically 1 or 2 substituents R 1d ; R 1a , R 1b , R 1c and R 1d are each independently selected from halogen, oxo, cyano, hydroxyl, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-(C1-C6) alkyl, halo(C1-C6) alkyl, halo(C1-C6) alkoxy, hydroxy(C1-C6) alkyl, (C1-C6) alkoxy-(C1-C6) alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 2(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, one or more substituents R, more specifically one to three, more specifically one or two substituents R 2a A (C3-C6) cycloalkyl group which may be substituted with one or more substituents R, more specifically one to three, more specifically one or two substituents R 2b A heterocycloalkyl which may be substituted with, or one or more substituents R, more specifically one to three, more specifically one or two substituents R 2c A phenyl which may be substituted with; R 2a , R 2b , and R 2c Each of these is 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, one or more substituents R, more specifically one to three, more specifically one or two substituents R 3f Even if replaced by C 2-7 Forming alkylenes, R 3f Each of these is independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl. and its pharmaceutically acceptable salts.

[0003] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains. Similar or equivalent methods and substances may be used in carrying out or testing the present invention, but suitable methods and substances are listed below.

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

[0005] Unless otherwise specified, the nomenclature used in this application is based on the IUPAC systematic nomenclature.

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

[0007] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to as many substitutions as possible, i.e., from the substitution of one hydrogen by a substituent to the substitution of all hydrogens, and more specifically, "one or more" refers to one, two or three, and most specifically, "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 in the parent molecule.

[0009] The term "substituted" indicates that the specified group supports one or more substituents. Any group can have multiple substituents, and if various possible substituents are provided, the substituents are independently selected and do not need to be the same. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is either 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 as many substitutions as possible, i.e., from the substitution of one hydrogen by a substituent to the substitution of all hydrogens.

[0010] The term “amino” refers to a group of the formula -NR'R'' [wherein 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, together with the nitrogen to which they are bound, form a heterocycloalkyl. The term “primary amino group” means a group in which both R' and R'' are hydrogen. The term “secondary amino” refers to a group in which R' is hydrogen and R'' is a non-hydrogen group, in particular R'' is (C1-C6) alkyl. The term “secondary amino” refers to a group in which both R' and R'' are non-hydrogen groups, in particular R' and R'' are both (C1-C6) alkyl. Certain secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine, dipropylamine, and diisopropylamine, with amino referring most specifically to ethylamine.

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

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

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

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

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

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

[0017] "(C3-C6)cycloalkyl-(C1-C6)alkyl" means one or more (C3-C6)cycloalkyl groups, in particular a (C1-C6) alkyl group substituted with one (C3-C6)cycloalkyl group, as defined above. More specifically, "(C3-C6)cycloalkyl-(C1-C6)alkyl" means, This means TIFF0007862408000002.tif19170.

[0018] The term "perhalo(C1-C3)alkyl" refers to the (C1-C3) alkyl group 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 the (C1-C6)alkyl as defined above, which is substituted with one or more halogen atoms, particularly with 1 to 3 halogen atoms. More specifically, halo(C1-C6)alkyl is chloro-(C1-C6)alkyl and fluoro-(C1-C6)alkyl. In some specific embodiments, halo(C1-C6)alkyl means perhalo(C1-C3)alkyl as defined herein. Most specifically, halo(C1-C6)alkyl is trifluoromethyl, difluoromethyl, or fluoromethyl.

[0020] "Halo(C1-C6)alkoxy" means the (C1-C6) alkoxy defined above, which is substituted with one or more halogen atoms, particularly with 1 to 3 halogen atoms. In particular, halo(C1-C6)alkoxys are chloro-(C1-C6)alkoxys and fluoro-(C1-C6)alkoxys. In some specific embodiments, halo(C1-C6)alkoxy means perhalo(C1-C3)alkoxys, such as trifluoromethoxy or difluoromethoxy.

[0021] "Hydroxy(C1-C6)alkyl" means an alkyl group defined above that is substituted with one or more hydroxyl groups, particularly one hydroxyl group. More specifically, hydroxy(C1-C6)alkyl means methyl hydroxide or ethyl hydroxide.

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

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

[0024] "Heteroaryl" is understood to mean a monocyclic or bicyclic moiety of 5 to 12 ring atoms, each having at least one aromatic ring containing one, two, or three ring heteroatoms independently selected from N, O, or S (preferably N or O), with the remaining ring atoms being carbon, and the bonding site of the heteroaryl moiety being 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, pyridadinyl, 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 their derivatives. In particular, "N-heteroaryl" means the heteroaryl as defined above, which contains at least one nitrogen atom. The N-heteroaryl bond to the rest of the molecule may be via a nitrogen atom or a carbocyclic atom. Examples of N-heteroaryls include pyridinyl, pyrazinyl, pyridadinyl, and pyrimidinyl.

[0025] The term "heterocycloalkyl" or "heterocyclic" refers to a monocyclic or bicyclic ring system of 4 to 9 ring atoms, which contains 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocycloalkyls include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 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 specifically, heterocycloalkyl means dihydrofuryl, 1,3-dioxolyl, dihydropyryl, dihydrothiophyll, dihydropyrazolyl, dihydroisoxazolyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiadyl, and 1,2,3,4-tetrahydropyradyl.

[0026] The term "therapeutic effective dose" refers to the amount of the compound or molecule of the present invention, when administered to a subject, that (i) treat or prevent a particular disease, symptom, or disorder; (ii) reduce, alleviate, or eliminate one or more symptoms of a particular disease, symptom, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, symptom, or disorder as described herein. The therapeutic effective dose will vary depending on the compound, the medical 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 situation described thereafter may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl group may or may not be present, and that the description includes both cases in which the aryl group is substituted with an alkyl group and cases in which the aryl group is not substituted with an alkyl group.

[0028] The terms “individual” or “subject” refer to mammals. Mammals include, but are not limited to, domesticated animals (e.g., cattle, 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 "compounds of this invention" and "compounds of the present invention" mean the compounds disclosed herein, as well as their stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts).

[0030] If the compounds of the present 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 fall within the scope of the present invention and the specified formulas.

[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 salt" refers to a pharmaceutically acceptable salt with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid) as well as with organic acids of the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid types (e.g., formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid).

[0033] The term "pharmaceutically acceptable base addition salt" means a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, naturally substituted amines, cyclic amines, and substituted amines including basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperidine, piperidine, N-ethylpiperidine, and salts of polyamine resins.

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

[0035] The term “pharmaceutical composition” or “pharmaceutical preparation” (or “preparation”) means a mixture or solution containing a therapeutically effective amount of a medicinal active ingredient together with pharmaceutically acceptable additives, which is used interchangeably and administered to a mammal, such as a human, that requires it.

[0036] The terms “pharmaceutically acceptable additive,” “pharmaceutically acceptable carrier,” and “therapeutically inactive excipient” refer to any pharmaceutically acceptable component in a pharmaceutical composition that is interchangeable and used in the compounding of pharmaceuticals, has no therapeutic activity, and is non-toxic to the target of administration, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants.

[0037] The terms “treating” or “treatment” of a medical condition include suppression of the condition, i.e., cessation of the onset of the condition or its clinical symptoms, or relief of the condition, i.e., temporary or permanent reduction of the condition or its clinical symptoms.

[0038] Compounds that have the same molecular formula but differ in the nature or arrangement of their atomic bonds, or in the spatial arrangement of their atoms, are called "isomers." Isomers with different spatial arrangements of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if one carbon atom is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their chiral center, described by the Kahn-Ingold-Prelogue R / S rule, or by the way the molecule rotates its plane of polarization, and are called dextrorotatory or levorotatory (i.e., (+) isomers or (-) isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0039] Compounds of formula I may have one or more chiral centers or chiral 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 determining stereochemistry and separating stereoisomers are well known in the prior art (see the discussion in Chapter 4 of "Advanced, Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 1992).

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

[0041] The compound of formula I has now been identified as a Mat2A inhibitor and may be used therapeutically for the treatment of cancerous disorders including lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, 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 produce S-adenosylmethionine (SAM), the primary methyl donor in cells, by encoding methionine adenosyltransferase activity. MAT1A is a liver-specific SAM-producing enzyme, while MAT2A is broadly 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. When MAT2B binds to MAT2A, the conformation of MAT2A changes, increasing its affinity for methionine and SAM. The net effect is that when bound to MAT2B, MAT2A is more active at low methionine concentrations but inhibited at high methionine concentrations.

[0043] Loss-of-function mutations in tumor suppressor genes are crucial to the molecular pathogenesis of cancer, yet effective targeting of tumor suppressors has been difficult. This is primarily because direct inhibition of mutated proteins for therapeutic benefit is not possible, and restoring mutated function (e.g., restoring function of mutated p53) has not been feasible to date. Recent clinical successes in inhibiting PARP in BRCA1 / 2 deficiency patients demonstrate that targeting conditional synthetic lethality (CSL) arising from loss-of-function mutations in tumor suppressors is an effective clinical approach to cancer treatment. The CSL relationship is not only effective for tumor suppressors but can also be extended to genes located in the same genetic region as tumor suppressors, and whose deletion in that region would result in loss. Methylthioadenosine phosphorylase (MTAP) is one such gene, located near the tumor suppressor CDKN2A, and is deleted in approximately 15% of all cancers. MTAP deletions occur in approximately 53% of glioblastoma multiforme (GBM), 25% of pancreatic adenocarcinoma (PDAC), 25% of melanoma, 23% of lung squamous cell carcinoma, 20% of head and neck squamous cell carcinoma, and 15% of lung adenocarcinoma, but are not limited to these. In fact, this deletion occurs across multiple manifestations, many of which are areas of high unmet medical need with limited effective therapies. In glioblastoma, the median survival is 14 months, and recent therapy approvals have not significantly extended overall survival (OS), with standard of care (SoC) remaining the same for 10 years. The same is true for the majority of PDAC patients with OS of less than one year. MTAP deletions are truncal events that occur early in tumor development and will likely persist throughout all stages of tumor progression, including metastasis. Therefore, its loss is a change unaffected by tumor heterogeneity, genetic background, or resistance to any approved clinically approved drugs. The CSL relationship identified in relation to MTAP deficiency would symbolize a true vulnerability for multiple tumor manifestations.

