 compound, pharmaceutical composition, and use of a pharmaceutically acceptable salt or compound ther
专利摘要:
compound, pharmaceutical composition, and use of a pharmaceutically acceptable salt or compound thereof or a pharmaceutical composition. The present disclosure generally relates to compounds that bind to the nr1h4 (fxr) receptor and act as fxr agonists. The description further relates to the use of the compounds for the preparation of a drug for the treatment of diseases and / or conditions by binding said nuclear receptor by said compounds and to a process for the synthesis of said compounds. 公开号:BR102017012319A2 申请号:R102017012319-7 申请日:2017-06-09 公开日:2018-12-04 发明作者:Peter A. Blomgren；Kevin S. Currie；Christian Gege；Jeffrey E. Kropf；Jianjun Xu 申请人:Gilead Sciences, Inc.； IPC主号:
专利说明:
(54) Title: COMPOUND, PHARMACEUTICAL COMPOSITION, AND USE OF A PHARMACEUTICALLY COMPOUND OR SALT ACCEPTABLE FROM THE SAME OR FROM A PHARMACEUTICAL COMPOSITION (51) Int. Cl .: C07D 413/14; C07D 401/14; C07D 413/12; A61K 31/4427; A61P 1/16. (30) Unionist Priority: 06/13/2016 US 62/349490. (71) Depositor (s): GILEAD SCIENCES, INC .. (72) Inventor (s): PETER A. BLOMGREN; KEVIN S. CURRIE; CHRISTIAN GEGE; JEFFREY E. KROPF; JIANJUN XU. (57) Abstract: COMPOUND, PHARMACEUTICAL COMPOSITION, AND USE OF A PHARMACEUTICALLY ACCEPTABLE COMPOUND OR SALT OF THE SAME OR PHARMACEUTICAL COMPOSITION. The present description generally relates to compounds that bind to the NR1H4 receptor (FXR) and act as FXR agonists. The description further relates to the use of the compounds for the preparation of a drug for the treatment of diseases and / or conditions by linking said nuclear receptor by said compounds and a process for the synthesis of said compounds. λιΚ [nMh] 1/91 “COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A PHARMACEUTICALLY ACCEPTABLE COMPOUND OR SALT OF THE SAME OR A PHARMACEUTICAL COMPOSITION” Field of the Invention [001] The present description relates to compounds that bind to the NR1H4 receptor (FXR) and act as FXR agonists or modulators. The description further relates to the use of the compounds for the treatment and / or prophylaxis of diseases and / or conditions through the binding of said nuclear receptor by said compounds. Fundamentals of the Invention [002] Multicellular organisms depend on advanced mechanisms of information transfer between cells and compartments of the body. The information transmitted can be highly complex and can result in the alteration of genetic programs involved in cell differentiation, proliferation or reproduction. The signals, or hormones, are often low molecular weight molecules, such as peptides, fatty acids or cholesterol derivatives. [003] Many of these signals produce their effects by ultimately altering the transcription of specific genes. A well-studied group of proteins that mediate cellular response to a variety of signals is the family of transcription factors, known as nuclear receptors, often referred to as NR. Members of this group include receptors for steroid hormones, vitamin D, ecdysone, cis and trans-retinoic acid, thyroid hormone, bile acids, cholesterol derivatives, fatty acids (and other peroxisomal proliferators), as well as so-called orphan receptors, proteins that are structurally similar to the other members of that group, but for which no ligand is known. Orphan receptors may be indicative of unknown signaling pathways in the cell, or they may be nuclear receptors that function Petition 870180126569, of September 4, 2018, p. 8/98 2/91 without ligand activation. Activation of transcription by some of these orphan receptors can occur in the absence of an exogenous ligand and / or via signal transduction pathways from the cell surface. [004] In general, three functional domains have been defined in NRs. An amino terminal domain is believed to have some regulatory function. It is followed by a DNA binding domain (hereinafter referred to as DBD), which generally comprises two zinc finger elements and recognizes a specific hormone-responsive element (hereinafter referred to as EDH) in the promoters of the responsive genes. Specific amino acid residues in DBD have been shown to confer binding specificity to the DNA sequence. A linker binding domain (hereinafter referred to as LBD) is in the carboxyl terminal region of known NRs. [005] In the absence of a hormone, LBD appears to interfere with the interaction of DBD with its HRE. The binding of the hormone appears to result in a conformational change in the NR and thus opens up this interference. An NR without LBD constitutively activates transcription, but at a low level. [006] It is proposed that transcription coactivators or activators make a link between the specific transcription factors in terms of sequence and the basal transcription machinery and furthermore, influence the chromatin structure of a target cell. Various proteins like SRC-1, ACTR, and Gripl interact with NRs in a reinforced way in terms of ligand. [007] Nuclear receptor modulators, such as steroid hormones, affect the growth and function of specific cells by binding to intracellular receptors and forming nuclear receptor-ligand complexes. Nuclear receptor-hormone complexes then interact with an HRE in the control region of specific genes and alter specific gene expression. Petition 870180126569, of September 4, 2018, p. 9/98 3/91 [008] The famesoide alpha X receptor (hereinafter also commonly referred to as NR1H4 when referring to the human receptor) is a prototypical nuclear receptor type 2, which activates genes by binding to a promoter region of target genes in a heterodimeric with the retinoid X receptor. The relevant physiological ligands of NR1H4 are bile acids. The most potent is chenodeoxycholic acid (CDCA), which regulates the expression of several genes that participate in bile acid homeostasis. Famesol and derivatives, together called famesoides, were originally described to activate the rat orthologist in high concentrations, but they do not activate the human or mouse receptor. FXR is expressed in the liver, throughout the gastrointestinal tract, including the esophagus, stomach, duodenum, small intestine, colon, ovary, adrenal gland and kidney. In addition to controlling intracellular gene expression, FXR also appears to be involved in paracrine and endocrine signaling by suppressing the expression of cytokine fibroblastic growth factor 15 (rodents) or 19 (monkeys, humans A). [009] Although several FXR agonists are known, there is a need for improved FXR agonists. SUMMARY [0010] The present description provides compounds that bind to the NR1H4 receptor (FXR) and act as agonists or modulators of the FXR. The description further relates to the use of the compounds for the treatment and / or prophylaxis of diseases and / or conditions through the binding of said nuclear receptor by said compounds. [0011] This description provides compounds according to formula (I): Petition 870180126569, of September 4, 2018, p. 10/98 4/91 (D where: Q is phenylene or pyridylene, each of which optionally substituted with one or two substituents independently selected from halogen, methyl, Cm alkoxy, Cm haloalkoxy, -CH2F, -CHF2 and -CF 3 ; Y is N or CH; A is pyridylene or phenylene, each of which optionally substituted with one or two groups independently selected from halogen, Cm alkoxy, Cm haloalkoxy, Cm alkyl and Cm haloalkyl; Z is Ri substituted isoxazole or R 1 substituted pyrazole; R 1 is C1-4 alkyl or C3.6 cycloalkyl, wherein said Cm alkyl is optionally substituted with 1 to 3 substituents selected independently from fluorine, hydroxyl, C1.3 alkoxy and C1 fluoralkoxy. 