Estrogen-related receptor alpha (ERRα) modulators

Abstract

The present invention is directed to compounds according to Formula I below, or a pharmaceutically acceptable salt thereof, which can be used as modulators of estrogen-related receptor alpha (ERRα) and have utility in the treatment of ERRα-mediated diseases or conditions. [Formula 1] JPEG2023501081000089.jpg94170

Description

[Background technology]

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

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

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

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

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

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

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

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

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

[0010] According to a first aspect of the present invention there is provided a compound according to formula I below, or a pharma- ceutically acceptable salt thereof. [ka] Where: Y is a carbon-carbon single bond or a carbon-carbon double bond, provided that when Y is a carbon-carbon double bond, R' 15 and R 16 does not exist; One of the three positions A1 to A3 is S or NR A and the remaining two of positions A1 to A3 are N or CR1, CR2, or CR3, respectively; R A is H or methyl; R1 to R3 are independently H, methyl, amino, or a halogen atom; A4 to A7 are CR4, CR5, CR6 and CR7, respectively; A8~A 12 are N or CR8, CR9, and CR 10 , C.R. 11 and CR 12 However, there are five positions A8 to A 12 No more than two of can be N at the same time; R4-R7 are independently H, a halogen atom, a C(1-3)alkoxy, or a C(1-3)alkyl; R8~R 12 are independently H, a halogen atom, C(1-3)alkoxy, C(1-4)alkyl, cyano, nitro, -C(=O)OR 17 , hydroxyl, C(3-6)cycloalkyl, benzyl, phenyl, -SF5, bicyclo[1.1.1]pentane; Or, R9 and R8 or R 10 is condensed with any one of the following to form a 5-7 membered aromatic or non-aromatic ring containing 2-7 carbon atoms and 0-3 heteroatoms, provided that all carbon atoms are optionally substituted with one or more methyl, halogen atoms, or hydroxyl; R 13 is H or methyl; R 14 is NH, O or S; R 15 and R' 15 are independently H, a halogen atom, a C(1-4) alkyl, -C(=O)OR 17 or -C(=O)NR 17 R 17 and; R 16 is H; and R 17 is H, methyl or ethyl.

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

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

[0013] In another embodiment, the present invention relates to a compound according to formula I, wherein R5 is C(1-3)alkoxy; and R4, R6 and R7 are H.

[0014] In another embodiment, the present invention relates to a compound according to formula I, wherein R5 is methoxy and R4, R6 and R7 are H.

[0015] In another embodiment, the present invention relates to A8 to A 12 are CR8, CR9, and CR 10 , C.R. 11 and CR 12 The present invention relates to compounds according to formula I, wherein

[0016] In another embodiment, the present invention relates to a compound represented by the formula: 12 are independently H, C(1-4)alkyl, halogen, hydroxyl, or C(1-3)alkoxy. For example, R to R 12 R and R can be independently H, C(1-4)alkyl, or a halogen atom. 11 are independently C(1-4) alkyl, halogen, hydroxyl or C(1-3) alkoxy, and R, R 10 and R 12 Good results were obtained when R9 and R 11 are independently C(1-4)alkyl, and R, R 10 and R 12 is H.

[0017] In another embodiment, the present invention relates to a compound having R and R 11 is CF3, and R8, R 10 and R 12 is H.

[0018] In another embodiment, the present invention provides a method for the preparation of a medicament comprising administering to a subject the 13 is H.

[0019] In another embodiment, the present invention provides a method for the preparation of a medicament comprising administering to a subject the 14 is O.

[0020] In another embodiment, the present invention provides a method for the preparation of a medicament comprising administering to a subject the15 and R' 15 is H.

[0021] In another embodiment, the present invention relates to a compound according to formula I, wherein Y is a carbon-carbon single bond.

[0022] The above embodiments relating to preferred forms of different substituents of formula (I) are not intended to be mutually exclusive of each other. Rather, combinations of these embodiments are contemplated within the scope of the present invention, and in certain circumstances, such combinations represent preferred structures for compounds of formula I. In that regard, A1 is N, A2 is NH, and A3 is CH; A4-A7 are CR4, CR5, CR6, and CR7, respectively, where R5 is C(1-3)alkoxy, and R4, R6, and R7 are H; A8-A9 are CR4, CR5, CR6, and CR7, respectively, where R5 is C(1-3)alkoxy, and R4, R6, and R7 are H; 12 are CR8, CR9, and CR 10 , C.R. 11 and CR 12 where R9 and R 11 are independently C(1-4) alkyl, halogen, hydroxyl or C(1-3) alkoxy, and R, R 10 and R 12 is H;R 13 is H;R 14 is O;R 15 and R' 15 are both H; Y is a carbon-carbon single bond; and R 16 Particular mention may be made of compounds according to formula I, wherein

[0023] A1 is N, A2 is NH, and A3 is CH; A4 to A7 are CR4, CR5, CR6, and CR7, respectively, where R5 is C(1-3)alkoxy, and R4, R6, and R7 are H; A8 to A 12 are CR8, CR9, and CR 10 , C.R. 11 and CR 12 where R9 and R 11are independently C(1-4)alkyl, and R, R 10 and R 12 is H;R 13 is H;R 14 is O;R 15 and R' 15 are both H; Y is a carbon-carbon single bond; and R 16 is H.

[0024] definition

[0025] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0026] As used herein, the words "comprising," "comprises," and "comprised of" are synonymous with "including," "includes," "containing," or "contains," and are inclusive or open-ended and do not exclude additional, unrecited members, elements, or method steps. As used herein, the phrase "consisting of" is closed and excludes all additional elements. Moreover, the phrase "consisting essentially of" excludes additional significant elements, but can include non-significant elements that do not materially alter the nature of the invention.

[0027] When amounts, concentrations, dimensions, and other parameters are expressed in the form of ranges, preferred ranges, upper values, lower values, or preferred upper and lower values, it is to be understood that any range obtained by combining any upper or preferred value with any lower limit or preferred value is also specifically disclosed, regardless of whether the resulting range is expressly stated in the context.

[0028] The words "preferred," "preferably," "desirably," and "particularly," or their equivalents, may be used frequently herein to refer to embodiments of the present disclosure that may offer certain advantages, under certain circumstances. However, the recitation of one or more preferred, preferred, desirable, or particular embodiments does not imply that other embodiments are not useful, and is not intended to exclude such other embodiments from the scope of the present disclosure.

[0029] As used throughout this application, the word "may" is used in its non-required sense, ie, in its permissive sense, i.e., meaning possible.

[0030] As used herein, "room temperature" is 23°C ± 2°C.

[0031] Unless otherwise stated, as used herein, the term "halo" or the term "halogen atom" or the term "halide" by itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom, with fluorine, chlorine, or bromine atom being indicated to be preferred.

[0032] As used herein, the term "heteroatom" refers to a nitrogen atom, an oxygen atom, or a sulfur atom.

[0033] As used herein, a "C(1-n) alkyl" group refers to a monovalent group containing 1 to n carbon atoms, which is a radical of an alkane, and includes linear and branched organic groups. Thus, "C1-C 30An "alkyl" group refers to a monovalent group containing 1 to 30 carbon atoms, which is an alkane radical and includes linear and branched organic groups. In the present invention, such alkyl groups may be unsubstituted or substituted with the groups mentioned hereinafter. Halogenated derivatives of hydrocarbon radicals may in particular be mentioned as examples of suitable substituted alkyl groups.

[0034] As used herein, the term "C(1-4) alkyl" refers to an alkyl group having 1 to 4 carbon atoms, i.e., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. Any carbon atom may be substituted with one or more halogen atoms or hydroxyl.

[0035] As used herein, the term "C(1-3) alkyl" refers to an alkyl group having 1 to 3 carbon atoms, i.e., methyl, ethyl, propyl, or isopropyl. Any carbon atom may be substituted with one or more halogen atoms or hydroxyl.

[0036] As used herein, the term "C(3-6)cycloalkyl" refers to a saturated cyclic hydrocarbon having 3 to 6 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, any of which may be substituted with one or more halogen atoms or methyl.