[0044] MTAP is located near the tumor suppressor CDKN2A on chromosome 9. When CDKN2A is deleted, MTAP is frequently co-deleted. This deletion is considered a bystander effect and is phenotypic neutral. MTAP is the basis of the intracellular adenine and methionine salvage pathway. The methionine salvage pathway flows into the SAM production pathway, and SAM levels are a major regulator of cancer cell proliferation that must be strictly controlled. This is because large changes in SAM concentration, either elevated or decreased, lead to cell cycle arrest. The importance of SAM levels for cancer growth lies in its central role in protein, DNA, and RNA methylation, which acts as a checkpoint for cellular health; decreased SAM can be read as hypomethylation, and increased SAM as hypermethylation. Cells lacking MTAP accumulate methylthioadenosine (MTA) and decarboxylated SAM (dcSAM) without adversely affecting the levels of any salvage metabolites / products, including SAM. This accumulation imposes new stress on cells where MTA acts as a competitive inhibitor of SAM-dependent responses due to its structural similarity. Loss of MTAP forces cells to adapt to a new MTA / SAM paradigm without the viability loss that MTAP-expressing cells (proficient cells) would not need to address. This adaptation creates a strong dependence in MTAP-deficient cells on methionine adenosyltransferase II alpha-2 (MAT2A), one of the enzymes that produce SAM. This conditioned synthetic lethality (CSL) relationship between MTAP loss and MAT2A dependence was identified in three large-scale shRNA screenings (Marjon Cell Reports 2016, Kryukov Science 2016, and Mavrakis Science 2016).

[0045] Targeting MAT2A through small molecule inhibition would benefit genetically defined patient populations representing many areas with high unmet medical needs.

[0046] The object of the present invention is the use of compounds of formula I or II for the preparation of pharmaceuticals for the treatment, prevention and / or delay of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma multiforme, and mesothelioma, more particularly for the treatment of cancer including lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, the manufacture thereof, and pharmaceuticals based on compounds of formula I according to the present invention.

[0047] A further object of the present invention is all forms of the compound of formula I that are optically pure enantiomers, racemates, or diastereomer mixtures.

[0048] In particular, the present invention relates to compounds of formula I: TIFF0007862408000003.tif64170[In the formula, X 1 is N or CR 3 It is either one of the following; R 1 teeth: - One or more substituents R, more specifically one to three, more specifically one or two substituents 1a (C3-C8) cycloalkyl groups may be substituted with - One or more substituents R, more specifically one to three, more specifically one or two substituents 1b A heteroaryl which may be substituted with - One or more substituents R, more specifically one to three, more specifically one or two substituents 1c Heterocycloalkyl which may be substituted with; or - One or more substituents R, more specifically one to three, more specifically one or two substituents 1d A phenyl which may be substituted with; R 1a , R 1b , R 1c , and R 1dEach of these is independently selected from halogen, oxo, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 2 (C1-C6)alkyl, halo(C1-C6)alkyl, one or more substituents R, more specifically one to three, more specifically one or two substituents R 2a A (C3-C6) cycloalkyl group which may be substituted with one or more substituents R, more specifically one to three, more specifically one or two substituents R 2b A heterocycloalkyl which may be substituted with, or one or more substituents R, more specifically one to three, more specifically one or two substituents R 2c A phenyl which may be substituted with; R 2a , R 2b , and R 2c Each of these is 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, one or more substituents R, more specifically one to three, more specifically one or two substituents R 3f Even if replaced by C 2-7 Forming alkylenes, R 3f Each of these is independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl. and its pharmaceutically acceptable salts.

[0049] In a particular embodiment, the present invention relates to a compound of formula I': TIFF0007862408000004.tif64170[where R 1 and R 2 and R 3 are as defined herein] and its pharmaceutically acceptable salts.

[0050] Furthermore, any embodiment regarding the specific X 1 and R 1 and R 1a and R 1b and R 1c and R 1d and R 2 and R 2a and R 2b and R 2c and R 3 and R 3a and R 3b and R 3c and R 3d and R 3e described herein can be combined with any other embodiment regarding another X 1 and R 1 and R 1a and R 1b and R 1c and R 1d and R 2 and R 2a and R 2b and R 2c and R 3 and R 3a and R 3b and R 3c and R 3d and R 3e described herein.

[0051] A specific embodiment of the present invention relates to a compound of formula I in which X 1 is CR 3 as defined herein.

[0052] A specific embodiment of the present invention relates to a compound of formula I or I' [where R 1 is (C3-C8) cycloalkyl optionally substituted with one substituent R 1a heteroaryl optionally substituted with one R 1b or heteroaryl optionally substituted with one or two R 1cheterocycloalkyl which may be replaced by, or one or two R 1d phenyl which may be replaced by; in particular, R 1 is (C3-C6) cycloalkyl which may be replaced by one R 1a pyridinyl which may be replaced by one R 1b pyrazinyl which may be replaced by one R 1b pyridizanyl which may be replaced by one R 1b thiazolyl which may be replaced by one R 1b 1,3-benzodioxolyl which may be replaced by one R 1c oxazolyl which may be replaced by one R 1c piperidinyl which may be replaced by one R 1c tetrahydrofuranyl which may be replaced by one R 1c tetrahydropyranyl which may be replaced by one R, or one or two R 1c phenyl which may be replaced by; more particularly, R 1d is cyclohexyl which may be replaced by one R 1 pyridinyl which may be replaced by one R 1a pyrazinyl which may be replaced by one R 1b pyridizanyl which may be replaced by one R 1b thiazolyl which may be replaced by one R, 1,3-benzodioxolyl 1b oxazolyl which may be replaced by one R 1b piperidinyl which may be replaced by one R 1c tetrahydrofuranyl which may be replaced by one R 1c tetrahydropyranyl or phenyl which may be replaced by one or two R 1c most particularly, R 1d is pyridinyl which may be replaced by one R, or one or two R 1 is phenyl which may be replaced by; 1b pyridinyl which may be replaced by one R, or one or two R 1dx phenyl which may be replaced by] relates to.

[0053] More specific embodiments of the present invention relate to compounds of formula I, I', or I'' [wherein R 1 is one R 1b A heteroaryl which may be substituted with, or one or two R 1d This concerns phenyl which may be substituted with [a different compound].

[0054] A particular embodiment of the present invention relates to a compound of formula I or I' [wherein R 1a , R 1b , R 1c , and R 1d Each is independently selected from halogen, oxo, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy, in particular, R 1a , R 1b , R 1c , and R 1d Each is independently selected from halogen, oxo, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy, and more specifically, R 1a , R 1b , R 1c , and R 1d Each is independently selected from halogen, oxo, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, and halo(C1-C3)alkyl, and more specifically, R 1a , R 1b , R 1c , and R 1d Each is independently selected from chloro, fluoro, oxo, cyano, methyl, ethyl, methoxy, trifluoromethyl, and difluoromethyl, most specifically, R 1a , R 1b , R 1c , and R 1d [Each of these is independently selected from chloro, fluoro, cyano, methyl, and methoxy.]

[0055] A particular embodiment of the present invention relates to a compound of formula I or I' [wherein R 1b , and R1d Each of these is independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy, in particular, R 1b Each of these is independently selected from halogen, (C1-C3)alkyl, (C1-C3)alkoxy, and halo(C1-C3)alkyl, R 1d Each is independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy, more specifically, R 1b Each is independently selected from chloro, methyl, and methoxy, and R 1d [Each of these is independently selected from fluoro, cyano, methyl, and methoxy.]

[0056] A particular embodiment of the present invention relates to a compound of formula I or I' [wherein 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-oxopiperidine-4-yl, 2-Ethylphenyl, 2-(Difluoromethoxy)phenyl, 5-Methyl-1,3-Oxazole-4-yl, 4-Methyl-1,3-Thiazol-5-yl, 2-Methyloxolan-3-yl, 3-Methyltetrahydrof Lan-2-yl, 3-cyano-2-methylphenyl, oxan-4-yl, 2-methylpyridine-3-yl, 2-oxopiperidine-4-yl, 2-methoxy-3-methylphenyl, 3-chloro-2-methoxyphenyl, 3-cyano-2-methoxyphenyl, oxan-3-yl, 3-methylpyrazine-2-yl, 2-methoxypyridine-3-yl, 2-chloropyridine-3-yl, 2-(trifluoromethyl)pyridine-3-yl, 3-methylpyridazine-4-yl, 3-methyl-1,2-thiazole-4-yl, or 3-methyltetrahydrofuran-2-yl, in particular, R 1This relates to 2-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 2-methylpyridine-3-yl, 3-cyano-2-methoxyphenyl, 2-methoxypyridine-3-yl, 2-chloropyridine-3-yl, or 2-methylphenyl.

[0057] Another embodiment of the present invention relates to a compound of formula I, I', or I'' [wherein R 2 (C1-C6)alkyl, halo(C1-C6)alkyl, one or two substituents R 2a (C3-C6) cycloalkyl, which may be substituted with one or two substituents R 2b A heterocycloalkyl or phenyl which may be substituted with R, in particular R 2 (C1-C3)alkyl, halo(C1-C3)alkyl, one or two substituents R 2a Cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, one or two substituents R may be substituted. 2b Azetidinyl, dihydrofuranyl, dihydropyranyl, azabicyclo[2.2.1]heptanyl, -azabicyclo[2.2.1]heptanyl, pyrrolidinyl, one or two substituents R may be substituted. 2b Azetidinyl or phenyl which may be substituted with R 2 i-butyl, t-butyl, trifluoromethyl, one or two substituents R 2a Cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, one or two substituents R may be substituted. 2b Azetidinyl, 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl, which may be substituted with R 2is cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclohexen-1-yl, azetidinyl, 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl, most specifically R 2 This relates to trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenten-1-yl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2-(trifluoromethyl)cyclopropyl, 2,3-dimethylcyclopropyl, 1-methylcyclopropyl, or 3,4-dihydropyran-6-yl.