3 , and said C3.6 cycloalkyl is optionally substituted with 1 to 3 substituents selected independently from fluorine, hydroxyl, C1 alkyl. 3, fluoralquila C1-3, C1-3 alkoxy and Cl - 3 fluoralcóxi; R 2 and R 3 are selected independently from hydrogen, halogen, methoxy, -CF3, -CHF2, -CH2F, -OCH2F, -OCHF2, -OCF3 and methyl; R 4 is -CO 2 R 5 or -C (O) NR 5 R 6 ; R 5 is hydrogen, Cm alkyl or Cm haloalkyl; and R 6 is hydrogen or Cl-6 alkyl, wherein said Cm alkyl is optionally substituted with 1 to 6 substituents selected independently from halogen, -SO3H and -CO2H; Petition 870180126569, of September 4, 2018, p. 11/98 5/91 or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [0012] Some embodiments include pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable excipient. [0013] Also provided in the present invention are methods of treating a patient with an FXR-mediated condition which comprises administering a compound of formula (I) to a patient who needs it. Detailed Description of the Figures [0014] FIG. 1: Exposure to plasma of Example 3 and Example Comparative 2 versus plasma levels of FGF19 in monkeys. [0015] FIG. 2: FGF19 levels generated in monkey-canine with increasing oral doses of Example 3 and Comparative Example 2. Detailed Description Definitions [0016] The description below sets out exemplary modalities of this technology. It should be recognized, however, that such a description is not intended to be a limitation on the scope of the present description, but instead it is provided as a description of exemplary modalities. [0017] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings as defined below, except to the extent that the context in which they are used indicates otherwise. [0018] The descriptions illustratively presented in that document can be practiced in the absence of any element or elements, limitations or limitations that are not specifically presented in the present invention. Thus, for example, terms comprising, including, containing, etc. should be read comprehensively and without Petition 870180126569, of September 4, 2018, p. 12/98 6/91 limitation. In addition, the terms and expressions used in this document have been used as terms of description and not of limitation, and there is no intention in using such terms and expressions to exclude any equivalents of the features shown and described, or parts thereof, but it is recognized that several modifications are possible within the scope of the claimed description. [0019] A dash that is not between two letters or symbols, is used to indicate a point of attachment for a substituent. For example, C (O) NH2 is linked via the carbon atom. A dash in front or at the end of a chemical group is a matter of convenience; chemical groups can be depicted with or without one or more strokes, without losing their common meaning. A wavy line across a line in a structure indicates a group fixation point. Unless chemically or structurally required, no directionality is indicated or implied in the order in which a chemical group is written or named. [0020] The prefix C u - V indicates that the related group has uav carbon atoms. For example, C1-6 alkyl indicates that the alkyl group has 1 to 6 carbon atoms. [0021] Reference to about a value or parameter of the present invention includes (and describes) modalities that are directed to that value or parameter alone. In certain embodiments, the term about includes the indicated amount ± 10%. In other embodiments, the term about includes the indicated amount ± 5%. In certain other embodiments, the term about includes the indicated amount ± 1%. Likewise, the term about X includes the description of X. Likewise, the singular forms one, one and o / a include references in the plural, unless the context clearly specifies otherwise. Thus, for example, the reference to the compound includes a plurality of such compounds, and Petition 870180126569, of September 4, 2018, p. 13/98 7/91 reference to the “test” includes reference to one or more tests and equivalents thereof known to persons skilled in the art. [0022] In the context of the present description, alkyl means a chain of saturated hydrocarbons, which can be linear or branched. In the context of the present description, C1-6 alkyl means a saturated alkyl chain having from 1 to 6 carbon atoms that can be linear or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl. [0023] The term haloalkyl means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen. A non-limiting example of this is CF3. [0024] A cycloalkyl group means a saturated or partially unsaturated mono, bi or spirocyclic hydrocarbon ring system. [0025] An alkoxy group refers to -O-alkyl, where alkyl is as defined herein. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, npentoxy, n-hexoxy and 1,2-dimethylbutoxy. [0026] Halogen or halo refers to an atom of F, Cl, Br or I. [0027] Hydroxyl or hydroxy refers to -OH. [0028] Haloalkoxy refers to an alkoxy group, as defined in this document, in which one or more hydrogen atoms in the alkyl chain are replaced by a halogen. [0029] Fluoralkyl refers to an alkyl group, as defined in this document, in which one or more hydrogen atoms in the alkyl chain are replaced by fluorine. [0030] Fluoralkoxy refers to an alkoxy group, as defined in this document, in which one or more hydrogen atoms in the alkyl chain are replaced by fluorine. Petition 870180126569, of September 4, 2018, p. 14/98 8/91 [0031] The terms optionally or optionally mean that the subsequently described event or circumstance may or may not occur, and that the description includes examples where that event or circumstance occurs, and examples where it does not. Likewise, the term optionally substituted refers to any one or more hydrogen atoms in the designated atom or group that may or may not be replaced by a different portion of