Estrogen-related receptor α (ERRα) modulators

Abstract

The present invention relates to compounds according to formula I and pharmaceutically acceptable salts thereof. The compounds can be used as modulators of estrogen-related receptor alpha (ERRα) and for the treatment of ERRα-mediated diseases or conditions.

Description

Background of the Invention

[0002] Estrogen-related receptor alpha (ERRα) is a 45.5 kilodalton (kDa), 423 amino acid residue protein that belongs to the nuclear receptor (NR) superfamily. The nuclear receptor family contains 48 genes encoding DNA-binding transcription factors involved in regulating diverse functions including, inter alia, homeostasis, reproduction, development, and metabolism. The ERR family (NR3B subgroup) consists of ERRα, ERR-β, and ERR-γ: To date, no endogenous ligands have been identified for any of the ERR subtypes, and they are therefore considered orphan receptors.

[0003] In Bookout et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network, Cell. 126: 789–99 (2006), the expression profile of the whole organism range of three ERR subtypes determined that ERRα is widely distributed, with significant protein expression in most adult tissues. Knockout studies of ERR family members have shown that each receptor has a tissue-specific and function-specific metabolic phenotype that is important for adapting to energy stress at the whole body level. Knockout studies also show limited in vivo compensation between ERR family members. In this context, it can be noted that Tremblay et al. The NR3B subgroup: an overview, Nuclear receptor signaling, 5: e009 (2007) disclosure in particular.

[0004] Genomic studies have shown that ERRα regulates a large number of genes. The following references are instructive 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 receptorα 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).

[0005] These references support a physiological model of the function of ERRα in regulating energy metabolism and, in particular, 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 α (GABPα), and peroxisome proliferator-activated receptor α (PPARα). Nuclear receptor coactivators (peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), PGC-1β, and peroxisome proliferator-activated receptor γ coactivator-related protein 1 (PPRC-1)) are involved in the regulation of these genes and the self-regulation of the expression of ERRα. PGC-1α is expressed at low basal levels but is induced by fasting and other metabolic stresses. PGC-1β is a related coactivator that has similar functions, but its expression may not be as sensitive as that regulated by changes in energy demand. In contrast, co-repressors that bind to ERRs, such as the co-repressor nuclear receptor interacting protein 140 (RIP140), compete with ERR coactivators to negatively regulate ERR-dependent gene expression.

[0006] The pleiotropic effects of ERRα activity on energy metabolism have aroused the inventors' interest in the possibility that it should be a target for the discovery of new therapies 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 new target for tumor therapy through its effects on the regulation of tumor cell energy metabolism associated with energy stress within the tumor microenvironment. And of particular interest is ERRα as a new 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)) that rely on mitochondrial respiration for meeting their energy needs.

[0007] It is particularly known that the initiation and development of cancer are associated with major metabolic changes, and mitochondria play a key role in tumorigenesis. A common abnormality observed in many cancer types (known as the Warburg effect) is the shift of glucose metabolism from oxidative phosphorylation to aerobic glycolysis, and is characterized by a sharp increase in glucose consumption accompanied by an elevated lactate secretion rate, regardless of oxygen abundance: aerobic glycolysis meets the metabolic needs of highly proliferative cells, including providing sufficient energy and providing accumulation of precursors for anabolic reactions. LeBleu et al. PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells topromote metastasis. Nat. Cell Biol. 16 (10): 992-1 (2014) demonstrated that tumor cells show metabolic plasticity to participate in glycolysis or oxidative phosphorylation according to the tumor environment and their proliferation or metastatic phenotype during cancer progression. It is therefore clear that targeting of metastatic progenitor cells and resistant tumor cells should occur not only via the glycolytic pathway, but also via mitochondrial oxidative phosphorylation.

[0008] 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 cancer cells and prostate cancer cells, and is associated with more aggressive disease and a higher risk of recurrence in both cancer types.

[0009] 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 implication of estrogen-related receptor (ERR) expression in ovarian cancers, J.Steroid Biochem.Mol.Biol.104, 301-304 (2007) record that ERRa is expressed in most cancers, and increased activity of the receptor is associated with negative results in breast and ovarian cancers. In the first of these references, it was confirmed that the transcription factor is involved in mitochondrial biogenesis and also in the regulation of oxidative phosphorylation. The latter point is considered important because the inhibition of the Kras pathway in pancreatic cancer, the BRAF inhibitors in melanoma, and the resistance to oxaliplatin and 5-fluorouracil in colon cancer are also associated with a shift to oxidative metabolism.

[0010] Therefore, the inventors believe that inhibition of ERRα activity will enable selective disruption of mitochondrial function in cancer, particularly in the aforementioned types of cancer. To this end, but also for use in the treatment of other ERRα-mediated diseases and conditions, they have developed non-covalent, non-steroidal ERRα inverse agonists. Summary of the invention

[0011] According to a first aspect of the present invention, there is provided a compound according to formula I

[0012]

[0013] or a pharmaceutically acceptable salt thereof, wherein:

[0014] Z is –OCH2– or –CH2O–;

[0015] 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;

[0016] One of the three positions A1–A3 is S or NR A , the other two positions of A1–A3 are N or CR1, CR2, and CR3 respectively;

[0017] R A is H or methyl;

[0018] R1-R3 are independently H, methyl or halogen;

[0019] A4–A7 are N or CR4, CR5, CR6, and CR7, respectively, provided that no more than two of the four positions A4–A7 can be N at the same time;

[0020] A8–A 12 N or CR8, CR9, CR 10 , CR 11 and CR 12 , the condition is A8–A 12 No more than two of the five positions can be N at the same time;

[0021] R4-R7 are independently H, halogen, 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, wherein all groups are optionally substituted by one or more halogen or hydroxyl;

[0022] R8–R 12 are independently H, halogen, 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, hydroxy, C(3-6)cycloalkyl, C(2-3)alkynyl, C(2-3)alkenyl, carboxyC(1-3)alkyl, C(1-3)alkylsulfonyl, aminosulfonyl, (di)C(1-3)alkylamino, benzyl, SF5 or CH(═O), all of which are optionally substituted by one or more halogen or hydroxyl;

[0023] Or R9 and R8 or R 10 fused to form an aromatic or non-aromatic five to seven membered ring containing two to seven carbon atoms and zero to three heteroatoms; wherein all groups are optionally substituted with one or more methyl, halogen or hydroxyl groups;

[0024] R 13 is H or methyl;

[0025] R 14 is NH, O or S;

[0026] R 15and R' 15 are independently H, halogen, C(1-4)alkyl, cyano, carboxylic acid, -C(O)OR 17 、-C(O)NR 17 R 17 ;

[0027] R 16 is H; and

[0028] R 17 is H, C(1-4)alkyl, aminoC(1-3)alkyl, C(1-5)heteroaryl or phenyl, all of which are optionally substituted by one or more halogen or hydroxy.

[0029] In one embodiment, the invention relates to compounds according to formula I, wherein A1 is N, A2 is NR A , and A3 is CR3.

[0030] In another embodiment the invention relates to compounds according to formula I, wherein A1 is N, A2 is NH, and A3 is CH.

[0031] In another embodiment the invention relates to compounds according to formula I, wherein the A4, A5, A6 and A7 positions are CR4, CR5, CR6 and CR7, respectively.

[0032] In another embodiment the invention relates to compounds according to formula I, wherein R5 is C(1-3)alkoxy, and R4, R6 and R7 are H.

[0033] In another embodiment the invention relates to compounds according to formula I, wherein R5 is methoxy, and R4, R6 and R7 are H.

[0034] In another embodiment, the invention relates to compounds according to formula I, wherein A8, A9, A 10 , A 11 and A 12 The positions are CR8, CR9, CR 10 , CR 11 and CR 12 .

[0035] In another embodiment, the present invention relates to compounds according to formula I, wherein R8-R 12 Independently, they are H, C(1-6)alkyl, halogen, hydroxy, NH2, acetyl, C(1-3)alkoxy or SF5.

[0036] In another embodiment, the present invention relates to compounds according to formula I, wherein R8-R 12 are independently H, C(1-6)alkyl or halogen.

[0037] In another embodiment, the invention relates to compounds according to formula I, wherein R8 and R 10 is C(1-6) alkyl, and R9, R 11 and R 12 It's H.

[0038] In another embodiment, the invention relates to compounds according to formula I, wherein R8 and R 10 is CF3, and R9, R 11 and R 12 It's H.

[0039] In another embodiment, the invention relates to compounds according to formula I, wherein R 13 It's H.

[0040] In another embodiment, the invention relates to compounds according to formula I, wherein R 14 It's O.

[0041] In another embodiment, the invention relates to compounds according to formula I, wherein R 15 and R' 15 It's H.

[0042] In another embodiment the invention relates to compounds according to formula I, wherein Z is -CH2O-, wherein CH2 is attached to the aromatic ring containing A4-A7.

[0043] In another embodiment the invention relates to compounds according to formula I, wherein Y is a carbon-carbon single bond.

[0044] When the above embodiments refer to preferred forms of different substituents of formula (I), they are not intended to be mutually exclusive. On the contrary, all combinations of these embodiments are envisioned within the scope of the present invention, and in some cases, such combinations represent preferred structures of compounds of formula I. In this regard, particular mention may be made of compounds according to formula I, wherein: R 14 is O; Z is -CH2O-, CH2 of which is attached to an aromatic ring containing A4-A7; and Y is a carbon-carbon single bond. Mention may also be made of compounds according to formula I, wherein: R8 and R 10 is CF3 and R9, R 11 and R 12 It is H; R 13 It is H; R 14 is O; Z is -CH2O-, wherein CH2 is attached to the aromatic ring containing A4-A7; and Y is a carbon-carbon single bond.

[0045] definition

[0046] As used herein, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0047] As used herein, the terms "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 components, elements, or method steps. If used, the phrase "consisting of is closed and excludes all additional elements. Furthermore, the phrase "consisting essentially of excludes additional essential elements, but permits the inclusion of insubstantial elements that do not significantly alter the nature of the invention.

[0048] When amounts, concentrations, sizes and other parameters are expressed in the form of ranges, preferred ranges, upper values, lower values, or upper and lower preferred values, it should be understood that any range obtainable by combining any upper limit or preferred value with any lower limit or preferred value is also specifically disclosed, regardless of whether the obtained range is clearly mentioned in the context.

[0049] In some cases, the words "preferred", "preferably", "desirably" and "particularly" or their synonyms may be frequently used herein to refer to embodiments of the present disclosure that may provide particular benefits. 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 those other embodiments from the scope of the present disclosure.

[0050] As used throughout this application, the word "may" is used in a permissive sense (meaning having a possibility), rather than in a mandatory sense.

[0051] As used herein, "room temperature" is 23°C ± 2°C.

[0052] As used herein, the term "halo" or "halogen" or "halide," by itself or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom, unless otherwise stated. Note that fluorine, chlorine, or bromine are preferred.

[0053] The term "heteroatom" as used herein means nitrogen, oxygen or sulfur.

[0054] The term "radical" is used herein in accordance with the definition of molecular entities in IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Edited by AD McNaught and A. Wilkinson, Blackwell Scientific Publications, Oxford (1997).

[0055] 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 straight-chain and branched organic groups. 30 An "alkyl" group refers to a monovalent group containing 1 to 30 carbon atoms, which is a radical of an alkane and includes straight-chain and branched organic groups. In the present invention, such an alkyl group may be unsubstituted or may be substituted with the groups mentioned herein below. Halogenated derivatives of hydrocarbon groups may especially be mentioned as examples of suitable substituted alkyl groups.

[0056] The term "C (1-6) alkyl" as used herein refers to a branched or straight chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. All carbon atoms may be optionally substituted by one or more halogens or hydroxyl groups.

[0057] The term "C(1-4)alkyl" as used herein refers to an alkyl group having 1 to 4 carbon atoms, i.e., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. All carbon atoms may be optionally substituted by one or more halogens or hydroxyl groups.

[0058] The term "C(1-3)alkyl" as used herein refers to an alkyl group having 1 to 3 carbon atoms, ie, methyl, ethyl, propyl or isopropyl. All carbon atoms may be optionally substituted by one or more halogens or hydroxyl groups.

[0059] The term "C(1-2)alkyl" as used herein refers to an alkyl group having 1-2 carbon atoms, ie, methyl or ethyl. All carbon atoms may be optionally substituted by one or more halogens or hydroxyl groups.

[0060] The term "C(3-6)cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon having 3 to 6 carbon atoms, ie, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. All carbon atoms may be optionally substituted by one or more halogens or methyl groups.

[0061] The term "C(2-3)alkynyl" as used herein refers to an alkynyl group having 2 to 3 carbon atoms, ie, ethynyl, 1-propynyl or 2-propynyl. All carbon atoms may be optionally substituted with one or more hydroxyl groups.

[0062] The term "C(2-3)alkenyl" as used herein refers to an alkenyl group having 2 to 3 carbon atoms, ie, ethylene, 1-propylene or 2-propylene.