[0058] More specific embodiments of the present invention are compounds of formula I or I' [wherein R 2 is a halo(C1-C6)alkyl, with one or two substituents R 2a (C3-C6) cycloalkyl groups which may be substituted with, or one or two substituents R 2b This concerns heterocycloalkyls that may be substituted with [a specific compound].

[0059] Another embodiment of the present invention relates to a compound of formula I, I', or I'' [wherein R 2a , R 2b , and R 2c Each is independently selected from halogen, (C1-C3)alkyl, and halo(C1-C3)alkyl, and in particular, R 2a , R 2b , and R 2c Each is independently selected from fluoro, methyl, and trifluoromethyl, and more specifically, R 2a Each is independently selected from fluoromethyl and trifluoromethyl, and R 2bは Regarding [each being fluoro].

[0060] A particular embodiment of the present invention relates to a compound of formula I or I' [wherein R 2 These are phenyl, 2-methylpropyl, pyrrolidine-1-yl, cyclopropyl, cyclohexen-1-yl, 3,4-dihydro-2-pyran-6-yl, cyclopenten-1-yl, azetidine-1-yl, trifluoromethyl, 3,3-difluoroazetidine-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, and in particular, R 2は The term refers to 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' [wherein R 3 is hydrogen or halogen, and in particular, R 3 R is hydrogen, chloro, or fluoro, and more specifically, 3 This concerns [that is hydrogen].

[0062] The specific compound of formula I of the present invention is selected from the group consisting of the following: (3-amino-6-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone (3-amino-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chlorophenyl)methanone (3-amino-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone [3-amino-6-(cyclohexen-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methoxyphenyl)methanone 2,2,2-trifluoroacetic acid (3-amino-5-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-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-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-5-fluoro-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chlorophenyl)methanone (3-amino-5-fluoro-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-(3,3-difluoroazetidine-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(tert-butyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)(o-tolyl)methanone (3-amino-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)(2-chlorophenyl)methanone (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(1,3-benzodioxol-4-yl)methanone (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methylphenyl)methanone (3-amino-7,7-dimethyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline-1-yl)(2-methoxyphenyl)methanone [3-amino-6-(3,4-dihydro-2H-pyran-6-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-(azetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(3,3-difluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(3,3-difluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-cyclopentylpyrazolo[3,4-b]pyridine-1-yl)-(2-methylphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methylphenyl)methanone (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methylphenyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-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]pyridine-1-yl)(cyclohexyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxycyclohexyl)methanone (3-amino-7-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline-1-yl)(2-methoxyphenyl)methanone (3-amino-6-((trans)-2-fluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(4-fluoro-2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone [3-amino-6-[rac-(1R,2R)-2-(trifluoromethyl)cyclopropyl]pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methoxyphenyl)methanone (3-amino-5-fluoro-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methoxyphenyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(3-fluoro-2-methoxyphenyl)methanone rac-(cis)-4-(3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-carbonyl)-3-methylpiperidine-2-one (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-ethylphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-(difluoromethoxy)phenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(5-methyloxazol-4-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(4-methylthiazole-5-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methyltetrahydrofuran-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-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]pyridine-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-3-yl)methanone 4-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-carbonyl)piperidine-2-one (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxy-3-methylphenyl)methanone (3-amino-6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-3-yl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methyltetrahydrofuran-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-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]pyridine-1-yl)(tetrahydro-2H-pyran-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-methylpyrazine-2-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxypyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chloropyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-(trifluoromethyl)pyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-methylpyridazine-4-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-methylisothiazol-4-yl)methanone [3-amino-6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)((2R,3S)-3-methyltetrahydrofuran-2-yl)methanone [3-amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone

[0063] The specific compound of formula I of the present invention is selected from the group consisting of the following: (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methoxyphenyl)methanone 2,2,2-trifluoroacetic acid (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methylphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methylphenyl)methanone (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(3-fluoro-2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-3-yl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-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]pyridine-1-yl)(2-methoxypyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chloropyridine-3-yl)methanone

[0064] In another embodiment, the present invention provides compounds according to formula I or I' described herein for use as therapeutically active substances.

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

[0066] In another embodiment, the present invention provides the use of compounds according to Formula I or I' described herein for the treatment, prevention and / or delay of progression of cancers, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma multiforme, and mesothelioma, and more particularly lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma, and more specifically for the treatment of these cancers.

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

[0068] In another embodiment, the present invention provides a method for treating, preventing and / or delaying the progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma multiforme, and mesothelioma, more specifically 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 for treating, preventing and / or delaying the progression of cancer, particularly lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma multiforme, and mesothelioma, more specifically 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.

[0070] In particular, Mat2A disorders or Mat2A-related diseases include cancers, especially lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma multiforme, and mesothelioma, more specifically lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0071] In one embodiment, the present application provides a pharmaceutical composition comprising one of the compounds of the above embodiments in a mixture with at least one pharmaceutically acceptable carrier, such as an additive or diluent.

[0072] In another embodiment, the present invention provides the use of compounds of formula I or I' in the preparation of pharmaceuticals for the treatment, prevention and / or delay of the progression of diseases related to Mat2A, more specifically for therapeutic purposes.

[0073] In further embodiments, the present invention provides pharmaceuticals comprising a compound of formula I or I' described herein or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, as well as methods for producing them, which include forming a herbal dosage form with one or more compounds of formula I or I' and / or pharmaceutically acceptable salts thereof and, optionally, one or more other therapeutically valuable substances together with one or more therapeutically inert carriers.

[0074] Other embodiments provide a pharmaceutical composition or pharmaceutically acceptable drug comprising the compound of the present invention, a therapeutically inert carrier, and a diluent or pharmaceutically acceptable additive, as well as a method for preparing such composition and pharmaceutically acceptable drug using the compound of the present invention.

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

[0076] The compounds of the present invention may be administered by any suitable means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, intrathecally, and epidurally, as well as intranasally, and, if desired for topical treatment, intrafocal administration. Parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

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

[0078] Typical formulations are prepared by mixing the compound of the present invention with a pharmaceutically acceptable carrier or excipient. Suitable pharmaceutically acceptable carriers and excipients are well known to those skilled in the art and are described in detail, for example, 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. The pharmaceutically acceptable carrier may be solid or liquid. Examples of solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material. In powders, the carrier is generally a micronized solid, which is a mixture with the micronized active ingredient. In tablets, the active ingredient is generally mixed in an appropriate proportion with a carrier having the required binding ability 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, but are not limited to, include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting-point waxes, and cocoa butter.

[0079] The dosage of the compound of the present invention can vary widely and, naturally, be adapted to the individual requirements of each specific case. Generally, for oral administration, the appropriate daily dose of the compound of formula I or I' per person should be approximately 0.01 to 1000 mg, but this upper limit may be exceeded if necessary.

[0080] An example of a suitable oral dosage form is a tablet containing approximately 100 mg to 500 mg of the compound of the present invention, comprising approximately 30 to 90 mg of anhydrous lactose, approximately 5 to 40 mg of croscarmellose sodium, approximately 5 to 30 mg of polyvinylpyrrolidone (PVP) K30, and approximately 1 to 10 mg of magnesium stearate. The powdered components 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, for example, 10 to 100 mg of the compound of the present invention in a suitable buffer solution, such as phosphate buffer, and optionally adding an isotonic agent (tonicizer), such as a salt like sodium chloride. To remove impurities and contaminants, the solution may be filtered using, for example, a 0.2 μm filter.

[0082] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound according to the present invention as described herein, or a stereoisomer thereof. A further embodiment includes a pharmaceutical composition comprising a compound according to the present invention as described herein, or a stereoisomer thereof, together with a pharmaceutically acceptable carrier or additive.

[0083] The compounds of the present invention can be used alone or in combination with other drugs for the treatment, prevention and / or delay of progression of Mat2A-related diseases, particularly cancers, specifically lung adenocarcinoma, melanoma, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma multiforme, and mesothelioma, more specifically lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, glioblastoma multiforme, and head and neck squamous cell carcinoma.

[0084] Specific embodiments of the present invention relate to a pharmaceutical composition comprising a compound of formula I or I' as described above or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable additives 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 cancer, glioblastoma multiforme, and mesothelioma, and 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 containing the compounds according to the present invention as described herein for use in the treatment, prevention and / or delay of the progression of Mat2A-related diseases, more specifically for therapeutic use.

[0086] In another embodiment, the present invention provides for the production of compounds of formula I or I' described herein.

[0087] The compounds of formula I or I' of the present invention may be prepared by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to react and purify 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] Furthermore, 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. A suitable reaction scheme for the preparation of such compounds is outlined below. The substituents and indices used in the following description of the method have the meanings set forth herein. Further examples can be found in the specific examples detailed below. [Modes for carrying out the invention]

[0089] General scheme More specifically, compounds of formula I or I' and their intermediates can be prepared by scheme 1 or 2 and by the description of specific examples.

[0090] Compounds of formula I or I' [wherein X 1 CR 3 And R 4 H is R 1 , R 2 , and R 3 The subgroups of [as defined above] can be prepared as outlined in Scheme 1 below. Scheme 1 TIFF0007862408000005.tif93170

[0091] Chloropyridine IIa is reacted with excess hydrazine in a polar solvent (e.g., ethanol, ethylene glycol) to form aminopyrazole IIIa (Canadian Journal of Chemistry, 1988, 420). These are then selectively coupled to carboxylic acid IVa using a mild activator (e.g., 1,1'-carbonyldiimidazole) in a polar solvent (e.g., DMF, DMA, NMP) at elevated temperature (80-120°C). Alternatively, pyrazole IIIa can be protected as benzaldehydeimine (VIa) by reacting it with benzaldehyde in ethanol at elevated temperature, then reacted with carboxylic acid IVa, and activated with a more reactive coupling agent (e.g., HATU, TBTU) under basic conditions (e.g., iPr2NEt, Et3N) in a polar solvent (e.g., DMF, DMA) at room temperature or gently heated (50°C) to obtain the protected product VIIa. The imine is readily hydrolyzed under mild acidic conditions (e.g., formic acid or 1N hydrochloric acid) to obtain the final product IIIa.