hydrogen. [0032] In addition, the compounds of the present description may be subject to tautomerism. Where tautomerism, for example, the ketoenolic tautomerism of the compounds of the present description, or their prodrugs, may occur, with individual forms such as, for example, the keto and enol form, each within the scope of the description, as well as mixtures in any proportion. The same applies to stereoisomers, for example, enantiomers, cis / trans isomers, conformers and the like. [0033] The term protecting group refers to a portion of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and protection / deprotection strategies are well known in the art. See, for example, Protection Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protection groups are often used to mask the reactivity of certain functional groups to aid efficiency of the desired chemical reactions, for example, making and breaking chemical bonds in an orderly and planned manner. [0034] The term unprotect refers to the removal of the protection group. A leaving group includes a molecular fragment that can break with a pair of electrons from a covalent bond to the carbon atom that reacts during a chemical reaction. [0035] It will be estimated by the person skilled in the art that, when Petition 870180126569, of September 4, 2018, p. 15/98 9/91 lists of alternative substituents include members who, because of their valency requirements or other reasons, cannot be used to replace a particular group, the list is intended to be read with the knowledge of the person skilled in the art to include only those members of the list who are suitable to replace the particular group. [0036] In some embodiments, the compounds of the present description can be in the form of a prodrug. The term "prodrug" is defined in the pharmaceutical field as a biologically inactive derivative of a drug that, after administration to the human body, is converted into the original biologically active drug according to some chemical or enzymatic pathways. Examples of prodrugs include esterified carboxylic acids. [0037] In the human liver, UDP-glucuronosyltransferases act on certain compounds with amino, carbamyl, thio (sulfhydryl) or hydroxyl groups to conjugate α-D-glucuronic acid uridine diphosphate through glycosidic bonds, or to esterify compounds with carboxyl groups or hydroxyl in the phase II metabolism process. The compounds of the present description can be glucuronidated, that is, conjugated with glucuronic acid, to form glucuronides, particularly (P-D) glucuronides. [0038] A step in the formation of bile is the conjugation of the individual bile acids with an amino acid, particularly with gbcine or taurine. The compounds of the present description can be conjugated to carbine or taurine in a replaceable position. [0039] The compounds of the present description can be in the form of a pharmaceutically acceptable salt. The term pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic acids or bases. In the event that the compounds of the present description contain one or more acidic or basic groups, the description also covers Petition 870180126569, of September 4, 2018, p. 16/98 10/91 their corresponding pharmaceutically or toxicologically acceptable salts, in particular, their pharmaceutically usable salts. Accordingly, the compounds of the present description that contain acidic groups that may be present in these groups can be used according to the description, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More accurate of these salts are examples of sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the present invention that contain one or more basic groups, i.e. groups that can be protonated, can be present and can be used according to the description, in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid , formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pyelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, glyconic acid, ascorbic acid, isonicotinic acid, citric acid adipic acid and other acids known to the person skilled in the art. If the compounds of the present invention contain both acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions). The respective salts can be obtained by the usual methods, which are known to the person skilled in the art, for example, by putting these in contact with an organic or inorganic acid or base in a solvent or dispersant, or by anionic or cationic exchange with others salts. The present description also includes all salts of the compounds of the Petition 870180126569, of September 4, 2018, p. 17/98 11/91 present invention which, due to low physiological compatibility, are not directly suitable for use in pharmaceutical products, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. [0040] In addition, the compounds of the present description can be present in the form of solvates, such as those which include water solvate, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol. A "solvate" is formed by the interaction of a solvent and a compound. [0041] In certain embodiments, optical isomers, racemates or other mixtures of the compounds described in that document are provided, or a pharmaceutically acceptable salt or a mixture thereof. If desired, the isomers can be separated by methods well known in the art, for example, by liquid chromatography. In these situations, the single enantiomer or diastereoisomer, that is, the optically active form, can be obtained by asymmetric synthesis or by resolution. Resolution can be carried out, for example, by conventional methods, such as crystallization, in the presence of a resolving agent, or chromatography, for example, using, for example, a high pressure liquid chromatography (HPLC) column. [0042] A stereoisomer refers to a compound formed by the same atoms linked by the bonds, but with different three-dimensional structures, which are not interchangeable. The present invention contemplates several stereoisomers and mixtures thereof, and includes enantiomers, which refers to two stereoisomers whose molecules are mirror images not overlapping one another. Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. [0043] The compounds described in the present invention and their salts Petition 870180126569, of September 4, 2018, p. 18/98 12/91 pharmaceutically acceptable can include an asymmetric center and therefore can give rise to enantiomers, diastereoisomers and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S), or as (D) or (L), for amino acids. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) and (S) or (D) and (L) isomers can be prepared using chiral syntones or chiral reagents, or separated using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis of an appropriate optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative), for example, by means of chiral high pressure liquid chromatography (HPLC ). When the compounds described in the present invention contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include the geometric E and Z isomers. The compositions provided in the present invention that include a compound described herein, or pharmaceutically acceptable salts, isomers or a mixture thereof can include racemic mixtures, which contain an enantiomeric excess of a single enantiomer or diastereoisomers or diastereoisomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention in the same way as if each isomeric form were specifically and individually listed. [0045] Any formula or structure presented here is also intended to represent both unmarked and isotopically marked forms of the compounds. Unveiling labeled compounds have structures depicted by the formulas given in this document, except that Petition 870180126569, of September 4, 2018, p. 19/98 13/91 one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the description include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium ), n C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 36 C1 and 123 I, respectively. Various isotopically labeled compounds of the present description, for example, those in which radioactive isotopes, such as 3 H, 13 C and 14 C, are incorporated. These isotopically labeled compounds can be useful in metabolic studies, reaction kinetics studies, detection or image capture techniques, such as positron emission tomography (PET) or single photon emission tomography (SPECT), including distribution in drug tissue or substrate, or in the radioactive treatment of patients. The isotopically identified compounds of that description and the prodrugs thereof can generally be prepared by carrying out procedures disclosed in the schemes or in the examples and preparations described below, by replacing a readily available isotopically labeled reagent with a non-isotopically reagent marked. [0046] The description also includes deuterated analogs of the compounds of formula (I), where 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds can exhibit increased resistance to metabolism and, therefore, be useful for increasing the half-life of any compound of Formula I when administered to a mammal, for example, a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Know. 5 (12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, using raw materials in which one or more hydrogens have been replaced by deuterium. Petition 870180126569, of September 4, 2018, p. 20/98 14/91 [0047] The deuterium-labeled or substituted compounds of the description may have enhanced DMPK properties (drug metabolism and pharmacokinetics), related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may yield certain therapeutic advantages resulting from greater metabolic stability, for example, longer half-life in vivo, reduced dosage requirements and / or improved therapeutic index. An 18 F labeled compound may be useful for PET or SPECT studies. [0048] The concentration of such a heavier isotope, specifically deuterium, can be defined by an isotopic enrichment factor. In the compounds of that description, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as Ή or hydrogen, it is understood that the position has hydrogen in its naturally abundant isotopic composition. Therefore, in the compounds of this description, any atom specifically designated as a deuterium (D) must represent deuterium. [0049] Furthermore, the present description refers to pharmaceutical compositions comprising at least one compound of the present description, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, together with with a pharmaceutically acceptable carrier. [0050] Pharmaceutical composition means one or more active ingredients and one or more inert ingredients that comprise the vehicle, as well as any product that results, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, or from the dissociation one or more of the ingredients, or other types of reactions or interactions of one or more of the ingredients. Per Petition 870180126569, of September 4, 2018, p. 21/98 15/91 (+) - BINAP 2-MeTHF ACN or MeCN aq. Bn BOC or Boc BSA BSS calcd DAST DCM DIBAL-H DMF DMSO AND THE EDTA ESI Et Et 2 O EtOAc FBS h or hr (s) HATU therefore, the pharmaceutical compositions of the present description encompass any composition made up of a mixture of at least one compound of the present description and a pharmaceutically acceptable carrier. List of abbreviations and acronyms Abbreviation Meaning (+) - 2,2 ’-bis (diphenylphosphino) -1,1 '-binaphthalene 2-methyltetrahydrofuran Acetonitrile Aqueous (a) Benzyl t-butyloxycarbonyl Bovine serum albumin Balanced saline solution Calculated (diethylamino) sulfur trifluoride Dichloromethane diisobutylaluminum hydride Dimethylformamide Dimethylsulfoxide ethyl acetate ethylenediamine tetraacetic acid Electrospray ethyl acetate (ethyl ether) ether ether ether - [bis (dimethylamino) methylene] -177-1,2,3-triazolo [4,5Z ] pyridinium-3-oxidohexafluorphosphate Petition 870180126569, of September 4, 2018, p. 22/98 16/91 HPLC high performance liquid chromatography IPA Isopropyl Alcohol IPTG isopropyl β-D-1-thiogalactopyranoside LCMS or LC / MS liquid chromatography coupled withpasta Me Methyl MEM essential minimum means MeOH Methanol min minute (s) MS mass spectrometry m / z mass: charge ratio NADPH adenine and diucleotide phosphatehydronicotinamide NMP N-methylpyrrolidone NMR nuclear magnetic resonance spectroscopy n-BuLi n-butyl lithium rpm rotations per minute PE Petroleum ether RT or rt room temperature sat. Saturated TBAF tetrabutylammonium fluoride TBDMS t-butyldimethylsilyl TBS t-butyldimethylsilyl TIME 2,2,6,6-tetramethylpiperidino-1-oxy TFA trifluoroacetic acid THF Tetrahydrofuran IMS trimethylsilyl UPLC ultra-efficient liquid chromatographyCompounds Petition 870180126569, of September 4, 2018, p. 23/98 17/91 [0051] The following compounds are provided in the present invention according to formula (I): (I) where: Q is phenylene or pyridylene, each of which optionally substituted with one or two substituents independently selected from halogen, methyl, Cm alkoxy, Cm haloalkoxy, -CH2F, -CHF2 and -CF 3 ; Y is N or CH; A is pyridylene or phenylene, each of which optionally substituted with one or two groups selected independently of halogen, C1-4 alkoxy, Cm haloalkoxy, C1-4 alkyl and Cm haloalkyl; Z is isoxazole substituted with R (pyrazole or substituted with R 1; R 1 is C1-4 alkyl or C3-6 cycloalkyl, wherein said C1-4 alkyl is optionally substituted with 1 to 3 substituents selected independently from fluorine, hydroxyl, C1.3 