Estrogen-related receptor alpha (ERRα) modulators

Abstract

The present invention is directed to compounds according to Formula I below, or a pharmaceutically acceptable salt thereof, which can be used as modulators of estrogen-related receptor alpha (ERRα) and have utility in the treatment of ERRα-mediated diseases or conditions. JPEG2022538363000213.jpg90170

Description

[Background technology]

[0001] Estrogen-related receptor alpha (ERRα) is a 45.5 kilodalton (kDa), 423 amino acid residue protein that belongs to the nuclear receptor (NR) superfamily. This nuclear receptor family is composed of 48 genes that encode DNA-binding transcription factors involved in the regulation of diverse functions, including homeostasis, reproduction, development, and metabolism, among others. The ERR family, i.e., the NR3B subgroup, is composed of ERRα, ERR-β, and ERR-γ: to date, no endogenous ligands have been identified for any of the ERR isoforms, and therefore they are considered orphan receptors.

[0002] In Bookout et al., Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network, Cell. 126:789-99 (2006), organism-wide expression profiling of the three ERR isoforms determined that ERRα is widely distributed, with significant protein expression in most adult tissues. Knockout studies of ERR family members revealed that each receptor has a tissue- and function-specific metabolic phenotype that is important for adaptation to energy stress at the systemic level. Knockout studies also showed limited in vivo compensation among ERR family members. Notably, Tremblay et al., The NR3B subgroup: an overview, Nuclear receptor signaling, 5:e009 (2007) may be noted in this context.

[0003] Genomic studies have shown that ERRα regulates a large number of genes. The following references are informative in this regard: Puigserver et al., A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis, Cell. 92(6):829-839 (1998); Yoon et al., Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1, Nature 413 (6852):131-138 (2001); Huss et al., Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor at signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle, Mol. Cell Biol. 24(20):9079-9091 (2004); and Mootha et al., ERRα and Gabpa / b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle, Proc. Natl. Acad. Sci. USA, 101(17):6570-6575 (2004).

[0004] These references support a physiological model of ERRα function in the regulation of energy metabolism, particularly in the transcriptional regulation of genes required for mitochondrial biogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, and lipid metabolism. In particular, ERRα induces the expression of Nuclear Respiratory Factor 1 (NRF1), GA-binding protein alpha (GABPα), and Peroxisome Proliferator-activated Receptor alpha (PPARα). The nuclear receptor coactivators Peroxisome Proliferator-activated Receptor gamma coactivator 1-alpha (PGC-1α), PGC-1β, and Peroxisome Proliferator-activated Receptor gamma Coactivator-related protein 1 (PPRC-1) are involved in the regulation of these genes and in the autoregulation of ERRα expression. PGC-1α is expressed at low basal levels but is induced by fasting and other metabolic stresses. PGC-1β, a related coactivator, has a similar function, but its expression may be less rapidly regulated by fluctuations in energy demand. Conversely, co-repressors that bind to ERR, such as the corepressor Receptor Interacting Protein 140 (RIP140), compete with ERR coactivators to negatively regulate ERR-dependent gene expression.

[0005] The pleiotropic effects of ERRα activity on energy metabolism interest us as a target for the discovery of new therapeutic approaches for diseases in which metabolic disorders or modifications play a central role, such as type 2 diabetes, progressive heart failure, osteoporosis and cancer. Of particular interest is ERRα as a novel target for tumor therapy, via its impact on the regulation of tumor cell energy metabolism associated with energy stress within the tumor microenvironment. And of particular interest is ERRα as a novel target for the therapeutic treatment of cancers with stem cell-like properties - Cancer Stem Cells (CSCs), Tumor Initiating Cells (TICs) and Circulating Tumor Cells (CTCs) - which depend on mitochondrial respiration for their energy requirements.

[0006] In particular, cancer initiation and development are known to be associated with major metabolic changes, and mitochondria play a key role in tumorigenesis. A common abnormality observed in many types of cancer, called the Warburg effect, is a shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, and is characterized by a dramatic increase in glucose consumption accompanied by an elevated ratio of lactate excretion rates, regardless of the amount of oxygen. Aerobic glycolysis meets the metabolic needs of highly proliferative cells, including providing sufficient energy and providing an accumulation of precursors for anabolic reactions. LeBleu et al., PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat. Cell Biol. 16(10):992-1 (2014) demonstrated that tumor cells exhibit metabolic plasticity involving either glycolysis or oxidative phosphorylation depending on the tumor environment and their proliferation or metastatic phenotype during cancer progression. It is therefore apparent that targeting of metastatic progenitor cells and resistant tumor cells should occur not only via the glycolytic pathway, but also via mitochondrial oxidative phosphorylation.

[0007] ERRα, together with PGC1α / β, controls the regulation of genes encoding enzymes in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. As discussed in Ariazi et al., Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer, Cancer Res. 62(22):6510-8 (2002), ERRα is expressed in a variety of cancer cells, including breast and prostate cancer cells, and is associated with more aggressive disease and a higher risk of recurrence in both of these cancer types.

[0008] Chang et al., The metabolic regulator ERRa, a downstream target of HER2 / IGF-1R, as a therapeutic target in breast cancer, Cancer Cell 20, 500-510 (2011), and Fujimoto et al., Clinical implications of estrogen-related receptor (ERR) expression in ovarian cancers, J. Steroid Biochem. Mol. Biol. 104, 301-304 (2007) document that ERRa is expressed in most cancers and that increased activity of this receptor is associated with negative outcomes in both breast and ovarian cancers. The first of these references identifies transcription factors as also involved in the regulation of mitochondrial biogenesis and oxidative phosphorylation. This latter point is thought to be important since resistance to inhibition of the Kras pathway in pancreatic cancer, BRAF inhibitors in melanoma, and oxaliplatin and 5-fluorouracil in colon cancer have also been associated with a shift toward oxidative metabolism. Summary of the Invention [Problem to be solved by the invention]

[0009] Therefore, the inventors opined that inhibition of ERRα activity would allow selective disruption of mitochondrial function in cancer, particularly in the types of cancer mentioned above.To this end, but also for utility in treating other ERRα mediated diseases and conditions, the inventors developed non-covalent, non-steroidal ERRα inverse agonists. [Means for solving the problem]

[0010] According to a first aspect of the present invention there is provided a compound according to formula I below, or a pharma- ceutically acceptable salt thereof. [ka] Where: Z is -OCH2- or -CH2O-; Y is a carbon-carbon single bond or a carbon-carbon double bond, provided that when Y is a carbon-carbon double bond, R' 15 and R 16 does not exist; One of the three positions A1 to A3 is S or NR A and the remaining two of positions A1 to A3 are N or CR1, CR2, or CR3, respectively; R A is H or methyl; R1 to R3 are independently H, methyl or a halogen atom; A4-A7 are each N or CR4, CR5, CR6 and CR7, with the proviso that no more than two of the four positions A4-A7 can be N simultaneously; A8~A 12 are N or CR8, CR9, and CR 10 , C.R. 11 and CR12 However, there are five positions A8 to A 12 No more than two of can be N at the same time; R4 to R7 are independently H, a halogen atom, C(1-6)alkyl, amino, (di)C(1-3)alkylamino, C(1-3)alkoxy, C(1-3)alkoxyC(1-3)alkoxy, -C(O)OR 17 , -C(O)NR 17 R 17 or nitro, all of which may be optionally substituted with one or more halogen atoms or hydroxyl; R8~R 12 are independently H, a halogen atom, C(1-3)alkoxy, C(1-6)alkyl, cyano, cyanoC(1-3)alkyl, amino, nitro, aminoC(1-3)alkyl, -C(O)OR 15 , -CH2C(O)OR 17 , -C(O)NR 17 R 17 , -NHC(O)R 17 , acetyl, hydroxyl, C(3-6)cycloalkyl, C(2-3)alkynyl, C(2-3)alkenyl, carboxylC(1-3)alkyl, C(1-3)alkylsulfonyl, aminosulfonyl, (di)C(1-3)alkylamino, benzyl, SF5, or CH(=O), all of which are optionally substituted with one or more halogen atoms or hydroxyl; Or, R9 and R8 or R 10 is condensed with any one of the following to form a 5-7 membered aromatic or non-aromatic ring containing 2-7 carbon atoms and 0-3 heteroatoms, with the proviso that all groups may be optionally substituted with one or more methyl, halogen atoms, or hydroxyl; R 13 is H or methyl; R 14 is NH, O or S; R 15 and R' 15 are independently H, a halogen atom, a C(1-4) alkyl, a cyano, a carboxylic acid, or -C(O)OR 17 , -C(O)NR 17 R 17and; R 16 is H; and R 17 is H, C(1-4)alkyl, aminoC(1-3)alkyl, C(1-5)heteroaryl, or phenyl, provided that all groups are optionally substituted with one or more halogen atoms or hydroxyl.

[0011] In one embodiment, the present invention relates to a compound in which A1 is N and A2 is NR A and A3 is CR3.

[0012] In another embodiment, the invention relates to compounds according to formula I, wherein A1 is N, A2 is NH, and A3 is CH.

[0013] In another embodiment, the invention relates to compounds according to formula I, wherein positions A4, A5, A6 and A7 are CR4, CR5, CR6 and CR7, respectively.

[0014] In another embodiment, the invention relates to a compound according to formula I, wherein R5 is C(1-3)alkoxy, and R4, R6 and R7 are H.

[0015] In another embodiment, the invention relates to a compound according to formula I, wherein R5 is methoxy and R4, R6 and R7 are H.

[0016] In another embodiment, the present invention relates to a method for the preparation of a compound having a structure at positions A8, A9, A 10 , A 11 and A 12 are CR8, CR9, and CR 10 , C.R. 11 and CR 12 The present invention relates to compounds according to formula I, wherein

[0017] In another embodiment, the present invention relates to a compound represented by the formula: 12is independently H, C(1-6)alkyl, a halogen atom, hydroxyl, NH2, acetyl, C(1-3)alkoxy, or SF5.

[0018] In another embodiment, the present invention relates to a compound represented by the formula: 12 is independently H, C(1-6)alkyl, or a halogen atom.

[0019] In another embodiment, the present invention relates to a compound having R and R 10 is C(1-6)alkyl, and R, R 11 and R 12 is H.

[0020] In another embodiment, the present invention relates to a compound having R and R 10 is CF3, and R9, R 11 and R 12 is H.

[0021] In another embodiment, the present invention provides a method for the preparation of 13 is H.

[0022] In another embodiment, the present invention provides a method for the preparation of 14 is O.

[0023] In another embodiment, the present invention provides a method for the preparation of 15 and R' 15 is H.

[0024] In another embodiment, the invention relates to a compound according to formula I, wherein Z is -CH2O-, where CH2 is attached to an aromatic ring comprising A4-A7.

[0025] In another embodiment, the invention relates to compounds according to formula I, wherein Y is a carbon-carbon single bond.

[0026] The above embodiments relating to preferred forms of the different substituents of formula (I) are not intended to be mutually exclusive of each other. Rather, all combinations of these embodiments are contemplated within the scope of the invention, and in certain circumstances, such combinations may be combined in any combination, even if R 14 represents a preferred structure of the compound of formula I in which R is O, Z is -CH2O-, where CH2 is bonded to an aromatic ring including A4-A7, and Y is a carbon-carbon single bond. 10 is CF3, and R9, R 11 and R 12 is H and R 13 is H and R 14 Further reference may be made to compounds according to formula I, wherein A is O, Z is -CH2O-, said CH2 being bonded to an aromatic ring comprising A4-A7, and Y is a carbon-carbon single bond. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] definition

[0028] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0029] As used herein, the words "comprising," "comprises," and "comprised of" are synonymous with "including," "includes," "containing," or "contains," and are inclusive or open-ended and do not exclude additional, unrecited members, elements, or method steps. As used herein, the phrase "consisting of" is closed and excludes all additional elements. Moreover, the phrase "consisting essentially of" excludes additional significant elements, but can include non-significant elements that do not materially alter the nature of the invention.

[0030] When amounts, concentrations, dimensions, and other parameters are expressed in the form of ranges, preferred ranges, upper values, lower values, or preferred upper and lower values, it is to be understood that any range obtained by combining any upper or preferred value with any lower or preferred value is also specifically disclosed, regardless of whether the resulting range is expressly stated in the context.

[0031] The words "preferred," "preferably," "desirably," and "particularly," or their equivalents, may be used frequently herein to refer to embodiments of the present disclosure that may offer certain advantages, under certain circumstances. However, the recitation of one or more preferred, preferred, desirable, or particular embodiments does not imply that other embodiments are not useful, and is not intended to exclude such other embodiments from the scope of the present disclosure.

[0032] As used throughout this application, the word "may" is used in its non-required sense, ie, in its permissive sense, i.e., meaning possible.

[0033] As used herein, "room temperature" is 23°C ± 2°C.

[0034] Unless otherwise stated, as used herein, the term "halo" or the term "halogen atom" or the term "halide" by itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom, with fluorine, chlorine, or bromine atom being indicated to be preferred.

[0035] As used herein, the term "heteroatom" refers to a nitrogen atom, an oxygen atom, or a sulfur atom.

[0036] The use of the word "radical" herein is consistent with the definition of the above molecular entities in IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson, Blackwell Scientific Publications, Oxford (1997).

[0037] As used herein, a "C(1-n) alkyl" group refers to a monovalent group containing 1 to n carbon atoms, which is a radical of an alkane, and includes linear and branched organic groups. Thus, "C1-C 30 An "alkyl" group refers to a monovalent group containing 1 to 30 carbon atoms, which is an alkane radical and includes linear and branched organic groups. In the present invention, such alkyl groups may be unsubstituted or substituted with the groups mentioned hereinafter. Halogenated derivatives of hydrocarbon radicals may in particular be mentioned as examples of suitable substituted alkyl groups.

[0038] As used herein, the term "C(1-6) alkyl" refers to a branched or unbranched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl, and n-hexyl. Any carbon atom may be substituted with one or more halogen atoms or hydroxyl.

[0039] As used herein, the term "C(1-4) alkyl" refers to an alkyl group having 1 to 4 carbon atoms, i.e., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. Any carbon atom may be substituted with one or more halogen atoms or hydroxyl.

[0040] As used herein, the term "C(1-3) alkyl" refers to an alkyl group having 1 to 3 carbon atoms, i.e., methyl, ethyl, propyl, or isopropyl. Any carbon atom may be substituted with one or more halogen atoms or hydroxyl.

[0041] As used herein, the term "C(1-2) alkyl" refers to an alkyl group having 1 to 2 carbon atoms, i.e., methyl or ethyl, any carbon atom may be substituted with one or more halogen atoms or hydroxyl.

[0042] As used herein, the term "C(3-6)cycloalkyl" refers to a saturated cyclic hydrocarbon having 3 to 6 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, any of which may be substituted with one or more halogen atoms or methyl.

[0043] As used herein, the term "C(2-3)alkynyl" refers to an alkynyl group having 2-3 carbon atoms, i.e., ethynyl, 1-propynyl, or 2-propynyl, any of which may be substituted with one or more hydroxyls.

[0044] As used herein, the term "C(2-3)alkenyl" means an alkenyl group having 2 to 3 carbon atoms, i.e., ethene, 1-propene, or 2-propene.

[0045] The term "C(1-3)alkoxy" refers to an alkoxy group having 1 to 3 carbon atoms, the alkyl portion being branched or unbranched. Any carbon atom may be substituted with one or more F or hydroxyl.

[0046] The term "C(1-3)alkoxyC(1-3)alkyl" means a C(1-3)alkoxy bonded to a C(1-3)alkyl, both of which have the same meaning as previously defined.

[0047] As used herein, the term "C(1-3)alkoxyC(1-3)alkoxy" means a C(1-3)alkoxy bonded to a C(1-3)alkoxy, wherein the term "C(1-3)alkoxy" has the same meaning as previously defined.

[0048] As used herein, the term "C(1-5)heteroaryl" refers to an aromatic group having 1-5 carbon atoms and 1-4 heteroatoms, which may be bonded via a nitrogen atom or a carbon atom, if possible. Examples include pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, furyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxazolyl, pyridinyl, pyrimidyl, pyrazinyl, and triazinyl. Any carbon atom may be substituted with one or more halogen atoms or methyl.

[0049] As used herein, the term "cyano" represents a group of formula -CN.

[0050] The term "cyanoC(1-3)alkyl" means a cyano group attached at any position to a C(1-3)alkyl group, the terms "cyano" and "C(1-3)alkyl" having the same meaning as previously defined.

[0051] As used herein, a "nitro group" or "nitro" refers to --NO.sub.2.

[0052] As used herein, the term "amino group" refers to a substituent of formula -NH2. The term also includes its protonated form (-NH3 + ).

[0053] The term "amino C(1-3) alkyl" means an amino group attached at any position to a C(1-3) alkyl group, wherein said moiety "C(1-3) alkyl" has the same meaning as previously defined.

[0054] As used herein, the term "(di)C(1-3)alkylamino" means an amino group which is independently mono- or di-substituted with one or more C(1-3)alkyl groups, wherein the C(1-3)alkyl groups have the same meaning as previously defined.