[0037] The term "C(1-3)alkoxy" refers to an alkoxy group having 1 to 3 carbon atoms, the alkyl portion being branched or unbranched. Any carbon atom may be substituted with one or more F or hydroxyl.

[0038] As used herein, the term "cyano" represents a group of formula -CN.

[0039] As used herein, a "nitro group" or "nitro" refers to --NO.sub.2.

[0040] The term "substituted" means that one or more hydrogens on a specified atom or atoms are replaced with a selection from a specified group, provided that the normal valence of the specified atom under the existing circumstances is not exceeded, and such substitutions result in stable compounds. Combinations of substituents are also permissible only if such combinations result in stable compounds. The term "stable compound" or "stable structure" refers to a compound or structure that is sufficiently robust to survive both isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0041] The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

[0042] As used herein, a "protecting group" refers to a moiety attached to a functional group to prevent undesired reactions. Preferably, the protecting group can be easily removed after protection of the functional group is no longer required.

[0043] Compounds of formula I can form salts, which are also within the scope of the present invention. References herein to compounds of formula I are understood to include references to the salts thereof, unless otherwise indicated.

[0044] The term "pharmaceutically acceptable salt" is used according to its standard definition in the art to denote salts that are suitable for use within the scope of medical judgment, particularly in contact with the tissues of humans and lower animals without undue toxicity, irritation and / or allergic reactions. Their use must be commensurate with a reasonable ratio of benefits to risks. Pharmaceutically acceptable salts are well known in the art. They may be obtained during the final isolation and purification of the compounds of the invention, or they may be obtained separately by reacting the free base function with a suitable mineral acid, including but not limited to hydrochloric acid, phosphoric acid or sulfuric acid; or an organic acid, including but not limited to ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid or methanesulfonic acid. The acid function of the compounds of the invention may be reacted with an organic or inorganic base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide. For completeness, organic bases include common hydrocarbyl and heterocyclic amine salts such as diethylamino, morpholine and piperidine salts.

[0045] The compounds of formula I may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula I, as well as mixtures thereof, including racemic mixtures, form part of the present invention. In particular, the stereoisomers of the compounds of formula I in the S configuration of the chiral center next to the 5-membered heterocycle according to the Cahn-Ingold-Prelog system of nomenclature, expressly form part of the present invention.

[0046] As will be appreciated by those skilled in the art, enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound, for example a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride; separating the diastereomers; and then converting the individual diastereomers into the corresponding pure enantiomers, for example by hydrolysis. Enantiomers can also be separated by use of a chiral HPLC column.

[0047] It will be further recognized that various tautomers of the compound of formula I may be possible. Therefore, it is intended that all tautomeric forms of the compound of formula I form part of the present invention. For completeness, as used herein, the term "tautomer" refers to the migration of a proton between adjacent single and double bonds. The tautomerization process is reversible. Tautomers generally reach an equilibrium state, where the double bond is resonantly shared between two bond lengths.

[0048] The present invention also relates to pharmaceutical compositions comprising a compound having general formula I or a pharma- ceutically acceptable salt thereof in admixture with a pharma- ceutically acceptable excipient and, optionally, other therapeutically active agents. The excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

[0049] The present invention further includes compounds of Formula I in combination with one or more other pharmaceutical agents.

[0050] The compositions may be any unit dosage form for administration, including, but not limited to, those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, topical, or rectal administration. For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granules, solutions, suspensions, and the like.

[0051] For parenteral administration, the pharmaceutical compositions of the invention can be presented in unit-dose or multi-dose containers, such as sealed vials and ampoules, in a predetermined amount of injection solution. The pharmaceutical compositions can also be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water, prior to use.

[0052] Mixed with such pharma- ceutically acceptable auxiliaries, the active agent can be compressed into solid dosage units, such as pills, tablets, or processed into capsules or suppositories. With pharma- ceutically acceptable liquids, the active agent can be applied as a fluid composition, for example in the form of a solution, suspension or emulsion, which can be included in the preparation of injections or in sprays, such as nasal drops.

[0053] To prepare solid dosage units, the use of conventional additives, such as fillers, colorants, polymeric binders, etc., is contemplated. In general, any pharma- ceutically acceptable additive that does not interfere with the function of the active compound can be used. Suitable carriers that can be used by the active agent of the present invention as a solid composition include lactose, starch, cellulose derivatives, etc., or mixtures thereof, when used in appropriate amounts. For parenteral administration, aqueous suspensions, isotonic saline, and sterile injectable solutions can be used, and these suspensions or solutions can contain pharma- ceutically acceptable dispersants and / or wetting agents, such as propylene glycol or butylene glycol.

[0054] The present invention further includes a pharmaceutical composition as described hereinbefore in combination with suitable packaging material for said composition, wherein said packaging material contains instructions for use of the composition for the purposes as described hereinbefore.

[0055] The exact dosage and administration regimen of the active ingredient or pharmaceutical composition thereof may vary depending on the particular compound, the route of administration, and the age and condition of the individual subject to which the drug is to be administered.

[0056] In general, parenteral administration requires lower dosages than other administration methods that are more dependent on absorption. That being said, dosages for humans preferably comprise 0.0001 to 100 mg per kg of body weight. The desired dose may be presented as a single dose or multiple subdoses administered at appropriate intervals throughout the day.

[0057] The compounds according to the invention or their pharma- ceutically acceptable salts may be used as drugs in therapy.

[0058] Another aspect of the invention resides in the use of a compound having general formula I or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of an ERRα-mediated disease or condition.In particular, the invention provides the use of a compound having general formula I or a pharma- ceutically acceptable salt thereof for the treatment of ERRα-mediated cancer.

[0059] The compound having general formula I or a pharma- ceutically acceptable salt thereof can be used in therapy to treat at least one condition selected from lung cancer, melanoma, endometrial cancer, and acute myeloid leukemia. Without intending to limit this aspect of the invention, the compound having general formula I or a pharma- ceutically acceptable salt thereof can be used in therapy to treat, in particular, superficial spreading melanoma, lentigo maligna, acro- lentiginous melanoma, nodular melanoma, amelanotic melanoma, ocular melanoma, vulvar melanoma, or vaginal melanoma.

[0060] In another aspect, the compounds having general formula I or a pharma- ceutically acceptable salt thereof can be used in therapy to treat at least one condition selected from breast cancer, bladder cancer, prostate cancer, pancreatic cancer, colorectal cancer, and ovarian cancer.

[0061] In another aspect, the compounds having general Formula I, or a pharma- ceutically acceptable salt thereof, can be used to treat type II diabetes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] As shown in the Examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedures: While the general methods depict the synthesis of certain compounds of the invention, it will be understood that the general methods below, and other methods known to those of skill in the art, can be applied to all compounds and subclasses and species of each of these compounds as described herein.

[0063] General method of preparation

[0064] The compounds described herein, such as compounds of general formula I, building block I and building block II, are prepared by the reaction schemes shown below. Moreover, in the schemes below where specific acids, bases, reagents, coupling agents, catalysts, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents, catalysts, solvents, etc. may be used and are within the scope of the present invention. Modifications to reaction conditions, such as temperature, duration of reaction, or combinations thereof, are contemplated as part of the present invention.

[0065] The compounds obtained by using the general reaction sequence may be of insufficient purity. The compounds can be purified by using organic compound purification methods, such as crystallization or silica gel or alumina column chromatography, using different solvents in appropriate ratios. All possible stereoisomers are contemplated within the scope of the present invention.

[0066] Abbreviations for materials used in the reaction schemes and examples below are as follows: AcOH: acetic acid;ACN: acetonitrile;DAST: (diethylamino)sulfur trifluoride;DCM: dichloromethane;DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone;DIAD: diisopropyl azodicarboxylate;DiBAl-H: diisobutylaluminum hydride;DMAP: 4-dimethylaminopyridine;DMF: N,N-dimethylformamide;DMSO: dimethylsulfoxide;EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;Et2O: diethyl Diethyl ether; EtOAc: ethyl acetate; EtOH: ethanol; HPLC: high performance liquid chromatography; MeOH: methanol; PhSCu(I): phenylsulfanyl copper; PPh3: triphenylphosphine; SFC: supercritical fluid chromatography; tBuOK: potassium tert-butoxide; tBuONO: tert-butylnitrile; TEMPO: 2,2,6,6-tetramethylpiperidinyloxyl; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TOSMIC: tosylmethyl isocyanide.