alkoxy and C1.3 fluoralkoxy, and said cycloalkyl C3-6 is optionally substituted with 1 to 3 substituents independently selected from fluorine, hydroxyl, C1.3 alkyl, C1.3 fluoralkyl, C1.3 alkoxy and C1.3 fluoralkoxy; R 2 and R 3 are selected independently from hydrogen, halogen, methoxy, -CF3, -CHF2, -CH2F, -OCH2F, -OCHF2, -OCF3 and methyl; R 4 is -CO 2 R 5 or -C (O) NR 5 R 6 ; R 5 is hydrogen, C 1.6 alkyl or C 1-6 haloalkyl; and R 6 is hydrogen or Cl-6 alkyl, wherein said C1-6 alkyl is Petition 870180126569, of September 4, 2018, p. 24/98 18/91 optionally substituted with 1 to 6 substituents independently selected from halogen, -SO3H and -CO2H; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [0052] One modality provides compounds of formula (Ia): (Ia) where: Q is phenylene or pyridylene, each of which optionally substituted with one or two substituents independently selected from halogen, methyl, Cm alkoxy, Cm haloalkoxy, -CH2F, -CHF2 and -CF 3 ; Y is N or CH; A is pyridylene or phenylene, each of which optionally substituted with one or two groups selected independently of halogen, C1.4 alkoxy, Cm haloalkoxy, C4.4 alkyl and Cm haloalkyl; R 1 is C 1.4 alkyl or C3.6 cycloalkyl, wherein said C1.4 alkyl is optionally substituted with 1 to 3 substituents selected independently from fluorine, hydroxyl, C1.3 alkoxy and C1.3 fluoralkoxy, and said C3 cycloalkyl .6 is optionally substituted with 1 to 3 substituents independently selected from fluorine, hydroxyl, C1.3 alkyl, C1.3 fluoralkyl, C1.3 alkoxy and C1.3 fluoralkoxy; R 2 and R 3 are selected independently from hydrogen, halogen, methoxy, -CF3, -CHF2, -CH2F, -OCH2F, -OCHF2, -OCF3 and methyl; Petition 870180126569, of September 4, 2018, p. 25/98 19/91 R 4 is -CO 2 R 5 or -C (O) NR 5 R 6 ; R 5 is hydrogen, C1-6 alkyl or C1-6 haloalkyl; R 6 is hydrogen or C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted with 1 to 6 substituents selected independently from halogen, -SO3H and -CO2H; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [0053] One modality provides compounds of formula (Ia): (Ia) where: Q is phenylene optionally substituted with one or two halogens; Y is N or CH; A is pyridylene optionally substituted with one or two groups selected independently from halogen and Cm alkoxy; R 1 is Cm alkyl or C3.6 cycloalkyl; R 2 and R 3 are independently selected from hydrogen and halogen; R 4 is -CO2R 5 or -C (O) NR 5 R 6 ; R 5 is hydrogen; and R 6 is C1.2 alkyl optionally substituted with -CO2H or SO3H; or pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. Petition 870180126569, of September 4, 2018, p. 26/98 20/91 [0054] In one embodiment, Q is phenylene or pyridylene, each of which is optionally substituted with one or two substituents independently selected from halogen, methyl, -CHF2 and -CF3. In some embodiments, Q is phenylene optionally substituted with one or two substituents independently selected from halogen, methyl and CF3. In some embodiments, Q is pyridylene optionally substituted with one or two substituents independently selected from halogen, methyl and -CF3. [0055] In one embodiment, Q is phenylene optionally substituted with one or two halogens. In some embodiments, Q is pyridylene optionally substituted with one or two halogens. In some embodiments, Q is phenylene optionally substituted with one or two chlorines. In some embodiments, Q is pyridylene optionally substituted with one or two chlorines. [0056] In one embodiment, Q is phenylene replaced with chlorine. In some embodiments, Q is pyridylene replaced with chlorine. [0057] In one embodiment, R 1 is C1.4 alkyl. In some embodiments, R 1 is C3.6 cycloalkyl. In some embodiments, R 1 is cyclopropyl or methyl. In some embodiments, R 1 is cyclopropyl. [0058] In one embodiment, R 2 and R 3 are not both hydrogen. In some modalities, R 2 and R 3 are independently selected from hydrogen, halogen, methoxy, -OCHF2, -OCF3 and methyl. In some modalities, R 2 and R 3 are independently selected from halogen, methoxy, -OCHF2, -OCF3 and methyl. [0059] In one mode, R 2 and R 3 are halogen. In some embodiments, R 2 and R 3 are chlorine. [0060] In one embodiment, one of R 2 and R 3 is halogen and the other is hydrogen. In one embodiment, one of R 2 and R 3 is chlorine and the other is hydrogen. In some modalities, one of R 2 and R 3 is fluorine and the other is Petition 870180126569, of September 4, 2018, p. 27/98 21/91 hydrogen. [0061] In one mode, Y is N. In some modes, Y is CH. [0062] In one embodiment, A is pyridylene optionally substituted with one or two halogens. In some embodiments, A is pyridylene optionally substituted with one or two C1-4 alkoxies. [0063] In one embodiment, A is pyridylene replaced with fluorine. In some embodiments, A is pyridylene replaced with a methoxy. In one embodiment, A is unsubstituted pyridylene. [0064] In one embodiment, A is phenylene optionally substituted with one or two halogens. In one embodiment, A is phenylene optionally substituted with one or two C1.4 alkoxides. [0065] In one embodiment, A is phenylene substituted with a fluorine. In one embodiment, A is phenylene substituted with a methoxy. In one embodiment, A is In an embodiment, A is unsubstituted phenylene. [0066] In one embodiment, R 4 is -CO2R5 and R 5 is hydrogen. In one embodiment, R 4 is -CO2R 5 and R 5 is C1-6 alkyl or C1-6 haloalkyl. [0067] In one embodiment, R 4 is -C (O) NR 5 R 6 , R 5 is C 1 alkyl. 6 or C1-6 haloalkyl, and R 6 is C1-2 alkyl, wherein said C1-2 alkyl is replaced with -SO3H or -CO2H. [0068] In one embodiment, R 4 is -C (O) NR 5 R 6 , R 5 is hydrogen and R 6 is C1-2 alkyl, wherein said C1-2 alkyl is replaced with -SO3H or -CCbH. [0069] In one mode, R 4 -A is: wherein the pyridylene is optionally substituted with one or two groups independently selected from halogen, C1-4 alkoxy, C1-4 halo-alkoxy, C1-4 alkyl and C1-4 halo-alkoxy. Petition 870180126569, of September 4, 2018, p. 28/98 22/91 [0070] In one embodiment, R 4 -A is: F [0071] In one embodiment, R 4 -A is: [0073] In one mode, R 4 -A is: [0074] In one embodiment, a compound selected from the group consisting of: Petition 870180126569, dc 09/04/2018, p. 29/98 23/91 or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [0075] In one embodiment, a compound with the following formula is provided in the present invention: or a pharmaceutically acceptable salt thereof. [0076] In one embodiment, a compound with the following formula is provided in the present invention: Petition 870180126569, of September 4, 2018, p. 30/98 24/91 [0077] The chemical name for each of these compounds is given in Table 1 below. Table 1 Example Structure IUPAC Name 1 -WoV, Vrí Cl Çf F 2- (3- (2-chloro-4 - ((5cyclopropyl-3- (2,4difluorfenyl) isoxazol-4yl) methoxy) phenyl) -3-hydroxyazetidinyl-yl) isonicotinic