[0055] The term "C(1-3)alkylsulfonyl" means a -S(O)2R group, where R is a C(1-3)alkyl group and the term "C(1-3)alkyl" has the same meaning as previously defined.

[0056] The term "aminosulfonyl" refers to the group -S(O)2-NH2 in which an amino group is attached to a sulfonyl moiety.

[0057] The term "carboxylC(1-3)alkyl" means a -C(O)OH group attached to a C(1-3)alkyl. The term "C(1-3)alkyl" has the same meaning as previously defined.

[0058] The term "substituted" means that one or more hydrogens on a specified atom or atoms are replaced with a selection from a specified group, provided that the normal valence of the specified atom under the existing circumstances is not exceeded, and such substitutions result in stable compounds. Combinations of substituents are also permissible only if such combinations result in stable compounds. The term "stable compound" or "stable structure" refers to a compound or structure that is sufficiently robust to survive both isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0059] The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

[0060] As used herein, a "protecting group" refers to a moiety attached to a functional group to prevent undesired reactions. Preferably, the protecting group can be easily removed after protection of the functional group is no longer required.

[0061] Compounds of formula I can form salts, which are also within the scope of the present invention. References herein to compounds of formula I are understood to include references to the salts thereof, unless otherwise indicated.

[0062] The term "pharmaceutically acceptable salt" is used according to its standard definition in the art to denote salts that are suitable for use within the scope of medical judgment, particularly in contact with the tissues of humans and lower animals without undue toxicity, irritation and / or allergic reactions. Their use must be commensurate with a reasonable benefit to risk ratio. Pharmaceutically acceptable salts are well known in the art. They may be obtained during the final isolation and purification of the compounds of the invention, or they may be obtained separately by reacting the free base function with a suitable mineral acid, including but not limited to hydrochloric acid, phosphoric acid or sulfuric acid; or an organic acid, including but not limited to ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid or methanesulfonic acid. The acid function of the compounds of the invention may be reacted with an inorganic base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an organic base. For completeness, organic bases include common hydrocarbyl and heterocyclic amine salts such as diethylamino, morpholine and piperidine salts.

[0063] The compounds of formula I may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula I, as well as mixtures thereof, including racemic mixtures, form part of the present invention. In particular, the stereoisomers of the compounds of formula I in the S configuration of the chiral center next to the pyrazole ring according to the Cahn-Ingold-Prelog system of nomenclature, expressly form part of the present invention.

[0064] As will be appreciated by those skilled in the art, enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound, for example a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride; separating the diastereomers; and then converting the individual diastereomers into the corresponding pure enantiomers, for example by hydrolysis. Enantiomers can also be separated by use of a chiral HPLC column.

[0065] It will be further recognized that various tautomers of the compound of formula I may be possible. Therefore, it is intended that all tautomeric forms of the compound of formula I form part of the present invention. For completeness, as used herein, the term "tautomer" refers to the migration of a proton between adjacent single and double bonds. The tautomerization process is reversible. Tautomers generally reach an equilibrium state, where the double bond is resonantly shared between two bond lengths.

[0066] The present invention also relates to pharmaceutical compositions comprising a compound having general formula I or a pharma- ceutically acceptable salt thereof in admixture with a pharma- ceutically acceptable excipient and, optionally, other therapeutically active agents. The excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0067] The present invention further includes compounds of Formula I in combination with one or more other pharmaceutical agents.

[0068] The compositions may be any unit dosage form for administration, including, but not limited to, those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, topical, or rectal administration. For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granules, solutions, suspensions, and the like.

[0069] For parenteral administration, the pharmaceutical compositions of the invention can be presented in unit-dose or multi-dose containers, such as sealed vials and ampoules, in a predetermined amount of injection solution. The pharmaceutical compositions can also be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water, prior to use.

[0070] Mixed with such pharma- ceutically acceptable auxiliaries, the active agent can be compressed into solid dosage units, such as pills, tablets, or processed into capsules or suppositories. With pharma- ceutically acceptable liquids, the active agent can be applied as a fluid composition, for example in the form of a solution, suspension or emulsion, which can be included in a spray, for example an injection or nasal drops.

[0071] To prepare solid dosage units, the use of conventional additives, such as fillers, colorants, polymeric binders, etc., is contemplated. In general, any pharma- ceutically acceptable additive that does not interfere with the function of the active compound can be used. Suitable carriers that can be used by the active agent of the present invention as a solid composition include lactose, starch, cellulose derivatives, etc., or mixtures thereof, when used in appropriate amounts. For parenteral administration, aqueous suspensions, isotonic saline, and sterile injectable solutions can be used, and these suspensions or solutions can contain pharma- ceutically acceptable dispersants and / or wetting agents, such as propylene glycol or butylene glycol.

[0072] The present invention further includes a pharmaceutical composition as described hereinbefore in combination with suitable packaging material for said composition, wherein said packaging material contains instructions for use of the composition for the purposes as described hereinbefore.

[0073] The exact dosage and administration regimen of the active ingredient or pharmaceutical composition thereof may vary depending on the particular compound, the route of administration, and the age and condition of the individual subject to which the drug is to be administered.

[0074] In general, parenteral administration requires lower dosages than other administration methods that are more dependent on absorption. That being said, dosages for humans preferably comprise 0.0001 to 100 mg per kg of body weight. The desired dose may be presented as a single dose or multiple subdoses administered at appropriate intervals throughout the day.

[0075] The compounds according to the invention or their pharma- ceutically acceptable salts can be used as drugs in therapy.

[0076] Another aspect of the invention resides in the use of compounds having general formula I or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of an ERRα-mediated disease or condition.In particular, the invention provides the use of compounds having general formula I or a pharma- ceutically acceptable salt thereof for the treatment of ERRα-mediated cancer.

[0077] The compounds having general formula I or their pharma- ceutically acceptable salts can be used in therapy to treat at least one condition selected from lung cancer, melanoma, endometrial cancer, and acute myeloid leukemia. Without intending to limit this aspect of the invention, the compounds having general formula I or their pharma-ceutically acceptable salts can be used in therapy to treat, in particular, superficial spreading melanoma, lentigo maligna, acro-lentiginous melanoma, nodular melanoma, amelanotic melanoma, ocular melanoma, vulvar melanoma, or vaginal melanoma.

[0078] In another aspect, the compounds having general formula I or pharma- ceutically acceptable salts thereof can be used in therapy to treat at least one condition selected from breast cancer, bladder cancer, prostate cancer, pancreatic cancer, colorectal cancer, and ovarian cancer.

[0079] In another aspect, the compounds having general Formula I, or a pharma- ceutically acceptable salt thereof, can be used to treat type II diabetes.

[0080] Also provided herein is a method for the treatment of at least one condition selected from lung cancer, melanoma, endometrial cancer, and acute myeloid leukemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to Formula I or a pharma- ceutical acceptable salt thereof.

[0081] Also provided is a method for the treatment of at least one condition selected from superficial spreading melanoma, lentigo maligna, acrole lentiginous melanoma, nodular melanoma, amelanotic melanoma, ocular melanoma, vulvar melanoma, or vaginal melanoma, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to Formula I or a pharma- ceutical acceptable salt thereof.

[0082] Also provided is a method for the treatment of at least one condition selected from breast cancer, bladder cancer, prostate cancer, pancreatic cancer, colorectal cancer, and ovarian cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to Formula I or a pharma- ceutical acceptable salt thereof.

[0083] There is also provided a method for the treatment of type II diabetes, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to formula I or a pharma- ceutical acceptable salt thereof.

[0084] As used herein, the phrase "therapeutically effective amount" means an amount of a subject compound or composition that is effective in producing the desired therapeutic effect.

[0085] As shown in the Examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedures: While the general methods depict the synthesis of certain compounds of the invention, it will be understood that the general methods below, and other methods known to those of skill in the art, can be applied to all compounds and subclasses and species of each of these compounds as described herein.

[0086] General method of preparation

[0087] The compounds described herein, such as compounds of general formula I, building block I and building block II, are prepared by the reaction schemes shown below. Moreover, in the schemes below where specific acids, bases, reagents, coupling agents, catalysts, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, catalysts, solvents, etc. may be used and are within the scope of the present invention. Modifications to reaction conditions, such as temperature, duration of reaction, or combinations thereof, are contemplated as part of the present invention.

[0088] The compounds obtained by using the general reaction sequence may be of insufficient purity. The compounds can be purified by using organic compound purification methods, such as crystallization or silica gel or alumina column chromatography, using different solvents in appropriate ratios. All possible stereoisomers are contemplated within the scope of the present invention.

[0089] The abbreviations for materials used in the reaction schemes and examples below are as follows:

[0090] AcOH: acetic acid;ACN: acetonitrile;AIBN: azobisisobutyronitrile;BH3·THF: borane-tetrahydrofuran;Boc2O: di-tert-butyl dicarbonate;DAST: (diethylamino)sulfur trifluoride;DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;DCM: dichloromethane;DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone;DIAD: diisopropyl azodicarboxylate;Di BAl-H: diisobutylaluminum hydride;DMAP: 4-dimethylaminopyridine;DMF: N,N-dimethylformamide;EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;Et2O: diethyl ether;EtOAc: ethyl acetate;HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;HOBt: hydroxybenzotriazole; KOAc: potassium acetate; MeMgBr: methylmagnesium bromide; MeOH: methanol; Me2S·BH3: borane dimethyl sulfide; NBS: N-bromosuccinimide; NMO: 4-methylmorpholine N-oxide; PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II) dichloride; Pd(dppf)Cl2: [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4: tetrakis( (triphenylphosphine)palladium(0); PhSCu(I): phenylsulfanyl copper; PPh3: triphenylphosphine; p-TsOH: paratoluenesulfonic acid; tBuOK: potassium tert-butoxide; tBuONO: tert-butylnitrile; TEA: triethylamine; TEMPO: 2,2,6,6-tetramethylperidinyloxy; THF: tetrahydrofuran; TMS-Cl: trimethylsilyl chloride; TOSMIC: tosylmethylisocyanide.

[0091] Chemical names are preferred IUPAC names generated by using Marvin Sketch 17.24.1. When a compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure prevails.

[0092] [ka]

[0093] conditions: i) Meldrum's acid, MeOH

[0094] As shown in Scheme 1, R 14 is an oxygen atom, and R 15 , R' 15 and R 16 The derivatives of the invention having the formula where each of Z, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A69, A70, A71, A72, A73, A74, A75 10 , A 11 and A 12 Derivatives of building blocks I, in which R 13 , A1, A2 and A3 have the meanings given above, can be obtained by reaction of a derivative of building block II with Meldrum's acid.

[0095] R 14 To obtain derivatives of formula I in which R is a sulfur atom, 14 Derivatives of formula I, in which is an oxygen atom, can be reacted, for example, with Lawesson's reagent.

[0096] R 14 To obtain derivatives of formula I in which R is a nitrogen atom, 14 Derivatives of formula I, in which is a sulfur atom, can be reacted with ammonia in MeOH, for example.

[0097] Building block I is R4~R 12 contains an amine or aldehyde moiety, this moiety must be protected with a suitable protecting group prior to reaction of the building block II derivative with Meldrum's acid, and then deprotected using well-known methods to obtain the desired analog of formula I. Via this route, an amine can be obtained which can be further derivatized using well-known methods to provide a secondary or tertiary amine or an amide.

[0098] When one of R4-R7 in the analogs of formula I is nitro, the nitro can be reduced using, for example, iron and ammonium chloride in a mixture of water / THF / MeOH to give analogs of formula I containing amines at R4-R7.

[0099] When one of R4-R7 in the analog of formula I is a methyl ester, the ester can be saponified under basic conditions to give the corresponding carboxylic acid, which when reacted with alcohols and amines can form esters and amides using methods known in the art.

[0100] [ka]

[0101] conditions: i) DDQ, 1,4-dioxane

[0102] Scheme 1b illustrates a compound in which Y is a carbon-carbon double bond and R 15 is H, and Z, R 13 , R 14 , A1, A2, A3, A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 The following general routes are shown for the preparation of analogs of formula I, where R has the meaning given above.

[0103] Derivatives of formula I where Y is a carbon-carbon single bond can be oxidized, for example using DDQ in a suitable solvent, to give derivatives of formula I where Y is a carbon-carbon double bond.

[0104] [ka]

[0105] conditions: i) TMS-Cl, KI, ACN; ii) K2CO3,ACN; iii) bis(pinacolato)diboron, Pd(DPPF)Cl2·DCM, KOAc, 1,4-dioxane; and iv) Pd(PPh3)4,K2CO3,1,4-dioxane / water

[0106] Scheme 1c illustrates a compound in which Y is a carbon-carbon double bond, Z is -OCH, A is NH, A and A are CH, and R 13 and R 15 is H, and R 14 An alternative method for making analogs of formula I where is =O is shown. A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 has the meaning given above. Bromopyrrolopyridine 1 can be demethylated using, for example, TMS-Cl and KI in ACN. When these conditions are applied, the bromine is replaced by iodine to give iodopyrrolopyridine. 2 Boronic ester building blocks 5 For example, use K2CO3 to prepare benzyl bromide. 3 and phenol 4 and then introducing the boronic ester using, for example, bis(pinacolato)diboron, Pd(dppf)Cl2·DCM and KOAc in 1,4-dioxane. 2 and 5When coupled via a palladium catalyzed reaction, for example using Pd(PPh3)4 and K2CO3 in 1,4-dioxane / water, the corresponding analogs of formula I were obtained.

[0107] [ka]

[0108] conditions: i) LiOH,THF / water; ii) LiOH,THF / water followed by Me2S·BH3,THF; iii) DiBAl-H,THF; iv) RNH2, EDC, DMAP, DCM; and v) ROH, EDC, DMAP, DMF

[0109] Scheme 1d shows A 10 CR 10 (where R 10 is COMe), Y is a carbon-carbon single bond, and R 15 , R' 15 and R 16 Several options are shown for functionalizing the analogs of formula I, where each of Z, R is H. 13 , R 14 , A1, A2, A3, A4, A5, A6, A7, A8, A9, A 11 and A 12 has the meaning given above. 10 If it contains an ester moiety, it can be saponified, for example, using LiOH in THF / water, to give the carboxylic acid analogs of formula I. The carboxylic acid analogs can be converted to the corresponding amides and esters, for example, by reaction with amines or alcohols using well-known methods. Alternatively, the ester moiety can be reduced to give either the -CHOH or -CHO analogs. In Scheme 1d, this is represented by R 10 These transformations are also illustrated for positions R4 to R 12can be applied to an ester moiety at any position of

[0110] [ka]

[0111] conditions: i) Ammonia in MeOH, Raney Nickel, MeOH

[0112] Scheme 1e illustrates a compound in which Y is a carbon-carbon single bond and R 15 , R' 15 and R 16 A general route for the preparation of analogs of formula I, in which each of Z, R is H, is shown. 13 , R 14 , A1, A2, A3, A4, A5, A6, A7, A8, A9, A 11 and A 12 has the meaning given above. 10 If R contains a nitrile moiety, it can be reduced, for example, using ammonia in MeOH and Raney nickel as a catalyst, to give the saturated alkyl analog of formula I. In Scheme 1e, this is 10 Although exemplified for positions R4 to R 12 can be applied to the nitrile moiety at any position of

[0113] [ka]

[0114] conditions: i) Hydrogen gas, Pd / C, MeOH

[0115] Scheme 1f illustrates a compound in which Y is a carbon-carbon single bond and R 15 , R' 15 and R 16 The general route for the preparation of analogs of formula I, where each of Z, R is H, is shown.13 , R 14 , A1, A2, A3, A4, A5, A6, A7, A8, A9, A 11 and A 12 has the meaning given above. 10 If it contains a triple bond, it can be reduced, for example, using hydrogen gas with Pd / C in MeOH to give the saturated alkyl analog of formula I. In Scheme 1f, this is R 10 These transformations are exemplified for positions R4 to R 12 The formula can be applied to a triple bond in any position of

[0116] [ka]

[0117] conditions: i) Allyltri-n-butyltin, Pd(PPh3) 2­ Cl, PPh3, DMF; and ii) OsO4, NMO, acetone / water

[0118] Scheme 1g illustrates a compound in which Y is a carbon-carbon single bond and A 10 is C-Br and R 15 , R' 15 and R 16 A general route for functionalization of analogs of formula I, where Z, R are each H, is shown. 13 , R 14 , A1, A2, A3, A4, A5, A6, A7, A8, A9, A 11 and A 12 has the meaning previously described. The bromine-containing analogue can be reacted with allyltri-n-butyltin under Stille conditions. The resulting allyl-containing analogue of formula I can be further reacted via Upjohn dihydroxylation to give the dihydroxyl-containing analogue of formula I. In Scheme 1g, this is represented by R 10 Although exemplified for positions R4 to R 12can be applied to the bromine moiety in any position of

[0119] [ka]

[0120] conditions: i) Meldrum's acid, MeOH; ii) ROH, DIAD, PPh3, THF; and iii) R2NH, EDC, DMAP, DCM

[0121] Scheme 1h illustrates a compound in which Y is a carbon-carbon single bond and R 14 is an oxygen atom, and R 15 is COOH, and R' 15 and R 16 A general route for the preparation of analogs of formula I, in which each of Z, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, A3 10 , A 11 and A 12 Derivatives of building blocks I, in which R 13 , A1, A2, A3 have the meanings given above, with Meldrum's acid at room temperature.