[0067] Chemical names are preferred IUPAC names generated by using Marvin Sketch 17.24.1. When a compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure prevails.

[0068] [ka]

[0069] conditions: i) Meldrum's acid, MeOH

[0070] As shown in Scheme 1, R 14 is an oxygen atom, and R 15 , R' 15 and R 16A general synthesis of derivatives of the invention having formula I, where A is H and Y is a carbon-carbon single bond. The derivatives can be prepared by methods known in the art of organic chemistry. Compounds of the invention include A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56 10 , A 11 and A 12 benzaldehyde derivatives of the building blocks I, in which R 13 , A1, A2 and A3 have the meanings given above, can be obtained by reaction of a derivative of building block II with Meldrum's acid.

[0071] R 14 To obtain derivatives of formula I in which R is a sulfur atom, 14 Derivatives of formula I, in which is an oxygen atom, can be reacted, for example, with Lawesson's reagent.

[0072] R 14 To obtain derivatives of formula I in which R is a nitrogen atom, 14 Derivatives of formula I, in which is a sulfur atom, can be reacted with ammonia in, for example, MeOH.

[0073] [ka]

[0074] conditions: i) DDQ, 1,4-dioxane

[0075] Scheme 1b illustrates a compound in which Y is a carbon-carbon double bond and R 15 is H, and R 13 , R 14 , A1, A2, A3, A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 The following general routes are shown for the preparation of analogs of formula I, where R has the meaning given above.

[0076] Y is a carbon-carbon single bond and R 15 , R' 15 and R 16 Derivatives of formula I where Y is H can be oxidized, for example using DDQ in a suitable solvent, to give derivatives of formula I where Y is a carbon-carbon double bond.

[0077] [ka]

[0078] conditions: i) K2CO3, DMF

[0079] Scheme 2 is A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12 A general method for preparing benzaldehyde building block I derivatives is shown, in which R has the meaning given above.

[0080] 4-Fluorobenzaldehyde using K2CO3 in DMF at 110 °C 1 Phenol 2 Aromatic substitution with gives the building block I derivatives. 12 For some substitutions in it may be beneficial to carry out the aromatic substitution by use of 4-hydroxybenzaldehyde derivatives and fluorobenzene derivatives.

[0081] [ka]

[0082] conditions: i) K2CO3, DMF; ii) DAST, DCM; iii) DiBAl-H, toluene.

[0083] Scheme 2b shows a compound in which A8 is C-CF2 and A4, A5, A6, A7, A9, A 10 , A 11 and A 12 A general method for preparing benzaldehyde building block I derivatives, in which R has the meaning given above, is shown. Under basic conditions, for example using K2CO3, fluorobenzaldehyde 4 4-Hydroxybenzonitrile 3 Aromatic substitution with 5 The aldehyde moiety can be converted to a CF2 group using a fluorinating agent, such as DAST. Through subsequent reduction of the nitrile, for example using DiBAl-H in toluene, the benzaldehyde building block I derivatives can be prepared. In scheme 2b, this is exemplified for R8, and these transformations can also be carried out at positions R4 to R 12 The aldehyde moiety can be applied to any position of R4 to R 12 For some substitutions it may be beneficial to use 4-fluorobenzonitrile with a hydroxybenzaldehyde derivative to carry out the aromatic substitution.

[0084] [ka]

[0085] conditions: i) Meldrum's acid, MeOH; ii) ROH, DIAD, PPh3, THF; and iii) RNH, EDC, DMAP, DCM.

[0086] Scheme 3 illustrates a compound in which Y is a carbon-carbon single bond and R 14 is an oxygen atom, and R 15 is COOH, and R' 15 and R 16A general route for the preparation of analogs of formula I, in which each of A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, A32, 10 , A 11 and A 12 Derivatives of building blocks I, in which R 13 , A1, A2, A3 have the meanings given above, with Meldrum's acid at room temperature.

[0087] R 15 When is COOH, this carboxylic acid moiety can be functionalized towards an ester, for example using an alcohol, DIAD and PPh3 in THF, or it can be functionalized towards an amide, for example using a primary or secondary amine, EDC and DMAP in DCM.

[0088] [ka]

[0089] conditions: i) CH3CH2OCOCH2P(Ph)3Br,tBuOK,Et2O; ii) CH2CHMgBr,PhSCu(I),THF; iii) TEMPO,tBuONO,1,4-dioxane; iv) TOSMIC,tBuOK,THF; and v) Zn,AcOH.

[0090] Scheme 4 illustrates a compound in which A1 and A3 are CH, A2 is NH, Y is a carbon-carbon single bond, and R 14 is an oxygen atom, and R 13 is H and R 15 , R' 15 and R 16 Each of these is H, and A4, A5, A6, A7, A8, A9, A 10 , A 11 and A 12indicates a general route for the formation of analogs of formula I, which have the meanings given above.

[0091] Intermediate 6 can be obtained via Wittig reaction of building block I, for example using CH3CHOCOCH2P(Ph)3Br and tBuOK in Et2O, followed by reaction with, for example, vinylmagnesium bromide and PPhSCu(I) in THF. Subsequent introduction of the nitro group in the E-conformation can be achieved, for example, by using TEMPO and tBuONO in 1,4-dioxane. Pyrrole intermediate 8 was obtained via [3+2] cycloaddition of intermediate 7, for example using TOSMIC and tBuOK in THF. Reduction of the nitro followed by ring closure to give the formula I analogue was carried out in a single step, for example by using zinc dust in AcOH.

[0092] Working Example

[0093] All building blocks used are commercially available, known to those skilled in the art or are prepared according to methods known to those skilled in the art.

[0094] Examples 1 to 86

[0095] Example 1: 4-[3-Methoxy-4-(3-methylphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0096] [ka]

[0097] i) To a solution of meta-cresol (44 μL) in DMF (4 mL) was added K2CO3 (175) and 4-fluoro-3-methoxybenzaldehyde (65 mg). The reaction mixture was heated to 110 °C and stirred overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The resulting oil was partitioned between DCM and water. The aqueous layer was extracted twice more with DCM and the combined organic layers were dried over MgSO4, filtered and concentrated. After reverse phase flash chromatography using a gradient of 10% to 100% ACN in water, 3-Methoxy-4-(3-methylphenoxy)benzaldehyde (66 mg) was obtained.

[0098] ii) The product obtained in the previous step (66 mg) was dissolved in 4 mL of MeOH. Meldrum's acid (39 mg) and 3-aminopyrazole (23 mg) were added and the reaction was stirred at 65° C. for 6 hours. The reaction was cooled to room temperature, Celite was added and the solvent was evaporated. After reverse phase chromatography, using solid loading, 4-[3-Methoxy-4-(3-methylphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (25 mg) was obtained. MS(ES + ) m / z 350.2 (M+H) +

[0099] The following compounds were prepared following procedures similar to those described in Example 1 using the appropriate starting materials.