acid 2 .0 χΊ V n V ^ ° V ° n Cl ClxJ ^ CI F 2- (3- (2-chloro-4 - ((5cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4yl) methoxy) phenyl) -3-hydroxyazetidinyl-yl) isonicotinic acid 3 - ( Z x > - N> - ( Z x ) -o v // L HO = N) = / Cl ClxJ ^ CI LV F 6- (3- (2-chloro-4 - (((5cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4yl) methoxy) phenyl) -3-hydroxyazetidinyl-yl) -5-fluoricotinic acid 4 / Voη Vo W / - ° vV N HO / = 7 γ Cl ClxJ ^ CI F 6- (3- (2-chloro-4 - (((3- (2,6dichloro-4-fluorophenyl) -5methylisoxazol-4-yl) methoxy) phenyl) -3hydroxyazetidin-l-yl) -5fluornicotinic acid 5 F OH / ^ Y O VVj ci vV 'ηο 2 οΆ ^ ν gi [1 Ί F 6- (3- (2-Chloro-4 - ((4cyclopropyl-1 - (2,6-dichloro-4fluorfenyl) -1 H-pyrazol-5yl) methoxy) phenyl) -3-hydroxyazetidinl-yl) -5- acid fluornicotinic Petition 870180126569, of September 4, 2018, p. 31/98 25/91 6 H02C n z N < OMe <0 υύ 01 F 5 - ((1 S, 3S) -3- (2-chloro-4 - (((5cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4yl) methoxy) phenyl) -3hydroxycyclobutyl) -6methoxycinicotinic acid Cl Cl 7 comeHNVo '' oh Cl > Cl γF 2- (6- (3- (2-chloro-4 - ((5cyclopropyl 1-3- (2,6-dichloro-4fluorfenyl) isoxazol-4yl) methoxy) phenyl) -3-hydroxyazetidin1 -yl) -5- acid fluoricotinamido) ethane-1 sulfonic 8 vurHN Cl -0 ^ck φF (6- (3- (2-chloro-4 - ((5-cyclopropyl-3 (2,6-dichloro-4-fluorophenyl) isoxazol4-yl) methoxy) phenyl) -3hydroxyzetidin-1-yl) -5fluornicotinoyl) glycineH ° Á Pharmaceutical compositions and modes of administration [0078] The present description further relates to pharmaceutical compositions comprising at least one compound of the present description, or a prodrug, or a pharmaceutically acceptable salt or solvate thereof, as an active ingredient, together with a pharmaceutically acceptable carrier. The pharmaceutical composition of the present description may additionally comprise one or more other compounds as active ingredients, such as a prodrug or other nuclear receptor modulators. [0080] The compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend the nature and severity of the conditions being treated and the nature of the active ingredient. Petition 870180126569, of September 4, 2018, p. 32/98 26/91 They can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. [0081] In practical use, the compounds of the present description can be combined as the active ingredient in intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical composition techniques. The vehicle can take a wide variety of forms, depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). In preparing compositions for the oral dosage form, any of the common pharmaceutical means can be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like, in the case of liquid oral preparations, such as, for example, suspensions, elixirs and solutions; or vehicles such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, in the case of solid oral preparations such as powders, hard and soft capsules and tablets, with solid oral preparations being preferred over liquid preparations. [0082] Due to the ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations must contain at least 0.1% of the active compound. The percentage of the active compound in these compositions can, of course, vary and can conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of the active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, such as drops of liquid or spray. Petition 870180126569, of September 4, 2018, p. 33/98 / 91 [0083] Tablets, pills, capsules and the like can also contain a binder such as tragacanth gum, a disintegrating agent such as corn starch, potato starch and alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. [0084] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets can be coated with shellac, sugar or both. A syrup or ebxir may contain, in addition to the active ingredient, saccharin as a sweetener, methyl and propylparabens as preservatives, a dye and a flavoring agent, such as cherry or orange flavor. [0085] Since the compounds of the present description mostly represent carboxylic acids or anionic isomers similar to them, and since the salt forms of ionic compounds can substantially affect bioavailability, the compounds of the present description can also be used as salts with various counterions to produce a formulation available orally. Such pharmaceutically acceptable cations can be among other mono or divalent ions, such as ammonium, sodium alkali metal potassium or sodium, or alkaline earth metals, such as magnesium or calcium, certain pharmaceutically acceptable amines such as tris (hydroxymethyl) aminomethane, ethylenediamine, diethylamine , piperazine or others, or certain cationic amino acids, such as Plant or arginine. [0086] The compounds of the present description can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water properly mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in gbcerol, liquid pobetylene glycols and mixtures thereof in Petition 870180126569, of September 4, 2018, p. 34/98 28/91 oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. [0087] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid, as long as there is easy syringability. It must be stable under manufacturing conditions and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils. Any suitable route of administration can be employed to provide a mammal, especially a human, with an effective dose of a compound of the present description. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal and the like can be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. In some embodiments, the compounds of the present description are administered orally. Kits [0089] Kits containing a description compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue thereof, and appropriate packaging are also provided in this document. In one embodiment, a kit also includes instructions for use. In one aspect, a kit includes a compound of the description, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue thereof, and a label and / or instructions for using the compounds in Petition 870180126569, of September 4, 2018, p. 35/98 29/91 treatment of indications, including the diseases or conditions described in the present invention. [0090] Articles of manufacture which include a compound described in the present invention or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue thereof in a suitable container are also provided in that document. The container can be a vial, a pot, an ampoule, a pre-filled syringe and an intravenous bag. Treatment methods and uses [0091] Treatment or treating is an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibition of the disease or condition (for example, decrease