[0122] R 15 When is COOH, this carboxylic acid moiety can be functionalized towards an ester, for example using an alcohol, DIAD and PPh3 in THF, or it can be functionalized towards an amide, for example using a primary or secondary amine, EDC and DMAP in DCM.

[0123] [ka]

[0124] conditions: i) CH3CH2OCOCH2P(Ph)3Br,tBuOK,Et2O; ii) CH2CHMgBr,PhSCu(I),THF; iii) TEMPO,tBuONO,1,4-dioxane; iv) TOSMIC,tBuOK,THF; and v) Zn,AcOH

[0125] Scheme 1i illustrates a compound in which A1 and A3 are CH, A2 is NH, Y is a carbon-carbon single bond, and R 14 is an oxygen atom, and R 13 is H and R 15 , R' 15 and R 16 A general route for the formation of analogs of formula I, in which each of Z, A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 has the meaning given above.

[0126] Intermediates 7 can be obtained via Wittig reaction of building block I using, for example, CH3CHOCOCH2P(Ph)3Br and tBuOK in Et2O, followed by reaction with, for example, vinylmagnesium bromide and PPhSCu(I) in THF. Subsequent introduction of a nitro group in the E-confirmation can be achieved by using, for example, TEMPO and tBuONO in 1,4-dioxane. Pyrrole intermediate 9 For example, using TOSMIC and tBuOK in THF, the intermediate 8 Reduction of the nitro followed by ring closure to give the analogs of formula I was carried out in a single step, for example by using zinc dust in AcOH.

[0127] [ka]

[0128] conditions: i) K2CO3,ACN

[0129] In Scheme 2, Z is -OCH2-, and A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 shows a general method for preparing benzaldehyde building block I derivatives having the meanings given above.

[0130] For example, K2CO3 is used to catalyze the synthesis of parahydroxybenzaldehyde under basic conditions. 10 Benzyl halide 3 Alkylation with gives the corresponding benzaldehyde derivative of building block I. 3 can also be obtained from the corresponding toluene or benzyl alcohol via bromination reactions that are well known in the art.

[0131] R8~R 12 The building block I derivatives containing one bromide in them can be further derivatized using palladium-catalyzed coupling after protection of the aldehyde with an acetal. After the coupling, the aldehyde is again deprotected to give the building block I analog. If an ester moiety is obtained after palladium-catalyzed coupling, this ester moiety is reduced to give R8-R8 before deprotection of the aldehyde. 12 The aldehyde can then be deprotected to give the desired building block I analog. In another embodiment, when an ester moiety is obtained after palladium catalysis, the ester can be reacted with a Grignard reagent to give a tertiary alcohol.

[0132] R 10Building block I analogs containing a hydroxyl group can be obtained from the corresponding bromine analogs of building block I by first protecting the aldehyde with an acetal. The bromine atom is then converted to a boronic ester via palladium-catalyzed coupling, followed by reaction with hydrogen peroxide to introduce the hydroxyl moiety. After deprotection of the aldehyde, the building block I analogs are obtained.

[0133] Building Block I R8~R 12 The bromine in can also be replaced with ethylene glycol, for example, by using copper(II) bromide and potassium carbonate.

[0134] In another embodiment, when R4-R7 in building block I are fluorine atoms, the fluorine atoms can be displaced using an appropriate amine under basic conditions, e.g., K2CO3 in DMF, at 110°C, to give the corresponding alkylamine analogs of building block I.

[0135] [ka]

[0136] conditions: (X=F; if A5=A6=N, then X=Cl) i) NaH, DMF

[0137] In Scheme 2b, Z is -OCH2-, and A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 represents an alternative method for preparing benzaldehyde building block I derivatives having the meanings given above.

[0138] Benzaldehyde 11 can be obtained by the synthesis of benzyl alcohol under basic conditions, for example by using sodium hydride in DMF. 12to give the building block I analogues.

[0139] Benzyl alcohol 12 can be obtained via reduction of the corresponding benzaldehyde, for example by using the BH3·THF complex.

[0140] [ka]

[0141] conditions: i) NBS, AIBN, CAN; and ii) DiBAl-H, toluene

[0142] Scheme 3 shows the reaction of a benzaldehyde compound, in which A4, A5, A6 and A7 have the previously described meanings. 15 General methods for preparing derivatives are given below.

[0143] For example, benzonitrile using NBS and AIBN in ACN 13 Bromination of benzonitrile 14 For example, the nitrile can be reduced to give benzaldehyde using DiBAl-H in toluene. 15 Derivatives can be prepared.

[0144] [ka]

[0145] conditions: i) K2CO3, DMF

[0146] In Scheme 3b, Z is -CH2O-, and A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12A general method for preparing benzaldehyde building block I derivatives is shown, in which R has the meaning given above.

[0147] Under basic conditions, e.g., using K2CO3, phenol 16 and benzaldehyde 1 Alkylation with affords the corresponding benzaldehyde derivative of building block I.

[0148] The resulting building block I is R 10 If the aryl group contains a bromine atom, this position can be functionalized using palladium catalysis, for example, Pd(PPh3)4, CuI, DBU, and propargyl alcohol.

[0149] [ka]

[0150] conditions: i) K2CO3,ACN; ii) DAST, DCM; and iii) DiBAl-H, toluene

[0151] Scheme 3c shows that A 10 is CF2, Z is -CH2O-, and A4, A5, A6, A7, A8, A9, A 11 and A 12 shows a general method for preparing benzaldehyde building block I derivatives having the meanings given above. 17 and benzonitrile 14 Alkylation with the corresponding aldehyde 18 The aldehyde can be converted to a CF2 group using a fluorinating agent such as DAST. Through reduction of the nitrile (e.g., using DiBAl-H in toluene), the benzaldehyde building block I derivative can be prepared. In Scheme 3c, this is represented by R10 Although exemplified for R4 to R 12 can be applied to the aldehyde moiety at any position of

[0152] The following examples are illustrative of the present invention and are not intended to limit the scope of the invention in any manner.

[0153] Working Example

[0154] All building blocks used are commercially available, known to those skilled in the art or are prepared according to methods known to those skilled in the art.

[0155] Examples 1 to 220

[0156] Example 1: 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0157] [ka]

[0158] i) To a solution of 2-(trifluoromethyl)benzyl bromide (0.93 g) in ACN (60 mL) was added K2CO3 (2.53 g) and vanillin (1.46 g). The reaction mixture was heated to 70° C. and stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting crude product was partitioned between water and DCM. The aqueous layer was extracted twice more with DCM and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 1.76 g of 3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}benzaldehyde. The product was used in the next step without further purification.

[0159] ii) The product obtained in the previous step (377 mg), Meldrum's acid (175 mg) and 3-aminopyrazole (101 mg) were dissolved in MeOH. The reaction mixture was heated to 65° C. and stirred overnight. After cooling to room temperature, the product precipitated. The solid was filtered off and washed with MeOH to give 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (289 mg) as an off-white solid. MS (ES): + ) m / z 418.2 (M+H) + .

[0160] The following compounds were prepared following procedures similar to those described for Example 1 using the appropriate starting materials.

[0161] Example 2: 4-{4-[(2-chlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0162] [ka]

[0163] MS(ES + ) m / z 384.2 (M+H) +

[0164] Example 3: 4-{4-[(4-chlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0165] [ka]

[0166] MS(ES + ) m / z 384.2 (M+H) +

[0167] Example 4: 4-{4-[(2-bromophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0168] [ka]

[0169] MS(ES + ) m / z 350.2 (M+H) +

[0170] Example 5: 4-[4-(benzyloxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0171] [ka]

[0172] MS(ES + ) m / z 428.2 (M+H) +

[0173] Example 6: 2-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzonitrile

[0174] [ka]

[0175] MS(ES + ) m / z 375.2 (M+H) +

[0176] Example 7: 4-(3-Methoxy-4-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0177] [ka]

[0178] MS(ES + ) m / z 418.2 (M+H) +

[0179] Example 8: 4-(4-{[2,4-bis(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0180] [ka]

[0181] MS(ES + ) m / z 486.2 (M+H) +

[0182] Example 9: 4-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0183] [ka]

[0184] MS(ES + ) m / z 436.2 (M+H) +

[0185] Example 10: 4-(3-Methoxy-4-{[3-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0186] [ka]

[0187] MS(ES + ) m / z 418.2 (M+H) +

[0188] Example 11: 4-{4-[(3-bromophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0189] [ka]

[0190] MS(ES + ) m / z 428.2 (M+H) +

[0191] Example 12: 4-{4-[(3-chlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0192] [ka]

[0193] MS(ES + ) m / z 384.2 (M+H) +

[0194] Example 13: 4-{4-[(2,1,3-benzoxadiazol-4-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0195] [ka]

[0196] MS(ES + ) m / z 392.1 (M+H) +

[0197] Example 14: 4-(4-{[2,5-bis(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0198] [ka]

[0199] MS(ES + ) m / z 486.2 (M+H) +

[0200] Example 15: 4-(4-{[4-chloro-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0201] [ka]

[0202] MS(ES + ) m / z 452.2 (M+H) +

[0203] Example 16: 4-{4-[(2-fluorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0204] [ka]

[0205] MS(ES + ) m / z 368.2 (M+H) +

[0206] Example 17: 4-(4-{[2-(difluoromethoxy)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0207] [ka]

[0208] MS(ES + ) m / z 416.2 (M+H) +

[0209] Example 18: 4-{3-methoxy-4-[(2-nitrophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0210] [ka]

[0211] MS(ES + ) m / z 395.2 (M+H) +

[0212] Example 19: 4-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0213] [ka]

[0214] MS(ES + ) m / z 448.2 (M+H) +

[0215] Example 20: 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzonitrile

[0216] [ka]

[0217] MS(ES + ) m / z 443.2 (M+H) +

[0218] Example 21: 4-(4-{[2-fluoro-6-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0219] [ka]

[0220] MS(ES + ) m / z 436.2 (M+H) +

[0221] Example 22: 4-{4-[(2,3-dichlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0222] [ka]

[0223] MS(ES + ) m / z 418.2 (M+H) +

[0224] Example 23: 4-{4-[(2-iodophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0225] [ka]

[0226] MS(ES + ) m / z 476.2 (M+H) +

[0227] Example 24: 4-(3-Methoxy-4-{[2-(trifluoromethoxy)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0228] [ka]

[0229] MS(ES + ) m / z 434.2 (M+H) +

[0230] Example 25: 4-{3-methoxy-4-[(2-methoxy-5-nitrophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0231] [ka]

[0232] MS(ES + ) m / z 425.2 (M+H) +

[0233] Example 26: Methyl 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoate

[0234] [ka]

[0235] MS(ES + ) m / z 408.2 (M+H) +

[0236] Example 27: 4-(4-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0237] [ka]

[0238] MS(ES + ) m / z 486.2 (M+H) +

[0239] Example 28: 4-(4-{[2-fluoro-3-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0240] [ka]

[0241] MS(ES + ) m / z 436.2 (M+H) +

[0242] Example 29: 4-{4-[(2,5-dichlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0243] [ka]

[0244] MS(ES + ) m / z 418.2 (M+H) +

[0245] Example 30: 4-{3-methoxy-4-[(2-methoxyphenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0246] [ka]

[0247] MS(ES + ) m / z 380.2 (M+H) +

[0248] Example 31: 4-{3-methoxy-4-[(2,3,5-trichlorophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0249] [ka]

[0250] MS(ES + ) m / z 452.2 (M+H) +

[0251] Example 32: 4-(3-Methoxy-4-{[5-methyl-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0252] [ka]

[0253] MS(ES + ) m / z 432.2 (M+H) +

[0254] Example 33: 4-(4-{[4-bromo-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0255] [ka]

[0256] MS(ES + ) m / z 496.2 (M+H) +

[0257] Example 34: 4-(3-Methoxy-4-{[4-nitro-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0258] [ka]

[0259] MS(ES + ) m / z 463.2 (M+H) +

[0260] Example 35: 4-(3-Methoxy-4-{[5-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0261] [ka]

[0262] MS(ES + ) m / z 448.2 (M+H) +

[0263] Example 36: 4-(3-Methoxy-4-{[3-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0264] [ka]

[0265] MS(ES + ) m / z 448.2 (M+H) +

[0266] Example 37: 4-(4-{[4-methanesulfonyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0267] [ka]

[0268] MS(ES + ) m / z 496.2 (M+H) +

[0269] Example 38: 4-{4-[(2-chloro-4-methanesulfonylphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0270] [ka]

[0271] MS(ES + ) m / z 462.2 (M+H) +

[0272] Example 39: 4-{4-[(2,3-dimethoxyphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0273] [ka]

[0274] MS(ES + ) m / z 410.2 (M+H) +

[0275] Example 40: 4-{4-[(2-tert-butylphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0276] [ka]

[0277] MS(ES + ) m / z 406.2 (M+H) +

[0278] Example 41: 4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0279] [ka]

[0280] MS(ES + ) m / z 460.1 (M+H) +

[0281] Example 42: 4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)benzoate methyl

[0282] [ka]

[0283] MS(ES + ) m / z 476.1 (M+H) +

[0284] Example 43: 4-{4-[(6-bromo-2H-1,3-benzodioxol-5-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0285] [ka]

[0286] MS(ES + ) m / z 472.0 (M+H) +

[0287] Example 44: 4-{4-[(2-ethynylphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0288] [ka]

[0289] MS(ES + ) m / z 374.1 (M+H) +

[0290] Example 45: 4-{4-[(1-benzothiophen-7-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0291] [ka]

[0292] MS(ES + ) m / z 406.1 (M+H) +

[0293] Example 46: 4-{4-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0294] [ka]

[0295] MS(ES + ) m / z 420.2 (M+H) +

[0296] Example 47: 4-{3-methoxy-4-[(quinolin-8-yl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0297] [ka]

[0298] MS(ES + ) m / z 401.2 (M+H) +

[0299] Example 48: Ethyl 2-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]benzoate

[0300] [ka]

[0301] MS(ES + ) m / z 422.2 (M+H) +

[0302] Example 49: 4-(4-{[2-(difluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0303] [ka]

[0304] MS(ES + ) m / z 400.1 (M+H) +

[0305] Example 50: 4-(3-Methoxy-4-{[3-(trifluoromethyl)pyridin-4-yl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0306] [ka]

[0307] MS(ES + ) m / z 419.1 (M+H) +

[0308] Example 51: 4-{4-[(3,4-dihydro-2H-1,5-benzodioxepin-6-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0309] [ka]

[0310] MS(ES + ) m / z 422.2 (M+H) +

[0311] Example 52: 4-{3-methoxy-4-[(2-methylphenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0312] [ka]

[0313] MS(ES + ) m / z 364.2 (M+H) +

[0314] Example 53: 4-{4-[(isoquinolin-5-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0315] [ka]

[0316] MS(ES + ) m / z 401.2 (M+H) +

[0317] Example 54: 4-{4-[(2-bromo-4,5-dimethoxyphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0318] [ka]

[0319] MS(ES + ) m / z 488.1 (M+H)+

[0320] Example 55: 4-{4-[(2,1,3-benzothiadiazol-4-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0321] [ka]

[0322] MS(ES + ) m / z 408.1 (M+H) +

[0323] Example 56: 4-(3-Methoxy-4-{[3-(trifluoromethyl)pyridin-2-yl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0324] [ka]

[0325] MS(ES + ) m / z 419.1 (M+H) +

[0326] Example 57: 4-{3-methoxy-4-[(pyridin-2-yl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0327] [ka]

[0328] MS(ES + ) m / z 351.1 (M+H) +

[0329] Example 58: 4-{4-[(2-bromophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0330] [ka]

[0331] MS(ES + ) m / z 398.2 (M+H) +

[0332] Example 59: 4-(4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0333] [ka]

[0334] MS(ES + ) m / z 388.2 (M+H) +

[0335] Example 60: 4-{4-[(2-chlorophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0336] [ka]

[0337] MS(ES + ) m / z 354.2 (M+H) +

[0338] Example 61: 4-(3,5-dimethoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0339] [ka]

[0340] MS(ES + ) m / z 448.2 (M+H) +

[0341] Example 62: 4-(3-ethoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0342] [ka]

[0343] MS(ES + ) m / z 432.2 (M+H) +

[0344] Example 63: 4-(5-{[2-(trifluoromethyl)phenyl]methoxy}pyridin-2-yl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0345] [ka]

[0346] MS(ES + ) m / z 389.2 (M+H) +

[0347] Example 64: 4-(2-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0348] [ka]

[0349] MS(ES + ) m / z 418.2 (M+H) +

[0350] Example 65: 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzoate methyl

[0351] [ka]

[0352] MS(ES + ) m / z 446.2 (M+H) +

[0353] Example 66: 4-(2-fluoro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0354] [ka]

[0355] MS(ES + ) m / z 406.2 (M+H) +

[0356] Example 67: 4-(3-nitro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0357] [ka]