[0100] Example 2: 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)-3-(trifluoromethyl)benzonitrile

[0101] [ka]

[0102] MS(ES + ) m / z 429.2 (M+H) +

[0103] Example 3: 4-[3-Methoxy-4-(2-nitrophenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0104] [ka]

[0105] MS(ES + ) m / z 381.2 (M+H) +

[0106] Example 4: 4-{3-methoxy-4-[2-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0107] [ka]

[0108] MS(ES + ) m / z 404.2 (M+H) +

[0109] Example 5: 4-{3-methoxy-4-[4-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0110] [ka]

[0111] MS(ES + ) m / z 404.2 (M+H) +

[0112] Example 6: 4-{3-methoxy-4-[3-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0113] [ka]

[0114] MS(ES + ) m / z 404.2 (M+H) +

[0115] Example 7: 4-[4-(2-bromophenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0116] [ka]

[0117] MS(ES + ) m / z 414.2 (M+H) +

[0118] Example 8: 4-[3-Methoxy-4-(2-methylphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0119] [ka]

[0120] MS(ES + ) m / z 350.2 (M+H) +

[0121] Example 9: 2-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzonitrile

[0122] [ka]

[0123] MS(ES +) m / z 361.2 (M+H) +

[0124] Example 10: 4-[4-(2-tert-butylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0125] [ka]

[0126] MS(ES + ) m / z 392.2 (M+H) +

[0127] Example 11: 4-[4-(2-chlorophenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0128] [ka]

[0129] MS(ES + ) m / z 370.2 (M+H) +

[0130] Example 12: 4-{3-methoxy-4-[2-(trifluoromethoxy)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0131] [ka]

[0132] MS(ES + ) m / z 420.2 (M+H) +

[0133] Example 13: 4-[3-Methoxy-4-(2-methoxyphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0134] [ka]

[0135] MS(ES + ) m / z 366.2 (M+H) +

[0136] Example 14: 4-[4-(3-bromophenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0137] [ka]

[0138] MS(ES + ) m / z 414.2 (M+H) +

[0139] Example 15: 4-[4-(3-tert-butylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0140] [ka]

[0141] MS(ES + ) m / z 392.2 (M+H) +

[0142] Example 16: 4-[4-(3-chlorophenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0143] [ka]

[0144] MS(ES + ) m / z 370.2 (M+H) +

[0145] Example 17: 4-{3-methoxy-4-[3-(trifluoromethoxy)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0146] [ka]

[0147] MS(ES + ) m / z 420.2 (M+H) +

[0148] Example 18: 4-[3-Methoxy-4-(3-methoxyphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0149] [ka]

[0150] MS(ES + ) m / z 366.2 (M+H) +

[0151] Example 19: Methyl 3-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzoate

[0152] [ka]

[0153] MS(ES +) m / z 394.2 (M+H) +

[0154] Example 20: 4-[4-(2-ethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0155] [ka]

[0156] MS(ES + ) m / z 364.2 (M+H) +

[0157] Example 21: 4-[4-(3-ethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0158] [ka]

[0159] MS(ES + ) m / z 364.2 (M+H) +

[0160] Example 22: 4-[3-Methoxy-4-(2-propylphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0161] [ka]

[0162] MS(ES + ) m / z 378.2 (M+H) +

[0163] Example 23: 4-{3-methoxy-4-[2-(propan-2-yl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0164] [ka]

[0165] MS(ES + ) m / z 378.2 (M+H) +

[0166] Example 24: 4-[3-Methoxy-4-(2-phenylphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0167] [ka]

[0168] MS(ES + ) m / z 412.2 (M+H) +

[0169] Example 25: 4-[4-(2-cyclopentylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0170] [ka]

[0171] MS(ES + ) m / z 404.2 (M+H) +

[0172] Example 26: 4-[4-(2-benzylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0173] [ka]

[0174] MS(ES + ) m / z 426.2 (M+H) +

[0175] Example 27: 4-[4-(2-tert-butyl-4-methoxyphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0176] [ka]

[0177] MS(ES + ) m / z 422.2 (M+H) +

[0178] Example 28: 4-[4-(2-cyclopropylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0179] [ka]

[0180] MS(ES + ) m / z 376.2 (M+H) +

[0181] Example 29: 4-[4-(3-tert-butyl-4-hydroxyphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0182] [ka]

[0183] MS(ES+ ) m / z 408.2 (M+H) +

[0184] Example 30: 4-{3-methoxy-4-[3-(propan-2-yl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0185] [ka]

[0186] MS(ES+) m / z 378.2 (M+H)+

[0187] Example 31: 4-[4-(3-cyclopropylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0188] [ka]

[0189] MS(ES + ) m / z 376.2 (M+H) +

[0190] Example 32: 4-[4-(2-tert-butyl-4-ethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0191] [ka]

[0192] MS(ES + ) m / z 420.2 (M+H) +

[0193] Example 33: 4-[4-(4-bromo-2-tert-butylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0194] [ka]

[0195] MS(ES + ) m / z 470.1 (M+H) +

[0196] Example 34: 4-[4-(2-tert-butyl-4-methylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0197] [ka]

[0198] MS(ES + ) m / z 406.2 (M+H) +

[0199] Example 35: 3-tert-butyl-4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzoate methyl

[0200] [ka]

[0201] MS(ES + ) m / z 450.2 (M+H) +

[0202] Example 36: 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)naphthalene-1-carboxylate methyl

[0203] [ka]

[0204] MS(ES + ) m / z 444.1 (M+H) +

[0205] Example 37: 4-[4-(2,4-di-tert-butylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0206] [ka]

[0207] MS(ES + ) m / z 448.3 (M+H) +

[0208] Example 38: 4-{3-methoxy-4-[3-methoxy-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0209] [ka]

[0210] MS(ES + ) m / z 434.1 (M+H) +

[0211] Example 39: 3-tert-butyl-4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzonitrile

[0212] [ka]

[0213] MS(ES + ) m / z 417.2 (M+H) +

[0214] Example 40: 4-{3-methoxy-4-[2-(pentafluoro-λ 6 -sulfanyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0215] [ka]

[0216] MS(ES + ) m / z 462.1 (M+H) +

[0217] Example 41: 3-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)-5-(trifluoromethyl)benzoate methyl

[0218] [ka]

[0219] MS(ES + ) m / z 462.1 (M+H) +

[0220] Example 42: 4-{4-[3-bromo-5-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0221] [ka]

[0222] MS(ES +) m / z 482.0 (M+H) +

[0223] Example 43: 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0224] [ka]

[0225] MS(ES + ) m / z 472.1 (M+H) +

[0226] Example 44: 4-[4-(3,5-di-tert-butylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0227] [ka]

[0228] MS(ES + ) m / z 448.3 (M+H) +

[0229] Example 45: 4-[4-(2-{bicyclo[1.1.1]pentan-1-yl}phenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0230] [ka]

[0231] MS(ES + ) m / z 402.2 (M+H) +

[0232] Example 46: 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)naphthalene-1-carbonitrile

[0233] [ka]

[0234] MS(ES + ) m / z 411.1 (M+H) +

[0235] Example 47: 4-[4-(2,3-dihydro-1H-inden-4-yloxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0236] [ka]

[0237] MS(ES + ) m / z 376.2 (M+H) +

[0238] Example 48: 4-{4-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0239] [ka]

[0240] MS(ES + ) m / z 406.2 (M+H) +

[0241] Example 49: 4-[4-(2,3-dihydro-1H-inden-5-yloxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0242] [ka]

[0243] MS(ES + ) m / z 376.2 (M+H) +

[0244] Example 50: 8-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)quinoline-5-carboxylate methyl

[0245] [ka]

[0246] MS(ES + ) m / z 445.1 (M+H) +

[0247] Example 51: 4-(3-Methoxy-4-phenoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0248] [ka]

[0249] MS(ES + ) m / z 336.1 (M+H) +

[0250] Example 52: 4-{3-bromo-4-[3-methoxy-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0251] [ka]

[0252] MS(ES + ) m / z 482.0 (M+H) +

[0253] Example 53: 3-tert-butyl-4-(4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzonitrile

[0254] [ka]

[0255] MS(ES + ) m / z 387.2 (M+H) +

[0256] Example 54: 4-{4-[3-methoxy-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0257] [ka]

[0258] MS(ES + ) m / z 404.1 (M+H) +

[0259] Example 55: 3-tert-Butyl-4-(2-methyl-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzonitrile

[0260] [ka]

[0261] MS(ES + ) m / z 400.2 (M+H) +

[0262] Example 56: 4-{4-[3-methoxy-5-(trifluoromethyl)phenoxy]-3-methylphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0263] [ka]

[0264] MS(ES + ) m / z 418.1 (M+H) +

[0265] Example 57: 4-{3-fluoro-4-[3-methoxy-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0266] [ka]