in one or more symptoms arising from the disease or condition, and / or decrease in the extent of the disease or condition); b) delay or interruption in the development of one or more clinical symptoms associated with the disease or condition (for example, stabilization of the disease or condition, prevention or delay of aggravation or progression of the disease or condition and / or prevention or delay of the spread ( for example, metastasis) of the disease or condition); and / or c) alleviation of the disease, that is, the regression of clinical symptoms (for example, improvement in the state of the disease, providing total or partial remission of the disease or condition, increased effects of another drug, delay in disease progression , increased quality of life and / or prolonged survival. [0092] Prevention or preventing means any treatment of a disease or condition that prevents the clinical symptoms of the disease or condition from developing. The compounds may, in some embodiments, be administered to an individual (including a human being) who is at risk or has a family history of the disease or condition. Petition 870180126569, of September 4, 2018, p. 36/98 30/91 [0093] Individual refers to an animal, such as a mammal (including a human being), that has been or will be the object of treatment, observation or experiment. The methods described herein can be useful in human therapy and / or in veterinary applications. In some embodiments, the individual is a mammal. In one embodiment, the individual is a human being. [0094] The term therapeutically effective amount or "effective amount" of a compound described in the present invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue thereof means an amount sufficient to carry out the treatment when administered to an individual to provide a therapeutic benefit, such as improving symptoms or delaying disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of Cot activity. The therapeutically effective amount may vary depending on the individual and the disease or condition being treated, the individual's weight and age, the severity of the disease or condition and the form of administration, which can be readily determined by a person ordinarily skilled in the art. [0095] The description further refers to the use of said compounds for the treatment and / or prophylaxis of diseases and / or conditions through the binding of said nuclear receptor by said compounds. In addition, the description relates to the use of said compounds for the preparation of a drug for the treatment and / or prophylaxis of diseases and / or conditions by linking said nuclear receptor by said compounds. [0096] Methods of treating a patient with an FXR-mediated condition comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition are also provided herein Petition 870180126569, of September 4, 2018, p. 37/98 31/91 comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. [0097] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of a FXR-mediated condition. [0098] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for the manufacture of a medicine for the treatment of an FXR-mediated condition. [0099] In some embodiments, the condition mediated by FXRé: a chronic intrahepatic condition or some form of an extrahepatic cholestatic condition; hepatic fibrosis; an obstructive inflammatory disorder of the liver; chronic inflammatory liver disorder; hepatical cirrhosis; hepatic steatosis or an associated syndrome; cholestatic or fibrotic effects that are associated with alcohol-induced cirrhosis or viral forms of hepatitis; liver failure or liver ischemia after major liver resection; Steatohepatitis associated with chemotherapy (CASH); acute liver failure; and Inflammatory Bowel Disease. [00100] In some embodiments, the condition mediated by FXR z and: Petition 870180126569, of September 4, 2018, p. 38/98 32/91 a bpidic and bpoprotein disorder; Type I diabetes; Type II diabetes; Clinical combinations of Type I and Type II Diabetes selected from the group consisting of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and other observed effects of long-term diabetic manifestations; Non-alcoholic Fatty Liver Disease (NAFLD); Non-alcoholic steatohepatitis (NASH); obesity; a metabolic syndrome selected from the group consisting of combined conditions of dyslipidemia, diabetes and abnormally high body mass index; acute myocardial infarction; acute stroke; and thrombosis that occurs as an end point of chronic obstructive atherosclerosis. [00101] In some forms of rehabilitation, the condition mediated by FXRé: a non-malignant hyperproliferative disorder; and a malignant hyperproliferative disorder selected from the group consisting of hepatocellular carcinoma, colon adenoma and polyposis; colon adenocarcinoma; breast cancer; pancreatic adenocarcinoma; Barrett's esophagus; and other forms of neoplastic diseases of the gastrointestinal tract and liver. [00102] In some forms of rehabilitation, the condition mediated by FXR Petition 870180126569, of September 4, 2018, p. 39/98 33/91 is non-alcoholic steatohepatitis (NASH). [00103] In some embodiments, the present description relates to the use of the compounds according to formula (I) in the preparation of a drug for the prophylaxis and / or treatment of chronic intrahepatic cholestasis or some forms of cholestatic conditions extrahepatic, hepatic fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory disorders arising from inadequate bibar composition, gastrointestinal conditions with reduced absorption of bpossoluble dietary and dietary fats, inflammatory bowel diseases, intestinal inflammatory disorders and bpoproteins, type II diabetes and clinical complications of type I and type II diabetes, conditions and diseases that result from chronic and fibrotic fatty degeneration of the organs due to the accumulation of lipids and, specifically, forced triglycerides and subsequent activation of profibrotic pathways, obesity and metabolic syndrome (combined conditions of dysbpidemia, diabetes and abnormally high body mass index), acute myocardial infarction, acute stroke, thrombosis that occurs as an endpoint of chronic obstructive atheriosclerosis, persistent infections by intracellular bacteria or parasitic protozoa, hyperproberative non-malignant disorders, hyperprobitive proliferative disorders, colon adenocarcinoma and hepatocellular carcinoma in particular, hepatic steatosis and associated syndromes, liver failure or liver malfunction as a result of chronic liver disease or surgical excision liver, hepatitis B infection, hepatitis C infection and / or cholestatic and fibrotic effects that are associated with alcohol-induced cirrhosis or with viral forms of