[0358] MS(ES + ) m / z 433.2 (M+H) +

[0359] Example 68: 4-[3-(difluoromethoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0360] [ka]

[0361] MS(ES + ) m / z 454.1 (M+H) +

[0362] Example 69: 4-[3-(trifluoromethoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0363] [ka]

[0364] MS(ES + ) m / z 472.1 (M+H) +

[0365] Example 70: 4-(3-bromo-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0366] [ka]

[0367] MS(ES + ) m / z 466.0 (M+H) +

[0368] Example 71: 4-(3-ethyl-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0369] [ka]

[0370] MS(ES + ) m / z 416.2 (M+H) +

[0371] Example 72: 4-(3-chloro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0372] [ka]

[0373] MS(ES + ) m / z 422.1 (M+H) +

[0374] Example 73: 4-(3-methyl-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0375] [ka]

[0376] MS(ES + ) m / z 402.1 (M+H) +

[0377] Example 74: 4-(3-fluoro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0378] [ka]

[0379] MS(ES + ) m / z 406.1 (M+H) +

[0380] Example 75: 4-(2-Fluoro-5-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0381] [ka]

[0382] MS(ES + ) m / z 436.1 (M+H) +

[0383] Example 76: 4-[3-(trifluoromethyl)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0384] [ka]

[0385] MS(ES + ) m / z 456.1 (M+H) +

[0386] Example 77: 4-(2-fluoro-4-{[3-fluoro-2-(trifluoromethyl)phenyl]methoxy}-5-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0387] [ka]

[0388] MS(ES + ) m / z 454.1 (M+H) +

[0389] Example 78: 4-(3-fluoro-5-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0390] [ka]

[0391] MS(ES + ) m / z 436.1 (M+H) +

[0392] Example 79: 7-{4-[(2-chlorophenyl)methoxy]-3-methoxyphenyl}-4H,5H,6H,7H-thieno[3,2-b]pyridin-5-one

[0393] [ka]

[0394] MS(ES + ) m / z 400.2 (M+H) +

[0395] Example 80: 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0396] [ka]

[0397] MS(ES+ ) m / z 432.2 (M+H) +

[0398] Example 81: 4-(3-Methoxy-4-{[3-(trifluoromethyl)phenyl]methoxy}phenyl)-3-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0399] [ka]

[0400] MS(ES + ) m / z 432.2 (M+H) +

[0401] Example 82: 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-3-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0402] [ka]

[0403] MS(ES + ) m / z 432.2 (M+H) +

[0404] Example 83: 4-{4-[(2-bromophenyl)methoxy]-3-methoxyphenyl}-1-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0405] [ka]

[0406] MS(ES + ) m / z 442.2 (M+H) +

[0407] Example 84: 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-1-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0408] [ka]

[0409] MS(ES + ) m / z 432.2 (M+H) +

[0410] Example 85: 7-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-4H,5H,6H,7H-thieno[3,2-b]pyridin-5-one

[0411] [ka]

[0412] MS(ES + ) m / z 434.2 (M+H) +

[0413] Example 86: 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-7-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0414] [ka]

[0415] MS(ES + ) m / z 432.2 (M+H) +

[0416] Example 87: 7-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one

[0417] [ka]

[0418] MS(ES + ) m / z 418.2 (M+H) +

[0419] Example 88: 7-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-4H,5H,6H,7H-[1,3]thiazolo[4,5-b]pyridin-5-one

[0420] [ka]

[0421] MS(ES + ) m / z 435.2 (M+H) +

[0422] Example 89: 7-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-imidazo[4,5-b]pyridin-5-one

[0423] [ka]

[0424] MS(ES + ) m / z 418.2 (M+H) +

[0425] Example 90: 7-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one

[0426] [ka]

[0427] MS(ES + ) m / z 419.2 (M+H) +

[0428] Example 91: 7-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one

[0429] [ka]

[0430] MS(ES + ) m / z 449.2 (M+H) +

[0431] Example 92: 7-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one

[0432] [ka]

[0433] MS(ES + ) m / z 448.2 (M+H) +

[0434] Example 93: 7-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one

[0435] [ka]

[0436] MS(ES + ) m / z 461.1 (M+H) +

[0437] Example 94: 7-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one

[0438] [ka]

[0439] MS(ES + ) m / z 460.1 (M+H) +

[0440] Example 95: 3-Fluoro-4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0441] [ka]

[0442] MS(ES + ) m / z 436.1 (M+H) +

[0443] Example 96: 4-(4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0444] [ka]

[0445] i) To a solution of 3-methoxy-4-methyl-benzonitrile (11.55 g) and NBS (16.76 g) in ACN (550 mL) was added AIBN (1.29 g). The reaction mixture was heated to 85° C. and stirred for 4.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the resulting crude product was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The compound was then purified on a silica column using a gradient of EtOAc / heptane 0 / 100 to 18 / 82 as the eluent to give 4-(bromomethyl)-3-methoxybenzonitrile (15.3 g).

[0446] ii) The product obtained in the previous step (15.3 g) was dissolved in anhydrous toluene under nitrogen atmosphere and cooled to 0° C. DiBAl-H (1.2 M in toluene, 85 mL) was added dropwise over 30 min and stirred at 0° C. for 1 h. The reaction was quenched by dropwise addition of 6N aqueous HCl (46 mL). The reaction was diluted with water and the product was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified on a silica column using a gradient of toluene and EtOAc 100 / 0 to 80 / 20, followed by reversed phase flash chromatography using a gradient of ACN / H2O 45 / 55 to 60 / 40 as eluent to give 4-(bromomethyl)-3-methoxybenzaldehyde (7.35 g).

[0447] iii) The product obtained in the previous step (2.85 g), -bromo-2-(trifluoromethyl)phenol (3.00 g) and K2CO3 (5.16 g) were placed in a 250 mL flask and ACN (50 mL) was added. The reaction mixture was heated to 70° C. and stirred for 1 h. Acetonitrile was evaporated and the crude product was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. The product was suspended in methanol and the solid was filtered off, washed with methanol and dried in a vacuum oven to give 4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-methoxybenzaldehyde (4.10 g).

[0448] iv) Analogously to the procedure described in Example 1, step ii), the compound obtained in the previous step was converted to 4-(4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (3.03 g). MS (ES + ) m / z 496.0 (M+H) + .

[0449] The following compounds were prepared following procedures similar to those described for Example 96, steps i)-iv) using the appropriate starting materials.

[0450] Example 97: 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0451] [ka]

[0452] MS(ES + ) m / z 462.2 (M+H)+

[0453] Example 98: 4-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0454] [ka]

[0455] MS(ES + ) m / z 448.1 (M+H) +

[0456] Example 99: 4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0457] [ka]

[0458] MS(ES + ) m / z 452.1 (M+H) +

[0459] Example 100: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0460] [ka]

[0461] MS(ES + ) m / z 486.1 (M+H) +

[0462] Example 101: 4-(3-methoxy-4-{[2-(pentafluoro-λ 6 -Sulfanyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0463] [ka]

[0464] MS(ES + ) m / z 476.1 (M+H) +

[0465] Example 102: 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0466] [ka]

[0467] MS(ES + ) m / z 418.1 (M+H) +

[0468] Example 103: 4-(4-{[4-acetyl-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0469] [ka]

[0470] MS(ES + ) m / z 460.1 (M+H) +

[0471] Example 104: 4-(4-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0472] [ka]

[0473] MS(ES + ) m / z 436.1 (M+H) +

[0474] Example 105: 4-[(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenyl)methoxy]-3-(trifluoromethyl)benzonitrile

[0475] [ka]

[0476] MS(ES + ) m / z 443.1 (M+H) +

[0477] Example 106: 4-(4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0478] [ka]

[0479] MS(ES + ) m / z 550.0 (M+H) +

[0480] Example 107: 4-(4-{[2-(pentafluoro-lambda 6-sulfanyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0481] [ka]

[0482] MS(ES + ) m / z 530.1 (M+H) +

[0483] Example 108: 4-[3-(trifluoromethoxy)-4-{[2-(trifluoromethyl)phenoxy]methyl}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0484] [ka]

[0485] MS(ES + ) m / z 472.1 (M+H) +

[0486] Example 109: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0487] [ka]

[0488] MS(ES + ) m / z 540.1 (M+H) +

[0489] Example 110: 4-(4-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0490] [ka]

[0491] MS(ES + ) m / z 490.1 (M+H) +

[0492] Example 111: 4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0493] [ka]

[0494] MS(ES + ) m / z 378.4 (M+H) +

[0495] Example 112: 4-(3-Methoxy-4-{[2-methyl-4-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0496] [ka]

[0497] MS(ES + ) m / z 432.4 (M+H) +

[0498] Example 113: 4-{4-[(3,5-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0499] [ka]

[0500] MS(ES + ) m / z 378.4 (M+H) +

[0501] Example 114: 4-(3-Methoxy-4-{[3-methyl-5-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0502] [ka]

[0503] MS(ES + ) m / z 432.4 (M+H) +

[0504] Example 115: 4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0505] [ka]

[0506] i) The product obtained in step i of Example 96 (14.13 g), 4-hydroxy-3-(trifluoromethyl)benzaldehyde (11.88 g) and K2CO3 (17.28 g) were suspended in ACN (400 mL) and heated to 70° C. for 2.5 h. The solvent was evaporated on a rotary evaporator, the crude product was suspended in water and the solid was filtered off. The solid was washed twice with EtOAc and dried in a vacuum oven at 40° C. to give 4-[[4-formyl-2-(trifluoromethyl)phenoxy]methyl]-3-methoxy-benzonitrile (19.49 g).

[0507] ii) The product obtained in the previous step (19.49 g) was suspended in DCM (400 mL) under nitrogen atmosphere. DAST (23 mL) was added dropwise and the reaction was stirred at room temperature for 5 days. During these days the reaction went into solution. The reaction was placed on a water bath and saturated aqueous NaHCO3 was carefully added until no more gas was evolved. The product was extracted three times with DCM and the combined organic layers were dried over MgSO4 and concentrated. The product was loaded onto Celite and purified on a silica column using a gradient of DCM / heptane 40 / 60 to 70 / 30 to give 4-[[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl]-3-methoxy-benzonitrile (19.4 g).

[0508] iii) The product obtained in the previous step (19.40 g, 51.6 mmol, 1 equiv.) was suspended in toluene (427.5 mL) under nitrogen atmosphere. The reaction was cooled to 0° C. and DiBAl-H (64 mL, 1.2 M in toluene) was added dropwise over 35 min. During the addition of DiBAl-H the reaction became clear and pale yellow. After the addition the reaction was stirred at 0° C. for 1.5 h. 6 M aqueous HCl (36 mL) was added dropwise followed by water. The product was extracted three times with EtOAc and the combined organic layers were washed with brine, dried over MgSO4 and concentrated to give 4-[[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl]-3-methoxy-benzaldehyde (19.23 g).

[0509] iv) Analogously to the procedure described in Example 1, step ii, the compound obtained in the previous step was converted to 4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (9.7 g). MS (ES + ) m / z 468.4 (M+H) + .

[0510] The following compounds were prepared following procedures similar to those described for Example 115 using the appropriate starting materials.

[0511] Example 116: 4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0512] [ka]

[0513] MS(ES + ) m / z 450.4 (M+H) +

[0514] Example 117: 4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0515] [ka]

[0516] MS(ES + ) m / z 468.4 (M+H) +

[0517] Example 118: 4-(4-{[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0518] [ka]

[0519] MS(ES + ) m / z 468.4 (M+H) +

[0520] Example 119: 4-(4-{[4-(3-hydroxyprop-1-yn-1-yl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0521] [ka]

[0522] i) The intermediate obtained in Example 96, step ii (1.00 g) was dissolved in THF (10 mL) along with CuI (0.05 g) and DBU (0.46 mL). The reaction mixture was degassed by bubbling nitrogen through the reaction mixture for 15 min. Pd(PPh3)4 (0.30 g) and propargyl alcohol (0.18 mL) were then added and the vial was sealed. The reaction was stirred in a microwave at 60° C. for 16 h. The reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was concentrated and the residue was taken up in EtOAc and washed successively with H2O / brine and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was dissolved in DCM, loaded onto Celite, and purified via flash chromatography using a gradient of EtOAc / heptane 20 / 80 to 80 / 20 as eluent to give 4-{[4-(3-hydroxyprop-1-yn-1-yl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxybenzaldehyde (0.81 g) as a beige powder.

[0523] ii) Analogously to the procedure described in Example 1, step ii, the compound obtained in the previous step was converted to 4-(4-{[4-(3-hydroxyprop-1-yn-1-yl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (8 mg). MS (ES + ) m / z 472.4 (M+H) + .

[0524] Example 120: 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzoic acid

[0525] [ka]

[0526] i) Example 42 (3.0 g) was suspended in THF (30 mL) and a solution of LiOH (0.45 g) in water (15 mL) was added. The resulting yellow solution was stirred at room temperature overnight. THF was evaporated, thereby resulting in the product. The aqueous suspension was filtered and the solid was washed successively with water, twice with CHCl, and Et2O. The residue was dried in a vacuum oven to give 4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzoic acid lithio (2.32 g) as a white powder.

[0527] ii) The compound obtained in the previous step (50 mg) was suspended in water (10 mL) and 2 M aqueous HCl (2 mL) was added. The resulting suspension was stirred vigorously for 30 min and then filtered. The residue was washed with water, ACN (2x), and Et2O and then dried under vacuum to give 4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzoic acid (34 mg) as a white powder. MS (ES): + ) m / z 462.2 (M+H) + .

[0528] Example 121: 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzamide

[0529] [ka]

[0530] i) In Example 120, step i), the product obtained (50 mg) was dissolved in DMF (0.5 mL) together with NH4Cl (12 mg), EDC (25 mg), TEA (45 μL) and HOBt (20 mg). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and water and stirred vigorously. A suspension was obtained which was filtered. The residue was washed successively with water, ACN (twice), and Et2O, then dried in vacuum to give 4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzamide (25 mg) as a white powder. MS (ES): + ) m / z 461.2 (M+H) + .

[0531] The following compounds were prepared following procedures similar to those described for Example 121 using the appropriate starting materials and solvents.

[0532] Example 122: 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-N-methyl-3-(trifluoromethyl)benzamide

[0533] [ka]

[0534] MS(ES + ) m / z 475.2 (M+H) +

[0535] Example 123: 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-N,N-dimethyl 3-(trifluoromethyl)benzamide

[0536] [ka]

[0537] MS(ES + ) m / z 489.2 (M+H) +

[0538] Example 124: 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-N-(1H-pyrazol-3-yl)-3-(trifluoromethyl)benzamide

[0539] [ka]

[0540] MS(ES + ) m / z 527.2 (M+H) +

[0541] Example 125: 2-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoate propyl

[0542] [ka]

[0543] MS(ES + ) m / z 436.2 (M+H) +

[0544] Example 126: Butyl 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoate

[0545] [ka]

[0546] MS(ES + ) m / z 450.2 (M+H)+

[0547] Example 127: 2-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoate propan-2-yl

[0548] [ka]

[0549] MS(ES + ) m / z 436.2 (M+H) +

[0550] Following procedures similar to those described for Example 120 and Example 121 using Example 65 as the starting material and the appropriate reagents and solvents, the following compounds were prepared.

[0551] Example 128: Ethyl 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzoate

[0552] [ka]

[0553] MS(ES + ) m / z 460.2 (M+H) +

[0554] Example 129: N,N-Dimethyl 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide

[0555] [ka]

[0556] MS(ES + ) m / z 459.2 (M+H) +

[0557] Example 130: 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide

[0558] [ka]

[0559] MS(ES + ) m / z 431.2 (M+H) +

[0560] Example 131: 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-N-(4H-1,2,4-triazol-3-yl)-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide

[0561] [ka]

[0562] MS(ES + ) m / z 498.2 (M+H) +

[0563] Example 132: 2-Hydroxyethyl 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzoate

[0564] [ka]

[0565] MS(ES + ) m / z 476.2 (M+H)+

[0566] Example 133: N-methyl-5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide

[0567] [ka]

[0568] MS(ES + ) m / z 445.2 (M+H) +

[0569] Example 134: N-(1H-imidazol-4-yl)-5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide

[0570] [ka]

[0571] MS(ES + ) m / z 497.2 (M+H) +

[0572] Example 135: 4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0573] [ka]

[0574] i) 4-Methyl-3-(trifluoromethyl)-aniline (4.88 g) was dissolved in 1,4-dioxane (15 mL) and saturated aqueous K2CO3 (15 mL) was added. Then Boc2O (7.40 g) was added and the reaction was stirred at room temperature overnight. The product was extracted three times with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give 8.89 g of tert-butyl N-[4-methyl-3-(trifluoromethyl)phenyl]carbamate.

[0575] ii) Analogously to the procedure described in Example 96, step i), the product obtained in the previous step was converted into tert-butyl N-[4-(bromomethyl)-3-(trifluoromethyl)phenyl]carbamate (9.01 g).

[0576] iii) Analogously to the procedure described in example 1, step i), the product obtained in the previous step was converted into tert-butyl N-{4-[(4-formyl-2-methoxyphenoxy)methyl]-3-(trifluoromethyl)phenyl}carbamate.