[0063] The term "C(1-3)alkoxy" refers to an alkoxy group having 1 to 3 carbon atoms, wherein the alkyl portion is branched or straight chain. All carbon atoms are optionally substituted by one or more F or hydroxyl groups.

[0064] The term "C(1-3)alkoxyC(1-3)alkyl" refers to a C(1-3)alkoxy group connected to a C(1-3)alkyl group, both having the same meaning as previously defined.

[0065] The term "C(1-3)alkoxy C(1-3)alkoxy" used herein refers to a C(1-3)alkoxy group attached to a C(1-3)alkoxy group, wherein the term C(1-3)alkoxy group has the same meaning as previously defined.

[0066] The term "C (1-5) heteroaryl" as used herein refers to an aromatic group having 1-5 carbon atoms and 1-4 heteroatoms, which may be attached via a nitrogen atom (if applicable) or a carbon atom. Examples include pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and triazinyl. All carbon atoms may be optionally substituted by one or more halogens or methyl.

[0067] As used herein, the term "cyano" refers to a group of formula -CN.

[0068] The term "cyano C(1-3)alkyl" refers to a cyano group attached to a C(1-3)alkyl group at any position, wherein the terms "cyano" and "C(1-3)alkyl" have the same meanings as previously defined.

[0069] As used herein, "nitro group" or "nitro" refers to -NO2.

[0070] As used herein, the term "amino group" refers to a substituent of the formula -NH2. It is intended that the term encompasses its protonated form (-NH3 + ).

[0071] The term "amino C(1-3)alkyl" refers to an amino group attached to a C(1-3)alkyl group at any position, and the part "C(1-3)alkyl" has the same meaning as previously defined.

[0072] The term "(di)C(1-3)alkylamino" as used herein refers to an amino group independently mono- or di-substituted by C(1-3)alkyl groups having the same meaning as previously defined.

[0073] The term "C(1-3)alkylsulfonyl" denotes a group -S(O)2R, wherein R is a C(1-3)alkyl group, wherein the term "C(1-3)alkyl" has the same meaning as previously defined.

[0074] The term "aminosulfonyl" refers to the group -S(O)2-NH2, wherein the amino group is attached to the sulfonyl moiety.

[0075] The term "carboxy C(1-3)alkyl" refers to a group -C(O)OH attached to a C(1-3)alkyl group. The term "C(1-3)alkyl" has the same meaning as previously defined.

[0076] The term "substituted" means that one or more hydrogens on the designated atom are replaced with a group selected from the indicated group, provided that: the normal valency of the designated atom under existing circumstances is not exceeded; and the substitution results in a stable compound. Combinations of substituents are 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 isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0077] The term "optionally substituted" refers to optional substitution of the specified group, radical or moiety.

[0078] As used herein, "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.

[0079] The compounds of formula I may form salts which are also within the scope of the present invention. Unless otherwise stated, references herein to compounds of formula I should be understood as including references to salts thereof.

[0080] The term "pharmaceutically acceptable salt" is used according to its standard definition in the art to mean those salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation and / or allergic reaction within the scope of medical judgment: such use must be commensurate with a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. They can be obtained during the final isolation and purification of the compounds of the invention, or they can be obtained separately by reacting the free base functional group with a suitable inorganic 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 functional group of the compounds of the invention can react with a mineral base such as sodium hydroxide, potassium hydroxide or lithium hydroxide or with an organic base. For the sake of completeness, organic bases include common alkyl or heterocyclic amine salts, such as diethylamino, morpholine and piperidine salts.

[0081] 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 and mixtures thereof, including racemic mixtures, form part of the present invention. In particular, stereoisomeric forms of the compounds of formula I that are S-configured on the chiral center immediately adjacent to the pyrazole ring following the Cahn-Ingold-Prelog nomenclature system definitely form part of the present invention.

[0082] Those skilled in the art will appreciate that enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride); separating the diastereomers; and converting the individual diastereomers into the corresponding pure enantiomers, for example, by hydrolysis. Enantiomers can also be separated by using a chiral HPLC column.

[0083] It should also be recognized that various tautomers of compounds of formula I may be possible: it is therefore intended that all tautomeric forms of compounds of formula I form part of the present invention. For the sake of completeness, the term "tautomer" as used herein refers to the migration of a proton between adjacent single and double bonds. The tautomerization process is reversible: tautomers will generally reach an equilibrium state in which the double bond is resonance shared between two bond lengths.

[0084] The present invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and optionally other therapeutically active agents in admixture with a pharmaceutically acceptable excipient. 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.

[0085] The present invention also includes compounds of formula I in combination with one or more other drugs.

[0086] Compositions include, but are not limited to, those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, topical or rectal administration, all of which are administered in unit dosage form. For oral administration, the active ingredient can be presented as discrete units, such as tablets, capsules, powders, granules, solutions, suspensions, etc.

[0087] For parenteral administration, the pharmaceutical composition of the present invention can be presented in unit dose or multi-dose containers, such as injection liquids presented in predetermined amounts in, for example, sealed vials and ampoules. The pharmaceutical composition can also be stored in a freeze-dried (lyophilized) condition, which only requires the addition of a sterile liquid carrier such as water before use.

[0088] Mixed with such pharmaceutically acceptable adjuvants, the active agent can be compressed into solid dosage units, such as pills, tablets, or processed into capsules or suppositories. Through pharmaceutically acceptable liquids, the active agent can be used as a fluid composition, such as in the form of a solution, suspension or emulsion, which can be included in an injection formulation or in a spray, such as a nasal spray.

[0089] In order to make solid dosage units, it is contemplated to use conventional additives such as fillers, colorants, polymer binders, etc. In general, any pharmaceutically acceptable additive that does not interfere with the function of the active compound may be used. When used in appropriate amounts, suitable carriers that can be administered with the active agent of the present invention in the form of a solid composition include lactose, starch, cellulose derivatives, etc., or mixtures thereof. For parenteral administration, aqueous suspensions, isotonic saline solutions, and sterile injectable solutions may be used, and the suspension or solution may contain a pharmaceutically acceptable dispersant and / or wetting agent, such as propylene glycol or butylene glycol.

[0090] The invention also includes a pharmaceutical composition as hereinbefore described in combination with packaging material suitable for use with said composition, said packaging material comprising instructions for using said composition for the purpose as hereinbefore described.

[0091] The exact dose and administration regimen of the active ingredient or pharmaceutical composition thereof may vary with the specific compound, the route of administration, and the age and condition of the individual subject to whom the drug is administered.

[0092] In general, parenteral administration requires lower dosages than other methods of administration that are more dependent on absorption. In addition, dosages for humans preferably contain 0.0001 to 100 mg / kg body weight. The desired dosage can be presented as one dose or as multiple sub-doses administered at appropriate intervals throughout the day.

[0093] The compounds according to the invention or their pharmaceutically acceptable salts can be used as medicaments in therapy.

[0094] Another aspect of the present invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of an ERRα-mediated disease or ERRα-mediated condition. In particular, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of ERRα-mediated cancer.

[0095] The compounds of Formula I or pharmaceutically acceptable salts thereof may be used in therapy for treating 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 of Formula I or pharmaceutically acceptable salts thereof may be particularly useful in therapy for treating: superficial spreading melanoma; lentigo maligna; acral lentiginous melanoma; nodular melanoma; amelanotic melanoma; ocular melanoma; vulvar melanoma; or vaginal melanoma.

[0096] In another aspect, the compound having the general formula I or a pharmaceutically acceptable salt thereof can be used in therapy for treating at least one condition selected from: breast cancer; bladder cancer; prostate cancer; pancreatic cancer; colorectal cancer; and ovarian cancer.

[0097] In another aspect, the compound having the general formula I or a pharmaceutically acceptable salt thereof can be used to treat type II diabetes.

[0098] Also provided herein is a method of treating at least one condition selected from: lung cancer; melanoma; endometrial cancer; and acute myeloid leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof.

[0099] Also provided is a method of treating at least one condition selected from the group consisting of superficial spreading melanoma; lentigo maligna; acral lentigo melanoma; nodular melanoma; amelanotic melanoma; ocular melanoma; vulvar melanoma; and 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 pharmaceutically acceptable salt thereof.

[0100] Also provided is a method of treating 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 pharmaceutically acceptable salt thereof.

[0101] Also provided is a method for treating 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 pharmaceutically acceptable salt thereof.

[0102] As used herein, the phrase "therapeutically effective amount" refers to an amount of a subject compound or composition effective to produce the desired therapeutic effect. DETAILED DESCRIPTION OF THE INVENTION

[0104] As shown in the following examples, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods depict the synthesis of certain compounds of the present invention, the following general methods and other methods known to those skilled in the art can be applied to all compounds as described herein and subclasses and substances of each of these compounds.

[0105] General preparation method

[0106] The compounds described herein, including compounds of Formula I, Building Block I and Building Block II, are prepared by the reaction schemes described below. In addition, in the following schemes, when specific acids, bases, reagents, coupling agents, catalysts, solvents, etc. are mentioned, it should be understood that other suitable acids, bases, reagents, coupling agents, catalysts, solvents, etc. can be used and are included within the scope of the present invention. Modifications to reaction conditions (e.g., temperature, duration of reaction, or a combination thereof) are contemplated as part of the present invention.

[0107] The compounds obtained by using the general reaction sequence may not be sufficiently pure. The compounds can be purified by using any of the methods used for purifying organic compounds, such as crystallization or silica gel or alumina column chromatography using different solvents in appropriate proportions. All possible stereoisomers are contemplated within the scope of the present invention.

[0108] The abbreviations of the materials used in the reaction schemes and examples are as follows:

[0109] 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; D iBAl-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: hydroxy Benzotriazole; 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(P Ph3)4: tetrakis(triphenylphosphine)palladium(0); PhSCu(I): phenylsulfonylcopper; PPh3: triphenylphosphine; p-TsOH: p-toluenesulfonic acid; tBuOK: potassium tert-butoxide; tBuONO: tert-butyl nitrite; TEA: triethylamine; TEMPO: 2,2,6,6-tetramethylpiperidinyloxy; THF: tetrahydrofuran; TMS-Cl: trimethylchlorosilane; TOSMIC: p-toluenesulfonylmethyl isocyanide.

[0110] Chemical names are preferred IUPAC names generated using Marvin Sketch 17.24.1. If both a chemical structure and a chemical name are used to refer to a chemical compound, and there is ambiguity between the structure and the name, the structure governs.

[0111] Solution 1

[0112]

[0113] condition: i) Meldrum's acid, MeOH

[0114] As shown in Scheme 1, the derivatives of the present invention having formula I can be prepared by methods known in the field of organic chemistry, wherein R 14 is oxygen, R 15 , R' 15 and R 16Each of A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 has the meaning as described above), derivatives of building block II (wherein R 13 , A1, A2 and A3 have the meanings as described above) and Meldrum's acid.

[0115] In order to obtain R 14 is a sulfur derivative of formula I, wherein R 14 The derivative of formula I which is oxygen is reacted with, for example, Lawesson's reagent.

[0116] In order to obtain R 14 is a nitrogen derivative of formula I, wherein R 14 The derivative of formula I which is sulfur is reacted with, for example, ammonia in MeOH.

[0117] If component I is at R4-R 12 If the analog contains an amine or aldehyde moiety, the moiety should be protected with an appropriate protecting group before reacting with the building block II derivative and Meldrum's acid, and should be deprotected using known methods afterwards to obtain the desired analog of formula I. By this route, amines can be obtained, which can be further derivatized using known methods to obtain secondary or tertiary amines or amides.

[0118] If one of R4-R7 in the Formula I analog is a nitro group, the nitro group can be reduced using, for example, iron and ammonium chloride in a water / THF / MeOH mixture to obtain a Formula I analog containing an amine at R4-R7.

[0119] If one of R4-R7 in the analog of Formula I is a methyl ester, the ester can be saponified under basic conditions to obtain the corresponding carboxylic acid. When the acid is reacted with alcohols and amines using methods known in the art, esters and amides can be formed.

[0120] Option 1b

[0121]

[0122] condition: i) DDQ, 1,4-dioxane

[0123] Scheme 1b depicts a general route for preparing analogs of Formula I, wherein Y is a carbon-carbon double bond, 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 Has the meaning as stated above.

[0124] The derivative of formula I wherein Y is a carbon-carbon single bond can be oxidized using, for example, DDQ in a suitable solvent to obtain the derivative of formula I wherein Y is a carbon-carbon double bond.

[0125] Solution 1c

[0126]

[0127] condition: i) TMS-Cl, KI, ACN;

[0128] ii) K2CO3, ACN;

[0129] iii) bis(pinacol)diboron, Pd(DPPF)Cl2·DCM, KOAc, 1,4-dioxane; and

[0130] iv) Pd(PPh3)4, K2CO3, 1,4-dioxane / water.