[0267] MS(ES + ) m / z 422.1 (M+H) +

[0268] Example 58: 4-{4-[2-(pentafluoro-lambda 6 -sulfanyl)phenoxy]-3-(trifluoromethoxy)phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0269] [ka]

[0270] MS(ES + ) m / z 516.1 (M+H) +

[0271] Example 59: 4-{4-[2-(pentafluoro-λ 6 -sulfanyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0272] [ka]

[0273] MS(ES + ) m / z 432.1 (M+H) +

[0274] Example 60: 4-[3-(trifluoromethoxy)-4-[2-(trifluoromethyl)phenoxy]phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0275] [ka]

[0276] MS(ES + ) m / z 458.1 (M+H) +

[0277] Example 61: 3-tert-butyl-4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzoic acid

[0278] [ka]

[0279] MS(ES + ) m / z 436.2 (M+H) +

[0280] Example 62: 3-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)-5-(trifluoromethyl)benzoic acid

[0281] [ka]

[0282] MS(ES + ) m / z 448.1 (M+H) +

[0283] Example 63: 4-{3-methoxy-4-[3-methyl-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0284] [ka]

[0285] MS(ES + ) m / z 418.4 (M+H) +

[0286] Example 64: 4-[4-(3,5-dimethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0287] [ka]

[0288] MS(ES + ) m / z 364.4 (M+H) +

[0289] Example 65: 4-{3-methoxy-4-[2-methyl-4-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0290] [ka]

[0291] MS(ES + ) m / z 418.4 (M+H) +

[0292] Example 66: 4-[4-(2,4-dimethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0293] [ka]

[0294] MS(ES + ) m / z 364.4 (M+H) +

[0295] Example 67: 4-[4-(2-tert-butyl-4-ethylphenoxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0296] [ka]

[0297] i) The compound of Example 32 (32 mg) was dissolved in 1.5 mL of 1,4-dioxane and DDQ (17 mg) was added. The reaction was heated to 50° C. and stirred for 1 h. The solvent was evaporated and saturated NaHCO3 solution was added to give a suspension. The suspension was sonicated and the solid was filtered off and washed three times with water. The solid was dried in a vacuum oven and 4-[4-(2-tert-butyl-4-ethylphenoxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (23mg). MS(ES + ) m / z 418.2 (M+H) +

[0298] The following compounds were prepared following procedures similar to those described in Example 67 using the appropriate starting materials.

[0299] Example 68: 4-[4-(2-tert-butyl-4-methoxyphenoxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0300] [ka]

[0301] MS(ES + ) m / z 420.2 (M+H) +

[0302] Example 69: 4-[4-(2-tert-butyl-4-methylphenoxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0303] [ka]

[0304] MS(ES + ) m / z 404.2 (M+H) +

[0305] Example 70: 4-[4-(4-bromo-2-tert-butylphenoxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0306] [ka]

[0307] MS(ES + ) m / z 468.1 (M+H) +

[0308] Example 71: 4-(2-Methoxy-4-{6-oxo-2H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)-3-(trifluoromethyl)benzonitrile

[0309] [ka]

[0310] MS(ES + ) m / z 427.1 (M+H) +

[0311] Example 72: Methyl 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0312] [ka]

[0313] i) Following a procedure similar to that described in Example 1, step i), using appropriate starting materials, 4-[3,5-Bis(trifluoromethyl)phenoxy]-3-methoxybenzaldehyde was obtained.

[0314] ii) The product obtained in the previous step (211 mg), Meldrum's acid (39 mg) and 3-aminopyrazole (48 mg) were dissolved in MeOH (5 mL). The reaction mixture was stirred at room temperature for 3.5 h and the solvent was evaporated under a stream of nitrogen, which gave 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5- The resulting carboxylic acid (200 mg) was obtained.

[0315] iv) DIAD (23 μL) was added dropwise to PPh3 (31.4 mg), MeOH (40 μL), and the product obtained in the previous step (50 mg) in anhydrous THF (1 mL) under nitrogen atmosphere. The reaction was stirred at room temperature overnight. Water was added and the product was extracted three times with DCM. The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by reverse phase chromatography using a gradient of 40-75% ACN (containing 0.1% TFA) in water. 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5- Methyl carboxylate (16.6 mg) was obtained. MS(ES + ) m / z 530.4 (M+H) +

[0316] The following compounds were prepared following procedures similar to those described in Example 72 using the appropriate starting materials.

[0317] Example 73: Ethyl 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0318] [ka]

[0319] MS(ES + ) m / z 544.4 (M+H) +

[0320] Example 74: 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-N,N-dimethyl-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0321] [ka]

[0322] i) The product obtained in Example 72, step ii) (50 mg), DMAP (20 mg) and dimethylamine HCl (12 mg) were dissolved in DCM (1 mL). EDC (30 mg) was added and the reaction was stirred at room temperature overnight. Water was added and the product was extracted three times with DCM. The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by reverse phase chromatography using a gradient of 40-75% ACN (containing 0.1% TFA) in water to give 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-N,N-dimethyl-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxamide (9.3 mg) was obtained. MS(ES + ) m / z 543.4 (M+H) +

[0323] The following compounds were prepared following procedures similar to those described in Example 74 using the appropriate starting materials.

[0324] Example 75: 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-N,N-diethyl-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxamide

[0325] [ka]

[0326] MS(ES + ) m / z 571.5 (M+H) +

[0327] Example 76: 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-1H,2H,3H,4H,6H-pyrrolo[3,4-b]pyridin-2-one

[0328] [ka]

[0329] i) Following a procedure similar to that described in Example 1, step i), using appropriate starting materials, 4-[3,5-Bis(trifluoromethyl)phenoxy]-3-methoxybenzaldehyde was obtained.

[0330] ii) (Ethoxycarbonylmethyl)triphenylphosphonium bromide (3.54 g) was added to a suspension of tBuOK (1.03 g) in Et2O (30 mL). The resulting mixture was stirred at 50° C. for 30 min and then cooled to room temperature. The compound obtained in the previous step (1.50 g) dissolved in Et2O (10 mL) was added to the reaction mixture. The reaction was stirred overnight, then quenched with water and the aqueous layer was extracted three times with Et2O. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica column using a gradient of 0-20% EtOAc in heptane to give Ethyl (E)-3-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}prop-2-enoate (1.42g) was obtained.

[0331] iii) Vinylmagnesium bromide (1.0M in THF, 9.67 mL) was added dropwise to a suspension of phenylsulfanylcopper (558 mg) in anhydrous THF (15 mL) at -40°C under nitrogen atmosphere. The reaction was allowed to reach -25°C and was cooled again to -40°C. The compound (1.4 g) obtained in the previous step in anhydrous THF (15 mL) was added dropwise and the reaction was stirred at -40°C for 30 min. The reaction was quenched by pouring the mixture into a saturated NH4Cl solution. The resulting solid was filtered off and the filtrate was extracted twice with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica column using a gradient of 0-30% EtOAc in heptane to give a 100% yield. Ethyl 3-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}pent-4-enoate (279 mg) was obtained.

[0332] iv) The product obtained in the previous step (275 mg), TEMPO (38 mg) and tBuONO (157 μL) were dissolved in 1,4-dioxane (5 mL), heated at 80° C. and stirred overnight. Water was added to the reaction and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica column using a gradient of 0-30% EtOAc in heptane. Ethyl (E)-3-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-5-nitropent-4-enoate (95mg) was obtained.

[0333] v) TOSMIC (37 mg) was added to a solution of tBuOK (42 mg) in anhydrous THF (1 mL) at -78 °C and stirred for 10 min. The compound obtained in the previous step (95 mg) was dissolved in anhydrous THF (4 mL) and added dropwise to the reaction mixture. After stirring for 10 min at -78 °C, the reaction was poured into saturated aqueous NH4Cl solution and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on a silica column using a gradient of 0-70% EtOAc in heptane to give ethyl 3-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-3-(4-nitro-1H-pyrrol-3-yl)propionate (48 mg).