[0577] iv) Analogously to the procedure described in example 1, step ii), the product obtained in the previous step was converted into tert-butyl N-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}carbamate.

[0578] v) The product obtained in the previous step (93 mg) was dissolved in DCM (1 mL) and HCl gas was bubbled through until the product precipitated. The reaction mixture was stirred for an additional 20 min and then concentrated under reduced pressure. The resulting residue was suspended in aqueous NaHCO3 and stirred for 5 min, then the solid was filtered off and washed with water. The crude product was dissolved in ACN / MeOH and purified by preparative HPLC to give 4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one as a white powder. MS (ES): + ) m / z 433.4 (M+H) + .

[0579] The following compounds were prepared following procedures similar to those described for Example 135 using the appropriate starting materials and solvents.

[0580] Example 136: 7-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one

[0581] [ka]

[0582] MS(ES + ) m / z 434.2 (M+H) +

[0583] Example 137: 7-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one

[0584] [ka]

[0585] MS(ES + ) m / z 433.2 (M+H) +

[0586] Example 138: 4-(4-{[4-(dimethylamino)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0587] [ka]

[0588] i) To a solution of Example 135 (25 mg) in acetic acid (1 mL) was added 43 μL of formaldehyde solution (37% in water), followed by portionwise addition of sodium cyanoborohydride (11 mg). After 40 min, the reaction mixture was concentrated and the resulting oil was basified with aqueous K2CO3, resulting in a white precipitate. The suspension was extracted twice with DCM and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by preparative HPLC (isocratic gradient 40% ACN / H2O) to give 3 mg of 4-(4-{[4-(dimethylamino)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one. MS (ES) + ) m / z 461.2 (M+H) + .

[0589] Example 139: N-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}acetamide

[0590] [ka]

[0591] i) DIPEA (121 μL) was added to a mixture of Example 135 (50 mg), HATU (44 mg) and AcOH (7 μL) in DMF (1 mL). The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a white solid. The crude product was purified by preparative HPLC to give N-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}acetamide (10 mg) as a white powder. MS (ES) + ) m / z 475.4 (M+H) + .

[0592] Example 140: 2-amino-N-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}acetamide

[0593] [ka]

[0594] i) Using Example 135 (100 mg) as starting material, similar to the procedure described in Example 139, tert-butyl N-[({4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}carbamoyl)methyl]carbamate (102 mg) was obtained as a white powder.

[0595] ii) Analogously to the procedure described in Example 135, step v), the compound obtained in the previous step (102 mg) was converted into 2-amino-N-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}acetamide (40 mg, white powder). MS (ES + ) m / z 490.2 (M+H) + .

[0596] Example 141: 4-(3-Methoxy-4-{[4-(methylamino)-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0597] [ka]

[0598] i) A solution of the building block (500 mg) obtained in Example 135, step iii) in 3 mL of anhydrous THF was added to a chilled (0° C.) suspension of NaH (94 mg, 60 wt %) in 2 mL of anhydrous THF under nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 20 min, then MeI (2.9 mL, 2 M in tert-butyl methyl ether) was added and the reaction was stirred overnight. The reaction mixture was diluted with H2O, extracted twice with EtOAc and washed with brine. The organic layers were combined, dried over MgSO4, filtered and concentrated to give a yellow oil. This was dissolved in DCM, loaded onto silica powder and purified by silica gel chromatography using an isocratic gradient of 15% EtOAc in heptane to give tert-butyl N-{4-[(4-formyl-2-methoxyphenoxy)methyl]-3-(trifluoromethyl)phenyl}-N-methylcarbamate (107 mg) as a colorless oil.

[0599] ii) Analogously to the procedure described in Example 1, step ii), the compound obtained in the previous step (107 mg) was converted into tert-butyl N-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}-N-methylcarbamate (88 mg, beige solid).

[0600] iii) Analogously to the procedure described in Example 135, step v), the compound obtained in the previous step (88 mg) was converted into 4-(3-methoxy-4-{[4-(methylamino)-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (4 mg, white powder). MS (ES + ) m / z 447.2 (M+H) + .

[0601] Example 142: 4-(3-Methoxy-4-{[4-(prop-2-en-1-yl)-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0602] [ka]

[0603] i) Anhydrous DMF (2.5 mL) and allyltri-n-butyltin (375 μL) were added to a vial containing Example 33 (500 mg), Pd(PPh3)2Cl2, and PPh3. The vial was capped and stirred in a microwave at 150 °C for 20 min. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified by reverse-phase flash chromatography using a gradient of 20% to 60% ACN in H2O as eluent to give 4-(3-methoxy-4-{[4-(prop-2-en-1-yl)-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (316 mg, white powder). MS (ES): + ) m / z 458.2 (M+H) + .

[0604] Example 143: 4-(4-{[4-(2,3-dihydroxypropyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0605] [ka]

[0606] i) To a solution of Example 142 (100 mg) in acetone (1 mL) and H2O (0.1 mL), NMO (51 mg) and OsO4 (catalytic amount) were added successively. The reaction mixture was stirred at room temperature for 3 h. A solution of sodium sulfite in 4 mL of H2O was added and the reaction mixture was stirred for an additional 20 min. The product was extracted with EtOAc and the organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give an oil. The crude product was purified by reverse-phase flash chromatography using a gradient of 10% to 100% ACN in HO as eluent to give 4-(4-{[4-(2,3-dihydroxypropyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (12 mg, white powder). MS (ES) + ) m / z 492.2 (M+H) + .

[0607] Example 144: 4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0608] [ka]

[0609] i) Analogously to the procedure described in example 1, step i), starting from 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene, 4-{[4-bromo-2-(trifluoromethyl)phenyl]methoxy}-3-methoxybenzaldehyde was obtained.

[0610] ii) A solution of the compound obtained in the previous step (5.91 g), ethylene glycol (8.49 mL), and p-TsOH monohydrate (0.29 g) in toluene (50 mL) was refluxed under Dean-Stark conditions for 7 h. The reaction was cooled to room temperature and NaHCO3 was added. Toluene was added and the organic layer was washed successively with saturated aqueous NaHCO3, H2O, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give 2-(4-{[4-bromo-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-1,3-dioxolane (6.29 g, beige powder).

[0611] iii) The compound obtained in the previous step (100 mg), K3PO4 (147 mg), and ethylboronic acid (51 mg) were placed in a vial. 1,4-Dioxane (1 mL) was added and the resulting mixture was degassed by bubbling nitrogen through the reaction mixture for 30 min. Pd(PPh3)2Cl2 was added and the vial was capped and stirred in a microwave at 90 °C for 90 min. The reaction mixture was diluted with EtOAc and washed successively with H2O, 2N aqueous HCl, 2N aqueous NaOH, H2O, and brine. The organic phase was dried over MgSO4, filtered, and concentrated to give 2-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-1,3-dioxolane (48 mg, yellow oil).

[0612] iv) To a solution of the compound obtained in the previous step (48 mg) in THF (1 mL) was added 0.41 ml of 6M aqueous HCl solution. The resulting solution was stirred at room temperature overnight. THF was evaporated and the resulting aqueous mixture was basified with saturated aqueous K2CO3. The mixture was then extracted with EtOAc and washed successively with saturated aqueous K2CO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated to give a yellow oil, which was dissolved in heptane. The yellow powder was filtered off and the filtrate was concentrated to give 4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxybenzaldehyde as a white powder.

[0613] v) Analogously to the procedure described in Example 1, step ii), the compound obtained in the previous step (57 mg) was added to 4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (17 mg, white powder). MS (ES + ) m / z 446.2 (M+H) + .

[0614] The following compounds were prepared following procedures similar to those described for Example 144 using the appropriate starting materials and solvents.

[0615] Example 145: 4-(4-{[4-cyclopropyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0616] [ka]

[0617] MS(ES + ) m / z 458.2 (M+H) +

[0618] Example 146: 4-(4-{[4-(3-hydroxyprop-1-yn-1-yl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0619] [ka]

[0620] MS(ES + ) m / z 472.2 (M+H) +

[0621] Example 147: 2-[4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)phenyl]acetonitrile

[0622] [ka]

[0623] MS(ES + ) m / z 457.2 (M+H) +

[0624] Example 148: 2-[4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)phenyl]acetate methyl

[0625] [ka]

[0626] MS(ES + ) m / z 490.2 (M+H) +

[0627] Example 149: 4-(4-{[4-(3-hydroxypropyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0628] [ka]

[0629] i) A solution of Example 146 (116 mg) in MeOH (10 mL) was degassed by bubbling nitrogen through the solution for 10 min. 10% Pd / C (52 mg, containing 50% HO) was added and hydrogen gas was bubbled through the reaction for 3 h. The reaction was filtered through Celite and the filtrate was concentrated. The crude product was purified by preparative HPLC to give 4-(4-{[4-(3-hydroxypropyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (48 mg, white powder). MS (ES): + ) m / z 476.5 (M+H) + .

[0630] Following procedures similar to those described for Example 149 using Example 147 as starting material and the appropriate reagents and solvents, the following compounds were prepared:

[0631] Example 150: 4-(4-{[4-(2-aminoethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0632] [ka]

[0633] MS(ES + ) m / z 461.2 (M+H) +

[0634] Example 151: 2-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}acetic acid

[0635] [ka]

[0636] i) Using a procedure similar to Example 120, steps i) and ii), 66 mg of Example 148 was converted to 2-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}acetic acid (21 mg, white powder). MS (ES + ) m / z 461.2 (M+H) + .

[0637] Example 152: 4-(4-{[4-(1-hydroxy-2-methylpropan-2-yl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0638] [ka]

[0639] i) Following a procedure similar to that described in Example 144, step iii), using the compound obtained from Example 144, step ii) (200 mg) and 1-methoxy-1-(trimethylsiloxy)-2-methyl-1-propene (121 mg), methyl 2-{4-[4-(1,3-dioxolan-2-yl)-2-methoxyphenoxymethyl]-3-(trifluoromethyl)phenyl}-2-methylpropanoate (58 mg) was obtained.

[0640] ii) To a cooled solution (0°C) of the product obtained in the previous step (58 mg) in anhydrous THF (1 mL) was added LiAlH4 (0.51 mL, 1M in Et2O) under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 30 min and then quenched by adding EtOAc dropwise while cooling. The mixture was washed twice with saturated aqueous potassium sodium tartrate solution, saturated aqueous NaHCO3, and brine, then dried over MgSO4, filtered, and concentrated to give a colorless oil. This was dissolved in DCM and purified by silica gel chromatography using a gradient of 0% to 50% EtOAc in heptane as eluent to give 15 mg of 2-(4-{[4-(1,3-dioxolan-2-yl)-2-methoxyphenoxy]methyl}-3-(trifluoromethyl)phenyl)-2-methylpropan-1-ol as a colorless oil.

[0641] iii) Following a procedure similar to that described in Example 144, step iv), followed by that described in Example 1, step ii), the compound obtained in the previous step (15 mg) was converted into 4-(4-{[4-(1-hydroxy-2-methylpropan-2-yl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (4 mg, white powder). MS (ES + ) m / z 490.2 (M+H) + .

[0642] Example 153: 4-(4-{[4-(2-hydroxy-2-methylpropyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0643] [ka]

[0644] i) Following a procedure similar to that described in Example 144, step iii), using the compound obtained from Example 144, step ii) (589 mg) and 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (512 mg), 2-(4-{[4-(1,3-dioxolan-2-yl)-2-methoxyphenoxy]methyl}-3-(trifluoromethyl)phenyl)methyl acetate (421 mg) was obtained.

[0645] ii) The compound obtained in the previous step (421 mg) was dissolved in 10 mL of anhydrous THF under nitrogen atmosphere. The reaction mixture was cooled to 10° C. and MeMgBr (1 mL, 3M in Et2O) was added slowly. The reaction mixture was stirred at room temperature for 30 min and then refluxed for 2 h. The reaction was cooled to room temperature, 2 mL of saturated aqueous NH4Cl was added and then the reaction mixture was stirred at room temperature overnight. 2 mL of 2M aqueous HCl was added and the mixture was stirred for 1 h. The product was extracted three times with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated to give 1-(4-{[4-(1,3-dioxolan-2-yl)-2-methoxyphenoxy]methyl}-3-(trifluoromethyl)phenyl)-2-methylpropan-2-ol (387 mg) as a yellow oil. The product was used in the next step without further purification.

[0646] iii) Following a procedure similar to that described in Example 1, step ii), the compound obtained in the previous step (387 mg) was converted to 4-(4-{[4-(2-hydroxy-2-methylpropyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (75 mg, white powder). MS (ES + ) m / z 490.2 (M+H) + .

[0647] Example 154: 4-(4-{[4-hydroxy-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0648] [ka]

[0649] MS(ES + ) m / z 434.1 (M+H) +

[0650] i) A solution of the compound obtained in Example 144, step ii) (100 mg), bis(pinacolato)diboron (88 mg) and KOAc (68 mg) in 1,4-dioxane (1 mL) was degassed with nitrogen for 20 min. Pd(dppf)Cl2 (19 mg) was added and the vial was capped and stirred in a microwave at 80 °C for 16 h. The reaction mixture was diluted with Et2O and filtered through Celite. The filtrate was concentrated to give a brown oil. The crude product was purified on a silica column using a gradient of 0% to 50% EtOAc in heptane as eluent to give 2-{4-[4-(1,3-dioxolan-2-yl)-2-methoxyphenoxymethyl]-3-(trifluoromethyl)phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (75 mg) as a colorless oil.

[0651] ii) To a solution of the compound obtained in the previous step (75 mg) in methanol (4 mL) was added 30% by weight hydrogen peroxide in water (425 μL). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was quenched with sodium sulfite (powder) and the organic solvent was evaporated under vacuum. The resulting aqueous suspension was diluted with water and extracted with EtOAc. The organic layer was washed successively with saturated aqueous NaHCO3, then with brine, then dried over MgSO4, filtered and concentrated to give 4-[4-(1,3-dioxolan-2-yl)-2-methoxyphenoxymethyl]-3-(trifluoromethyl)phenol (60 mg) as a pale yellow oil. The product was used in the next step without further purification.

[0652] iii) Following a procedure similar to that described in Example 144, step iv), followed by that described in Example 1, step ii, the compound obtained in the previous step (60 mg) was converted into 4-(4-{[4-(1-hydroxy-2-methylpropan-2-yl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (23 mg). MS (ES + ) m / z 434.2 (M+H) + .

[0653] Example 155: 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0654] [ka]

[0655] i) To a solution of the compound obtained in Example 151, step i) (93 mg) in anhydrous THF (1 mL) at 0° C., LiAlH4 (0.86 mL, 1M in Et2O) was added under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 90 min and then quenched by adding EtOAc dropwise while cooling. The mixture was washed twice with saturated aqueous potassium sodium tartrate solution, saturated aqueous NaHCO3, and brine, then dried over MgSO4, filtered, and concentrated to give 2-{4-[4-(1,3-dioxolan-2-yl)-2-methoxyphenoxymethyl]-3-(trifluoromethyl)phenyl}ethan-1-ol (60 mg) as a colorless oil. The product was used in the next step without further purification.

[0656] ii) Following a procedure similar to that described in Example 144, step iv), followed by that described in Example 1, step ii), the compound obtained in the previous step (60 mg) was converted into 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (5 mg). MS (ES + ) m / z 462.2 (M+H) + .

[0657] The following compounds were prepared following procedures similar to those described for Example 155 using the appropriate starting materials.

[0658] Example 156: 7-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one

[0659] [ka]

[0660] MS(ES +) m / z 462.2 (M+H) +

[0661] Example 157: 7-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one

[0662] [ka]

[0663] MS(ES + ) m / z 463.2 (M+H) +

[0664] Example 158: 4-(4-{[4-(hydroxymethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0665] [ka]

[0666] i) The compound obtained in Example 120, step i) (200 mg) was suspended in anhydrous THF (4 mL) and BH3-Me2S (321 μL, 2M in THF) was added dropwise. After stirring for 2 h at room temperature, another 321 μL of BH3-Me2S (2M in THF) was added dropwise and the reaction mixture was stirred for 1 h. 0.5 M aqueous HCl was added and the product was extracted twice with DCM and with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by preparative HPLC using an isocratic gradient of 35% ACN in HO as eluent to give 4-(4-{[4-(hydroxymethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (6 mg) as a white powder. MS (ES) + ) m / z 448.2 (M+H) + .

[0667] Example 159: 4-[(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)benzaldehyde

[0668] [ka]

[0669] i) Example 42 (146 mg) was dissolved in anhydrous THF (5 mL) under nitrogen atmosphere. The solution was cooled to -78°C and DiBAl-H (921 μL, 1M in toluene) was added. The reaction was stirred at -78°C for 4 h and then quenched with 1M aqueous HCl. The reaction was warmed to room temperature and the product was extracted three times with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give 176 mg of crude product. The crude product was suspended in CAN and the solids were filtered off and washed with ACN. The filtrate was evaporated and the crude product was purified twice by reverse phase flash chromatography to give 4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)benzaldehyde. ( 14 mg, white powder). MS(ES + ) m / z 446.2 (M+H) + .