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

[0093] Alternatively, pyridine IIa can be synthesized by cyclizing intermediate VIIIa with 2-cyanoacetamide using a base (e.g., NaOEt) in a polar solvent such as DMF under increasing temperature, yielding the corresponding hydroxypyridine IXa. Hydroxypyridine IXa can be converted to pyridine Ia using a dehydrating agent such as POCl3 under increasing temperature.

[0094] General procedure General Procedure A: Suzuki-Miyaura type cross coupling 2,6-dihalo-3-nitrile pyridine dissolved in dioxane / water (4:1 ratio, 0.1-0.2 M) was then mixed with K2CO3 or Na2CO3 (3 equivalents), followed by boronic acid or ester (1.5 equivalents). The resulting reaction mixture was subjected to sonication and degassed by bubbling with argon. Pd(dppf)2Cl2·CH2Cl2 complex or palladium tetrakiss (triphenylphosphine) (0.05-0.2 equivalents) was added, and the reaction mixture was heated to 100°C until LCMS showed complete consumption of the pyridine starting material (0.5h-16h). The reaction mixture was then diluted with ethyl acetate, washed with brine, and dried over Na2SO4 to concentrate. The crude product may be purified by 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), DIPEA or TEA (2 equivalents) and a secondary amine (1.1 equivalents) were added. The reaction was stirred at room temperature or at a higher temperature until LC-MS showed complete consumption of the pyridine starting material (maximum 24 hours). The reaction was then diluted with SiO2, washed with brine, dried over Na2SO4, and concentrated. The product may be purified by 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 equivalents) was added, and the reaction mixture was stirred at 70-120°C until LC-MS showed complete consumption of chloropyridine (up to 16 hours). The reaction mixture was concentrated, and the crude product was purified by flash silica gel chromatography or isolated by simply suspending in water and filtering.

[0097] General Procedure D: Pyridone Synthesis To a crude solution of appropriate ene-one VIII in DMF (0.2-0.4 M) (prepared with modifications to the procedure in J.Med.Chem. 2011, 54, 7974-7985), 2-cyanoacetamide (3 equivalents) and NaOEt (3 equivalents) as a base were added. The resulting reaction mixture was heated to 100°C until LCMS showed complete consumption of the starting material VIII (approximately 16 hours). The reaction mixture was then diluted with SiO2, washed with brine, and dried over Na2SO4 to concentrate. The product may be purified by flash silica gel chromatography.

[0098] General Procedure E: Pyridyl Chloride Synthesis Hydroxypyridine was dissolved in POCl3 (10-20 equivalents), and the resulting reaction mixture was heated to 100°C until LC-MS showed complete reaction (approximately 16 hours). The reaction mixture was then concentrated under reduced pressure, diluted with ethyl acetate, and filtered. The organic layer was diluted with water and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude chloropyridine product may be purified by flash silica gel chromatography.

[0099] General procedure F1: Amide coupling with CDI As described in Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, 1088, carbonyldiimidazole (1.5 equivalents) was added to a solution of a suitable carboxylic acid (1.5 equivalents) dissolved in DMF (0.1-0.2 M), and the mixture was stirred at ambient temperature for 0.5-1 hour. Then, the required pyrazolo[3,4-b]pyridine-3-amine (1 equivalent) was added, and the mixture was heated at 100°C-140°C until LCMS showed complete reaction (24-48 hours). The reaction product was then concentrated to dryness and purified by reverse-phase preparative HPLC.

[0100] General Procedure F2: Amide coupling of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium with tetrafluoroborate (TBTU) and benzimine deprotection To a solution of a suitable carboxylic acid (1.1 equivalents) dissolved in DMF (0.1-0.2 M), TBTU (1.1 equivalents) and triethylamine (2 equivalents) were added, followed by (E)-N-(6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-1-phenylmethaneimine (1 equivalent). The mixture was stirred at ambient temperature for 16-48 hours until LC-MS showed complete reaction, or heated to 50°C to accelerate the reaction. Subsequently, 1N hydrochloric acid (aqueous solution) was added dropwise, and the reaction was stirred at ambient temperature for 1 hour. The reaction was then concentrated to dryness and purified by reverse-phase preparative HPLC.

[0101] A particular embodiment of the present invention relates to a compound of formula (I') [wherein X 1 , R 1 , and R 2 The present invention relates to a method for preparing a pharmaceutically acceptable salt thereof as defined herein, as defined herein. The method comprises coupling a compound of formula (III) with carboxylic acid IVa in a polar solvent (e.g., DMF, DMA, NMP) at a rising temperature (80-120°C) using a mild activator (e.g., 1,1'-carbonyldiimidazole) to obtain a compound of formula (I), as shown in Scheme 2. Scheme 2 TIFF0007862408000006.tif65170

[0102] These compounds were examined according to the tests described below.

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

[0104] Recombinant human Mat2a (12.5 nM) and the compound serially diluted in DMSO (concentration range of 10 μM to 508 pM) or control (DMSO) are incubated for 15 minutes at room temperature (RT) in an assay buffer containing 50 mM HEPES (pH 7.5), 50 mM KCl, 50 mM MgCl2, 0.01% Tween 20, and 10 mM DTT. The combined substrates, ATP, and methionine are added to a final concentration of 100 μM each to initiate the reaction. The final assay conditions are 12.5 nM Mat2a, 100 μM ATP and methionine (substrates), and 2% DMSO. After 120 minutes of incubation at RT, the reaction is stopped by adding Biomol Green. The absorption signal is measured at λ=635 nm using a multiplate reader (BMG Pherastar reader or equivalent) after 30 minutes of equilibrium at RT. TIFF0007862408000007.tif251170TIFF0007862408000008.tif255170TIFF0007862408000009.tif255170TIFF0007862408000010.tif31170

[0105] abbreviation The following abbreviations will be used in the experimental section. Ar = argon; nBuLi = n-butyllithium; DCM = Dichloromethane; DIPEA = Diisopropylethylamine; DMSO = Dimethyl sulfoxide; DMF = Dimethylformamide; EtOH = ethanol; alkyl = ethyl acetate; HCl = hydrochloric acid; HPLC = High-Performance Liquid Chromatography; LDA = lysylmucodiisopropylamide; 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-tetramethylaminiumtetrafluoroborate; THF = tetrahydrofuran; TEMPO = 2,2,6,6-tetramethylpiperidinyl oxyl; TBAF = tetra-n-butylammonium fluoride; TLC = Thin-Layer Calculation

[0106] Starting material The 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] intermediate Intermediate 1: 6-phenyl-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000011.tif37170 Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-6-phenylnicotinonitrile (CN106146493A) and hydrazine at 70°C. + Prepared 211.1).

[0108] Intermediate 2: 6-Isobutyl-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000012.tif36170 Process 1: 2-Chloro-6-isobutylnicotinonitrile 2,6-Dichloronicotinonitrile (250 mg, 1.45 mmol) was dissolved in dioxane (5 ml), and 2-methylpropyl zinc bromide (3.47 ml, 0.5 M in THF, 1.73 mmol) was added. The reaction mixture was sparged with argon. Pd(dppf)2Cl2·CH2Cl2 complex (12 mg, 15 μmol) was added, and the reaction mixture was heated in a shielded tube at 90°C for 18 hours. Then, the second portion of 2-methylpropyl zinc bromide (3.47 ml, 0.5 M in THF, 1.73 mmol) and Pd(dppf)2Cl2·CH2Cl2 complex (12 mg, 15 μmol) were added, and the reaction mixture was heated for a further 2 hours at 70°C. The reaction mixture was concentrated to dryness. The residue was purified by flash silica gel chromatography (ethyl acetate:n-heptane 0:1~1:0) to obtain 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]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-6-isobutylnicotinonitrile (step 1) and hydrazine at 70°C. + Prepared 191.3).

[0110] Intermediate 3: 6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000013.tif39170 Process 1: 2-Chloro-6-(pyrrolidine-1-yl)nicotinonitrile Following general procedure B, the title compound ([M+H]) is obtained from 2,6-dichloronicotinonitrile and pyrrrolidine in THF, with DIPEA as the base. + Prepared 208.1).

[0111] Step 2: 6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-6-(pyrrolidine-1-yl)nicotinonitrile (step 1) and hydrazine at 100°C. + 204.2) was prepared and isolated from water by filtration.

[0112] Intermediate 4: 6-(cyclohexen-1-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000014.tif39170 Step 1: 2-Chloro-6-(cyclohexa-1-en-1-yl)nicotinonitrile Following general procedure A, the title compound ([M+H,Cl]) is obtained from 2,6-dichloronicotinonitrile and cyclohexa-1-en-1-ylboronic acid under tetrakis(triphenylphosphine)palladium catalysis at 110°C. + Prepared 219.1).

[0113] Step 2: 6-(cyclohexen-1-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is prepared from 2-chloro-6-(cyclohexa-1-en-1-yl)nicotinonitrile (step 1) and hydrazine at 100°C. + Prepared 215.2).

[0114] Intermediate 5: Cyclopropyl-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000015.tif36170 Following general procedure C, the title compound ([M+H]) is prepared from 2-chloro-6-cyclopropylnicotinonitrile (38041-19-9) and hydrazine at 100°C. + Prepared 175.4).

[0115] Intermediate 6: 5-Fluoro-6-phenyl-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000016.tif43170 Project 1: 2-Chloro-5-fluoro-6-phenylnicotinonitrile According to General Procedure A, from 2,6-dichloro-5-fluoronicotinonitrile and phenylboronic acid, under the Pd(dppf)2Cl2·CH2Cl2 complex catalyst, the title compound ([M+H+MeCN,Cl] + 275.1) was prepared at 90 °C.

[0116] Project 2: 6-(Cyclohexen-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine According to General Procedure C, from 2-chloro-5-fluoro-6-phenylnicotinonitrile (Project 1) and hydrazine, the title compound ([M+H] + 229.3) was prepared at 75 °C.