[0334] vi) To a solution of the compound obtained in the previous step (45 mg) in AcOH (1.5 mL) was added zinc dust (54 mg). The reaction was heated to 50° C. and stirred for 30 min. The reaction mixture was filtered through Celite and the filter cake was rinsed with EtOAc. The filtrate was washed with saturated aqueous NaHCO3 and water, and then dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography using a gradient of 40-90% CAN in water to give 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-1H,2H,3H,4H,6H-pyrrolo[3,4-b]pyridin-2-one (8.7 mg) was obtained. MS(ES + ) m / z 471.4 (M+H) +

[0335] Example 77: 4-{4-[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0336] [ka]

[0337] i) 4-Fluoro-3-methoxy-benzonitrile (250 mg), 3-hydroxy-5-(trifluoromethyl)benzaldehyde (0.23 mL) and K2CO3 (457 mg) were suspended in DMF (10 mL). The reaction was heated to 90° C. and stirred overnight. The reaction was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted two more times with EtOAc and the combined organic layers were washed with brine, dried over MgSO4 and concentrated. The crude product was purified by reverse phase chromatography using a gradient of 10-100% CAN in water to give 4-[3-Formyl-5-(trifluoromethyl)phenoxy]-3-methoxy-benzonitrile (46mg) was obtained.

[0338] ii) The product obtained in the previous step (96 mg) was dissolved in DCM (6 mL) under nitrogen atmosphere. DAST (0.14 mL) was added dropwise and the reaction was stirred at room temperature overnight. The reaction was placed on a water bath and saturated NaHCO3 solution (15 mL) was added. The mixture was stirred vigorously for 10 min. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSO4 and concentrated. 4-[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]-3-methoxy-benzonitrile (102 mg).

[0339] iii) The compound obtained in the previous step (101 mg) was dissolved in toluene (4.5 mL) under nitrogen atmosphere and cooled to 0° C. A 1.2 M solution of DiBAl-H in toluene (0.37 mL) was added dropwise and the reaction was stirred for 1.5 h. 6N aqueous HCl (1.5 mL) was added and the mixture was stirred until effervescence ceased. The mixture was warmed to room temperature and partitioned between EtOAc and half-saturated aqueous NaHCO3. The aqueous layer was further extracted twice with EtOAc and the combined organic layers were washed with brine, dried over MgSO4 and concentrated. The crude product was purified on a silica column using a gradient of 0-25% EtOAc in heptane. 4-[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]-3-methoxy-benzaldehyde (71 mg) was obtained.

[0340] iv) Following a procedure similar to that described in Example 1, step ii), the compound obtained in the previous step is 4-{4-[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (28 mg). MS(ES + ) m / z 454.4 (M+H) +

[0341] Example 78: 4-{4-[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0342] [ka]

[0343] i) 4-Hydroxy-3-methoxybenzonitrile (250 mg), 2-fluoro-5-(trifluoromethyl)benzaldehyde (322 mg) and K2CO3 (463 mg) were suspended in DMF (8 mL) and stirred at 90 °C for 2.5 h. The reaction was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was further extracted twice with EtOAc and the combined organic layers were washed with brine, dried over MgSO4 and concentrated. The crude product was purified on a silica column using a gradient of 0-30% EtOAc in heptane to give 4-[2-Formyl-4-(trifluoromethyl)phenoxy]-3-methoxy-benzonitrile (402 mg) was obtained.

[0344] ii) Following procedures similar to those described in Example 77, steps ii) to iv), using appropriate starting materials, the compound obtained in the previous step may be: 4-{4-[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one (78 mg). MS(ES + ) m / z 454.4 (M+H) +

[0345] The single enantiomers of Example 43 can be obtained by chiral separation. 2 g of racemic Example 43 was dissolved in EtOH (50 mg / mL). The solution was repeatedly injected into a chiral SFC using an IG column (available from Daicel, amylose tris(3-chloro-5-methylphenylcarbamate) chiral stationary phase) and an isocratic gradient of 30% EtOH, 70% liquid CO2 to obtain 0.9 g of (+) enantiomer (Example 79) with 99.6% enantiomeric excess, and 0.9 g of (-) enantiomer (Example 80) with 99.0% enantiomeric excess. The optical purity of the enantiomers was determined by chiral HPLC.

[0346] The absolute configurations of the compounds of Examples 79-86 are not known. These compounds were dissolved in DMSO (10 mg / mL) and characterized by their optical rotation using a Jasco P-2000 polarimeter with the following configuration: a tungsten halogen (WI) light source; a Glan-Taylor Prism Polarizer; a Quartz Faraday Cell; and a monitor wavelength of 589 nm.

[0347] Example 79: (+)-4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0348] Example 80: (-)-4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0349] Using appropriate starting materials and HPLC methods, procedures similar to those described in Examples 79 and 80 were performed.

[0350] Example 81: (+)-4-[4-(3,5-dimethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0351] Example 82: (-)-4-[4-(3,5-dimethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0352] Example 83: (+)-4-{3-methoxy-4-[3-methyl-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0353] Example 84: (-)-4-{3-methoxy-4-[3-methyl-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0354] Example 85: (+)-4-{4-[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0355] Example 86: (-)-4-{4-[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one

[0356] Working Example 87

[0357] ERRα AlphaScreen Assay This assay was based on the knowledge that nuclear receptors interact with cofactors in ligand-dependent substrates. The site of interaction has been mapped to an LXXLL motif present in the co-activator sequence. Short peptide sequences containing the LXXLL motif mimic the behavior of full-length coactivators.

[0358] The ERRα alpha screen assay described herein relies on the interaction of a coactivator peptide with purified, bacterially expressed ERRα ligand binding domain (ERRα-LBD); upon ligand binding, the ERRα protein may undergo a conformational change, resulting in a loss of coactivator binding.

[0359] Compounds of the invention were tested for their ability to disrupt ERRα-LBD protein binding to coactivator peptides using AlphaScreen® technology (Perkin Elmer). ERRα-LBD protein was expressed in E. coli as a 6xHis Small Ubiquitin-like Modifier (SUMO) fusion. Bacterially expressed 6His-SUMO-ERRα-LBD protein was purified using affinity chromatography. All experiments were performed at room temperature in 384-well white non-binding plates (Greiner) using 50 mM Tris-HCl (pH 7.5), 100 mM NaCl, 0.1% Pluronic F-127, 0.05% BSA, and 5 mM TCEP as buffer. The final DMSO concentration in the assay was 1%. Compounds were assayed in triplicate and incubated with 0.81 nM ERRα-LBD protein, 10 μg / mL streptavidin donor beads and 10 μg / mL Ni-chelate acceptor beads at room temperature for 1 h, followed by incubation with 15 nM biotin-PGC1α-3 peptide (QRRPCSELLKYLTTNDDPP) corresponding to amino acids 202-220 for 2 h.

[0360] AlphaScreen signals were measured using an Envision Xcite plate reader (Perkin Elmer). Data were normalized and curve fitting analysis was performed in GraphPad Prism7 using a four-parameter dose-response fit.

[0361] All exemplified compounds of formula I (Examples 1-86) had an average pIC of 5 or greater. 50 It was found to have value.

[0362] Examples 1, 2, 4, 5, 6, 7, 14, 17, 20, 21, 22, 24, 25, 26, 49, 59, 60, 65, 66, 71, 72, 79, 81, 83, and 85, mean pIC 50 The value was found to be greater than or equal to 6 and less than 7.

[0363] Examples 10, 12, 15, 23, 28, 30, 31, 40, 41, 42, 43, 44, 45, 46, 47, 48, 52, 53, 54, 55, 56, 57, 58, 61, 64, 76, 77, 7, and 82 show average pIC 50 The value was found to be greater than or equal to 7 and less than 8.

[0364] Examples 27, 29, 32, 33, 34, 35, 36, 37, 38, 39, 63, 67, 68, 69, 70, 80, 84, and 86 show average pIC 50 The value was found to be 8 or higher.

[0365] Working Example 88 Full-length ERRα reporter gene assay Inhibitors of the Examples 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 52, 53, 54, 55, 56 , 57 , 58 , 59 , 60 , 61 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , and 86 were tested for their ability to inhibit ERRα activity in a full-length ERRα reporter gene assay.