[0670] Example 160: 4-(4-{[3-(2-hydroxyethoxy)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0671] [ka]

[0672] i) Analogously to the procedure described in example 1, step i), starting from 1-bromo-3-(bromomethyl)-2-(trifluoromethyl)benzene, 4-{[3-bromo-2-(trifluoromethyl)phenyl]methoxy}-3-methoxybenzaldehyde was obtained.

[0673] ii) Analogously to the procedure described in Example 144, step ii), the compound obtained in the previous step (4.53 g) was converted into 2-(4-{[3-bromo-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-1,3-dioxolane (4.5 g, white solid).

[0674] iii) A mixture of the compound obtained in the previous step (100 mg), copper(II) bromide (16 mg) and K2CO3 (96 mg) in anhydrous ethylene glycol (0.5 mL) was stirred at 130 °C overnight. The reaction mixture was diluted with EtOAc and washed successively with H2O, saturated aqueous NaHCO3 and brine. The organic layer was then dried over MgSO4, filtered and concentrated to give a yellow solid, which was dissolved in CAN and purified by reversed-phase flash chromatography to give 2-(3-{[4-(1,3-dioxolan-2-yl)-2-methoxyphenoxy]methyl}-2-(trifluoromethyl)phenoxy)ethan-1-ol (28 mg, beige solid).

[0675] iv) Following the procedure described in Example 144, step iv), followed by the procedure described in Example 1, step ii), the compound obtained in the previous step (28 mg) was converted into 4-(4-{[3-(2-hydroxyethoxy)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (12 mg, white powder). MS (ES + ) m / z 478.2 (M+H) + .

[0676] Example 161: 4-(3-amino-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0677] [ka]

[0678] i) A solution of NH4Cl (14 mg) in water (1 mL) was added to a solution of Example 67 (30 mg) in THF / MeOH (0.5 mL / 0.5 mL), followed by iron powder (15 mg). The reaction mixture was stirred at 70° C. for 4 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, filtered through Celite, and concentrated to give a colorless oil. The oil was purified by preparative HPLC to give 4-(3-amino-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (14 mg). MS (ES) + ) m / z 403.2 (M+H) + .

[0679] Example 162: 4-[2-(dimethylamino)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0680] [ka]

[0681] i) Following a procedure similar to that described in Example 1, step i), 2-fluoro-4-hydroxybenzaldehyde (2 g) was converted to 2-fluoro-4-{[2-(trifluoromethyl)phenyl]methoxy}benzaldehyde (4.1 g).

[0682] ii) The compound obtained in the previous step (100 mg) was dissolved in DMF (2 mL) and dimethylamine HCl (32 mg) and K2CO3 (109 mg) were added. The reaction mixture was heated to 110°C and stirred for 5 days. The reaction mixture was cooled to room temperature and 10 mL of water was added. The product was extracted three times with EtOAc and the combined organic layers were washed three times with brine, dried over MgSO4, filtered and concentrated to give 2-(dimethylamino)-4-{[2-(trifluoromethyl)phenyl]methoxy}benzaldehyde (107 mg). The product was used in the next step without further purification.

[0683] iii) Following a procedure similar to that described in Example 1, step ii), the compound obtained in the previous step (107 mg) was converted into 4-[2-(dimethylamino)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (9 mg). MS (ES + ) m / z 431.2 (M+H) + .

[0684] Example 163: 4-[3-(3-methoxypropoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0685] [ka]

[0686] i) 4-Fluoro-3-hydroxybenzaldehyde (300 mg) and 1-bromo-3-methoxypropane (327 mg) were dissolved in ACN (10 mL), K2CO3 (647 mg) was added, and the reaction mixture was heated at 70 °C overnight. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and water. The aqueous layer was extracted twice more with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified on a silica column using a gradient of 0% to 30% EtOAc in heptane as eluent to give 4-fluoro-3-(3-methoxypropoxy)benzaldehyde (198 mg).

[0687] ii) To a cooled (0°C) solution of [2-(trifluoromethyl)phenyl]methanol (193 mg) in anhydrous DMF (5 mL) was added NaH (14 mg) under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 15 min, then the compound obtained in the previous step (109 mg) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice more with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified on a silica column using a gradient of 0% to 30% EtOAc in heptane as eluent to give 3-(3-methoxypropoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}benzaldehyde (96 mg).

[0688] iii) Following a procedure similar to that described in Example 1, step ii), the compound obtained in the previous step (96 mg) was converted into 4-[3-(3-methoxypropoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (11 mg). MS (ES + ) m / z 476.2 (M+H) + .

[0689] The following compounds were prepared following procedures similar to those described for Example 163 using the appropriate starting materials.

[0690] Example 164: 4-[3-(2-methoxyethoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0691] [ka]

[0692] MS(ES + ) m / z 462.2 (M+H) +

[0693] Example 165: 4-(2-{[2-(trifluoromethyl)phenyl]methoxy}pyrimidin-5-yl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0694] [ka]

[0695] i) 2-Chloropyrimidine-5-carbaldehyde (200 mg) and Cs2CO3 (914 mg) were placed in a flask and 15 mL of ACN was added. Then, 2-(trifluoromethyl)benzyl alcohol (186 μL) was added and the reaction was stirred at room temperature for 4 days. The solvent was evaporated and the crude product was partitioned between EtOAc and water. The aqueous layer was extracted twice more with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by reverse phase flash chromatography to give 32 mg of 2-{[2-(trifluoromethyl)phenyl]methoxy}pyrimidine-5-carbaldehyde.

[0696] ii) Following a procedure similar to that described in Example 1, step ii), the compound obtained in the previous step (32 mg) was converted to 4-(2-{[2-(trifluoromethyl)phenyl]methoxy}pyrimidin-5-yl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (18 mg). MS (ES + ) m / z 390.1 (M+H) + .

[0697] Example 166: 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-6-thione

[0698] [ka]

[0699] i) Example 1 (80 mg) was suspended in anhydrous DCM (10 mL) under nitrogen atmosphere. Lawesson's reagent (39 mg) was added and the reaction was heated to 30° C. and stirred overnight. The solvent was evaporated and the crude product was purified by reverse phase flash chromatography using solid loading to give 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-6-thione (48 mg). MS (ES): + ) m / z 434.1 (M+H) + .

[0700] Example 167: 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-imine

[0701] [ka]

[0702] i) Example 166 (18 mg) was dissolved in 7N ammonia in MeOH (1.5 mL) under nitrogen atmosphere. The reaction was stirred for 4 h. The solvent was evaporated and the crude product was purified by preparative HPLC to give 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-imine (17 mg). MS (ES): + ) m / z 417.1 (M+H) + .

[0703] Example 168: 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-1H,6H,7H-pyrrolo[2,3-b]pyridin-6-one

[0704] [ka]

[0705] i) Following a procedure similar to that described in example 1, step i), 4-bromo-2-methoxyphenol (2.6 g) and 2-(trifluoromethyl)benzyl bromide (3.06 g) were converted to 4-bromo-2-methoxy-1-{[2-(trifluoromethyl)phenyl]methoxy}benzene (4.64 g).

[0706] ii) Following a procedure similar to that described in Example 154, step i), the compound obtained in the previous step (2.32 g) was converted into 2-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.32 g).

[0707] iii) 4-Bromo-6-methoxy-1H-pyrrolo[2,3-b]pyridine (243 mg), potassium iodide (355 mg) and TMS-Cl (272 μL) were dissolved in 15 mL of CAN, heated to 80° C. and stirred for 3.5 h. The solvent was evaporated and the crude product was partitioned between water and EtOAc. The aqueous layer was extracted twice more with EtOAc and the combined organic layers were washed with brine, dried over MgSO4 and concentrated. The crude product was suspended in ACN / water. The solid was filtered off and washed with ACN to give 4-iodo-1H-pyrrolo[2,3-b]pyridin-6-ol (46 mg).

[0708] iv) 4-Iodo-1H-pyrrolo[2,3-b]pyridin-6-ol (Example 168, step iii)) (46 mg), 2-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Example 168, step ii)) (108 mg) and K2CO3 (49 mg) were dissolved in 2 mL of 1,4-dioxane / water (3 / 1) in a microwave vial. The mixture was degassed with nitrogen for 15 min, Pd(PPh3)4 (20 mg) was added and the vial was capped. The reaction was stirred at 100 °C in a microwave for 6 h. The reaction was diluted with EtOAc and filtered through Celite. The filtrate was evaporated and the crude product was suspended in ACN with a small amount of water. The solid was filtered off and washed with ACN to give 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-1H,6H,7H-pyrrolo[2,3-b]pyridin-6-one (4 mg). MS (ES + ) m / z 415.1 (M+H) + .

[0709] Example 169: 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0710] [ka]

[0711] i) A solution of Example 1 (40 mg) and DDQ (131 mg) in 1,4-dioxane (1 mL) was stirred at 70° C. for 1 h. The solvent was evaporated and saturated aqueous K2CO3 was added to the crude product. The aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The product was dissolved in a small amount of ACN, THF and water. THF was evaporated and then the product was precipitated. The solid was filtered off and dried in a vacuum oven to give 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (3 mg) as a light brown solid. MS (ES) + ) m / z 416.2 (M+H) + .

[0712] The following compounds were prepared following procedures similar to those described for Example 169 using the appropriate starting materials.

[0713] Example 170: 4-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0714] [ka]

[0715] MS(ES + ) m / z 446.2 (M+H) +

[0716] Example 171: 4-{3-methoxy-4-[(2-methoxyphenyl)methoxy]phenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0717] [ka]

[0718] MS(ES + ) m / z 378.2 (M+H) +

[0719] Example 172: 4-(3-Methoxy-4-{[3-(trifluoromethyl)pyridin-4-yl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0720] [ka]

[0721] MS(ES + ) m / z 417.2 (M+H) +

[0722] Example 173: 4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0723] [ka]

[0724] MS(ES + ) m / z 431.2 (M+H) +

[0725] Example 174: 4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0726] [ka]

[0727] MS(ES + ) m / z 458.2 (M+H) +

[0728] Example 175: 4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0729] [ka]

[0730] MS(ES + ) m / z 444.2 (M+H) +

[0731] Example 176: 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0732] [ka]

[0733] MS(ES + ) m / z 460.2 (M+H) +

[0734] Example 177: 4-(3-Methoxy-4-{[3-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0735] [ka]

[0736] MS(ES + ) m / z 446.1 (M+H) +

[0737] Example 178: 4-(3-Methoxy-4-{[5-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0738] [ka]

[0739] MS(ES + ) m / z 446.1 (M+H) +

[0740] Example 179: 4-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0741] [ka]

[0742] MS(ES + ) m / z 434.1 (M+H) +

[0743] Example 180: 4-(4-{[2-(difluoromethoxy)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0744] [ka]

[0745] MS(ES + ) m / z 414.1 (M+H) +

[0746] Example 181: 4-[(2-methoxy-4-{6-oxo-2H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)benzonitrile

[0747] [ka]

[0748] MS(ES + ) m / z 441.1 (M+H) +

[0749] Example 182: 4-{3-methoxy-4-[(2-methoxy-5-nitrophenyl)methoxy]phenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0750] [ka]

[0751] MS(ES + ) m / z 423.1 (M+H) +

[0752] Example 183: 4-[4-(benzyloxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0753] [ka]

[0754] MS(ES + ) m / z 348.1 (M+H) +

[0755] Example 184: 4-{4-[(2-bromo-4,5-dimethoxyphenyl)methoxy]-3-methoxyphenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0756] [ka]

[0757] MS(ES + ) m / z 486.1 (M+H) +

[0758] Example 185: 4-{3-methoxy-4-[(pyridin-2-yl)methoxy]phenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0759] [ka]

[0760] MS(ES + ) m / z 349.1 (M+H) +

[0761] Example 186: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0762] [ka]

[0763] MS(ES + ) m / z 484.1 (M+H) +

[0764] Example 187: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxylate methyl

[0765] [ka]

[0766] i) Following procedures similar to those described for example 96, step i) to step iii), using appropriate starting materials, 4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxybenzaldehyde was obtained.

[0767] ii) The product obtained in the previous step (50 mg), Meldrum's acid (19 mg) and 3-aminopyrazole (11 mg) were dissolved in MeOH. The reaction mixture was stirred at room temperature for 5 hours and the solvent was evaporated by a stream of nitrogen. This resulted in 4-[4-[[2,4-bis(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]-6-oxo-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-5-carboxylic acid (69 mg) as a yellow oil.

[0768] iii) DIAD (33 μL) was added dropwise to a cooled (0° C.) solution of PPh3 (44 mg) in anhydrous THF (1.5 mL) under nitrogen atmosphere. After stirring for 30 min, MeOH (53 μL) was added, followed by the dropwise addition of the product (69 mg) obtained in the previous step, dissolved in anhydrous THF (1 mL). The reaction was allowed to warm to room temperature and stirred for 1 h. Water was added and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The crude product was purified on a silica column using a gradient of 0-5% MeOH in DCM followed by reverse phase flash chromatography using a gradient of ACN / HO 20 / 80-90 / 10 as eluent to give methyl 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxylate (18 mg). MS (ES) + ) m / z 544.4 (M+H) + .

[0769] Example 188: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-N,N-dimethyl 6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0770] [ka]

[0771] i) The product obtained in Example 187, step ii) (16 mg), DMAP (4.8 mg) and dimethylamine HCl (2.7 mg) were dissolved in DCM (1 mL) under nitrogen atmosphere. EDC (8.1 mg) was added and the reaction was stirred at room temperature for 1 h. Water was added and the aqueous layer was extracted with DCM three times. The combined organic layers were washed with brine, dried on a phase separation filter and concentrated. The product was purified by reversed-phase preparative HPLC using a gradient of ACN / H2O 10 / 90 to 100 / 0 to give 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-N,N-dimethyl 6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxamide (6 mg). MS (ES) + ) m / z 557.5 (M+H) + .

[0772] Example 189: 4-(3-Methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0773] [ka]

[0774] i) Analogously to the procedure described in example 144, step ii), starting from the product obtained in example 96, step iii), 2-[4-[[4-bromo-2-(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]-1,3-dioxolane was obtained.

[0775] ii) Trimethylboroxine (0.38 mL) and Pd(II)Cl2(PPh3)2 (30 mg) were added to a degassed suspension of the product obtained in the previous step (190 mg) and K3PO4 (280 mg) in 1,4-dioxane (1 mL). The reaction was heated to 100 °C for 1 h in a microwave. The reaction was diluted with EtOAc and washed with water, 2N aqueous HCl, 2N aqueous NaOH, water, and brine. The organic phase was filtered through Celite, dried over MgSO4, and concentrated in vacuo to give 3-methoxy-4-[[4-methyl-2-(trifluoromethyl)phenoxy]methyl]phenyl]-1,3-dioxolane (164 mg).

[0776] iii) Analogously to the procedure described in example 144, step iv), the compound obtained in the previous step (164 mg) was converted into 3-methoxy-4-[[4-methyl-2-(trifluoromethyl)phenoxy]methyl]benzaldehyde (74 mg).

[0777] iv) Analogously to the procedure described in Example 1, step ii), the compound obtained in the previous step (73 mg) was converted into 4-(3-methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (37 mg). MS (ES + ) m / z 432.4 (M+H) + .

[0778] Example 190: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-1H,2H,3H,4H,6H-pyrrolo[3,4-b]pyridin-2-one

[0779] [ka]

[0780] i) Following procedures similar to those described for Example 96, steps i) to iii), using appropriate starting materials, 4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxybenzaldehyde was obtained.

[0781] ii) (Ethoxycarbonylmethyl)triphenylphosphonium bromide (2.27 g) was added to a suspension of tBuOK (654 mg) in Et2O (20 mL). The resulting mixture was stirred at 50° C. for 30 min and then cooled to room temperature. The compound obtained in the previous step (1.01 g) was dissolved in Et2O (15 mL) and added to the reaction mixture. The reaction was stirred overnight, then quenched with water, and the aqueous layer was extracted three times with Et2O. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica column using a gradient of 0-20% EtOAc in heptane to give ethyl (E)-3-[4-[[2,4-bis(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]prop-2-enoate (932 mg).

[0782] iii) Vinylmagnesium bromide (1.0M in THF, 6.25 mL) was added dropwise to a suspension of phenylsulfanylcopper (362 mg) in anhydrous THF (10 mL) at -40°C under nitrogen atmosphere. The reaction was allowed to reach -25°C and cooled again to -40°C. The compound obtained in the previous step (930 mg) in anhydrous THF (10 mL) was added dropwise and the reaction was stirred at -40°C for 15 minutes. The reaction was quenched by pouring the mixture into saturated aqueous NH4Cl. The resulting solid was filtered off and the filtrate was extracted twice with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica column using a gradient of 0 to 30% EtOAc in heptane to give ethyl 3-[4-[[2,4-bis(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]pent-4-enoate (300 mg).