[0131] Scheme 1c shows another way to prepare analogs of Formula I, wherein Y is a carbon-carbon double bond, Z is -OCH2, A1 is NH, A2 and A3 are CH, R 13 and R 15 is H, and R 14 =O. A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 has the meaning as described above. Bromopyrrolopyridine can be prepared using, for example, TMS-Cl and KI in ACN 1 Demethylation. When these conditions are applied, the bromine is replaced by iodine to give an iodopyrrolopyridine 2 Benzyl bromide is prepared by using, for example, K2CO3 3 With phenol 4 The boronate building block is then obtained by coupling with, for example, bis(pinacolato)diboron, Pd(dppf)Cl2·DCM and KOAc in 1,4-dioxane. 5 When using, for example, Pd(PPh3)4 and K2CO3 in 1,4-dioxane / water to make the building blocks 2 and 5 Upon coupling via a palladium catalyzed reaction, the corresponding analogues of formula I are obtained.

[0132] Scheme 1d

[0133]

[0134] condition: i) LiOH, THF / water;

[0135] ii) LiOH, THF / water, then Me2S·BH3, THF;

[0136] iii) DiBAl-H, THF;

[0137] iv) RNH2, EDC, DMAP, DCM; and

[0138] v)ROH, EDC, DMAP, DMF

[0139] Scheme 1d depicts several options for functionalizing analogs of Formula I, where A 10 Yes CR 10 , where R 10 is CO2Me, Y is a carbon-carbon single bond, and R 15 , R' 15 and R 16 Each of them is H. Z, R 13 , R 14 ,A1,A2,A3,A4,A5,A6,A7,A8,A9,A 11 and A 12 Has the meaning as described above. 10 When the ester moiety is present in the formula, this can be saponified using, for example, LiOH in THF / water to obtain the carboxylic acid analog of Formula I. The carboxylic acid analog can be converted to the corresponding amide and ester using well-known methods, such as by reaction with an amine or alcohol. In another case, the ester moiety can be reduced to obtain a -CH2OH or -CHO analog. In Scheme 1d, this is R 10 To illustrate, these transformations can also be applied to R4 to R 12 The ester moiety in any of the positions.

[0140] Option 1e

[0141]

[0142] condition: i) Ammonia in MeOH, Raney nickel, MeOH.

[0143] Scheme 1e depicts a general route for preparing analogs of Formula I wherein Y is a carbon-carbon single bond and R 15 , R' 15 and R 16 Each of them is H. Z, R 13 , R14 ,A1,A2,A3,A4,A5,A6,A7,A8,A9,A 11 and A 12 Has the meaning as described above. 10 When the nitrile moiety is present in the reaction mixture, this can be reduced using, for example, ammonia in MeOH and Raney nickel as a catalyst to afford the saturated alkyl analog of Formula I. In Scheme 1e, this is represented by R 10 to illustrate, but these transformations can also be applied to R4 to R 12 The nitrile moiety in any of the positions.

[0144] Scheme 1f

[0145]

[0146] condition: i) Hydrogen, Pd / C, MeOH.

[0147] Scheme 1f depicts a general route for preparing analogs of Formula I wherein Y is a carbon-carbon single bond and R 15 , R' 15 and R 16 Each of them is H. Z, R 13 , R 14 ,A1,A2,A3,A4,A5,A6,A7,A8,A9,A 11 and A 12 Has the meaning as described above. 10 When there is a triple bond in the , this can be reduced using, for example, hydrogen with Pd / C in MeOH to afford the saturated alkyl analog of Formula I. Although in Scheme 1f, this is R 10 to illustrate, but these transformations can also be applied to R4 to R 12 Three-key portion in any of the positions.

[0148] Solution 1g

[0149]

[0150] condition: i) allyltri-n-butyltin, Pd(PPh3)2Cl, PPh3, DMF; and

[0151] ii) OsO4, NMO, acetone / water

[0152] Scheme 1g depicts a general route for functionalizing analogs of Formula I, wherein Y is a carbon-carbon single bond, A 10 is C-Br, R 15 , R' 15 and R16 Each of them is H, and Z, R 13 , R 14 ,A1,A2,A3 A4,A5,A6,A7,A8,A9,A 11 and A 12 has the meaning as previously described. The bromine-containing analog can be reacted with allyl tri-n-butyltin under Stille conditions. The obtained allyl-containing analog of Formula I can be further reacted by Upjohn dihydroxylation to obtain the dihydroxy-containing analog of Formula I. Although in Scheme 1g, this is R 10 to illustrate, but these transformations can also be applied to R4 to R 12 A bromine moiety in any of the positions.

[0153] Program 1h

[0154]

[0155] condition: i) Meldrum's acid, MeOH;

[0156] ii) ROH, DIAD, PPh3, THF; and

[0157] iii) R2NH, EDC, DMAP, DCM.

[0158] Scheme 1h depicts a general route for preparing analogs of Formula I, wherein Y is a carbon-carbon single bond, R 14 is oxygen, R 15 is COOH, and R' 15 and R 16 Each of A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 has the meaning as described above), derivatives of building block II (wherein R 13 , A1, A2, A3 have the meanings as described above) and Meldrum's acid at room temperature to obtain it.

[0159] When R 15 In the case of COOH, the carboxylic acid moiety can be functionalized as an ester using, for example, an alcohol, DIAD and PPh3 in THF. Alternatively, it can be functionalized as an amide using, for example, a primary or secondary amine, EDC and DMAP in DCM.

[0160] Option 1i

[0161]

[0162] Conditions: i) CH3CH2OCOCH2P(Ph)3Br, tBuOK, Et2O;

[0163] ii) CH2CHMgBr, PhSCu(I), THF;

[0164] iii) TEMPO, tBuONO, 1,4-dioxane;

[0165] iv) TOSMIC, tBuOK, THF; and

[0166] v) Zn, AcOH.

[0167] Scheme 1i illustrates a general route to form analogs of Formula I wherein A1 and A3 are CH, A2 is NH, Y is a carbon-carbon single bond, and R 14 is oxygen, R 13 Yes H, R 15 , R' 15 and R 16 Each of is H, and Z, A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 Has the meaning as stated above.

[0168] Intermediates 7 It can be obtained by Wittig reaction of building block I using, for example, CH3CH2OCOCH2P(Ph)3Br and tBuOK in Et2O followed by reaction with, for example, vinylmagnesium bromide and PhSCu(I) in THF. The nitro group can then be introduced in 1,4-dioxane in the E-configuration using, for example, TEMPO and tBuONO. The nitro group can be obtained by reacting the building block I in E-configuration using, for example, TOSMIC and tBuOK in THF via an intermediate 8 [3+2] cycloaddition to obtain pyrrole intermediate 9 Reduction of the nitro group is carried out in a single step by using, for example, zinc powder in AcOH followed by ring closure to afford the formula I analogs.

[0169] Solution 2

[0170]

[0171] condition: i) K2CO3, ACN

[0172] Scheme 2 describes a general method for preparing derivatives of benzaldehyde building blocks I wherein Z is -OCH2- and A4, A5, A6, A7, A8, A9, A 10 , A 11 and A12 Has the meaning as stated above.

[0173] Using for example K2CO3 under basic conditions with a benzyl halide 3 p-Hydroxybenzaldehyde 10 Alkylation is carried out to give the corresponding benzaldehyde derivative of building block I. The desired benzyl halide 3 It can also be obtained from the corresponding toluene or benzyl alcohol by bromination reaction known in the art.

[0174] After acetal protection of the aldehyde, palladium-catalyzed coupling can be used to make the R8-R 12 The building block I derivative containing a bromine in the aldehyde is further derivatized. After coupling, the aldehyde is again deprotected to obtain the building block I analog. When the ester moiety is obtained after the palladium-catalyzed coupling, the ester moiety can be reduced before deprotection of the aldehyde to obtain R8-R 12 The hydroxylated alkyl moiety in is then deprotected to obtain the desired analog of building block I. In another embodiment, when the ester moiety is obtained after the palladium catalyzed reaction, the ester can be reacted with Grignard's reagent to obtain a tertiary alcohol.

[0175] The aldehydes in R can be obtained from the corresponding bromo analogs of building blocks I by first protecting the aldehyde with an acetal. 10 Building block I analogs containing hydroxyl groups. The bromine is then converted to the boronate ester by palladium-catalyzed coupling, followed by reaction with hydrogen peroxide to introduce the hydroxyl moiety. After deprotection of the aldehyde, the building block I analog is obtained.

[0176] By using, for example, copper(II) bromide and potassium carbonate, R8-R 12 The bromine in the molecule can also be replaced by ethylene glycol.

[0177] In another embodiment, when R4-R7 in building block I is fluorine, the fluorine can be replaced with an appropriate amine under basic conditions (eg, K2CO3 in DMF at 110°C) to obtain the corresponding alkylamine analog of building block I.

[0178] Option 2b

[0179]

[0180] condition: (X=F; when A5=A6=N, X=Cl)

[0181] i) NaH, DMF

[0182] Scheme 2b depicts an alternative method for preparing derivatives of benzaldehyde building blocks I wherein Z is -OCH2- and A4, A5, A6, A7, A8, A9, A10 , A 11 and A 12 Has the meaning as stated above.

[0183] Benzaldehyde can be precipitated under basic conditions using, for example, sodium hydride in DMF. 11 With benzyl alcohol 12 Reaction to obtain building block I analogs.

[0184] Benzyl alcohol 12 It can be obtained by reduction of the corresponding benzaldehyde using, for example, a BH3·THF complex.

[0185] Solution 3

[0186]

[0187] condition: i) NBS, AIBN, ACN; and

[0188] ii) DiBAl-H, toluene

[0189] Scheme 3 describes the preparation of benzaldehyde 15 General methods for the preparation of derivatives, wherein A4, A5, A6 and A7 have the meanings as described above.

[0190] For example, NBS and AIBN were used to synthesize benzonitrile in ACN. 13 Bromination to give benzonitrile 14 Benzaldehyde can be prepared after reduction of the nitrile using, for example, DiBAl-H in toluene 15 derivative.

[0191] Option 3b

[0192]

[0193] condition: i) K2CO3, DMF

[0194] Scheme 3b describes a general method for preparing derivatives of benzaldehyde building blocks I wherein Z is -CH2O- and A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 Has the meaning as stated above.

[0195] Under alkaline conditions, such as using K2CO3 with benzaldehyde 15 Phenol 16 Alkylation affords the corresponding benzaldehyde derivative of building block I.

[0196] When the obtained component I is in R10 When bromine is present, this position can be functionalized using a palladium-catalyzed reaction, for example with Pd(PPh3)4, CuI, DBU and propargyl alcohol.

[0197] Solution 3c

[0198]

[0199] condition: i) K2CO3, ACN;

[0200] ii) DAST, DCM; and

[0201] iii) DiBAl-H, toluene.

[0202] Scheme 3c describes a general method for preparing derivatives of benzaldehyde building blocks I, wherein A 10 is CF2, Z is –CH2O–, and A4, A5, A6, A7, A8, A9, A 11 and A 12 Has the meaning as described above. Under alkaline conditions using, for example, K2CO3, with benzonitrile 14 Phenol 17 Alkylation to give the corresponding aldehyde 18 The aldehyde can be converted to a CF2 group using a fluorinating agent such as DAST. The benzaldehyde building block I derivative can be prepared by reducing the nitrile using, for example, DiBAl-H in toluene. In Scheme 3c, this is represented by R 10 For example, these transformations can also be applied to R4 to R 12 The aldehyde moiety in any of the positions.

[0203] The following examples are illustrative of the present invention and are not intended to limit the scope of the present invention in any way. Example

[0204] All components used are commercially available, known or prepared according to methods known to those skilled in the art.

[0205] Example 1-220

[0206] 1: 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0207]

[0208] i) K2CO3 (2.53 g) and vanillin (1.46 g) were added to a solution of 2-(trifluoromethyl)benzyl bromide (0.93 g) in ACN (60 mL). 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 distributed between water and DCM. The aqueous layer was extracted twice 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.

[0209] 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 out and washed with MeOH to obtain 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-6-one (289 mg) as an off-white solid. MS (ES) + )m / z418.2(M+H) + .

[0210] The following compounds were prepared following a procedure similar to that described in Example 1 using appropriate starting materials.

[0211] 2: 4-{4-[(2-chlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0212]

[0213] MS(ES + )m / z 384.2(M+H) + .

[0214] 3: 4-{4-[(4-chlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0215]

[0216] MS(ES + )m / z 384.2(M+H) + .

[0217] 4: 4-{4-[(2-bromophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0218]

[0219] MS(ES + )m / z 350.2(M+H) + .

[0220] 5: 4-[4-(Benzyloxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0221]

[0222] MS(ES + )m / z 428.2(M+H) + .

[0223] 6: 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzonitrile

[0224]

[0225] MS(ES + )m / z 375.2(M+H) + .

[0226] 7: 4-(3-methoxy-4-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0227]

[0228] MS(ES + )m / z 418.2(M+H) + .