[0117] Intermediate 7: 5-Fluoro-6-pyrrolidin-1-yl-1H-pyrazolo[3,4-b]pyridin-3-ylamine In ethanol (2 ml), pyrrolidine (124 μl, 0.2 mmol) was added to a solution of 2,6-dichloro-5-fluoro-3-pyridine-carbonitrile (200 mg, 1 mmol), and the reaction mixture was heated at 95 °C for 6 h. The reaction mixture was concentrated, and the residue was redissolved in ethylene glycol (2 ml), and hydrazine monohydrate (0.75 ml, 15.0 mmol) was added. The reaction mixture was heated at 130 °C for 3 h. The reaction mixture was adsorbed onto silica gel and purified by flash silica gel column chromatography (ethyl acetate:n-heptane 0:1~1:0) to obtain 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 TIFF0007862408000018.tif Process 1: 2-Chloro-6-(3,3-difluoroazetidin-1-yl)-5-fluoronicotinonitrile According to General Procedure B, the title compound was prepared from 2,6-dichloro-5-fluoronicotinonitrile and 3,3-difluoroazetidine hydrochloride in DMF using triethylamine as the base. 1 H NMR (DMSO-d6, 300 MHz) δ 8.18 (d, 1H, J = 11.3 Hz), 4.70 (dt, 4H, J = 1.8, 12.4 Hz)

[0119] Process 2: 6-(3,3-Difluoroazetidin-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-amine According to General Procedure C, the title compound ([M+H] + 244.1) was prepared from 2-chloro-5-fluoro-6-phenylnicotinonitrile (Process 1) and hydrazine in ethylene glycol at 120 °C.

[0120] Intermediate 9: 6-(Pyrrolidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-amine TIFF0007862408000019.tif Process 1: 4-Chloro-2-(pyrrolidin-1-yl)pyrimidine-alkyl nitrile According to General Procedure B, the title compound ([M+H,Cl] + 209.1) was prepared from 2,4-dichloropyrimidine-5-carbonitrile and pyrrolidine in THF using DIPEA as the base.

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

[0122] Intermediate 10:6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-amine TIFF0007862408000020.tif34170 Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbonitride and hydrazine at 100°C in ethanol. + Prepared 217.2).

[0123] Intermediate 11: 6-(3,4-dihydro-2H-pyran-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000021.tif48170 Step 1: 2-Chloro-6-(3,4-dihydro-2H-pyran-6-yl)nicotinonitrile Following general procedure A, the title compound ([M+H,Cl]) is obtained from 2,6-dichloro-5-fluoronicotinonitrile and 2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane under tetrakis(triphenylphosphine)palladium catalysis at 90°C. + Prepared 221.1).

[0124] Step 2: 6-(3,4-dihydro-2H-pyran-6-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-6-(3,4-dihydro-2H-pyran-6-yl)nicotinonitrile (step 1) and hydrazine at 100°C in ethanol. + Prepared 217.1).

[0125] Intermediate 12: 6-(cyclopenten-1-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000022.tif48170 Step 1: 2-Chloro-6-(cyclopenta-1-en-1-yl)nicotinonitrile Following general procedure A, the title compound ([M+H,Cl]) is obtained from 2,6-dichloro-5-fluoronicotinonitrile and cyclopenta-1-en-1-ylboronic acid under tetrakis(triphenylphosphine)palladium catalysis at 90°C. + Prepared 205.1).

[0126] Step 2: 6-(cyclopenten-1-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-6-(cyclopenta-1-en-1-yl)nicotinonitrile (step 1) and hydrazine at 100°C in ethanol. + Prepared 201.1).

[0127] Intermediate 13: 6-(azetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000023.tif361706-bromo-1H-pyrazolo[3,4-b]pyridine-3-amine (100 mg, 0.5 mmol) was dissolved in azetidine (0.5 ml, 12.5 mmol) and stirred in a shielded tube at 70°C for 72 hours. The reaction mixture was poured into water, the resulting precipitate was filtered, and the filtrate was allowed to stand for several days to crystallize. The result was purified by filtration to obtain the title compound (12 mg, 13%) as a white solid. ([M+H] + 190.1)

[0128] Intermediate 14: 6-(3,3-difluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000024.tif42170 Process 1::4-Chloro-2-(pyrrolidine-1-yl)pyrimidine-5-carbonitrile Following general procedure B, the title compound ([M+H,Cl]) is prepared from 2,6-dichloronicotinonitrile and 3,3-difluoroazetidine hydrochloride in ethanol with DIPEA as the base. + Prepared 230.0).

[0129] Step 2: 6-(3,3-difluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 4-chloro-2-(pyrrolidine-1-yl)pyrimidine-5-carbonitrile (step 1) and hydrazine at 80°C in ethanol. + Prepared 205.2).

[0130] Intermediate 15: 6-cyclopentyl-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000025.tif381706-(cyclopenta-1-en-1-yl)-1H-pyrazolo[3,4-b]pyridine-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 carbon (6 mg, 6 μmol) was added. The reaction mixture was then stirred at 50°C for 18 hours under a hydrogen balloon atmosphere. The reaction mixture was cooled to ambient temperature, filtered through Dykalite®, and concentrated to obtain the title compound (55 mg, 87%) as a yellow solid. ([M+H] + 203.1)

[0131] Intermediate 16: 6-Cyclobutyl-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000026.tif39170 Step 1: 1-Cyclobutyl-3-(dimethylamino)propa-2-en-1-one To a solution of 1-cyclobutylethane-1-one (2.22 ml, 20.4 mmol) in DMF (5 ml), 1,1-dimethoxy-N,N-dimethylmethaneamine (5.43 ml, 40.8 mmol) and sodium methoxide (50 mg, 0.9 mmol) were added, and the mixture was stirred at 100 °C for 16 hours. At this time, the 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 According to general procedure D, 1-cyclobutyl-3-(dimethylamino)prop-2-en-1-one (step 2) and cyanoacetamide were used to prepare the title compound ([M+H] + 175.1).

[0133] Step 3: 2-Chloro-6-cyclobutylnicotinonitrile According to general procedure E, 6-cyclobutyl-2-hydroxynicotinonitrile (step 2) and POCl3 were used to prepare the title compound ([M+H,Cl]+ 193.0).

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

[0135] Intermediate 17: 6-((1RS,2RS)-2-Methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridin-3-amine TIFF0007862408000027.tif39170 Step 1: 2-Hydroxy-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile Using NaOMe as a base, the 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 method modified from the procedure of J.Med.Chem. 2011, 54, 7974) and 2-cyanoacetamide was used to prepare the title compound ([M+H] + 175.0) (general procedure G).

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

[0137] Step 3: 6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile (step 2) and hydrazine at 75°C in ethanol. + Prepared 189.1).

[0138] Intermediate 18: 6-(2,5-dihydrofuran-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000028.tif37170 Following general procedure A, 6-bromo-1H-pyrazolo[3,4-b]pyridine-3-amine and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane are converted to the title compound ([M+H]) at 110°C under tetrakis(triphenylphosphine)palladium catalysis. + Prepared 203.1).

[0139] Intermediate 19: 7-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline-3-amine TIFF0007862408000029.tif30170 Following general procedure C, the title compound ([M+H]) was obtained from 2-chloro-7-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitride and hydrazine in ethanol at 75°C. + Prepared 203.2).

[0140] Intermediate 20: 6-((1RS,2SR)-2-fluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000030.tif33170 Step 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)propa-2-en-1-one (prepared from 1-(2-fluorocyclopropyl)ethanone by a modified procedure of J.Med.Chem.2011, 54, 7974) (WO2016 / 161960A1,2016)) and 2-cyanoacetamide using NaOMe as a base (general procedure G).

[0141] Step 2: 2-Chloro-6-((1RS,2SR)-2-fluorocyclopropyl)nicotinonitrile Title compound ( 1 ¹H NMR (CHLOROFORM-d, 300MHz) δ values ​​of 7.84 (d, 1H, J=7.9Hz), 7.30 (d, 1H, J=7.9Hz), 4.70-5.20 (m, 1H), 2.40-2.60 (m, 1H), 1.60-1.80 (m, 1H), and 1.50-1.60 (m, 1H) were prepared by the 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]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-6-((1RS,2RS)-2-methylcyclopropyl)nicotinonitrile (step 2) and hydrazine at 75°C in ethanol. + Prepared 193.0).

[0143] Intermediate 21: 6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000031.tif33170 Process 1: 2-Chloro-6-vinylnicotinonitrile Following general procedure A, the title compound ([M+H,Cl]) is obtained from 2,6-dichloronicotinonitrile and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane under the catalysis of a Pd(dppf)2Cl2·CH2Cl2 complex at 100°C. + Prepared 165.0).

[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), trimethyl(trifluoromethyl)silane (112 μL, 0.76 mmol) and NaI (9.2 mg, 0.06 mmol) were added. The reaction mixture was stirred in a shielded tube at 65°C for 2 hours. Further trimethyl(trifluoromethyl)silane (112 μL, 0.76 mmol) and NaI (9.2 mg, 0.06 mmol) were added, and the reaction mixture was stirred for a further 1 hour at 65°C. Then, further trimethyl(trifluoromethyl)silane (112 μL, 0.76 mmol) and NaI (9.2 mg, 0.06 mmol) were added, and the reaction mixture was stirred for a further 3 hours. The reaction was diluted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and brine, dried, and concentrated to (Na2SO4). The title compound (27 mg, 41%) was obtained as a yellow oily substance by flash silica gel chromatography (ethyl acetate:n-heptane 0:1~1:1). ([M+H,Cl] + 215.1)

[0145] Step 3: 6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-6-(2,2-difluorocyclopropyl)nicotinonitrile (step 2) and hydrazine at 100°C in ethanol. + Prepared 211.1).

[0146] Intermediate 22: 6-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000032.tif38170 Step 1: 2-Chloro-6-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]pyridine-3-carbonitrile Following general procedure A, the title compound ([M+H,Cl]) is converted from 2,6-dichloronicotinonitrile and potassium trifluoro((1RS,2RS)-2-(trifluoromethyl)cyclopropyl)borate under butyldi-1-adamantylphosphine / palladium(II) acetate catalyst in toluene / water at 120°C. + 247.0) was prepared. The desired product could not be separated 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]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from chloro-6-[(1RS,2RS)-2-(trifluoromethyl)cyclopropyl]pyridine-3-carbonitrile (step 2) and hydrazine at 100°C in ethanol. + Prepared 243.1).