[0783] iv) The product obtained in the previous step (300 mg), TEMPO (40 mg) and tBuONO (167 uL) were dissolved in 1,4-dioxane (5 mL), heated to 80° C. and stirred for 2 days. Water was added to the reaction and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica column using a gradient of 0-30% EtOAc in heptane to give ethyl (E)-3-[4-[[2,4-bis(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]-5-nitro-pent-4-enoate (190 mg).

[0784] v) TOSMIC (72 mg) was added to a solution of tBuOK (83 mg) in anhydrous THF (1 mL) at -78°C and stirred for 10 min. The compound obtained in the previous step (190 mg) was dissolved in anhydrous THF (4 mL) and added dropwise to the reaction mixture. After stirring for 10 min at -78°C, the reaction was poured into saturated aqueous NH4Cl and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica column using a gradient of 0-50% EtOAc in heptane to give ethyl 3-[4-[[2,4-bis(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]-3-(4-nitro-1H-pyrrol-3-yl)propanoate (70 mg).

[0785] vi) To a solution of the compound obtained in the previous step (50 mg) in AcOH (1.5 mL) was added zinc dust (59 mg). The reaction was heated to 50° C. and stirred for 30 min. The reaction mixture was filtered through Celite and the filter cake was rinsed with EtOAc. The filtrate was washed with saturated aqueous NaHCO3, water and then dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica column using a gradient of 0-4% MeOH in DCM followed by reverse phase flash chromatography using a gradient of 40-90% ACN in H2O (containing 0.1% TFA) to give 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-1H,2H,3H,4H,6H-pyrrolo[3,4-b]pyridin-2-one (11 mg).

[0786] MS(ES + ) m / z 485.4 (M+H) + .

[0787] Example 191: (4R)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one [(+)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one]

[0788] [ka]

[0789] Example 192: (4S)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one [(-)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one]

[0790] [ka]

[0791] The single enantiomers of Example 100 can be obtained by chiral separation. 20 mg of racemic Example 100 was dissolved in 1 mL of IPA. The solution was injected into a chiral preparative HPLC using an AD column and an isocratic gradient of 5% EtOH, 12% IPA, and 83% heptane to obtain 7 mg of the (+) enantiomer (Example 191) and 7 mg of the (-) enantiomer (Example 192).

[0792] The absolute configurations of the compounds of Examples 193 to 220 are not known. These compounds have been characterized by their optical rotations using a polarimeter.

[0793] The following compounds were prepared following procedures similar to those described for Example 191 and Example 192 using the appropriate starting materials and HPLC methods.

[0794] Example 193: (+)-4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0795] Example 194: (-)-4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0796] Example 195: (+)-4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0797] Example 196: (-)-4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0798] Example 197: (+)-4-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0799] Example 198: (-)-4-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0800] Example 199: (+)-4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0801] Example 200: (-)-4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0802] Example 201: (+)-7-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one

[0803] Example 202: (-)-7-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one

[0804] Example 203: (+)-4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-+-one

[0805] Example 204: (-)-4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0806] Example 205: (+)-7-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one

[0807] Example 206: (-)-7-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one

[0808] Example 207: (+)-4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0809] Example 208: (-)-4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0810] Example 209: (+)-4-(4-{[4-hydroxy-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0811] Example 210: (-)-4-(4-{[4-hydroxy-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0812] Example 211: (+)-4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0813] Example 212: (-)-4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0814] Example 213: (+)-4-(3-Methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0815] Example 214: (-)-4-(3-methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0816] Example 215: (+)-4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0817] Example 216: (-)-4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0818] Example 217: (+)-4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0819] Example 218: (-)-4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0820] Example 219: (+)-4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0821] Example 220: (-)-4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0822] Example 221 ERRα AlphaScreen Assay This assay was based on the knowledge that nuclear receptors interact with cofactors in ligand-dependent substrates. The site of interaction has been mapped to an LXXLL motif present in the co-activator sequence. Short peptide sequences containing the LXXLL motif mimic the behavior of full-length coactivators.

[0823] The ERRα alpha screen assay described herein relies on the interaction of a coactivator peptide with purified, bacterially expressed ERRα ligand binding domain (ERRα-LBD); upon ligand binding, the ERRα protein may undergo a conformational change, resulting in a loss of coactivator binding.

[0824] Compounds of the invention were tested for their ability to disrupt ERRα-LBD protein binding to coactivator peptides using AlphaScreen® technology (Perkin Elmer). ERRα-LBD protein was expressed in E. coli as a 6xHis Small Ubiquitin-like Modifier (SUMO) fusion. Bacterially expressed 6His-SUMO-ERRα-LBD protein was purified using affinity chromatography. All experiments were performed at room temperature in 384-well white non-binding plates (Greiner) using 50 mM Tris-HCl (pH 7.5), 100 mM NaCl, 0.1% Pluronic F-127, 0.05% BSA, and 5 mM TCEP as buffer. The final DMSO concentration in the assay was 1%. Compounds were assayed in triplicate and incubated with 0.81 nM ERRα-LBD protein, 10 μg / mL streptavidin donor beads and 10 μg / mL Ni-chelate acceptor beads at room temperature for 1 h, followed by incubation with 15 nM biotin-PGC1α-3 peptide (QRRPCSELLKYLTTNDDPP) corresponding to amino acids 202-220 for 2 h.

[0825] AlphaScreen signals were measured using an Envision Xcite plate reader (Perkin Elmer). Data were normalized and curve fitting analysis was performed in GraphPad Prism7 using a four-parameter dose-response fit.

[0826] Multiple ICs for the same compound-protein pair 50 The average pIC for each compound is annotated 50 All exemplified compounds of Formula I (Examples 1-220) had an average pIC of 5 or greater. 50It was found to have value.

[0827] Examples 11, 18, 21, 22, 25, 28, 29, 30, 31, 37, 39, 46, 47, 48, 49, 50, 51, 58, 60, 63, 66, 67, 76, 77, 78, 79, 80, 82, 86, 88, 94, 95, 110, 113, 114, 118, 120, 121, 125, 126, 1 27, 130, 131, 132, 137, 140, 147, 148, 150, 151, 160, 161, 162, 165, 167, 168, 172, 183, 184, 187, 188, 191, 199, 215, 217, and 219 were found to have average pIC50 values ​​of ≥6 and <7.

[0828] Examples 2, 4, 9, 14, 17, 20, 26, 34, 35, 43, 44, 45, 59, 64, 65, 69, 70, 71, 72, 73, 74, 75, 85, 87, 92, 93, 103, 104, 105, 106, 107, 108, 109, 111, 112, 116, 117, 128, 139, 152, 153, 156, 159, 163, 164, 171, 181, 182, 190, 193, 195, 201, 203, 206, 209, 211, 213, and 216 were found to have average pIC50 values ​​of 7 or more and less than 8.

[0829] Examples 1, 8, 15, 19, 23, 24, 32, 33, 36, 40, 41, 42, 62, 68, 89, 90, 91, 96, 97, 98, 99, 100, 101, 102, 115, 119, 135, 136, 138, 141, 142, 143, 144, 145, 146, 149, 154, 155, 157, 166 , 169, 170, 173, 174, 175, 176, 177, 178, 179, 180, 186, 189, 192, 194, 196, 197, 198, 200, 202, 204, 205, 207, 208, 210, 212, 214, 218, and 220 were found to have average pIC50 values ​​of 8 or greater.

[0830] Example 222 Full-length ERRα reporter gene assay Inhibitors of the Examples Inhibitors 1, 4, 5, 8, 9, 13, 14, 15, 17, 18, 19, 20, 23, 24, 26, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 54, 57, 59, 62, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 7 9, 80, 82, 84, 85, 86, 87, 88, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 115, 116, 117, 119, 128, 130, 132, 135, 136, 138, 139, 140, 141, 142, 1 43, 144, 145, 146, 147, 149, 150, 152, 153, 155, 156, 157, 159, 160, 161, 163, 164, 165, 166, 167, 168, 169, 170, 171, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 186, 188, 189, 190, 191, 192 , 193, 194, 195, 196, 197, 198, 199, 200, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, and 220 were tested for their ability to inhibit ERRα activity in a full-length ERRα reporter gene assay.

[0831] A method was established to quantitatively screen the potency of compounds with inverse agonist activity against the nuclear receptor ERRα of human species. The assay allows intracellular screening of ERRα inverse agonists in SK-BR-3 cells using an over-expression construct encoding full-length ERRα and a reporter construct containing an ERRα response element (RE) and a luciferase gene for readout. The activity is expressed as a logIC50 value and can be used to determine the SAR of a compound family or to deselect compounds.

[0832] In this assay, reporter cells are obtained by transient co-transfection of the two constructs in SK-BR-3 cells using standard transfection techniques. The first construct contains the response element of the nuclear receptor ERRα (plasmid pLP2175, reporter construct ERRα-RE / luc2P, a cloned variant of ERRa_v2_synthRE, Switchgear Genomics, catalog number S900089). This sequence drives the transcription of a luciferase reporter gene in response to binding of the ERRα protein encoded by the second construct (plasmid pLP2124: full-length ERRα expression construct using pcDNA3.1 / Hygro(+) as background, Invitrogen catalog number V87020). The overexpressed full-length ERRα is constitutively active, and therefore the expression of luciferase is reduced by inverse agonists of the nuclear receptor ERRα.

[0833] The day after transfection, cells were seeded into 96-well plates, test compounds were added, and the plates were incubated overnight. Firefly luciferase activity was then quantified using a luciferase detection reagent and luminescence readout.

[0834] Detailed assay description Transfection is performed on pre-seeded SK-BR-3 cells in a T175 flask. Depending on the confluency of the transfected cells, one transfected T175 flask is sufficient to seed 3-4 MW96 plates the next day.

[0835] Two different media are used for cell treatment in this protocol: 1) Culture Medium, McCoy's 5a with Phenol Red (BioWhittaker supplier number 12-688F), 10% FBS, and Penstrep.; and 2) Assay Medium, Penstrep.; McCoy's 5a Medium Phenol Red Free (HyClone product code SH30270.01) with 2% Charcoal Stripped FBS and 1x Penstrep. Compound dilutions are prepared in Assay Medium.

[0836] Cells are seeded at least 2 days in advance to allow the cells to fully attach to the flask before transfection. On the day of transfection, cells should be 50-80% confluent.

[0837] SKBR3 cells were transfected with the transcriptional reporter construct pLP2175 and the ERRα expression construct pLP2124 (as described above).

[0838] 68 μL of Lipofectamine LTX transfection reagent (Invitrogen Catalog No. 15338-100) was added dropwise to 8.9 ml of Opti-MEM I Reduced Serum Medium (Gibco Catalog No. 51985-026) and incubated at room temperature for 5-20 minutes. 8.9 ml of this reagent mixture was added to 22 μg of pLP2175 + 22 μg of pLP2124 (1:1 ratio and 10 ml total volume) and incubated at room temperature for 25 minutes.

[0839] 10 min before adding the transfection mix to SKBR3 cells in a T175 flask, the medium was refreshed with 20 mL of medium, then 10 mL of the DNA-Opti-MEM-Lipofectamine mixture was gently added to the cells, followed by overnight (16-24 h) incubation at 37°C and 5% CO2.

[0840] To harvest SKBR3 cells from a T175 flask, the medium was first removed. The cells were then washed with Phosphate Buffered Saline (PBS) (Lonza), after which the PBS was removed. To detach the cells, 2 ml of TrypLE Express (Invitrogen) was added to the flask, followed by incubation at 37°C for 5 minutes. The flask was gently tapped until the cells were detached from the bottom. The cells were harvested in 8 mL of medium (McCoy's 5a, 10% FBS, penstrep) to achieve a single cell suspension. After cell counting, the cells were spun down at 300 g for 5 minutes. The cell pellet was then resuspended in 25,000 cells / 80 μL assay medium (McCoy's 5a phenol red-free, 2% charcoal-stripped FBS, penstrep.).

[0841] For compound screening, cells were harvested (as described above) and 80 μL of cell suspension (25,000 cells) was seeded per well into white, flat-bottom, tissue culture-treated, 96-well screening plates (Greiner).

[0842] Test compounds were diluted in three dilution steps starting from a 10 mM dimethyl sulfoxide (DMSO) stock solution. The first dilution step was a 12-point serial dilution of 4-fold in DMSO. These dilutions were further diluted 10-fold in phenol red-free assay medium containing 2% charcoal-stripped FBS and penstrep. The final step was a further 20-fold dilution in assay medium to obtain 5-fold concentrated dilutions with a DMSO concentration of 0.5%. As a final step, compound dilutions were diluted 5-fold in cell plates.

[0843] A DMSO dilution series was constructed with 12 concentrations, with final concentrations on the cell plate ranging from 10 μM to 2.4 fM.

[0844] The plates were incubated overnight (16-24 hours) at 37° C. and 5% CO2.

[0845] To read luciferase, luciferase reagent (BriteLite Plus, Perkin Elmer) was warmed to room temperature. 100 μL of 2.5-fold diluted BriteLite Plus reagent was added to each test well of the screening plate and incubated at room temperature for 5 min. Luciferase luminescence signals were measured using a Wallac Victor Microplate Reader (Perkin Elmer).

[0846] Half-maximal inhibitory concentration values ​​(IC50) for test compounds were calculated from the luciferase signal using GraphPad Prism software (GraphPad Software). For completeness, multiple IC50 values ​​for the same compound and cell line pair were annotated and the average pIC for each compound was calculated. 50 It was decided.

[0847] From the exemplified compounds of formula I, Examples 1, 8, 9, 15, 19, 24, 32, 33, 36, 40, 62, 68, 89, 91, 93, 96, 97, 98, 99, 100, 101, 102, 106, 107, 115, 119, 140, 142, 143, 144, 145, 146, 147, 149, 150, 155, 157, 159, 166, 169, 170, 174, 175, 176, 177, 178, 179, 186, 189, 192, 194, 196, 198, 200, 202, 207, 208, 211, 212, and 214 had an average pIC 50 The values ​​were found to be 6.5 or higher.

[0848] Example 223 B16F10 melanoma syngeneic mouse model Example inhibitors 100, 191, 192, 194 and 196 were tested for their ability to inhibit tumor growth in the B16F10 melanoma syngeneic mouse model.

[0849] Cell lines and tumor models: Allograft model derived from the B16F10 melanoma cell line in C57BL / 6 mice.

[0850] Mouse B16F10 melanoma cells were supplied by the American Type Culture Collection (ATCC) (USA). Cells were cultured in DMEM (Invitrogen, Cat. No. 31600-034) supplemented with 10% FBS (Invitrogen, Cat. No. 10438-026) and 1% penicillin-streptomycin (Thermo Fisher Scientific, Cat. No. 15140-122). To establish allografts, cells were harvested by trypsinization when they reached approximately 70-80% confluence, and 100,000 B16F10 cells were suspended in 50 μL of serum-free medium and mixed with matrigel in a 1:1 ratio before being implanted subcutaneously into the dorsal right flank of mice using a 1 mL BD syringe attached to a 24-gauge needle.

[0851] B16F10 tumor grafts were measured 5 days after cell inoculation when they were palpable. After randomization of animals into different treatment groups, while maintaining tumor volume and number of animals, the mean tumor volume of each group remained the same between groups, with the mean tumor volume reaching approximately 58 mm. 3 Animals were dosed when they reached a dose of 0.01 mg / kg / day. Dosing was by mouth (per os, or po) once daily (quaque, or qd) on a per kilogram body weight basis.

[0852] Tumor size (length (l) and breadth (b)) was measured with calipers on the day animals were randomized based on tumor volume (day 1) and then three times a week until the end of the study. Tumor volume was calculated according to the formula b 2 * l * 0.52 (where l = length, b = width) was used (Dusan Djokovic et al., BMC Cancer, 2010, 10:641). Tumor growth inhibition was calculated after normalizing the tumor volume on a given day to the tumor volume on day 1.

[0853] The average tumor volume was 58 mm 3 When this was reached, administration of the test item was initiated.

[0854] Test article administration was performed until day 14, and tumor volume measurements were performed until day 13 to calculate percent tumor growth inhibition (TGI). The results of the study are listed in Table 1 below.

[0855] [Table 1]

[0856] In view of the above description and examples, it will be apparent to those skilled in the art that equivalent modifications can be made without departing from the scope of the claims. [Section 1] A compound according to formula I below or a pharma- ceutically acceptable salt thereof.