[0229] 8: 4-(4-{[2,4-bis(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0230]

[0231] MS(ES + )m / z 486.2(M+H) + .

[0232] 9: 4-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0233]

[0234] MS(ES + )m / z 436.2(M+H) + .

[0235] 10: 4-(3-methoxy-4-{[3-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0236]

[0237] MS(ES + )m / z 418.2(M+H) + .

[0238] 11: 4-{4-[(3-bromophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0239]

[0240] MS(ES + )m / z 428.2(M+H) + .

[0241] 12: 4-{4-[(3-chlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0242]

[0243] MS(ES + )m / z 384.2(M+H) + .

[0244] 13: 4-{4-[(2,1,3-benzoxazol-4-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0245]

[0246] MS(ES + )m / z 392.1(M+H) +

[0247] 14: 4-(4-{[2,5-bis(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0248]

[0249] MS(ES + )m / z 486.2(M+H) + .

[0250] 15: 4-(4-{[4-chloro-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0251]

[0252] MS(ES + )m / z 452.2(M+H) + .

[0253] 16: 4-{4-[(2-fluorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0254]

[0255] MS(ES + )m / z 368.2(M+H) + .

[0256] 17: 4-(4-{[2-(difluoromethoxy)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0257]

[0258] MS(ES + )m / z 416.2(M+H) + .

[0259] 18: 4-{3-methoxy-4-[(2-nitrophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0260]

[0261] MS(ES + )m / z 395.2(M+H)+ .

[0262] 19: 4-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0263]

[0264] MS(ES + )m / z 448.2(M+H) + .

[0265] 20: 4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzonitrile

[0266]

[0267] MS(ES + )m / z 443.2(M+H) + .

[0268] 21: 4-(4-{[2-fluoro-6-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0269]

[0270] MS(ES + )m / z 436.2(M+H) + .

[0271] 22: 4-{4-[(2,3-dichlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0272]

[0273] MS(ES + )m / z 418.2(M+H) + .

[0274] 23: 4-{4-[(2-iodophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0275]

[0276] MS(ES+ )m / z 476.2(M+H) + .

[0277] 24: 4-(3-methoxy-4-{[2-(trifluoromethoxy)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0278]

[0279] MS(ES + )m / z 434.2(M+H) + .

[0280] 25: 4-{3-methoxy-4-[(2-methoxy-5-nitrophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0281]

[0282] MS(ES + )m / z 425.2(M+H) + .

[0283] 26: Methyl 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoate

[0284]

[0285] MS(ES + )m / z 408.2(M+H) + .

[0286] 27: 4-(4-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0287]

[0288] MS(ES + )m / z 486.2(M+H) + .

[0289] 28: 4-(4-{[2-fluoro-3-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0290]

[0291] MS(ES + )m / z 436.2(M+H) + .

[0292] 29: 4-{4-[(2,5-dichlorophenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0293]

[0294] MS(ES + )m / z 418.2(M+H) + .

[0295] 30: 4-{3-methoxy-4-[(2-methoxyphenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0296]

[0297] MS(ES + )m / z 380.2(M+H) + .

[0298] 31: 4-{3-methoxy-4-[(2,3,5-trichlorophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0299]

[0300] MS(ES + )m / z 452.2(M+H) + .

[0301] 32: 4-(3-methoxy-4-{[5-methyl-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0302]

[0303] MS(ES + )m / z 432.2(M+H) + .

[0304] 33: 4-(4-{[4-bromo-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0305]

[0306] MS(ES + )m / z 496.2(M+H) + .

[0307] 34: 4-(3-methoxy-4-{[4-nitro-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0308]

[0309] MS(ES + )m / z 463.2(M+H) +

[0310] 35: 4-(3-methoxy-4-{[5-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0311]

[0312] MS(ES + )m / z 448.2(M+H) +

[0313] 36: 4-(3-methoxy-4-{[3-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0314]

[0315] MS(ES + )m / z 448.2(M+H) +

[0316] 37: 4-(4-{[4-methylsulfonyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0317]

[0318] MS(ES + )m / z 496.2(M+H) +

[0319] 38: 4-{4-[(2-chloro-4-methylsulfonylphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0320]

[0321] MS(ES + )m / z 462.2(M+H) +

[0322] 39: 4-{4-[(2,3-dimethoxyphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0323]

[0324] MS(ES + )m / z 410.2(M+H) +

[0325] 40: 4-{4-[(2-tert-butylphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0326]

[0327] MS(ES + )m / z 406.2(M+H) +

[0328] 41: 4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0329]

[0330] MS(ES + )m / z 460.1(M+H) +

[0331] 42: 4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)benzoic acid methyl ester

[0332]

[0333] MS(ES + )m / z 476.1(M+H) +

[0334] 43: 4-{4-[(6-bromo-2H-1,3-benzodioxolan-5-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0335]

[0336] MS(ES + )m / z 472.0(M+H) +

[0337] 44: 4-{4-[(2-ethynylphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0338]

[0339] MS(ES + )m / z 374.1(M+H) +

[0340] 45: 4-{4-[(1-Benzothiophene-7-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0341]

[0342] MS(ES + )m / z 406.1(M+H) +

[0343] 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

[0344]

[0345] MS(ES + )m / z 420.2(M+H) +

[0346] 47: 4-{3-methoxy-4-[(quinolin-8-yl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0347]

[0348] MS(ES+ )m / z 401.2(M+H) +

[0349] 48: 2-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]benzoic acid ethyl ester

[0350]

[0351] MS(ES + )m / z 422.2(M+H) +

[0352] 49: 4-(4-{[2-(difluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0353]

[0354] MS(ES + )m / z 400.1(M+H) +

[0355] 50: 4-(3-methoxy-4-{[3-(trifluoromethyl)pyridin-4-yl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0356]

[0357] MS(ES + )m / z 419.1(M+H) +

[0358] 51: 4-{4-[(3,4-dihydro-2H-1,5-benzodioxepan-6-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0359]

[0360] MS(ES + )m / z 422.2(M+H) +

[0361] 52: 4-{3-methoxy-4-[(2-methylphenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0362]

[0363] MS(ES + )m / z 364.2(M+H) +

[0364] 53: 4-{4-[(isoquinolin-5-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0365]

[0366] MS(ES + )m / z 401.2(M+H) +

[0367] 54: 4-{4-[(2-bromo-4,5-dimethoxyphenyl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0368]

[0369] MS(ES + )m / z 488.1(M+H) +

[0370] 55: 4-{4-[(2,1,3-benzothiadiazol-4-yl)methoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0371]

[0372] MS(ES + )m / z 408.1(M+H) +

[0373] 56: 4-(3-methoxy-4-{[3-(trifluoromethyl)pyridin-2-yl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0374]

[0375] MS(ES + )m / z 419.1(M+H) +

[0376] 57: 4-{3-methoxy-4-[(pyridin-2-yl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0377]

[0378] MS(ES + )m / z 351.1(M+H) +

[0379] 58: 4-{4-[(2-bromophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0380]

[0381] MS(ES + )m / z 398.2(M+H) +

[0382] 59: 4-(4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0383]

[0384] MS(ES + )m / z 388.2(M+H) +

[0385] 60: 4-{4-[(2-chlorophenyl)methoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0386]

[0387] MS(ES + )m / z 354.2(M+H) +

[0388] 61: 4-(3,5-dimethoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0389]

[0390] MS(ES + )m / z 448.2(M+H) +

[0391] 62: 4-(3-ethoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0392]

[0393] MS(ES + )m / z 432.2(M+H) +

[0394] 63: 4-(5-{[2-(trifluoromethyl)phenyl]methoxy}pyridin-2-yl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0395]

[0396] MS(ES + )m / z 389.2(M+H) +

[0397] 64: 4-(2-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0398]

[0399] MS(ES + )m / z 418.2(M+H) +

[0400] 65: 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzoic acid methyl ester

[0401]

[0402] MS(ES + )m / z 446.2(M+H) +

[0403] 66: 4-(2-Fluoro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0404]

[0405] MS(ES + )m / z 406.2(M+H) +

[0406] 67: 4-(3-nitro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0407]

[0408] MS(ES + )m / z 433.2(M+H) +

[0409] 68: 4-[3-(difluoromethoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0410]

[0411] MS(ES + )m / z 454.1(M+H) +

[0412] 69: 4-[3-(trifluoromethoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0413]

[0414] MS(ES + )m / z 472.1(M+H) +

[0415] 70: 4-(3-Bromo-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0416]

[0417] MS(ES + )m / z 466.0(M+H) +

[0418] 71: 4-(3-ethyl-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0419]

[0420] MS(ES + )m / z 416.2(M+H) +

[0421] 72: 4-(3-Chloro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0422]

[0423] MS(ES + )m / z 422.1(M+H) +

[0424] 73: 4-(3-methyl-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0425]

[0426] MS(ES + )m / z 402.1(M+H) +

[0427] 74: 4-(3-Fluoro-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0428]

[0429] MS(ES + )m / z 406.1(M+H) +

[0430] 75: 4-(2-Fluoro-5-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0431]

[0432] MS(ES + )m / z 436.1(M+H) +

[0433] 76: 4-[3-(Trifluoromethyl)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0434]

[0435] MS(ES + )m / z 456.1(M+H) +

[0436] 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

[0437]

[0438] MS(ES + )m / z 454.1(M+H) +

[0439] 78: 4-(3-Fluoro-5-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0440]

[0441] MS(ES + )m / z 436.1(M+H) +

[0442] 79: 7-{4-[(2-chlorophenyl)methoxy]-3-methoxyphenyl}-4H,5H,6H,7H-thieno[3,2-b]pyridin-5-one

[0443]

[0444] MS(ES + )m / z 400.2(M+H) +

[0445] 80: 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0446]

[0447] MS(ES + )m / z 432.2(M+H) +

[0448] 81: 4-(3-methoxy-4-{[3-(trifluoromethyl)phenyl]methoxy}phenyl)-3-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0449]

[0450] MS(ES +)m / z 432.2(M+H) +

[0451] 82: 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-3-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0452]

[0453] MS(ES + )m / z 432.2(M+H) +

[0454] 83: 4-{4-[(2-bromophenyl)methoxy]-3-methoxyphenyl}-1-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0455]

[0456] MS(ES + )m / z 442.2(M+H) +

[0457] 84: 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-1-methyl-1H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0458]

[0459] MS(ES + )m / z 432.2(M+H) +

[0460] 85: 7-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-4H,5H,6H,7H-thieno[3,2-b]pyridin-5-one

[0461]

[0462] MS(ES + )m / z 434.2(M+H) +

[0463] 86: 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-7-methyl-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0464]

[0465] MS(ES + )m / z 432.2(M+H) +

[0466] 87: 7-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one

[0467]

[0468] MS(ES + )m / z 418.2(M+H) +

[0469] 88: 7-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-4H,5H,6H,7H-[1,3]thiazolo[4,5-b]pyridin-5-one

[0470]

[0471] MS(ES + )m / z 435.2(M+H) +

[0472] 89: 7-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-3H,4H,5H,6H,7H-imidazo[4,5-b]pyridin-5-one

[0473]

[0474] MS(ES + )m / z 418.2(M+H) +

[0475] 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

[0476]

[0477] MS(ES + )m / z 419.2(M+H) +

[0478] 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

[0479]

[0480] MS(ES + )m / z 449.2(M+H) +

[0481] 92: 7-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one

[0482]

[0483] MS(ES + )m / z 448.2(M+H) +

[0484] 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

[0485]

[0486] MS(ES + )m / z 461.1(M+H) +

[0487] 94: 7-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one

[0488]

[0489] MS(ES + )m / z 460.1(M+H) +

[0490] 95: 3-Fluoro-4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0491]

[0492] MS(ES + )m / z 436.1(M+H) +

[0493] 96: 4-(4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0494]

[0495] i) AIBN (1.29 g) was added to a solution of 3-methoxy-4-methyl-benzonitrile (11.55 g) and NBS (16.76 g) in ACN (550 mL). The reaction mixture was heated to 85 ° C and stirred for 4.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was distributed between water and EtOAc. The aqueous layer was extracted twice with EtOAc, 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 gel column using a gradient of EtOAc / heptane 0 / 100 to 18 / 82 as eluent to give 4-(bromomethyl)-3-methoxybenzonitrile (15.3 g).

[0496] Ii) under nitrogen atmosphere, the product obtained in the previous step (15.3g) was dissolved in anhydrous toluene and cooled to 0°C. DiBAl-H (1.2M toluene solution, 85mL) was added dropwise over a period of 30 minutes and stirred at 0°C for 1 hour. The reaction was quenched by adding 6NHCl aqueous solution (46mL). The reaction was diluted with water and the product was extracted 3 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 gel column using a gradient of toluene and EtOAc 100 / 0 to 80 / 20, followed by reverse phase flash chromatography using a gradient of ACN / H2O45 / 55 to 60 / 40 as eluent to obtain 4-(bromomethyl)-3-methoxybenzaldehyde (7.35g).