[0148] Intermediate 23: 6-((1rs,2RS,3SR)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000033.tif41170 Step 1: 6-((1,rs,2RS,3SR)-2,3-dimethylcyclopropyl)-2-hydroxynicotinonitrile Using NaOMe as a base, the title compound ([M+H]) is obtained by the reaction of (E)-3-(dimethylamino)-1-((2RS,3SR)-2,3-dimethylcyclopropyl)propa-2-en-1-one (prepared from 1-[rac-(2R,3S)-2,3-dimethylcyclopropyl]ethanone (J. Org. Chem. 1978, 3422) by a modified procedure of J. Med. Chem. 2011, 54, 7974) and 2-cyanoacetamide. + Prepared (General Procedure G) (189.1).

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

[0150] Step 3: 6-((1rs,2RS,3SR)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-6-((1rs,2RS,3SR)-2,3-dimethylcyclopropyl)nicotinonitrile (step 2) and hydrazine at 75°C in ethanol. + Prepared 203.1).

[0151] Intermediate 24: 6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000034.tif51170 Step 1: 2-Hydroxy-6-(1-methylcyclopropyl)nicotinonitrile Using NaOMe as a base, the title compound ([M+H]) is obtained by the reaction of (E)-3-(dimethylamino)-1-(1-methylcyclopropyl)propa-2-en-1-one (prepared from Chem. Berichte, 1981, 3831) and 2-cyanoacetamide in a modified manner from the procedure in J. Med. Chem. 2011, 54, 7974. + Prepared (General Procedure G) (189.1).

[0152] Step 2: 2-Chloro-6-(1-methylcyclopropyl)nicotinonitrile The title compound (¹H NMR (CHLOROFORM-d, 300MHz) 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]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 2-chloro-6-(1-methylcyclopropyl)nicotinonitrile (step 2) and hydrazine at 75°C in ethanol. + Prepared 189.1).

[0154] Intermediate 25: 6-(3-azabicyclo[2.2.1]heptan-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine TIFF0007862408000035.tif43170 Step 1: 6-(3-azabicyclo[2.2.1]heptan-3-yl)-2-chloropyridine-3-carbonitrile Following general procedure B, the title compound ( 1¹H NMR (400MHz, DMSO-d6) δ=7.93-7.71 (m,2H), 6.72 (br d,J=8.8Hz,1H), 6.37 (br d,J=8.8Hz,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=9.6Hz,1H), 2.70-2.61 (m,2H), 1.76-1.62 (m,6H), 1.57-1.35 (m,6H)) were prepared from 2,6-dichloronicotinonitrile and 3-azabicyclo[2.2.1]heptane in THF with TEA as the base.

[0155] Step 2: 6-(3-azabicyclo[2.2.1]heptan-3-yl)-1H-pyrazolo[3,4-b]pyridine-3-amine Following general procedure C, the title compound ([M+H]) is obtained from 6-(3-azabicyclo[2.2.1]heptan-3-yl)-2-chloropyridine-3-carbonitrile (step 1) and hydrazine at 80°C in ethanol. + Prepared 205.2).

[0156] Intermediate 26: [3-amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone TIFF0007862408000036.tif45170 Step 1: 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-chloropyridine-3-carbonitrile Following general procedure B, the title compound ( 1 ¹H NMR (400MHz, DMSO-d6) δ=8.01 (d,J=1.3Hz,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 the base.

[0157] Step 2: [3-amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone Following general procedure C, the title compound ( 1 ¹H NMR (400MHz, DMSO-d6) δ = 11.47-11.24 (m, 1H), 7.84-7.68 (m, 1H), 6.52 (d, J = 8.8Hz, 1H), 5.26-5.08 (s, 2H), 4.61-4.35 (s, 2H), 1.71-1.60 (m, 4H), 1.50-1.37 (m, 4H)) was prepared from 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-chloropyridine-3-carbonitrile (Step 1) and hydrazine at 80°C in ethanol.

[0158] Intermediate 27: (3RS,4RS)-3-methyl-2-oxopiperidine-4-carboxylic acid TIFF0007862408000037.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. The reaction mixture was stirred under a hydrogen (balloon) atmosphere for 72 hours. The reaction mixture was filtered with Hyflo®, thoroughly washed with MeOH, and concentrated to obtain 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]pyridine-3-yl)-1-phenylmethanymine TIFF0007862408000038.tif541706-Cyclopropyl-1H-pyrazolo[3,4-b]pyridine-3-amine (intermediate 5) (200 mg, 1.15 mmol) was suspended in EtOH (4 ml) and benzaldehyde (0.13 ml, 1.26 mmol) was added. The mixture was heated at 80°C for 1 hour. The reaction was cooled to ambient temperature, and the title product was isolated as an off-white solid by filtration (309 mg, quant.). 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] Examples TIFF0007862408000039.tif220170TIFF0007862408000040.tif208170TIFF0007862408000041.tif230170TIFF00078624080 00042.tif223170TIFF0007862408000043.tif250170TIFF0007862408000044.tif247170TIFF0007862408000045.tif215170 TIFF0007862408000046.tif215170TIFF0007862408000047.tif238170TIFF0007862408000048.tif252170TIFF00078624080 00049.tif240170TIFF0007862408000050.tif245170TIFF0007862408000051.tif238170TIFF0007862408000052.tif245170 TIFF0007862408000053.tif243170TIFF0007862408000054.tif238170TIFF0007862408000055.tif252170TIFF00078624080 00056.tif247170TIFF0007862408000057.tif252170TIFF0007862408000058.tif230170TIFF0007862408000059.tif252170 TIFF0007862408000060.tif215170TIFF0007862408000061.tif252170TIFF0007862408000062.tif223170TIFF00078624080 00063.tif252170TIFF0007862408000064.tif208170TIFF0007862408000065.tif250170TIFF0007862408000066.tif223170

[0161] Aspects of the present invention: 1. Compounds of formula I: TIFF0007862408000067.tif64170[In the formula, X 1 is N or CR3 It is either one of the following; R 1 teeth: - One or more substituents R, more specifically one to three, more specifically one or two substituents 1a (C3-C8) cycloalkyl groups may be substituted with - One or more substituents R, more specifically one to three, more specifically one or two substituents 1b A heteroaryl which may be substituted with - One or more substituents R, more specifically one to three, more specifically one or two substituents 1c A heterocycloalkyl which may be substituted with; or - One or more substituents R, more specifically one to three, more specifically one or two substituents 1d A phenyl which may be substituted with; R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from halogen, oxo, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 2 (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, one or more substituents R, more specifically one to three, more specifically one or two substituents R 2a A (C3-C6) cycloalkyl group which may be substituted with one or more substituents R, more specifically one to three, more specifically one or two substituents R 2b A heterocycloalkyl which may be substituted with, or one or more substituents R, more specifically one to three, more specifically one or two substituents R 2c A phenyl which may be substituted with; R 2a , R2b , and R 2c Each of these is 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, one or more substituents R, more specifically one to three, more specifically one or two substituents R 3f Even if replaced by C 2-7 Forming alkylenes, R 3f Each of these is independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl. and its pharmaceutically acceptable salts.

[0162] 2. Compound of formula I': TIFF0007862408000068.tif64170[where, R 1 teeth: - One or more substituents R, more specifically one to three, more specifically one or two substituents 1a (C3-C8) cycloalkyl groups may be substituted with - One or more substituents R, more specifically one to three, more specifically one or two substituents 1b A heteroaryl which may be substituted with - One or more substituents R, more specifically one to three, more specifically one or two substituents 1c Heterocycloalkyl which may be substituted with; or - One or more substituents R, more specifically one to three, more specifically one or two substituents 1d A phenyl which may be substituted with; R 1a , R 1b , R 1c , and R 1dEach of these is independently selected from halogen, oxo, cyano, hydroxyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, heteroaryl, heterocycloalkyl, and phenyl; R 2 (C1-C6)alkyl, halo(C1-C6)alkyl, one or more substituents R, more specifically one to three, more specifically one or two substituents R 2a A (C3-C6) cycloalkyl group which may be substituted with one or more substituents R, more specifically one to three, more specifically one or two substituents R 2b A heterocycloalkyl which may be substituted with, or one or more substituents R, more specifically one to three, more specifically one or two substituents R 2c A phenyl which may be substituted with; R 2a , R 2b , and R 2c Each of these is 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, one or more substituents R, more specifically one to three, more specifically one or two substituents R 3f Even if replaced by C 2-7 Forming alkylenes, R 3f Each of these is independently selected from halogen, (C1-C6)alkyl, and halo(C1-C6)alkyl. The compound according to Embodiment 1, as well as a pharmaceutically acceptable salt thereof.

[0163] 3. X 1 CR3 The compound described in Embodiment 1.

[0164] 4. R 1 However, one substituent R 1a (C3-C8) cycloalkyl, one R may be substituted 1b A heteroaryl which may be substituted with one or two R 1c A heterocycloalkyl which may be substituted with, or one or two R 1d The compound according to any one of embodiments 1 to 3, which is a phenyl that may be substituted with [a specific compound].

[0165] 5. R 1 However, one R 1a (C3-C6) cycloalkyl groups may be substituted with one R 1b Pyridinyl may be substituted with one R 1b Pyrazinyl may be substituted with one R 1b Pyridizanyl may be substituted with one R 1b Thiazolyl may be substituted with one R 1c 1,3-benzodioxolyl, which may be substituted with one R 1c Oxazolyl may be substituted with one R 1c Piperidinyl may be substituted with one R 1c Tetrahydrofuranyl may be substituted with one R 1c Tetrahydropyranyl which may be substituted with, or one or two R 1d The compound according to any one of embodiments 1 to 4, which is a phenyl that may be substituted with a phenyl compound.