[0366] A method was established to quantitatively screen the potency of compounds with inverse agonist activity against the nuclear receptor ERRα of human species. The assay allows intracellular screening of ERRα inverse agonists in SK-BR-3 cells using an over-expression construct encoding full-length ERRα and a reporter construct containing an ERRα response element (RE) and a luciferase gene for readout. The activity is expressed as a logIC50 value and can be used to determine the SAR of a compound family or to deselect compounds.

[0367] In this assay, reporter cells are obtained by transient co-transfection of the two constructs in SK-BR-3 cells using standard transfection techniques. The first construct contains the response element of the nuclear receptor ERRα (plasmid pLP2175, reporter construct ERRα-RE / luc2P, a cloned variant of ERRa_v2_synthRE, Switchgear Genomics, catalog number S900089). This sequence drives the transcription of a luciferase reporter gene in response to binding of the ERRα protein encoded by the second construct (plasmid pLP2124: full-length ERRα expression construct using pcDNA3.1 / Hygro(+) as background, Invitrogen catalog number V87020). The overexpressed full-length ERRα is constitutively active, and therefore the expression of luciferase is reduced by inverse agonists of the nuclear receptor ERRα.

[0368] The day after transfection, cells were seeded into 96-well plates, test compounds were added, and the plates were incubated overnight. Firefly luciferase activity was then quantified using a luciferase detection reagent and luminescence readout.

[0369] Detailed assay description Transfection is performed on pre-seeded SK-BR-3 cells in a T175 flask. Depending on the confluency of the transfected cells, one transfected T175 flask is sufficient to seed 3-4 MW96 plates the next day.

[0370] Two different media are used for cell treatment in this protocol: 1) Culture Medium, McCoy's 5a with Phenol Red (BioWhittaker supplier number 12-688F), 10% FBS, and Penstrep.; and 2) Assay Medium, Penstrep.; McCoy's 5a Medium Phenol Red Free (HyClone product code SH30270.01) with 2% Charcoal Stripped FBS and 1x Penstrep. Compound dilutions are prepared in Assay Medium.

[0371] Cells are seeded at least 2 days in advance to allow the cells to fully attach to the flask before transfection. On the day of transfection, cells should be 50-80% confluent.

[0372] SKBR3 cells were transfected with the transcriptional reporter construct pLP2175 and the ERRα expression construct pLP2124 (as described above).

[0373] 68 μL of Lipofectamine LTX transfection reagent (Invitrogen Catalog No. 15338-100) was added dropwise to 8.9 ml of Opti-MEM I Reduced Serum Medium (Gibco Catalog No. 51985-026) and incubated at room temperature for 5-20 minutes. 8.9 ml of this reagent mixture was added to 22 μg of pLP2175 + 22 μg of pLP2124 (1:1 ratio and 10 ml total volume) and incubated at room temperature for 25 minutes.

[0374] 10 min before adding the transfection mix to SKBR3 cells in a T175 flask, the medium was refreshed with 20 mL of medium, then 10 mL of the DNA-Opti-MEM-Lipofectamine mixture was gently added to the cells, followed by overnight (16-24 h) incubation at 37°C and 5% CO2.

[0375] To harvest SKBR3 cells from a T175 flask, the medium was first removed. The cells were then washed with Phosphate Buffered Saline (PBS) (Lonza), after which the PBS was removed. To detach the cells, 2 ml of TrypLE Express (Invitrogen) was added to the flask, followed by incubation at 37°C for 5 minutes. The flask was gently tapped until the cells were detached from the bottom. The cells were harvested in 8 mL of medium (McCoy's 5a, 10% FBS, penstrep) to achieve a single cell suspension. After cell counting, the cells were spun down at 300 g for 5 minutes. The cell pellet was then resuspended in 25,000 cells / 80 μL assay medium (McCoy's 5a phenol red-free, 2% charcoal-stripped FBS, penstrep.).

[0376] For compound screening, cells were harvested (as described above) and 80 μL of cell suspension (25,000 cells) was seeded per well into white, flat-bottom, tissue culture-treated, 96-well screening plates (Greiner).

[0377] Test compounds were diluted in three dilution steps starting from a 10 mM dimethyl sulfoxide (DMSO) stock solution. The first dilution step was a 12-point serial dilution of 4-fold in DMSO. These dilutions were further diluted 10-fold in phenol red-free assay medium containing 2% charcoal-stripped FBS and penstrep. The final step was a further 20-fold dilution in assay medium to obtain 5-fold concentrated dilutions with a DMSO concentration of 0.5%. As a final step, compound dilutions were diluted 5-fold in cell plates.

[0378] A DMSO dilution series was constructed with 12 concentrations, with final concentrations on the cell plate ranging from 10 μM to 2.4 fM.

[0379] The plates were incubated overnight (16-24 hours) at 37° C. and 5% CO2.

[0380] To read luciferase, luciferase reagent (BriteLite Plus, Perkin Elmer) was warmed to room temperature. 100 μL of 2.5-fold diluted BriteLite Plus reagent was added to each test well of the screening plate and incubated at room temperature for 5 min. Luciferase luminescence signals were measured using a Wallac Victor Microplate Reader (Perkin Elmer).

[0381] Half-maximal inhibitory concentration values ​​(IC50) for test compounds were calculated from the luciferase signal using GraphPad Prism software (GraphPad Software).

[0382] From the exemplified compounds of formula I, Examples 10, 29, 32, 33, 34, 35, 37, 38, 39, 40, 41, 43, 63, 67, 68, 69, 70, 84, and 86 had average pIC 50 The values ​​were found to be 6.5 or higher.

[0383] Working Example89 B16F10 melanoma syngeneic mouse model Example inhibitor 80 was tested for its ability to inhibit tumor growth in a B16F10 melanoma syngeneic mouse model.

[0384] Cell lines and tumor models: Allograft model derived from the B16F10 melanoma cell line in C57BL / 6 mice.

[0385] Mouse B16F10 melanoma cells were supplied by the American Type Culture Collection (ATCC) (USA). Cells were cultured in DMEM (Invitrogen, Cat. No. 31600-034) supplemented with 10% FBS (Invitrogen, Cat. No. 10438-026) and 1% penicillin-streptomycin (Thermo Fisher Scientific, Cat. No. 15140-122). To establish allografts, cells were harvested by trypsinization when they reached approximately 70-80% confluence, and 100,000 B16F10 cells were suspended in 50 μL of serum-free medium and mixed with matrigel in a 1:1 ratio before being implanted subcutaneously into the dorsal right flank of mice using a 1 mL BD syringe attached to a 24-gauge needle.

[0386] B16F10 tumor grafts were measured 5 days after cell inoculation when they were palpable. After randomization of animals into different treatment groups, while maintaining tumor volume and number of animals, the mean tumor volume in each group was kept the same between groups, with the mean tumor volume reaching approximately 58 mm. 3 Animals were dosed when they reached a daily dose of 0.01 mg / kg / day. Dosing was by mouth (per os, or po) once a day (quaque die, or qd) on a per kilogram body weight basis.

[0387] Tumor size (length (l) and breadth (b)) was measured with calipers on the day animals were randomized based on tumor volume (day 1) and then three times a week until the end of the study. Tumor volume was calculated according to the formula b 2 * l * 0.52 (where l = length, b = width) was used (Dusan Djokovic et al., BMC Cancer, 2010, 10:641). Tumor growth inhibition was calculated after normalizing the tumor volume on a given day to the tumor volume on day 1.

[0388] The average tumor volume was 58 mm 3 When this was reached, administration of the test item was initiated.

[0389] Test article administration was performed until day 14, and tumor volume measurements were performed until day 13 to calculate percent tumor growth inhibition (TGI). The results of the study are listed in Table 1 below.

[0390] [Table 1]

[0391] In view of the above description and examples, it will be apparent to those skilled in the art that equivalent modifications can be made without departing from the scope of the claims.