[0497] iii) the product obtained in the previous step (2.85g), 4-bromo-2-(trifluoromethyl)phenol (3.00g) and K2CO3 (5.16g) are loaded in a 250mL flask, and ACN (50mL) is added. The reaction mixture is heated to 70°C and stirred for 1 hour. The acetonitrile is evaporated and the crude product is distributed between water and EtOAc. The organic layer is washed with salt water, dried and concentrated with MgSO4. The product is suspended in methanol, solid is filtered out, washed with methanol, and dried in a vacuum oven to obtain 4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-methoxybenzaldehyde (4.10g).

[0498] iv) The compound obtained in the previous step was converted into 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) in a similar manner to the procedure described in step ii of Example 1. MS (ES) + )m / z 496.0(M+H) + .

[0499] The following compounds were prepared following procedures similar to those described in Example 96 steps i) to iv) using appropriate starting materials.

[0500] 97: 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0501]

[0502] MS(ES + )m / z 462.2(M+H) +

[0503] 98: 4-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0504]

[0505] MS(ES + )m / z 448.1(M+H) +

[0506] 99: 4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0507]

[0508] MS(ES + )m / z 452.1(M+H) +

[0509] 100: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0510]

[0511] MS(ES + )m / z 486.1(M+H) +

[0512] 101: 4-(3-methoxy-4-{[2-(pentafluoro-λ 6 -thio)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0513]

[0514] MS(ES + )m / z 476.1(M+H) +

[0515] 102: 4-(3-methoxy-4-{[2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0516]

[0517] MS(ES + )m / z 418.1(M+H) +

[0518] 103: 4-(4-{[4-acetyl-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0519]

[0520] MS(ES + )m / z 460.1(M+H) +

[0521] 104: 4-(4-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0522]

[0523] MS(ES + )m / z 436.1(M+H) +

[0524] 105: 4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenyl)methoxy]-3-(trifluoromethyl)benzonitrile

[0525]

[0526] MS(ES + )m / z 443.1(M+H) +

[0527] 106: 4-(4-{[4-bromo-2-(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0528]

[0529] MS(ES + )m / z 550.0(M+H) +

[0530] 107: 4-(4-{[2-(pentafluoro-λ 6 -(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0531]

[0532] MS(ES + )m / z 530.1(M+H) +

[0533] 108: 4-[3-(trifluoromethoxy)-4-{[2-(trifluoromethyl)phenoxy]methyl}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0534]

[0535] MS(ES + )m / z 472.1(M+H) +

[0536] 109: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0537]

[0538] MS(ES + )m / z 540.1(M+H) +

[0539] 110: 4-(4-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-3-(trifluoromethoxy)phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0540]

[0541] MS(ES + )m / z 490.1(M+H) +

[0542] 111: 4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0543]

[0544] MS(ES + )m / z 378.4(M+H) +

[0545] 112: 4-(3-methoxy-4-{[2-methyl-4-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0546]

[0547] MS(ES + )m / z 432.4(M+H) +

[0548] 113: 4-{4-[(3,5-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0549]

[0550] MS(ES + )m / z 378.4(M+H) +

[0551] 114: 4-(3-methoxy-4-{[3-methyl-5-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0552]

[0553] MS(ES + )m / z 432.4(M+H)+

[0554] 115: 4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0555]

[0556] 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 hours. 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).

[0557] Ii) under nitrogen atmosphere, the product obtained in the previous step (19.49g) is suspended in DCM (400mL).Drop DAST (23mL), and the reaction is stirred at room temperature for 5 days.During these days, the reaction becomes a solution.The reaction is placed on a water bath and carefully adds saturated NaHCO the aqueous solution, until no longer having gas to emit.The product is extracted three times with DCM, the organic layer MgSO4 combined is dried and concentrated.The product is loaded on diatomite and purified on a silica gel column, using the gradient of DCM / heptane 40 / 60 to 70 / 30, obtain 4-[[4-(difluoromethyl)-2-(trifluoromethyl) phenoxy] methyl]-3-methoxy-benzonitrile (19.4g).

[0558] iii) The product obtained in the previous step (19.40 g, 51.6 mmol, 1 equivalent) was suspended in toluene (427.5 mL) under a nitrogen atmosphere. The reaction was cooled to 0 ° C, and DiBAl-H (64 mL, 1.2 M toluene solution) was added dropwise over a period of 35 minutes. During the addition of DiBAl-H, the reaction became transparent and light yellow. After addition, the reaction was stirred at 0 ° C for 1.5 hours. 6M HCl aqueous solution (36 mL) was added dropwise, and then water was added. The product was extracted 3 times with EtOAc, and the combined organic layers were washed with brine, dried with MgSO4 and concentrated to give 4-[[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl]-3-methoxy-benzaldehyde (19.23 g).

[0559] iv) 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) in a similar manner to the procedure described in step ii of Example 1. MS (ES) + )m / z 468.4(M+H) + .

[0560] The following compounds were prepared following a procedure similar to that described in Example 115 using appropriate starting materials.

[0561] 116: 4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0562]

[0563] MS(ES + )m / z 450.4(M+H) +

[0564] 117: 4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0565]

[0566] MS(ES + )m / z 468.4(M+H) +

[0567] 118: 4-(4-{[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0568]

[0569] MS(ES + )m / z 468.4(M+H) +

[0570] 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

[0571]

[0572] i) The intermediate (1.00 g) obtained in step iii of Example 96 was dissolved in THF (10 mL) together with CuI (0.05 g) and DBU (0.46 mL). The reaction mixture was degassed for 15 minutes by bubbling with nitrogen therein. Pd(PPh3)4 (0.30 g) and propargyl alcohol (0.18 mL) were then added and the vial was sealed. The reaction was stirred at 60 ° C in a microwave for 16 hours. The reaction mixture was diluted with EtOAc and filtered through diatomaceous earth. The filtrate was concentrated, the residue was dissolved in EtOAc, and washed with H2O / brine and brine in sequence. The organic layer was dried with MgSO4, filtered and concentrated. The crude product was dissolved in DCM, loaded onto celite and purified by 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 as a beige powder (0.81 g).

[0573] 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) in a similar manner to the procedure described in step ii) of Example 1. MS (ES) + )m / z 472.4(M+H) +

[0574] 120: 4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzoic acid

[0575]

[0576] I) Example 42 (3.0g) is suspended in THF (30mL), and a solution of LiOH (0.45g) in water (15mL) is added. The yellow solution obtained is stirred at room temperature overnight. THF is evaporated, which results in the precipitation of the product. The aqueous suspension is filtered, and the solid is washed with water, ACN twice and Et2O successively. The residue is dried in a vacuum oven to obtain 4-(2-methoxy-4-{6-oxo-2H, 4H, 5H, 6H, 7H-pyrazolo [3,4-b] pyridin-4-yl} phenoxymethyl)-3-(trifluoromethyl) benzoic acid lithium (2.32g), which is a white powder.

[0577] Ii) The compound obtained in the previous step (50 mg) was suspended in water (10 mL) and a 2M HCl aqueous solution (2 mL) was added. The resulting suspension was stirred vigorously for 30 minutes 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) +

[0578] 121: 4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)-3-(trifluoromethyl)benzamide

[0579]

[0580] i) The product obtained in step i) of Example 120 (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 and filtered. The residue was washed with water, ACN twice and Et2O in sequence, and then dried in vacuo 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 / z461.2(M+H) +

[0581] The following compounds were prepared following procedures similar to those described in Example 121 using appropriate starting materials and solvents.

[0582] 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

[0583]

[0584] MS(ES + )m / z 475.2(M+H) +

[0585] 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

[0586]

[0587] MS(ES + )m / z 489.2(M+H) +

[0588] 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

[0589]

[0590] MS(ES + )m / z 527.2(M+H) +

[0591] 125: 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoic acid propyl ester

[0592]

[0593] MS(ES + )m / z 436.2(M+H) +

[0594] 126: 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoic acid butyl ester

[0595]

[0596] MS(ES + )m / z 450.2(M+H) +

[0597] 127: 2-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxymethyl)benzoic acid propan-2-yl ester

[0598]

[0599] MS(ES +)m / z 436.2(M+H) +

[0600] The following compounds were prepared following procedures similar to those described in Examples 120 and 121 using Example 65 as starting material and appropriate reagents and solvents.

[0601] 128: 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzoic acid ethyl ester

[0602]

[0603] MS(ES + )m / z 460.2(M+H) +

[0604] 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

[0605]

[0606] MS(ES + )m / z 459.2(M+H) +

[0607] 130: 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide

[0608]

[0609] MS(ES + )m / z 431.2(M+H) +

[0610] 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

[0611]

[0612] MS(ES + )m / z 498.2(M+H) +

[0613] 132: 2-Hydroxyethyl 5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzoate

[0614]

[0615] MS(ES + )m / z 476.2(M+H) +

[0616] 133: N-methyl-5-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}-2-{[2-(trifluoromethyl)phenyl]methoxy}benzamide

[0617]

[0618] MS(ES + )m / z 445.2(M+H) +

[0619] 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

[0620]

[0621] MS(ES + )m / z 497.2(M+H) +

[0622] 135: 4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0623]

[0624] i) 4-methyl-3-(trifluoromethyl)-aniline (4.88 g) was dissolved in 1,4-dioxane (15 mL) and saturated KCO aqueous solution (15 mL) was added. Then BocO (7.40 g) was added and the reaction was stirred at room temperature overnight. The product was extracted three times with EtOAc, the combined organic layers were washed with brine, dried over MgSO, filtered and concentrated to give 8.89 g of tert-butyl N-[4-methyl-3-(trifluoromethyl)phenyl]carbamate.

[0625] 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).

[0626] 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.

[0627] iv) Analogously to the procedure described in step ii) of Example 1, 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.

[0628] V) the product obtained in the previous step (93mg) is dissolved in DCM (1mL), and HCl gas is bubbled therein until the product precipitates. The reaction mixture is stirred for another 20 minutes, then concentrated under reduced pressure. The obtained residue is suspended in NaHCO3 aqueous solution, stirred for 5 minutes, then the solid is filtered out, and washed with water. The crude product is dissolved in ACN / MeOH, and purified by preparative HPLC to obtain 4- (4- { [4- amino -2- (trifluoromethyl) phenyl] methoxy} -3- methoxyphenyl) -2H, 4H, 5H, 6H, 7H- pyrazolo [3,4-b] pyridine -6- one, which is a white powder (21mg). MS (ES) + )m / z 433.4(M+H) +

[0629] The following compounds were prepared following a procedure similar to that described in Example 135 using appropriate starting materials and solvents.

[0630] 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

[0631]

[0632] MS(ES + )m / z 434.2(M+H) +

[0633] 137: 7-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one

[0634]

[0635] MS(ES + )m / z 433.2(M+H) +

[0636] 138: 4-(4-{[4-(dimethylamino)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0637]

[0638] 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 the addition of sodium cyanoborohydride (11 mg) in portions. After 40 minutes, the reaction mixture was concentrated and the resulting oil was basified with aqueous K2CO3 solution, 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) +

[0639] 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

[0640]

[0641] 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 a NaHCO3 aqueous solution 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), which was a white powder. MS (ES) +)m / z 475.4(M+H) +

[0642] 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

[0643]

[0644] i) Analogously to the procedure described in Example 139 using Example 135 (100 mg) as starting material, 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.

[0645] ii) Analogously to the procedure described in step v) of Example 135, 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) +

[0646] 141: 4-(3-methoxy-4-{[4-(methylamino)-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0647]

[0648] i) Under nitrogen atmosphere, a solution of the component (500 mg) obtained in step iii) of Example 135 in 3 mL of anhydrous THF was added to a cooling (0 ° C) suspension of NaH (94 mg, 60 wt%) in 2 mL of anhydrous THF. The reaction was heated to room temperature and stirred for 20 minutes, then MeI (2.9 mL, 2 M tert-butyl methyl ether solution) 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 merged, dried with MgSO4, filtered and concentrated to give a yellow oil. It was dissolved in DCM, loaded on silica powder and purified by silica gel chromatography, using an isocratic gradient of a heptane solution of 15% EtOAc to give N-{4-[(4-formyl-2-methoxyphenoxy)methyl]-3-(trifluoromethyl)phenyl}-N-methylcarbamic acid tert-butyl ester (107 mg), which was a colorless oil.

[0649] ii) Analogously to the procedure described in step ii) of Example 1, 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).

[0650] iii) Analogously to the procedure described in step v) of Example 135, 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 / z447.2(M+H) +

[0651] 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

[0652]

[0653] 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 minutes. 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) +

[0654] 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

[0655]

[0656] i) To a solution of Example 142 (100 mg) in acetone (1 mL) and H2O (0.1 mL) were added NMO (51 mg) and OsO4 (catalytic amount) in sequence. The reaction mixture was stirred at room temperature for three hours. A solution of sodium sulfite in 4 ml H2O was added and the reaction mixture was stirred for an additional 20 minutes. The product was extracted with EtOAc, 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 H2O as eluent to obtain 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 / z492.2(M+H) +

[0657] 144: 4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0658]

[0659] 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.