[0166] 6. R 1 However, one R 1a Even if substituted with cyclohexyl, one R 1b Pyridinyl may be substituted with one R 1b Pyrazinyl may be substituted with one R 1b Pyridizanyl may be substituted with one R1b Thiazolyl, 1,3-benzodioxolyl, one R may be substituted. 1c Oxazolyl may be substituted with one R 1c Piperidinyl may be substituted with one R 1c Tetrahydrofuranyl, which may be substituted with one or two R 1d The compound according to any one of embodiments 1 to 5, which is tetrahydropyranyl or phenyl that may be substituted with tetrahydropyranyl.

[0167] 7. In most detail, R 1 However, one R 1b Pyridinyl which may be substituted with, or one or two R 1d The compound according to any one of embodiments 1 to 6, which is a phenyl that may be substituted with [a specific compound].

[0168] 8. R 1 However, one R 1b A heteroaryl which may be substituted with, or one or two R 1d The compound according to any one of embodiments 1 to 4, which is a phenyl that may be substituted with [a specific compound].

[0169] 9. R 1a , R 1b , R 1c , and R 1d The compound according to any one of embodiments 1 to 8, wherein each is 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 1dThe compound according to any one of embodiments 1 to 9, wherein each is 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 The compound according to any one of embodiments 1 to 10, wherein each 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 The compounds according to any one of embodiments 1 to 11, each independently selected from chloro, fluoro, cyano, methyl, and methoxy.

[0173] 13. R 1b , and R 1d The compound according to any one of embodiments 1 to 10, wherein each is independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy.

[0174] 14. R 1b However, each is independently selected from halogen, (C1-C3)alkyl, (C1-C3)alkoxy, and halo(C1-C3)alkyl, R 1d The compound according to any one of embodiments 1 to 10, wherein each is independently selected from halogen, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkyl, and halo(C1-C3)alkoxy.

[0175] 15. R 1bHowever, each is independently selected from chloro, methyl, and methoxy, R 1d The compound according to any one of embodiments 1 to 10, wherein each is independently selected from fluoro, cyano, methyl, and methoxy.

[0176] 16. R 1 However, 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-oxopiperidine-4-yl, 2-ethylphenyl, 2-(difluoromethoxy)phenyl, 5-methyl-1,3-oxazole-4-yl, 4-methyl-1,3-thiazole-5-yl, 2-methyloxolan-3-yl, 3-methyltetrahydrofuran-2-yl, The compound according to any one of embodiments 1 to 15, which is 3-cyano-2-methylphenyl, oxan-4-yl, 2-methylpyridine-3-yl, 2-oxopiperidine-4-yl, 2-methoxy-3-methylphenyl, 3-chloro-2-methoxyphenyl, 3-cyano-2-methoxyphenyl, oxan-3-yl, 3-methylpyrazine-2-yl, 2-methoxypyridine-3-yl, 2-chloropyridine-3-yl, 2-(trifluoromethyl)pyridine-3-yl, 3-methylpyridazine-4-yl, 3-methyl-1,2-thiazole-4-yl, or 3-methyltetrahydrofuran-2-yl.

[0177] 17. R 1 The compound according to any one of embodiments 1 to 16, wherein the compound is 2-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 2-methylpyridine-3-yl, 3-cyano-2-methoxyphenyl, 2-methoxypyridine-3-yl, 2-chloropyridine-3-yl, or 2-methylphenyl.

[0178] 18. R 2However, (C1-C6)alkyl, halo(C1-C6)alkyl, one or two substituents R 2a (C3-C6) cycloalkyl, which may be substituted with one or two substituents R 2b The compound according to any one of embodiments 1 to 17, which is a heterocycloalkyl or phenyl compound that may be substituted with a phenyl compound.

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

[0180] 20. R 2 However, i-butyl, t-butyl, trifluoromethyl, one or two substituents R 2a Cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, one or two substituents R may be substituted. 2b The compound according to any one of embodiments 1 to 19, which is azetidinyl, 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl, which may be substituted with.

[0181] twenty one. R 2 However, halo(C1-C6)alkyl, one or two substituents R 2a (C3-C6) cycloalkyl groups which may be substituted with, or one or two substituents R 2bThe compound according to any one of embodiments 1 to 17, which is a heterocycloalkyl that may be substituted with [a specific compound].

[0182] twenty two. R 2a , R 2b , and R 2c The compound according to any one of embodiments 1 to 21, wherein each is independently selected from halogen, (C1-C3)alkyl, and halo(C1-C3)alkyl.

[0183] twenty three. R 2a , R 2b , and R 2c The compound according to any one of embodiments 1 to 22, wherein each is independently selected from fluoromethyl and trifluoromethyl.

[0184] twenty four. R 2a However, each is independently selected from fluoromethyl and trifluoromethyl, R 2b A compound according to any one of embodiments 1 to 23, wherein each of the elements is fluoro.

[0185] twenty five. R 2 The compound according to any one of embodiments 1 to 24, wherein the compound is cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclohexen-1-yl, azetidinyl, 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl.

[0186] 26. R 2The compound according to any one of embodiments 1 to 25, wherein the compound is trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenten-1-yl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2-(trifluoromethyl)cyclopropyl, 2,3-dimethylcyclopropyl, 1-methylcyclopropyl, or 3,4-dihydropyran-6-yl.

[0187] 27. R 2 The compound according to any one of embodiments 1 to 26, wherein the compound is phenyl, 2-methylpropyl, pyrrolidine-1-yl, cyclopropyl, cyclohexen-1-yl, 3,4-dihydro-2-pyran-6-yl, cyclopenten-1-yl, azetidine-1-yl, trifluoromethyl, 3,3-difluoroazetidine-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 embodiments 1 to 26, wherein the compound is cyclopropyl, cyclopenten-1-yl, trifluoromethyl, or cyclobutyl, 2,5-dihydrofuran-3-yl.

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

[0190] 30. R 3 The compound according to any one of embodiments 1 to 29, wherein the compound is hydrogen, chloro, or fluoro.

[0191] 31. R 3A compound according to any one of embodiments 1 to 30, wherein the compound 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]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chlorophenyl)methanone (3-amino-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone [3-amino-6-(cyclohexen-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methoxyphenyl)methanone 2,2,2-trifluoroacetic acid (3-amino-5-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-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-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-5-fluoro-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chlorophenyl)methanone (3-amino-5-fluoro-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-(3,3-difluoroazetidine-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(tert-butyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)(o-tolyl)methanone (3-amino-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)(2-chlorophenyl)methanone (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(1,3-benzodioxol-4-yl)methanone (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methylphenyl)methanone (3-amino-7,7-dimethyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline-1-yl)(2-methoxyphenyl)methanone [3-amino-6-(3,4-dihydro-2H-pyran-6-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-(azetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(3,3-difluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(3,3-difluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-cyclopentylpyrazolo[3,4-b]pyridine-1-yl)-(2-methylphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methylphenyl)methanone (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methylphenyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-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]pyridine-1-yl)(cyclohexyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxycyclohexyl)methanone (3-amino-7-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline-1-yl)(2-methoxyphenyl)methanone (3-amino-6-((trans)-2-fluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(4-fluoro-2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone [3-amino-6-[rac-(1R,2R)-2-(trifluoromethyl)cyclopropyl]pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methoxyphenyl)methanone (3-amino-5-fluoro-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methoxyphenyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(3-fluoro-2-methoxyphenyl)methanone rac-(cis)-4-(3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-carbonyl)-3-methylpiperidine-2-one (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-ethylphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-(difluoromethoxy)phenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(5-methyloxazol-4-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(4-methylthiazole-5-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methyltetrahydrofuran-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-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]pyridine-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-3-yl)methanone 4-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-carbonyl)piperidine-2-one (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxy-3-methylphenyl)methanone (3-amino-6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-3-yl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methyltetrahydrofuran-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-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]pyridine-1-yl)(tetrahydro-2H-pyran-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-methylpyrazine-2-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxypyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chloropyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-(trifluoromethyl)pyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-methylpyridazine-4-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-methylisothiazol-4-yl)methanone [3-amino-6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)((2R,3S)-3-methyltetrahydrofuran-2-yl)methanone [3-amino-6-(7-azabicyclo[2.2.1]heptan-7-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone A compound according to any one of embodiments 1 to 30, selected from the group consisting of the following.

[0193] 33. below: (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methoxyphenyl)methanone 2,2,2-trifluoroacetic acid (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methylphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methylphenyl)methanone (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(3-fluoro-2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-3-yl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-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]pyridine-1-yl)(2-methoxypyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chloropyridine-3-yl)methanone A compound according to any one of embodiments 1 to 30, selected from the group consisting of the following.

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

[0195] 35. A pharmaceutical composition comprising a compound of formula I or I' described in any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives.

[0196] 36. A compound of formula I or I' according to any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0197] 37. Compounds of formula I or I' according to any one of embodiments 1 to 33, or pharmaceutically acceptable salts thereof, for use in 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 cancer, glioblastoma multiforme, and mesothelioma.

[0198] 38. The 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, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma multiforme, and mesothelioma, comprising administering a compound of formula I described in any one of embodiments 1 to 33 of the above-mentioned model, or a pharmaceutically acceptable salt thereof, to the subject.

[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. Use of a compound of formula I described in any one of embodiments 1 to 33 or a pharmaceutically acceptable salt thereof 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 cancer, glioblastoma multiforme, and mesothelioma.

[0202] 42. Use of the 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 pharmaceutically acceptable salt thereof, as described in any one of embodiments 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 cancer, glioblastoma multiforme, and mesothelioma.