[208] JPEG0007606479000209.jpg101170 where, Z is -OCH2- or -CH2O-; Y is a carbon-carbon single bond or a carbon-carbon double bond, provided that when Y is a carbon-carbon double bond, R' 15 and R 16 does not exist; One of the three positions A1 to A3 is S or NR A and the remaining two of positions A1 to A3 are N or CR1, CR2, or CR3, respectively; R A is H or methyl; R1 to R3 are independently H, methyl or a halogen atom; A4-A7 are each N or CR4, CR5, CR6 and CR7, with the proviso that no more than two of the four positions A4-A7 can be N simultaneously; A8~A 12 are N or CR8, CR9, and CR 10 , C.R.11 and CR 12 However, there are five positions A8 to A 12 No more than two of can be N at the same time; R4 to R7 are independently H, a halogen atom, C(1-6)alkyl, amino, (di)C(1-3)alkylamino, C(1-3)alkoxy, C(1-3)alkoxyC(1-3)alkoxy, -C(O)O R 17 , -C(O)NR 17 R 17 or nitro, all of which may be optionally substituted with one or more halogen atoms or hydroxyl; R8~R 12 are independently H, a halogen atom, C(1-3)alkoxy, C(1-6)alkyl, cyano, cyanoC(1-3)alkyl, amino, nitro, aminoC(1-3)alkyl, -C(O)OR 17 , -CH2C(O)OR 17 , -C(O)NR 17 R 17 , -NHC(O)R 17 , acetyl, hydroxyl, C(3-6)cycloalkyl, C(2-3)alkynyl, C(2-3)alkenyl, carboxylC(1-3)alkyl, C(1-3)alkylsulfonyl, aminosulfonyl, (di)C(1-3)alkylamino, benzyl, SF5, or CH(=O), all of which are optionally substituted with one or more halogen atoms or hydroxyl; Or, R9 and R8 or R 10 is condensed with any one of the following to form a 5-7 membered aromatic or non-aromatic ring containing 2-7 carbon atoms and 0-3 heteroatoms, with the proviso that all groups may be optionally substituted with one or more methyl, halogen atoms, or hydroxyl; R 13 is H or methyl; R 14 is NH, O or S; R 15 and R' 15 are independently H, a halogen atom, a C(1-4) alkyl, a cyano, a carbo Xyl group , -C(O)OR17 , -C(O)NR 17 R 17 and; R 16 is H; and R 17 is H, C(1-4)alkyl, aminoC(1-3)alkyl, C(1-5)heteroaryl, or phenyl, provided that all groups are optionally substituted with one or more halogen atoms or hydroxyl. [Section 2] A1 is N and A2 is NR A and A3 is CR3. [Section 3] The compound according to item 2, wherein A1 is N, A2 is NH, and A3 is CH. [Section 4] The compound according to any one of items 1 to 3, wherein A4 to A7 are CR4 to CR7. [Section 5] Item 5. The compound according to item 4, wherein R5 is C(1-3)alkoxy, and R4, R6 and R7 are H. [Section 6] Item 6. The compound according to item 5, wherein R5 is methoxy, and R4, R6 and R7 are H. [Section 7] A8~A 12 CR8~CR 12 Item 7. The compound according to any one of items 1 to 6, wherein [Section 8] R8~R 12 are independently H, C(1-6)alkyl, a halogen atom, hydroxyl, NH2, acetyl, C(1-3)alkoxy, or SF5. [Section 9] R8~R 12 are independently H, C(1-6)alkyl, or a halogen atom. [Section 10] R8 and R 10 is C(1-6)alkyl, and R, R 11 and R 12 Item 10. The compound according to item 9, wherein is H. [Section 11] R8 and R 10 is CF3, and R9, R 11 and R 12 Item 11. The compound according to item 10, wherein [Section 12] R 13 Item 12. The compound according to any one of items 1 to 11, wherein is H. [Section 13] R 14 Item 13. The compound according to any one of items 1 to 12, wherein is O. [Section 14] R 15 and R' 15 Item 14. The compound according to any one of items 1 to 13, wherein is H. [Section 15] Item 15. The compound according to any one of items 1 to 14, wherein Z is -CH2O-, and CH2 is bonded to an aromatic ring including A4 to A7. [Section 16] Item 16. The compound according to any one of items 1 to 15, wherein Y is a carbon-carbon single bond. [Section 17] 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-chlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(4-chlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-bromophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(benzyloxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 2-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzonitrile; 4-(3-Methoxy-4-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[3-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(3-bromophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(3-chlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2,1,3-benzoxadiazol-4-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,5-bis(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-chloro-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-fluorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2-(difluoromethoxy)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[(2-nitrophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzonitrile; 4-(4-{[2-fluoro-6-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2,3-dichlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-iodophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[2-(trifluoromethoxy)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[(2-methoxy-5-nitrophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; Methyl 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoate; 4-(4-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2-fluoro-3-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2,5-dichlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[(2-methoxyphenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[(2,3,5-trichlorophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[5-methyl-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-bromo-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[4-nitro-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[5-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[3-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-methanesulfonyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-chloro-4-methanesulfonylphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2,3-dimethoxyphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-tert-butylphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; Methyl 4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)benzoate; 4-{4-[(6-bromo-2H-1,3-benzodioxol-5-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-ethynylphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(1-benzothiophen-7-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[(quinolin-8-yl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; Ethyl 2-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]benzoate; 4-(4-{[2-(difluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[3-(trifluoromethyl)pyridin-4-yl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(3,4-dihydro-2H-1,5-benzodioxepin-6-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[(2-methylphenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(isoquinolin-5-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-bromo-4,5-dimethoxyphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2,1,3-benzothiadiazol-4-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[3-(trifluoromethyl)pyridin-2-yl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[(pyridin-2-yl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-bromophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-chlorophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3,5-dimethoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-ethoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(5-{[2-(trifluoromethyl)phenyl]methoxy}pyridin-2-yl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(2-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzoate methyl; 4-(2-fluoro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-nitro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-(difluoromethoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-(trifluoromethoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-bromo-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-ethyl-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-chloro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-methyl-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-fluoro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(2-fluoro-5-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-(trifluoromethyl)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(2-fluoro-4-{[3-fluoro-2-(trifluoromethyl)phenyl]methoxy}-5-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-fluoro-5-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 7-{4-[(2-chlorophenyl)methoxy]-3-methoxyphenyl}-4H,5H,6H,7H-thieno[3,2-b]pyridin-5-one; 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[3-(trifluoromethyl)phenyl]methoxy}phenyl)-3-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-3-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-bromophenyl)methoxy]-3-methoxyphenyl}-1-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-1-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 7-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-4H,5H,6H,7H-thieno[3,2-b]pyridin-5-one; 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-7-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 7-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one; 7-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-4H,5H,6H,7H-[1,3]thiazolo[4,5-b]pyridin-5-one; 7-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-imidazo[4,5-b]pyridin-5-one; 7-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one; 7-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one; 7-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one; 7-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one; 7-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one; 3-Fluoro-4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[2-(pentafluoro-λ 6 -sulfanyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-acetyl-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenyl)methoxy]-3-(trifluoromethyl)benzonitrile; 4-(4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2-(pentafluoro-λ 6 -sulfanyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-(trifluoromethoxy)-4-{[2-(trifluoromethyl)phenoxy]methyl}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[2-methyl-4-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(3,5-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[3-methyl-5-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(3-hydroxyprop-1-yn-1-yl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzoic acid; 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzamide; 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-N-methyl-3-(trifluoromethyl)benzamide; 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-N,N-dimethyl 3-(trifluoromethyl)benzamide; 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-N-(1H-pyrazol-3-yl)-3-(trifluoromethyl)benzamide; 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoate propyl; Butyl 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoate; 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoate propan-2-yl; Ethyl 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzoate; N,N-dimethyl 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide; 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide; 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-N-(4H-1,2,4-triazol-3-yl)-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide; 2-hydroxyethyl 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzoate; N-methyl-5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide; N-(1H-imidazol-4-yl)-5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide; 4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 7-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one; 7-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one; 4-(4-{[4-(dimethylamino)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; N-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}acetamide; 2-Amino-N-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}acetamide; 4-(3-Methoxy-4-{[4-(methylamino)-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-methoxy-4-{[4-(prop-2-en-1-yl)-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(2,3-dihydroxypropyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-cyclopropyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(3-hydroxyprop-1-yn-1-yl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 2-[4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)phenyl]acetonitrile; 2-[4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)phenyl]acetate methyl; 4-(4-{[4-(3-hydroxypropyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(2-aminoethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 2-{4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)phenyl}acetic acid; 4-(4-{[4-(1-hydroxy-2-methylpropan-2-yl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(2-hydroxy-2-methylpropyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-hydroxy-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 7-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one; 7-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one; 4-(4-{[4-(hydroxymethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)benzaldehyde; 4-(4-{[3-(2-hydroxyethoxy)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-amino-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[2-(dimethylamino)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-(3-methoxypropoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-(2-methoxyethoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(2-{[2-(trifluoromethyl)phenyl]methoxy}pyrimidin-5-yl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-6-thione; 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-imine; 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-1H,6H,7H-pyrrolo[2,3-b]pyridin-6-one; 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[(2-methoxyphenyl)methoxy]phenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[3-(trifluoromethyl)pyridin-4-yl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[3-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[5-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2-(difluoromethoxy)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[(2-methoxy-4-{6-oxo-2H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)benzonitrile; 4-{3-methoxy-4-[(2-methoxy-5-nitrophenyl)methoxy]phenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(benzyloxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2-bromo-4,5-dimethoxyphenyl)methoxy]-3-methoxyphenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[(pyridin-2-yl)methoxy]phenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; Methyl 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxylate; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-N,N-dimethyl 6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxamide; 4-(3-Methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-1H,2H,3H,4H,6H-pyrrolo[3,4-b]pyridin-2-one; (+)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-7-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one; (-)-7-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one; (+)-4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-7-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one; (-)-7-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-b]pyridin-5-one; (+)-4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[4-hydroxy-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[4-hydroxy-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(3-methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(3-methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; and (-)-4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one The compound according to item 1, selected from the group consisting of: [Section 18] The following (4R)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one:

[209] JPEG0007606479000210.jpg52170; or The following (4S)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one [C210] Item 3. The compound according to item 1, wherein the compound is JPEG0007606479000211.jpg51170. [Section 19] Item 19. A pharmaceutical comprising a compound of formula I according to any one of items 1 to 18 or a pharma- ceutically acceptable salt thereof. [Section 20] 20. A compound of formula I as defined in any one of clauses 1 to 18 or a pharma- ceutically acceptable salt thereof for use in therapy. [Section 21] 19. A compound of formula I according to any one of clauses 1 to 18 or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of an ERRα mediated disease or condition. [Section 22] A compound of formula I according to any one of items 1 to 18 or a pharma- ceutically acceptable salt thereof for the treatment of ERRα-mediated cancer. [Section 23] A compound of formula I according to any one of items 1 to 18 or a pharma- ceutically acceptable salt thereof for the treatment of at least one condition selected from lung cancer, melanoma, endometrial cancer, and acute myeloid leukemia. [Section 24] Item 18. A compound of formula I or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 18, for the treatment of at least one condition selected from breast cancer, bladder cancer, prostate cancer, pancreatic cancer, colorectal cancer, and ovarian cancer. [Section 25] A compound of formula I according to any one of items 1 to 18 or a pharma- ceutically acceptable salt thereof for the treatment of type II diabetes. [Section 26] 19. A pharmaceutical composition comprising a compound of formula I according to any one of items 1 to 18 or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients. [Section 27] 27. The pharmaceutical composition of claim 26, further comprising at least one additional therapeutically active agent.

Claims

1. A compound according to formula I below or a pharma- ceutically acceptable salt thereof. 【Chemistry 01】 Where: Z is -CH 2 O-, said CH 2 being attached to an aromatic ring containing A 4 -A 7 ; Y is a carbon-carbon single bond or a carbon-carbon double bond, provided that when Y is a carbon-carbon double bond, R' 15 and R 16 does not exist; 3 Position A 1 ~A 3 One of the following is S or NR: A Either 1 ~A 3 The remaining two of them are N or CR. 1 , C.R. 2 , C.R. 3 and R A is H or methyl; R 1 ~R 3 are independently H, methyl or a halogen atom; A 4 ~A 7 are N or CR, respectively. 4 , C.R. 5 , C.R. 6 and CR 7 However, there are four positions A 4 ~A 7 No more than two of can be N at the same time; A 8 ~A 12 are N or CR, respectively. 8 , C.R. 9 , C.R. 10 , C.R. 11 and CR 12 However, there are five positions A 8 ~A 12 No more than two of can be N at the same time; R 4 ~R 7 are independently H, a halogen atom, C(1-6)alkyl, amino, (di)C(1-3)alkylamino, C(1-3)alkoxy, C(1-3)alkoxyC(1-3)alkoxy, -C(O)OR 17 , -C(O)NR 17 R 17 or nitro, all of which may be optionally substituted with one or more halogen atoms or hydroxyl; R 8 ~R 12 are independently H, a halogen atom, C(1-3)alkoxy, C(1-6)alkyl, cyano, cyanoC(1-3)alkyl, amino, nitro, aminoC(1-3)alkyl, -C(O)OR 17, -CH 2 C(O)OR 17 , -C(O)NR 17 R 17 , -NHC(O)R 17 , acetyl, hydroxyl, C(3-6)cycloalkyl, C(2-3)alkynyl, C(2-3)alkenyl, carboxylC(1-3)alkyl, C(1-3)alkylsulfonyl, aminosulfonyl, (di)C(1-3)alkylamino, benzyl, SF 5 or CH(=O), all of which may be optionally substituted with one or more halogen atoms or hydroxyl; Or, R 9 And, R 8 or R 10 or any of the following may be fused to form a 5-7 membered aromatic or non-aromatic ring containing 2-7 carbon atoms and 0-3 heteroatoms, provided that all groups are optionally substituted with one or more methyl, halogen or hydroxyl; R 13 is H or methyl; R 14 is NH, O or S; R 15 and R' 15 are independently H, halogen atoms, C(1-4) alkyl, cyano, carboxyl groups, -C(O)OR 17 , -C(O)NR 17 R 17 and R 16 is H; and R 17 is H, C(1-4)alkyl, aminoC(1-3)alkyl, C(1-5)heteroaryl, or phenyl, provided that all groups are optionally substituted with one or more halogen atoms or hydroxyl.

2. A 1 is N and A 2 NR A and A 3 CR 3 2. The compound of claim 1 ,

3. A 1 is N and A 2 is NH, and A 3 The compound of claim 2, wherein is CH.

4. A 4 ~A 7 CR 4 ~CR 7 The compound according to any one of claims 1 to 3,

5. R 5 is C(1-3)alkoxy, and R 4 , R 6 and R 7 The compound of claim 4, wherein is H.

6. R 5 is methoxy, and R 4 , R 6 and R 7 The compound of claim 5 , wherein

7. A 8 ~A 12 CR 8 ~CR 12 The compound according to any one of claims 1 to 6,

8. R 8 ~R 12 are independently H, C(1-6) alkyl, halogen atoms, hydroxyl, NH 2 , acetyl, C(1-3)alkoxy, or SF 5 8. The compound of claim 7,

9. R 8 ~R 12 is independently H, C(1-6)alkyl, or a halogen atom.

10. R 8 and R 10 is C(1-6)alkyl, and R 9 , R 11 and R 12 The compound of claim 9, wherein is H.

11. R 8 and R 10 CF 3 and R 9 , R 11 and R 12 The compound of claim 10, wherein is H.

12. R 13 The compound according to any one of claims 1 to 11, wherein is H.

13. R 14 The compound according to any one of claims 1 to 12, wherein is O.

14. R 15 and R' 15 The compound according to any one of claims 1 to 13, wherein is H.

15. The compound according to any one of claims 1 to 14, wherein Y is a carbon-carbon single bond.

16. 4-(4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[2-(pentafluoro-λ 6 -sulfanyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-Methoxy-4-{[2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-acetyl-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenyl)methoxy]-3-(trifluoromethyl)benzonitrile; 4-(4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2-(pentafluoro-λ 6 -sulfanyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-(trifluoromethoxy)-4-{[2-(trifluoromethyl)phenoxy]methyl}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-methoxy-4-{[2-methyl-4-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(3,5-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(3-methoxy-4-{[3-methyl-5-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[4-(3-hydroxyprop-1-yn-1-yl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; Methyl 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxylate; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-N,N-dimethyl 6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxamide; 4-(3-methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-1H,2H,3H,4H,6H-pyrrolo[3,4-b]pyridin-2-one; (+)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(3-methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(3-methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; and (-)-4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one 2. The compound of claim 1 selected from the group consisting of:

17. The following (4R)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one: 【Chemistry 02】 or The following (4S)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one 【Chemistry 03】 2. The compound of claim 1 ,

18. A pharmaceutical preparation comprising a compound of formula I according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof.

19. A compound of formula I, or a pharma- ceutically acceptable salt thereof, as defined in any one of claims 1 to 17 for use in therapy.

20. A compound of formula I or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 17 for use in the therapeutic and / or prophylactic treatment of an ERRα mediated disease or condition.

21. A compound of formula I, or a pharma- ceutically acceptable salt thereof, according to any one of claims 1 to 17 for use in the treatment of ERRα-mediated cancer.

22. 20. A compound of formula I, or a pharma- ceutically acceptable salt thereof, as defined in any one of claims 1 to 17, for use in the treatment of at least one condition selected from lung cancer, melanoma, endometrial cancer, and acute myeloid leukemia.

23. 18. A compound of formula I as claimed in any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, for use in the treatment of at least one condition selected from breast cancer, bladder cancer, prostate cancer, pancreatic cancer, colorectal cancer, and ovarian cancer.

24. A compound of formula I, or a pharma- ceutically acceptable salt thereof, as defined in any one of claims 1 to 17 for use in the treatment of type II diabetes.

25. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

26. 26. The pharmaceutical composition of claim 25, further comprising at least one additional therapeutically active agent.

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