[0660] ii) Under Dean-Stark conditions, 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 for 7 hours. The reaction was cooled to room temperature and NaHCO3 was added. Toluene was added and the organic layer was washed with saturated NaHCO3 aqueous solution, H2O and brine in sequence. 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).

[0661] iii) the compound obtained in the previous step (100mg), K3PO4 (147mg) and ethylboric acid (51mg) are loaded into a vial. 1,4-dioxane (1mL) is added, and the resulting mixture is degassed by bubbling with nitrogen therein for 30 minutes. Pd(PPh3)2Cl2 is added, the vial is capped and stirred in a microwave at 90°C for 90 minutes. The reaction mixture is diluted with EtOAc and washed with H2O, 2N HCl aqueous solution, H2O and brine successively. The organic phase is dried with MgSO4, filtered and concentrated to give 2-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-1,3-dioxolane (48mg, yellow oil).

[0662] iv) add 0.41ml6M HCl aqueous solution to the solution of the compound (48mg) obtained in the previous step in THF (1mL). The obtained solution is stirred at room temperature overnight. THF is evaporated, and the aqueous mixture obtained is alkalized with saturated K2CO3 aqueous solution. Then the mixture is extracted with EtOAc, and saturated K2CO3 aqueous solution and salt water washing are used successively. The organic layer is dried with MgSO4, filtered and concentrated to obtain a yellow oil, which is dissolved in heptane. Filter out yellow powder, concentrate the filtrate, and obtain 4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxybenzaldehyde, which is a white powder.

[0663] v) The compound obtained in the previous step (57 mg) was converted into 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) in analogy to the procedure described in step ii) of Example 1. MS (ES) +)m / z446.2(M+H) +

[0664] The following compounds were prepared following procedures similar to those described in Example 144 using appropriate starting materials and solvents.

[0665] 145: 4-(4-{[4-cyclopropyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0666]

[0667] MS(ES + )m / z 458.2(M+H) +

[0668] 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

[0669]

[0670] MS(ES + )m / z 472.2(M+H) +

[0671] 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

[0672]

[0673] MS(ES + )m / z 457.2(M+H) +

[0674] 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

[0675]

[0676] MS(ES + )m / z 490.2(M+H) +

[0677] 149: 4-(4-{[4-(3-hydroxypropyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0678]

[0679] i) A solution of Example 146 (116 mg) in MeOH (10 mL) was degassed by bubbling nitrogen therein for 10 minutes. 10% Pd / C (52 mg, containing 50% H2O) was added and the reaction was bubbled with hydrogen for 3 hours. The reaction was filtered through celite and the filtrate was concentrated. The crude product was purified on 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) +

[0680] The following compounds were prepared following procedures similar to those described in Example 149 using Example 147 as starting material and appropriate reagents and solvents.

[0681] 150: 4-(4-{[4-(2-aminoethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0682]

[0683] MS(ES + )m / z 461.2(M+H) +

[0684] 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

[0685]

[0686] i) Using a procedure analogous to steps i) and ii) of Example 120, 66 mg of Example 148 was converted into 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) +

[0687] 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

[0688]

[0689] i) Following a procedure analogous to that described in Example 144, step iii), using the compound obtained from Example 144, step ii) (200 mg) and 1-methoxy-1-(trimethylsilyloxy)-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.

[0690] Ii) LiAlH4 (0.51 mL, 1M Et2O solution) was added to the cooled (0°C) solution of the product (58 mg) obtained in the previous step in anhydrous THF (1 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 30 minutes and then quenched by dropping EtOAc under cooling. The mixture was washed with saturated sodium potassium tartrate aqueous solution twice, saturated NaHCO3 aqueous solution and brine, then dried with MgSO4, filtered and concentrated to give a colorless oil. It 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 2-(4-{[4-(1,3-dioxolane-2-yl)-2-methoxyphenoxy]methyl}-3-(trifluoromethyl)phenyl)-2-methylpropan-1-ol as a colorless oil.

[0691] iii) Following a procedure analogous to that described in step iv) of Example 144, and then following a procedure analogous to that described in step ii) of Example 1, the compound obtained in the previous step (15 mg) was converted to 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 / z490.2(M+H) +

[0692] 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

[0693]

[0694] 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-methoxyethylene (512 mg), methyl 2-(4-{[4-(1,3-dioxolan-2-yl)-2-methoxyphenoxy]methyl}-3-(trifluoromethyl)phenyl)acetate (421 mg) was obtained.

[0695] Ii) the compound obtained in the previous step (421mg) was dissolved in 10mL of anhydrous THF under a nitrogen atmosphere. The reaction mixture was cooled to 10°C, and MeMgBr (1mL, 3M Et2O solution) was slowly added. The reaction mixture was stirred at room temperature for 30 minutes and then refluxed for 2 hours. The reaction was cooled to room temperature, 2mL of saturated NH4Cl aqueous solution was added, and the reaction mixture was stirred at room temperature overnight. 2mL of 2M HCl aqueous solution was added, and the mixture was stirred for 1h. The product was extracted three times with EtOAc, and the combined organic layers were dried with MgSO4, filtered and concentrated to give 1-(4-{[4-(1,3-dioxolane-2-yl)-2-methoxyphenoxy]methyl}-3-(trifluoromethyl)phenyl)-2-methylpropan-2-ol, which was a yellow oil (387mg). The product was used in the next step without further purification.

[0696] iii) Following a procedure similar to that described in step ii) of Example 1, the compound obtained in the previous step (387 mg) was converted into 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) +

[0697] 154: 4-(4-{[4-hydroxy-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0698]

[0699] MS(ES+ )m / z 434.1(M+H) +

[0700] i) The compound obtained in step ii) of Example 144 (100 mg), bis(pinacolato)diboron (88 mg) and KOAc (68 mg) in 1,4-dioxane (1 mL) was degassed with nitrogen for 20 minutes. Pd(dppf)Cl2 (19 mg) was added, the vial was capped and stirred at 80 ° C in a microwave for 16 hours. The reaction mixture was diluted with Et2O and filtered through diatomaceous earth. The filtrate was concentrated to give a brown oil. The crude product was purified on a silica gel column using a gradient of 0% to 50% EtOAc in heptane as an eluent to give 2-{4-[4-(1,3-dioxolane-2-yl)-2-methoxyphenoxymethyl]-3-(trifluoromethyl)phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborane (75 mg) as a colorless oil.

[0701] Ii) 30wt% aqueous hydrogen peroxide solution (425 μL) is added to the solution of the compound (75mg) obtained in the previous step in methanol (4mL). The resulting solution is stirred at room temperature for 1 hour. The reaction mixture is quenched with sodium sulfite (powder), and the organic solvent is evaporated under vacuum. The resulting aqueous suspension is diluted with water and extracted with EtOAc. The organic layer is washed with saturated NaHCO3 aqueous solution and brine successively, then dried with MgSO4, filtered and concentrated to obtain 4-[4-(1,3-dioxolane-2-yl)-2-methoxyphenoxymethyl]-3-(trifluoromethyl)phenol (60mg), which is a light yellow oil. The product is used in the next step without further purification.

[0702] iii) Following a procedure analogous to that described in step iv) of Example 144, and then following a procedure analogous to that described in step ii of Example 1, the compound obtained in the previous step (60 mg) was converted to 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) +

[0703] 155: 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0704]

[0705] i) LiAlH4 (0.86 mL, 1M Et2O solution) was added to the compound obtained in step i) of Example 151 at 0°C in anhydrous THF (1 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 90 minutes and then quenched by dropping EtOAc under cooling. The mixture was washed with saturated sodium potassium tartrate aqueous solution twice, saturated NaHCO3 aqueous solution and brine, then dried with MgSO4, filtered and concentrated to give 2-{4-[4-(1,3-dioxolane-2-yl)-2-methoxyphenoxymethyl]-3-(trifluoromethyl)phenyl}ethan-1-ol (60 mg), which was a colorless oil. The product was used in the next step without further purification.

[0706] ii) Following a procedure analogous to that described in step iv) of Example 144, and then following a procedure analogous to that described in step ii) of Example 1, the compound obtained in the previous step (60 mg) was converted to 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) +

[0707] The following compounds were prepared following a procedure similar to that described in Example 155 using appropriate starting materials.

[0708] 156: 7-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[4,3-b]pyridin-5-one

[0709]

[0710] MS(ES + )m / z 462.2(M+H) +

[0711] 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

[0712]

[0713] MS(ES + )m / z 463.2(M+H) +

[0714] 158: 4-(4-{[4-(hydroxymethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0715]

[0716] i) The compound obtained in step i) of Example 120 (200 mg) was suspended in anhydrous THF (4 mL) and BH3-Me2S (321 μL, 2M THF solution) was added dropwise. After stirring at room temperature for 2 hours, another 321 μL of BH3-Me2S (2M THF solution) was added dropwise, and the reaction mixture was stirred for 1 hour. 0.5M HCl aqueous solution 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 H2O 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 / z448.2(M+H) +

[0717] 159: 4-[(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)benzaldehyde

[0718]

[0719] i) Example 42 (146 mg) was dissolved in anhydrous THF (5 mL) under a nitrogen atmosphere. The solution was cooled to -78 ° C, and DiBAl-H (921 μL, 1M toluene solution) was added. The reaction was stirred at -78 ° C for 4 hours and then quenched with 1M HCl aqueous solution. The reaction was warmed to room temperature, and the product was extracted three times with EtOAc, the combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated to give 176 mg of crude product. The crude product was suspended in ACN, the solid was filtered out 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)+

[0720] 160: 4-(4-{[3-(2-hydroxyethoxy)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0721]

[0722] 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.

[0723] 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).

[0724] iii) The compound obtained in the previous step (100 mg), copper (II) bromide (16 mg) and K2CO3 (96 mg) were stirred overnight at 130 ° C in anhydrous ethylene glycol (0.5 mL). The reaction mixture was diluted with EtOAc and washed with H2O, saturated NaHCO3 aqueous solution and brine in sequence. The organic layer was then dried over MgSO4, filtered and concentrated to give a yellow solid. It was dissolved in ACN and purified by reverse phase flash chromatography to give 2-(3-{[4-(1,3-dioxolane-2-yl)-2-methoxyphenoxy]methyl}-2-(trifluoromethyl)phenoxy)ethane-1-ol (28 mg, beige solid).

[0725] iv) Analogously to the procedure described in step iv) of Example 144, and then following the procedure described in step ii) of Example 1, 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) +

[0726] 161: 4-(3-amino-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0727]

[0728] 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 the addition of iron powder (15 mg). The reaction mixture was stirred at 70 °C for 4 hours. The reaction mixture was then cooled to room temperature, diluted with EtOAc, filtered on celite and concentrated to give a colorless oil. The oil was purified on 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) +

[0729] 162: 4-[2-(Dimethylamino)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0730]

[0731] i) Following a procedure analogous 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).

[0732] Ii) the compound obtained in the previous step (100mg) was dissolved in DMF (2mL), and dimethylamine HCl (32mg) and K2CO3 (109mg) were added. The reaction mixture was heated to 110°C and stirred for 5 days. The reaction mixture was cooled to room temperature, and 10mL of water was added. The product was extracted three times with EtOAc, the combined organic layer was washed three times with brine, and MgSO4 was dried, filtered and concentrated to obtain 2-(dimethylamino)-4-{[2-(trifluoromethyl)phenyl]methoxy}benzaldehyde (107mg). The product was used in the next step without further purification.

[0733] iii) Following a procedure similar to that described in step ii) of Example 1, the compound obtained in the previous step (107 mg) was converted to 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) +

[0734] 163: 4-[3-(3-methoxypropoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0735]

[0736] 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 to 70°C overnight. The reaction mixture was cooled to room temperature and then distributed between EtOAc and water. The aqueous layer was extracted twice more with EtOAc, and the combined organic layers were dried with MgSO4, filtered and concentrated. The crude product was purified on a silica gel column using a gradient of 0% to 30% EtOAc in heptane as eluent to give 4-fluoro-3-(3-methoxypropoxy)benzaldehyde (198 mg).

[0737] Ii) NaH (14 mg) was added to a cooled (0°C) solution of [2-(trifluoromethyl)phenyl]methanol (193 mg) in anhydrous DMF (5 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 15 minutes, then the compound (109 mg) obtained in the previous step was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was distributed between EtOAc and water. The aqueous layer was extracted twice more with EtOAc, and the combined organic layers were dried with MgSO4, filtered and concentrated. The crude product was purified on a silica gel 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).

[0738] iii) Following a procedure similar to that described in step ii) of Example 1, the compound obtained in the previous step (96 mg) was converted to 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) +

[0739] The following compounds were prepared following a procedure similar to that described in Example 163 using appropriate starting materials.