[0204] 44. Use of the 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. Compound of formula I: [In the formula, X １ is N or CR ３ It is either one of the following; R １ teeth: - One or more substituents R １ａ It may be replaced with (C ３ -C ８ ) Cycloalkyl, - One or more substituents R １ｂ A heteroaryl which may be substituted with - One or more substituents R １ｃ A heterocycloalkyl which may be substituted with, - phenyl optionally substituted by one or more substituents R １ｄ ; and R １ａ , R １ｂ , R １ｃ , and R １ｄ These are, independently, halogen, oxo, cyano, hydroxyl, and (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 is, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy, Halo (C １ -C ６ ) alkyl, halo(C １ -C ６ ) Alkyl, one or more substituents R ２ａ It may be replaced with (C ３ -C ６ ) Cycloalkyl, one or more substituents R ２ｂ A heterocycloalkyl group which may be substituted with, or one or more substituents R ２ｃ A phenyl which may be substituted with; R ２ａ , R ２ｂ , and R ２ｃ These are, independently, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy, Halo (C １ -C ６ ) alkyl, and halo(C １ -C ６ ) Selected from alkoxy; R ３ is hydrogen, halogen, or (C １ -C ６ ) is alkyl; Or, R ２ , and R ３ Together, one or more substituents R ３ｆ C may be replaced with ２－７ Forming alkylenes, R ３ｆ These are, independently, halogen, (C １ -C ６ ) alkyl, halo(C １ -C ６ ) Selected from alkyl groups] or a pharmaceutically acceptable salt thereof.

2. The compound is the compound of formula I': [In the formula, R １ teeth: - One or more substituents R １ａ It may be replaced with (C ３ -C ８ ) Cycloalkyl, - One or more substituents R １ｂ A heteroaryl which may be substituted with - One or more substituents R １ｃ A heterocycloalkyl which may be substituted with, - One or more substituents R １ｄ A phenyl which may be substituted with; R １ａ 、 R １ｂ 、 R １ｃ 、 and R １ｄ are each independently selected from 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 ) alkoxy-(C ６ -C １ ) alkyl, heteroaryl, heterocycloalkyl, and phenyl;​​ R ２ is, (C １ -C ６ ) alkyl, halo(C １ -C ６ ) alkyl, one or more substituents R ２ａ It may be replaced with (C ３ -C ６ ) Cycloalkyl, one or more substituents R ２ｂ A heterocycloalkyl group which may be substituted with, or one or more substituents R ２ｃ A phenyl which may be substituted with; R ２ａ , R ２ｂ , and R ２ｃ These are, independently, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy, Halo (C １ -C ６ ) alkyl, and halo(C １ -C ６ ) Selected from alkoxy; R ３ is hydrogen, halogen, or (C １ -C ６ ) is alkyl; Or, R ２ , and R ３ Together, one or more substituents R ３ｆ C may be replaced with ２－７ Forming alkylenes, R ３ｆ These are, independently, halogen, (C １ -C ６ ) alkyl, and halo(C １ -C ６ ) Selected from alkyl groups] The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. X １ CR ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ However, one R １ａ A cyclohexyl which may be substituted with one R １ｂ Pyridinyl which may be substituted with one R １ｂ Pyrazinyl which may be substituted with one R １ｂ Pyridizanil may be substituted with one R １ｂ Thiazolyl, 1,3-benzodioxolyl, one R may be substituted. １ｃ Oxazolyl may be substituted with one R １ｃ Piperidinyl may be substituted with one R １ｃ Tetrahydrofuranyl which may be substituted with one or two R １ｄ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is tetrahydropyranyl or phenyl, which may be substituted with tetrahydropyranyl or phenyl.

5. R １ａ , R １ｂ , R １ｃ , and R １ｄ However, each is independently selected from chloro, fluoro, cyano, methyl, and methoxy, and is a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. R １ｂ , and R １ｄ However, each is independent of halogen, cyano, (C １ -C ３ ) alkyl, (C １ -C ３ ) Alkoxy, Halo (C １ -C ３ ) alkyl, and halo(C １ -C ３ ) A compound according to any one of claims 1 to 4, selected from alkoxys, or a pharmaceutically acceptable salt thereof.

7. R １ｂ However, each is independent of halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) Alkoxy and halo(C １ -C ３ ) Selected from alkyl, R １ｄ However, each is independent of halogen, cyano, (C １ -C ３ ) alkyl, (C １ -C ３ ) Alkoxy, Halo (C １ -C ３ ) alkyl, and halo(C １ -C ３ ) A compound according to any one of claims 1 to 6, selected from alkoxys, or a pharmaceutically acceptable salt thereof.

8. R １ｂ However, each is independently selected from chloro, methyl, and methoxy, R １ｄ However, each is independently selected from fluoro, cyano, methyl, and methoxy compounds or pharmaceutically acceptable salts thereof according to any one of claims 1 to 7.

9. R １ However, 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-oxopiperidine-4-yl, 2-ethylphenyl, 2-(difluoromethoxy)phenyl, 5-methyl-1,3-oxazole-4-yl, 4-methyl-1,3-thiazole-5-yl, 2-methyloxolan-3-yl, 3-methyltetrahydrofuran-2-yl, 3-cyano-2- A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is methylphenyl, oxan-4-yl, 2-methylpyridine-3-yl, 2-oxopiperidine-4-yl, 2-methoxy-3-methylphenyl, 3-chloro-2-methoxyphenyl, 3-cyano-2-methoxyphenyl, oxan-3-yl, 3-methylpyrazine-2-yl, 2-methoxypyridine-3-yl, 2-chloropyridine-3-yl, 2-(trifluoromethyl)pyridine-3-yl, 3-methylpyridazine-4-yl, 3-methyl-1,2-thiazole-4-yl, or 3-methyltetrahydrofuran-2-yl.

10. R １ The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein the compound is 2-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 2-methylpyridine-3-yl, 3-cyano-2-methoxyphenyl, 2-methoxypyridine-3-yl, 2-chloropyridine-3-yl, or 2-methylphenyl.

11. R ２ But, Hello (C １ -C ６ ) alkyl, one or two substituents R ２ａ It may be replaced with (C ３ -C ６ ) Cycloalkyl, or one or two substituents R ２ｂ A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, which is a heterocycloalkyl which may be substituted with.

12. R ２ａ However, each is independently selected from fluoromethyl and trifluoromethyl, R ２ｂ A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein each of the elements is fluoro.

13. R ２ The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclohexen-1-yl, azetidinyl, 2,5-dihydrofuran-3-yl, 3,4-dihydropyran-6-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, pyrrolidinyl, or phenyl.

14. R ２ The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein the compound is phenyl, 2-methylpropyl, pyrrolidine-1-yl, cyclopropyl, cyclohexen-1-yl, 3,4-dihydro-2-pyran-6-yl, cyclopenten-1-yl, azetidine-1-yl, trifluoromethyl, 3,3-difluoroazetidine-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.

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

16. R ３ A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

17. The compound, (3-amino-6-phenyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-isobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chlorophenyl)methanone (3-amino-6-(pyrroridine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone [3-amino-6-(cyclohexen-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methoxyphenyl)methanone 2,2,2-trifluoroacetic acid (3-amino-5-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-5-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-5-fluoro-6-phenyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-5-fluoro-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-5-fluoro-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chlorophenyl)methanone (3-amino-5-fluoro-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-(3,3-difluoroazetidine-1-yl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(tert-butyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)(o-tolyl)methanone (3-amino-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)(2-chlorophenyl)methanone (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(1,3-benzodioxol-4-yl)methanone (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methylphenyl)methanone (3-amino-7,7-dimethyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline-1-yl)(2-methoxyphenyl)methanone [3-amino-6-(3,4-dihydro-2H-pyran-6-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-(azetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-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-difluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(3,3-difluoroazetidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-cyclopentylpyrazolo[3,4-b]pyridine-1-yl)-(2-methylphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methylphenyl)methanone (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methylphenyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2,3-dimethylphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(cyclohexyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxycyclohexyl)methanone (3-amino-7-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline-1-yl)(2-methoxyphenyl)methanone (3-amino-6-((trans)-2-fluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(4-fluoro-2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-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]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methoxyphenyl)methanone (3-amino-5-fluoro-6-(pyrrolidine-1-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-fluoro-2-methoxyphenyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(3-fluoro-2-methoxyphenyl)methanone rac-(cis)-4-(3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-carbonyl)-3-methylpiperidine-2-one (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-ethylphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-(difluoromethoxy)phenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(5-methyloxazole-4-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(4-methylthiazole-5-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methyltetrahydrofuran-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-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]pyridine-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-3-yl)methanone 4-(3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-carbonyl)piperidine-2-one (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxy-3-methylphenyl)methanone (3-amino-6-(1-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-3-yl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methyltetrahydrofuran-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-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]pyridine-1-yl)(tetrahydro-2H-pyran-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-methylpyrazine-2-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxypyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chloropyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-(trifluoromethyl)pyridine-3-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-methylpyridazine-4-yl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(3-methylisothiazol-4-yl)methanone [3-amino-6-[(1R,4S)-3-azabicyclo[2.2.1]heptan-3-yl]pyrazolo[3,4-b]pyridine-1-yl]-(2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-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]pyridine-1-yl]-(2-methoxyphenyl)methanone A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

18. The compound, (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methoxyphenyl)methanone 2,2,2-trifluoroacetic acid (3-amino-6-cyclopropylpyrazolo[3,4-b]pyridine-1-yl)-(2-methylphenyl)methanone [3-amino-6-(cyclopenten-1-yl)pyrazolo[3,4-b]pyridine-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]pyridine-1-yl]-(2-methylphenyl)methanone (3-amino-6-cyclobutyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(o-tolyl)methanone (3-amino-6-((1RS,2RS)-2-methylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone (3-amino-6-((1r,2R,3S)-2,3-dimethylcyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methoxyphenyl)methanone [3-amino-6-(2,5-dihydrofuran-3-yl)pyrazolo[3,4-b]pyridine-1-yl]-(3-fluoro-2-methoxyphenyl)methanone (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-3-yl)methanone (3-amino-6-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-methylpyridine-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]pyridine-1-yl)(2-methoxypyridine-3-yl)methanone, and (3-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-1-yl)(2-chloropyridine-3-yl)methanone A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives.

20. A pharmaceutical agent 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 cancer, glioblastoma multiforme, and mesothelioma, comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

21. The pharmacopoeia according to claim 20, 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.

22. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically 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 cancer, glioblastoma multiforme, and mesothelioma.

23. The use according to claim 22 for the preparation of a pharmacopoeia 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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