Claims

1. A compound according to formula I or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 Where: Y is a carbon-carbon single bond or a carbon-carbon double bond, provided that when Y is a carbon-carbon double bond, R' 15 and R 16 does not exist; 3 Position A 1 ~A 3 One of the following is S or NR: A Either 1 ~A 3 The remaining two of them are N or CR. 1 , C.R. 2 , C.R. 3 and R A is H or methyl; R 1 ~R 3 are independently H, methyl, amino, or a halogen atom; A 4 ~A 7 are CR 4 , C.R. 5 , C.R. 6 and CR 7 and A 8 ~A 12 are N or CR, respectively. 8 , C.R. 9 , C.R. 10 , C.R. 11 and CR 12 However, there are five positions A 8 ~A 12 No more than two of can be N at the same time; R 4 ~R 7 are independently H, a halogen atom, C(1-3)alkoxy, or C(1-3)alkyl; R 8 ~R 12 are independently H, a halogen atom, C(1-3)alkoxy, C(1-4)alkyl, cyano, nitro, -C(=O)OR 17 , hydroxyl, C(3-6)cycloalkyl, benzyl, phenyl, -SF 5 , bicyclo[1.1.1]pentane; Or, R 9 And, R 8 or R 10 is fused to any of the following to form a 5-7 membered aromatic or non-aromatic ring containing 2-7 carbon atoms and 0-3 heteroatoms, provided that all carbon atoms are optionally substituted with one or more methyl, halogen atoms, or hydroxyl; R 13 is H or methyl; R 14 is NH, O or S; R' 15 is H, halogen atom, C(1-4) alkyl, -C(=O)OR 17 or -C(=O)NR 17 R 17 and R 15 is H, a halogen atom or C(1-4)alkyl; R 16 is H; and R 17 is H, methyl or ethyl.

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

3. A 1 is N and A 2 is NH and A 3 or a pharma- ceutically acceptable salt thereof.

4. R 5 is C(1-3)alkoxy and R 4 , R 6 and R 7 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein

5. R 5 is methoxy and R 4 , R 6 and R 7 or a pharma- ceutically acceptable salt thereof.

6. A 8 ~A 12 are CR 8 , C.R. 9 , C.R. 10 , C.R. 11 and CR 12 6. The compound according to any one of claims 1 to 5, wherein:

7. R 8 ~R 12 or a pharma- ceutically acceptable salt thereof, according to claim 6, wherein: is independently H, C(1-4)alkyl, a halogen atom, hydroxyl, or C(1-3)alkoxy.

8. R 9 and R 11 is C(1-4)alkyl, and R 8 , R 10 and R 12 or a pharma- ceutically acceptable salt thereof.

9. R 9 and R 11 CF 3 and R 8 , R 10 and R 12 or a pharma- ceutically acceptable salt thereof.

10. R 13 The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein

11. R 14 The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein is O.

12. R 15 and R' 15 or a pharma- ceutically acceptable salt thereof.

13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein Y is a carbon-carbon single bond.

14. 4-[3-methoxy-4-(3-methylphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)-3-(trifluoromethyl)benzonitrile; 4-[3-Methoxy-4-(2-nitrophenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[2-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[4-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[3-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-bromophenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-methoxy-4-(2-methylphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 2-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzonitrile; 4-[4-(2-tert-butylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-chlorophenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[2-(trifluoromethoxy)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-methoxy-4-(2-methoxyphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(3-bromophenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(3-tert-butylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(3-chlorophenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[3-(trifluoromethoxy)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-Methoxy-4-(3-methoxyphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; Methyl 3-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzoate; 4-[4-(2-ethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(3-ethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-methoxy-4-(2-propylphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[2-(propan-2-yl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-Methoxy-4-(2-phenylphenoxy)phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-cyclopentylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-benzylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-tert-butyl-4-methoxyphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-cyclopropylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(3-tert-butyl-4-hydroxyphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[3-(propan-2-yl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(3-cyclopropylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-tert-butyl-4-ethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(4-bromo-2-tert-butylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-tert-butyl-4-methylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 3-tert-butyl-4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzoate methyl; Methyl 4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)naphthalene-1-carboxylate; 4-[4-(2,4-di-tert-butylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[3-methoxy-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 3-tert-butyl-4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzonitrile; 4-{3-Methoxy-4-[2-(pentafluoro-λ 6 -sulfanyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; Methyl 3-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)-5-(trifluoromethyl)benzoate; 4-{4-[3-bromo-5-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(3,5-di-tert-butylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-{bicyclo[1.1.1]pentan-1-yl}phenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)naphthalene-1-carbonitrile; 4-[4-(2,3-dihydro-1H-inden-4-yloxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2,3-dihydro-1H-inden-5-yloxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 8-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)quinoline-5-carboxylate methyl; 4-(3-Methoxy-4-phenoxyphenyl)-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-bromo-4-[3-methoxy-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 3-tert-butyl-4-(4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzonitrile; 4-{4-[3-methoxy-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 3-tert-Butyl-4-(2-methyl-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzonitrile; 4-{4-[3-methoxy-5-(trifluoromethyl)phenoxy]-3-methylphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-fluoro-4-[3-methoxy-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[2-(pentafluoro-lambda 6 -sulfanyl)phenoxy]-3-(trifluoromethoxy)phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[2-(pentafluoro-lambda 6 -sulfanyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[3-(trifluoromethoxy)-4-[2-(trifluoromethyl)phenoxy]phenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 3-tert-butyl-4-(2-methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)benzoic acid; 3-(2-Methoxy-4-{6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)-5-(trifluoromethyl)benzoic acid; 4-{3-methoxy-4-[3-methyl-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(3,5-dimethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{3-methoxy-4-[2-methyl-4-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2,4-dimethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-tert-butyl-4-ethylphenoxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-tert-butyl-4-methoxyphenoxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(2-tert-butyl-4-methylphenoxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-[4-(4-bromo-2-tert-butylphenoxy)-3-methoxyphenyl]-2H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-(2-Methoxy-4-{6-oxo-2H,6H,7H-pyrazolo[3,4-b]pyridin-4-yl}phenoxy)-3-(trifluoromethyl)benzonitrile; 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxylate methyl; Ethyl 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxylate; 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-N,N-dimethyl-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxamide; 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-N,N-diethyl-6-oxo-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridine-5-carboxamide; 4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-1H,2H,3H,4H,6H-pyrrolo[3,4-b]pyridin-2-one; 4-{4-[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; 4-{4-[2-(difluoromethyl)-4-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-[4-(3,5-dimethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-[4-(3,5-dimethylphenoxy)-3-methoxyphenyl]-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-{3-methoxy-4-[3-methyl-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (-)-4-{3-methoxy-4-[3-methyl-5-(trifluoromethyl)phenoxy]phenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; (+)-4-{4-[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; and (-)-4-{4-[3-(difluoromethyl)-5-(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one 2. The compound of claim 1, selected from the group consisting of:

15. (+)-4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one; or (-)-4-{4-[3,5-bis(trifluoromethyl)phenoxy]-3-methoxyphenyl}-2H,4H,5H,6H,7H-pyrazolo[3,4-b]pyridin-6-one 2. The compound of claim 1, wherein:

16. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 15 or a pharma- ceutically acceptable salt thereof.

17. 16. A compound of formula I, or a pharma- ceutically acceptable salt thereof, as defined in any one of claims 1 to 15 for use in therapy.

18. A compound of formula I as defined in any one of claims 1 to 15 or a pharma- ceutically acceptable salt thereof for use in the therapeutic and / or prophylactic treatment of an ERRα mediated disease or condition.

19. 16. A compound of formula I, or a pharma- ceutically acceptable salt thereof, as defined in any one of claims 1 to 15 for use in the treatment of ERRα-mediated cancer.

20. 16. A compound of formula I as defined in any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, for use in the treatment of at least one condition selected from lung cancer, melanoma, endometrial cancer, and acute myeloid leukemia.

21. 16. A compound of formula I as claimed in any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, for use in the treatment of at least one condition selected from breast cancer, bladder cancer, prostate cancer, pancreatic cancer, colorectal cancer, and ovarian cancer.

22. 16. A compound of formula I, or a pharma- ceutically acceptable salt thereof, as defined in any one of claims 1 to 15 for use in the treatment of type II diabetes.

23. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 15 or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients.

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