[0740] 164: 4-[3-(2-methoxyethoxy)-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0741]

[0742] MS(ES + )m / z 462.2(M+H) +

[0743] 165: 4-(2-{[2-(trifluoromethyl)phenyl]methoxy}pyrimidin-5-yl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0744]

[0745] I) 2-chloropyrimidine-5-carboxaldehyde (200mg) and Cs2CO3 (914mg) are loaded into a flask and 15mL ACN is added. Then 2-(trifluoromethyl)benzyl alcohol (186μL) is added, and the reaction is stirred at room temperature for 4 days. The solvent is evaporated and the crude product is distributed between EtOAc and water. The water layer is extracted twice more with EtOAc, the combined organic layers are washed with brine, dried with MgSO4, filtered and concentrated. The crude product is purified by reverse phase flash chromatography to obtain 32mg 2-{[2-(trifluoromethyl)phenyl]methoxy}pyrimidine-5-carboxaldehyde.

[0746] ii) Following a procedure similar to that described in step ii) of Example 1, 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) +

[0747] 166: 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-6-thione

[0748]

[0749] 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) +

[0750] 167: 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-6-imine

[0751]

[0752] i) Example 166 (18 mg) was dissolved in 7N ammonia in MeOH (1.5 mL) under nitrogen. The reaction was stirred for 4 hours. 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]pyridine-6-imine (17 mg). MS (ES) + )m / z417.1(M+H) +

[0753] 168: 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-1H,6H,7H-pyrrolo[2,3-b]pyridin-6-one

[0754]

[0755] i) Following a procedure analogous 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).

[0756] 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).

[0757] 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 ACN, heated to 80 ° C and stirred for 3.5 hours. The solvent was evaporated and the crude product was distributed between water and EtOAc. The aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with brine, dried with 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]pyridine-6-ol (46 mg).

[0758] iv) In a microwave vial, 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 1,4-dioxane / water (3 / 1). The mixture was degassed with nitrogen for 15 minutes, Pd(PPh3)4 (20 mg) was added and the vial was capped. The reaction was stirred in a microwave at 100°C for 6 hours. 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) +

[0759] 169: 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0760]

[0761] 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 hour. The solvent was evaporated, and a saturated aqueous solution of 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 the product precipitated. The solid was filtered out and dried in a vacuum oven to give 4-(3-methoxy-4-{[2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridine-6-one (3 mg) as a light brown solid. MS (ES + )m / z 416.2(M+H) +

[0762] The following compounds were prepared following a procedure similar to that described in Example 169 using appropriate starting materials.

[0763] 170: 4-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0764]

[0765] MS(ES + )m / z 446.2(M+H) +

[0766] 171: 4-{3-methoxy-4-[(2-methoxyphenyl)methoxy]phenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0767]

[0768] MS(ES + )m / z 378.2(M+H) +

[0769] 172: 4-(3-methoxy-4-{[3-(trifluoromethyl)pyridin-4-yl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0770]

[0771] MS(ES + )m / z 417.2(M+H) +

[0772] 173: 4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0773]

[0774] MS(ES + )m / z 431.2(M+H) +

[0775] 174: 4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0776]

[0777] MS(ES + )m / z 458.2(M+H) +

[0778] 175: 4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0779]

[0780] MS(ES + )m / z 444.2(M+H) +

[0781] 176: 4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0782]

[0783] MS(ES + )m / z 460.2(M+H) +

[0784] 177: 4-(3-methoxy-4-{[3-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0785]

[0786] MS(ES + )m / z 446.1(M+H) +

[0787] 178: 4-(3-methoxy-4-{[5-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0788]

[0789] MS(ES + )m / z 446.1(M+H) +

[0790] 179: 4-(4-{[4-fluoro-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0791]

[0792] MS(ES + )m / z 434.1(M+H) +

[0793] 180: 4-(4-{[2-(difluoromethoxy)phenyl]methoxy}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0794]

[0795] MS(ES + )m / z 414.1(M+H) +

[0796] 181: 4-[(2-methoxy-4-{6-oxo-2H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)methyl]-3-(trifluoromethyl)benzonitrile

[0797]

[0798] MS(ES + )m / z 441.1(M+H) +

[0799] 182: 4-{3-methoxy-4-[(2-methoxy-5-nitrophenyl)methoxy]phenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0800]

[0801] MS(ES + )m / z 423.1(M+H)+

[0802] 183: 4-[4-(Benzyloxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0803]

[0804] MS(ES + )m / z 348.1(M+H) +

[0805] 184: 4-{4-[(2-bromo-4,5-dimethoxyphenyl)methoxy]-3-methoxyphenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0806]

[0807] MS(ES + )m / z 486.1(M+H) +

[0808] 185: 4-{3-methoxy-4-[(pyridin-2-yl)methoxy]phenyl}-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0809]

[0810] MS(ES + )m / z 349.1(M+H) +

[0811] 186: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0812]

[0813] MS(ES + )m / z 484.1(M+H) +

[0814] 187: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxylic acid methyl ester

[0815]

[0816] i) Following a procedure analogous to that described in Example 96 steps i) to iii) using appropriate starting materials, 4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxybenzaldehyde was obtained.

[0817] 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 obtaining 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), which was a yellow oil.

[0818] iii) Under nitrogen atmosphere, DIAD (33 μL) was added dropwise to a cooled (0°C) solution of PPh3 (44 mg) in anhydrous THF (1.5 mL). After stirring for 30 minutes, MeOH (53 μL) was added, followed by the dropwise addition of the product (69 mg) from the previous step dissolved in anhydrous THF (1 mL). The reaction was warmed to room temperature and stirred for 1 hour. 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 gel column using a gradient of 0 to 5% MeOH in DCM followed by reverse phase flash chromatography using a gradient of ACN / H2O2 0 / 80 to 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) +

[0819] 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

[0820]

[0821] i) The product obtained in step ii) of Example 187 (16 mg), DMAP (4.8 mg) and dimethylamine HCl (2.7 mg) were dissolved in DCM (1 mL) under a nitrogen atmosphere. EDC (8.1 mg) was added and the reaction was stirred at room temperature for 1 hour. Water was added and the aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried on a phase separation filter and concentrated. The product was purified by reverse 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) +

[0822] 189: 4-(3-methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0823]

[0824] i) Analogously to the procedure described in step ii) of example 144, starting from the product obtained in step iii) of example 96, 2-[4-[[4-bromo-2-(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]-1,3-dioxolane was obtained.

[0825] ii) trimethylcyclotriboroxane (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 hour in a microwave. The reaction was diluted with EtOAc and washed with water, 2N HCl aqueous solution, 2N NaOH aqueous solution, water and brine. The organic phase was filtered through diatomaceous earth, dried over MgSO4 and concentrated in vacuo to give 3-methoxy-4-[[4-methyl-2-(trifluoromethyl)phenoxy]methyl]phenyl]-1,3-dioxolane (164 mg).

[0826] iii) Analogously to the procedure described in step iv) of Example 144, the compound obtained in the previous step (164 mg) was converted into 3-methoxy-4-[[4-methyl-2-(trifluoromethyl)phenoxy]methyl]benzaldehyde (74 mg).

[0827] iv) Analogously to the procedure described in step ii) of Example 1, 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) +

[0828] 190: 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-1H,2H,3H,4H,6H-pyrrolo[3,4-b]pyridin-2-one

[0829]

[0830] i) Following a procedure analogous to that described in Example 96 steps i) to iii) using appropriate starting materials, 4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxybenzaldehyde was obtained.

[0831] 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 minutes 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 and then quenched with water, and the aqueous layer was extracted three times with Et2O. The combined organic layers were dried with MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using a heptane solution gradient of 0 to 20% EtOAc to obtain (E)-3-[4-[[2,4-bis(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]prop-2-enoic acid ethyl ester (932 mg).

[0832] iii) under nitrogen atmosphere at -40 ° C, vinyl magnesium bromide (1.0M THF solution, 6.25mL) was added dropwise to a suspension of phenylsulfonyl copper (362mg) in anhydrous THF (10mL). The reaction was allowed to reach -25 ° C and cooled to -40 ° C again. The compound (930mg) obtained in the previous step in anhydrous THF (10mL) was added dropwise, and the reaction was stirred at -40 ° C for 15 minutes. The reaction was quenched by pouring the mixture into a saturated NH4Cl aqueous solution. The resulting solid was filtered out and the filtrate was extracted twice with EtOAc. The combined organic layers were dried with MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using a heptane solution gradient of 0 to 30% EtOAc to give ethyl 3-[4-[[2,4-bis(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]pent-4-enoate (300mg).

[0833] 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 gel column using a gradient of 0 to 30% EtOAc in heptane to give (E)-3-[4-[[2,4-bis(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]-5-nitro-pent-4-enoic acid ethyl ester (190 mg).

[0834] 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 minutes. 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 at -78 ° C for 10 minutes, the reaction was poured into a saturated NH4Cl aqueous solution, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried with MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using a heptane solution gradient of 0 to 50% EtOAc to obtain 3-[4-[[2,4-bis(trifluoromethyl)phenoxy]methyl]-3-methoxy-phenyl]-3-(4-nitro-1H-pyrrole-3-yl)ethyl propionate (70 mg).

[0835] vi) Add zinc powder (59 mg) to a solution of the compound obtained in the previous step (50 mg) in AcOH (1.5 mL). The reaction was heated to 50 ° C and stirred for 30 minutes. The reaction mixture was filtered through diatomaceous earth and the filter cake was rinsed with EtOAc. The filtrate was washed with saturated NaHCO3 aqueous solution and water, then dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using a 0 to 4% MeOH solution gradient in DCM, followed by reverse phase flash chromatography using a 40 to 90% ACN solution gradient 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]pyridine-2-one (11 mg).

[0836] MS(ES + )m / z 485.4(M+H) +

[0837] 191: (4R)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0838] [(+)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one]

[0839]

[0840] 192: (4S)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0841] [(-)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one]

[0842]

[0843] Single enantiomers of Example 100 can be obtained by chiral separation. 20 mg of racemic Example 100 was dissolved in 1 mL IPA. The solution was injected on 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).

[0844] The absolute configuration of the compounds of Examples 193 to 220 is unknown. These compounds were characterized by their optical rotation using a polarimeter.

[0845] The following compounds were prepared following procedures similar to those described in Examples 191 and 192 using the appropriate starting materials and HPLC methods.

[0846] 193: (+)-4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0847] 194: (-)-4-(4-{[4-chloro-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0848] 195: (+)-4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0849] 196: (-)-4-(4-{[4-(difluoromethyl)-2-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0850] 197: (+)-4-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0851] 198: (-)-4-(3-methoxy-4-{[4-methoxy-2-(trifluoromethyl)phenyl]methoxy}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0852] 199: (+)-4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0853] 200: (-)-4-(4-{[4-acetyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0854] 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

[0855] 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

[0856] 203: (+)-4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0857] 204: (-)-4-(4-{[4-amino-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0858] 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

[0859] 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

[0860] 207: (+)-4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0861] 208: (-)-4-(4-{[4-ethyl-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0862] 209: (+)-4-(4-{[4-hydroxy-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0863] 210: (-)-4-(4-{[4-hydroxy-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0864] 211: (+)-4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0865] 212: (-)-4-(4-{[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenyl]methoxy}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0866] 213: (+)-4-(3-methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0867] 214: (-)-4-(3-methoxy-4-{[4-methyl-2-(trifluoromethyl)phenoxy]methyl}phenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0868] 215: (+)-4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0869] 216: (-)-4-(4-{[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0870] 217: (+)-4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0871] 218: (-)-4-(4-{[2,4-bis(difluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0872] 219: (+)-4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0873] 220: (-)-4-{4-[(2,4-dimethylphenoxy)methyl]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0874] Embodiment 221

[0875] ERRαAlphaScreen assay

[0876] The assay is based on the knowledge that nuclear receptors interact with cofactors in a ligand-dependent manner. The interaction site has been mapped to a LXXLL motif present in the coactivator sequence. Short peptide sequences containing the LXXLL motif mimic the behavior of the full-length coactivator

[0877] The ERRαAlphaScreen assay described herein relies on the interaction of coactivator peptides with purified bacterially expressed ERRα ligand-binding domain (ERRα-LBD); upon ligand binding, the ERRα protein can undergo conformational changes resulting in a loss of coactivator binding.

[0878] use The compounds of the present invention were tested for their ability to disrupt the binding of the ERRα-LBD protein to the coactivator peptide using the ELISA technology (Perkin Elmer). The ERRα-LBD protein was expressed as a 6xHis small ubiquitin-like modifier (SUMO) fusion in Escherichia coli (E. coli). The bacterially expressed 6His-SUMO-ERRα-LBD protein was purified using affinity chromatography. All experiments were performed in 384-well white non-binding plates (Greiner) at room temperature using 50mM Tris-HCl pH 7.5, 100mM NaCl, 0.1% Pluronic F-127, 0.05% BSA and 5mM TCEP as buffers. The final DMSO concentration in the assay was 1%. Compounds were assayed in triplicate and incubated with 0.81 nM ERRα-LBD protein and 10 μg / mL streptavidin donor beads and 10 μg / mL Ni-chelated acceptor beads for 1 hour at room temperature; followed by incubation with 15 nM biotin-PGC1α-3 peptide (QRRPCSELLKYLTTNDDPP) corresponding to amino acids 202 to 220 for 2 hours.

[0879] AlphaScreen signals were measured using an Envision Xcite microplate reader (Perkin Elmer). Data were normalized and curve fit analysis was performed in GraphPad Prism 7 using a four-parameter dose-response fit.

[0880] Since multiple ICs are annotated for the same compound-protein pair 50 values, so the average pIC was determined for each compound 50 All exemplified compounds of Formula I (Examples 1-220) were found to have an average pIC greater than or equal to 5. 50 value.

[0881] 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, 127, 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 an average pIC of greater than or equal to 6 but less than 7. 50 value.

[0882] It was found that 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 had an average pIC greater than or equal to 7 but less than 8 50 value.

[0883] It was found that 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 have an average pIC greater than or equal to 8 50 value.

[0884] Embodiment 222

[0885] Full-length ERRα reporter gene assay

[0886] Inhibitors of Example 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, 79, 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, 143, 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 82, 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.

[0887] A method was established to quantitatively screen the potency of compounds with inverse agonist activity against the nuclear receptor ERRα of the human species. The assay allows intracellular screening of ERRα inverse agonists in SK-BR-3 cells using an overexpression construct encoding full-length ERRα and a reporter construct containing the ERRα response element (RE) and a luciferase gene for readout. The activity is expressed as logIC50 values ​​and can be used to determine the SAR of a compound family or to deselect compounds.

[0888] In this assay, reporter cells were obtained by transiently co-transfecting two constructs in SK-BR-3 cells using standard transfection techniques. The first construct contained a response element for 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 transcription of the 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). Overexpressed full-length ERRα is constitutively active, so luciferase expression is reduced by inverse agonists of the nuclear receptor ERRα.

[0889] The day after transfection, cells were seeded into 96-well plates, test compounds were added and the plates were incubated overnight. Subsequently, firefly luciferase activity was quantified using luciferase detection reagents and luminescence readout.

[0890] Detailed assay description

[0891] Transfections were performed on pre-seeded SK-BR-3 cells in T175 flasks. Depending on the confluency of the transfected cells, one transfected T175 flask was sufficient to seed 3 to 4 MW96 plates the following day.

[0892] Two different media were used for cell treatment in this protocol: 1) culture medium, i.e., McCoy's 5a with phenol red (BioWhittaker supplier number 12-688F) containing 10% FBS and 1x penicillin-streptomycin (Penstrep.); and 2) assay medium, i.e., McCoy's 5a medium without phenol red (HyClone product number SH30270.01) containing 2% charcoal-stripped FBS and 1x penicillin-streptomycin. Compound dilutions were prepared in assay medium.

[0893] Seed the cells at least two days in advance to allow the cells to attach well to the flask before transfection. On the day of transfection, the cells should be 50-80% confluent.

[0894] SKBR3 cells were transfected with the transcriptional reporter construct pLP2175 and the ERRα expression construct pLP2124 (as described above).

[0895] 68 μL of Lipofectamine LTX transfection reagent (Invitrogen catalog number 15338-100) was added dropwise to 8.9 ml of Opti-MEM I reduced serum medium (Gibco catalog number 51985-026) and incubated at room temperature for 5 to 20 minutes. 8.9 ml of this reagent mixture was added to 22 μg pLP2175 + 22 μg pLP2124 (ratio 1:1 and total volume of 10 ml) and incubated at room temperature for 25 minutes.

[0896] 10 minutes before adding the transfection mixture to the SKBR3 cells in the T175 flask, the culture medium was renewed with 20 mL of culture medium. Subsequently, 10 mL of DNA-Opti-MEM-Lipofectamine mixture was gently added to the cells and then incubated overnight (16-24 hours) at 37°C and 5% CO2.

[0897] To harvest SKBR3 cells from a T175 flask, the culture medium was first removed. Subsequently, the cells were washed with phosphate buffered saline (PBS) (Lonza) and the PBS was removed. To dissociate the cells, 2 ml of TrypLE Express (Invitrogen) was added to the flask and then incubated at 37 ° C for 5 minutes. The flask was tapped until the cells were separated from the bottom. The cells were collected in 8 mL of culture medium (McCoy's 5a, 10% FBS, penicillin-streptomycin) to achieve a single cell suspension. After cell counting, the cells were spun down at 300 g for 5 minutes. The cell mass was then resuspended to 25,000 cells / 80 μl of assay medium (McCoy's 5a without phenol red, 2% charcoal-treated FBS, penicillin-streptomycin).

[0898] For compound screening, cells were harvested (as described above). 80 μL of cell suspension (25,000 cells) were plated per well into white, flat-bottom, tissue culture treated 96-well screening plates (Greiner).

[0899] Starting from a 10 mM dimethyl sulfoxide (DMSO) stock solution, the test compounds were diluted in 3 dilution steps. The first dilution step was a 4-fold 12-point serial dilution in DMSO. These dilutions were further diluted 10-fold in phenol red-free assay medium containing 2% charcoal-treated FBS and penicillin-streptomycin. The last step was another 20-fold dilution in assay medium to obtain a 5x concentrated dilution with a DMSO concentration of 0.5%. As a last step, the compound dilutions were diluted 5x in the cell plate.

[0900] The DMSO dilution series consisted of 12 concentrations with final concentrations in the cell plate ranging from 10 μM to 2.4 fM.

[0901] The plates were incubated at 37°C and 5% CO2 overnight (16-24 hours).

[0902] For luciferase readout, luciferase reagent (BriteLite Plus, Perkin Elmer) was allowed to reach room temperature. 100 μL of 2.5-fold diluted BriteLite Plus reagent was added to each test well of the screening plate and then incubated at room temperature for 5 minutes. Luciferase luminescence signal was measured using a Wallac Victor microplate reader (Perkin Elmer).

[0903] The half maximal inhibitory concentration (IC50) values ​​of the test compounds were calculated from the luciferase signal using GraphPad Prism software (GraphPad Software). For completeness, multiple IC50 values ​​were annotated for the same compound-cell line pair. 50 values ​​and determine the average pIC for each compound 50 .

[0904] Among 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 were found to have average pIC50 values ​​greater than or equal to 6.5.

[0905] Embodiment 223

[0906] B16F10 melanoma syngeneic mouse model

[0907] Example inhibitors 100, 191, 192, 194 and 196 were tested for their ability to inhibit tumor growth in the B16F10 melanoma syngeneic mouse model.

[0908] Cell Lines and Tumor Models: Allogeneic transplant models derived from the B16F10 melanoma cell line in C57BL / 6 mice.

[0909] Mouse B16F10 melanoma cells are derived from the American Type Culture Collection (ATCC) of the United States. Cells are grown in DMEM (Invitrogen, catalog number 31600-034) supplemented with 10% FBS (Invitrogen, catalog number 10438-026) and 1% penicillin-streptomycin (Thermo Fisher Scientific, catalog number 15140-122). In order to establish allogeneic grafts, when cells reach about 70 to 80% fusion, cells are harvested by trypsinization, and 100,000 B16F10 cells are suspended in 50 μl serum-free culture medium, and mixed with matrigel in a ratio of 1: 1, and then subcutaneously implanted into the right side of the back of mice using a 1mL BD syringe attached to a 24-gauge needle.

[0910] B16F10 tumor xenografts were measured 5 days after cell inoculation, once they became palpable. The average tumor volume reached approximately 58 mm 3 When the animals were randomized to different treatment groups, the tumor volume and the number of animals were maintained in such a way that the average tumor volume of each group remained the same between the groups. The drug was administered orally once a day (quaque die, qd) on a per kg basis (per os, po).

[0911] Tumor dimensions (length (l) and width (b)) were measured by caliper on the day animals were randomized based on tumor volume (Day 1) and three times weekly thereafter until study termination. 2 *l*0.52 to calculate tumor volume, where l = length, b = width (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.

[0912] When the tumor volume reaches 58 mm 3 The mean value was used to start the test item administration.

[0913] Administration of the test items was performed until day 14 and tumor volume was measured until day 13 to calculate the percent tumor growth inhibition (TGI).The results of the study are listed in Table 1 herein below.

[0914] Table 1

[0915]

[0916] With reference to the foregoing description and embodiments, it will be apparent to those skilled in the art that equivalent modifications may be made without departing from the scope of the claims.

Claims

1. Compounds according to formula I or a pharmaceutically acceptable salt thereof, wherein: Z is –CH2O–, wherein CH2 is attached to the aromatic ring containing A4-A7; 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–A3 is S or NR A , the other two positions of A1–A3 are N or CR1, CR2, and CR3 respectively; R A is H or methyl; R1-R3 are independently H, methyl or halogen; A4–A7 are N or CR4, CR5, CR6, and CR7, respectively, provided that no more than two of the four positions A4–A7 can be N at the same time; A8–A 12 N or CR8, CR9, CR 10 , CR 11 and CR 12 , the condition is A8–A 12 No more than two of the five positions can be N at the same time; R4-R7 are independently H, halogen, 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, wherein all groups are optionally substituted by one or more halogen or hydroxyl; R8–R 12 are independently H, halogen, 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, hydroxy, C(3-6)cycloalkyl, C(2-3)alkynyl, C(2-3)alkenyl, carboxyC(1-3)alkyl, C(1-3)alkylsulfonyl, aminosulfonyl, (di)C(1-3)alkylamino, benzyl, SF5 or CH(═O), all of which are optionally substituted by one or more halogen or hydroxyl; Or R9 and R8 or R 10 fused to form an aromatic or non-aromatic five to seven membered ring containing two to seven carbon atoms and zero to three heteroatoms; wherein all groups are optionally substituted with one or more methyl, halogen or hydroxyl groups; R 13 is H or methyl; R 14 is NH, O or S; R 15 is H or C(1-4)alkyl; R' 15 is H, halogen, C(1-4)alkyl, cyano, carboxylic acid, -C(O)OR 17 or -C(O)NR 17 R 17 ; R 16 is H; and R 17 is H, C(1-4)alkyl, aminoC(1-3)alkyl, C(1-5)heteroaryl or phenyl, all of which are optionally substituted by one or more halogen or hydroxy.

2. The compound according to claim 1, wherein A1 is N, A2 is NR A , and A3 is CR3.

3. The compound of claim 2, wherein A1 is N, A2 is NH, and A3 is CH.

4. The compound according to any one of claims 1 to 3, wherein A4-A7 is CR4-CR7.

5. The compound according to claim 4, wherein R5 is C(1-3)alkoxy, and R4, R6 and R7 are H.

6. The compound of claim 5, wherein R5 is methoxy, and R4, R6 and R7 are H.

7. A compound according to any one of claims 1 to 3, wherein A8-A 12 It is CR8-CR 12 .

8. The compound according to claim 7, wherein R8-R 12 Independently, it is H, C(1-6)alkyl, halogen, hydroxy, NH2, acetyl, C(1-3)alkoxy or SF5, wherein all carbon atoms of C(1-6)alkyl and C(1-3)alkoxy are optionally substituted by one or more halogen or hydroxy.

9. The compound according to claim 8, wherein R8-R 12 is independently H, C(1-6)alkyl or halogen, wherein all carbon atoms of the C(1-6)alkyl are optionally substituted with one or more halogen or hydroxyl.

10. The compound according to claim 9, wherein R8 and R 10 is C(1-6) alkyl, and R9, R 11 and R 12 is H, wherein all carbon atoms of the C(1-6)alkyl group are optionally substituted by one or more halogen or hydroxyl groups.

11. The compound according to claim 10, wherein R8 and R 10 is CF3, and R9, R 11 and R 12 It's H.

12. A compound according to any one of claims 1 to 3, wherein R 13 It's H.

13. A compound according to any one of claims 1 to 3, wherein R 14 It's O.

14. A compound according to any one of claims 1 to 3, wherein R 15 and R' 15 It's H.

15. The compound according to any one of claims 1 to 3, wherein Y is a carbon-carbon single bond.

16. The compound according to claim 1, which is selected from: 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-λ6-thio)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-λ6-thio)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; 4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxylic acid methyl ester; 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.

17. The compound according to claim 1, which is: (4R)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one or (4S)-4-(4-{[2,4-bis(trifluoromethyl)phenoxy]methyl}-3-methoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one 18. A drug, characterized in that It comprises a compound of formula I according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the therapeutic and / or prophylactic treatment of an ERRα-mediated disease or condition.

20. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ERRα-mediated cancer.

21. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating at least one condition selected from: lung cancer; melanoma; endometrial cancer; and acute myeloid leukemia.

22. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating at least one condition selected from: breast cancer; bladder cancer; prostate cancer; pancreatic cancer; colorectal cancer; and ovarian cancer.

23. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating type II diabetes.

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

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