hepatitis. [00104] Drugs, as referred to in the present invention, can be prepared by conventional processes, including combining a compound according to the present description and a pharmaceutically acceptable carrier. Petition 870180126569, of September 4, 2018, p. 40/98 34/91 [00105] FXR is proposed to be a nuclear bile acid sensor. As a result, it modulates both the synthetic bile acid product in the liver and its recycling product in the intestine (regulating the proteins that bind to bile acids). But in addition to the physiology of bile acids, FXR seems to be involved in the regulation of many diverse physiological processes that are relevant in the etiology and for the treatment of diseases as diverse as cholesterol gallstones, metabolic disorders such as type II diabetes, dyslipidemia or obesity , chronic inflammatory diseases such as inflammatory bowel diseases or chronic intrahepatic forms of cholestasis and many other diseases. [00106] FXR regulates a complex pattern of response genes in the liver and gastrointestinal tract. The gene products have an impact on several physiological processes. During the functional analysis of FXR, the first regulatory network that was analyzed was the regulation of bile acid synthesis. While LXRs induce the key enzyme for the conversion of cholesterol to bile acids, Cyp7Al, through the induction of the regulatory nuclear receptor LRH-1, FXR suppresses the induction of Cyp7Al through the suppression of the mRNA encoding SHP, an additional nuclear receptor which is repressive dominant over LRH-1. As FXR binds to the end products of this pathway, mainly to primary bile acids, such as cholic acid (CA) or CDCA, it can be considered an example of inhibition by feedback at the level of gene expression. In parallel with the suppression of bile acid synthesis through SHP, FXR induces a variety of carriers called ABC (for ATP binding cassette) that are responsible for exporting toxic bile acids from the hepatocyte cytosol to the canaliculi, the branches of small bile ducts where bile originates. This hepatoprotective FXR function was first evident with the analysis of mice with FXR deactivated genes, where the under- or overexpression of various transporters Petition 870180126569, of September 4, 2018, p. 41/98 35/91 ABC in the liver has been demonstrated. Further detailed analysis revealed that the main BSEP or ABCB11 bibar salt excretory pumps (as well as the key enzyme that mediates the transfer of bpoproteins to phosphobpids, PLTP and the two key canalicular membrane transporters for phosphobpids, MRP-2 (ABCC4) and MDR-3 (ABCB4) are direct targets for FXR-targeted transcriptional activation. [00107] The fact that FXR appears to be the main sensor and regulator of metabolites for the synthesis, export and recirculation of bile acids has suggested the use of FXR binders to induce the flow of bile and alter the composition of bibar acids for a composition more hydrofflic. With the development of the first synthetic FXR ligand GW4064 as a resource compound and the semisynthetic artificial barbaric acid 6-alphaethyl-CDCA, the effects of over-stimulation of FXR by potent agonists could be analyzed. Both ligands have been shown to induce the flow of bile in animals with attached bile ducts. In addition, in addition to choleretic effects, hepatoprotective effects could also be demonstrated. This hepatoprotective effect was further reduced to an antifibrotic effect, which results from the repression of tissue inhibitors of matrix metalloproteinases, TIMP-1 and 2, the induction of matrix metalloproteinases that result in collagen deposits in liver star cells and the consequent reduction of collagen-alpha mRNA and transforming growth factor beta (TGF-beta) mRNA, both of which are pro-fibrotic factors by FXR agonists. In addition, anti-cholestatic activity has been demonstrated in animal models connected to the barbaric duct, as well as in animal models of estrogen-induced cholestasis. [00108] Genetic studies demonstrate that, in hereditary forms of cholestasis (progressive famibar intrahepatic cholestasis = PFIC, type I - IV) any nuclear location of the FXR itself is reduced as a result of a mutation in the FIC1 gene (in PFIC type I , also known as disease Petition 870180126569, of September 4, 2018, p. 42/98 36/91 de Byler) (F. Chen et al., Gastroenterology 2004, 126, 756; L. Alvarez et al., Hum. Mol. Genet. 2004, 13, 2451) or levels of the FXR target gene encoding the export pump of MDR-3 phospholipids are reduced (in PFIC type III). Taken together, there is increasing evidence that compounds that bind to FXR will demonstrate substantial clinical utility in the therapeutic regimen of chronic cholestatic conditions, such as primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). [00109] The profound impact that the activation of FXR has on the metabolism and excretion of bile acids is not only relevant for cholestatic syndromes, but even more directly for a therapy against the formation of gallstones. Cholesterol gallstones are formed due to the low solubility of cholesterol, which is actively pumped out of liver cells in the lumen of canaliculi. It is the relative percentage of the content of the three main components, bile acids, phospholipids and free cholesterol, that determines the formation of mixed micelles and, therefore, the apparent solubility of free cholesterol in bile. FXR polymorphisms map the loci of quantitative characteristics as a contributing factor to gallstone disease. Using the synthetic FXR compound GW4064, it can be demonstrated that the activation of FXR leads to an improvement in the cholesterol saturation index (CSI) and, directly, to a suppression of the formation of gallstones in mice susceptible to gallstones. C57L, while drug treatment in mice with genes disabled for FXR shows no effect on the formation of gallstones. [00110] These results qualify the FXR as a good target for the development of small molecule agonists that can be used to prevent the formation of bipolar cholesterol stones or to prevent the reformation of bibary stones after surgical removal or wave btotripsy. shock. Petition 870180126569, of September 4, 2018, p. 43/98 37/91 [00111] Thus, in an embodiment of the description, the compound according to formula (I) and pharmaceutical compositions comprising said compound is used for the prophylaxis and / or treatment of obstructive or chronic inflammatory disorders that arise due to the inadequate composition of bile, such as cholelithiasis, also known as cholesterol gallstones. [00112] In addition to its strong hepatoprotective and choleretic effects, as well as the antifibrotic effects that FXR shows in relation to the activation stimulated by small molecules in the liver, FXR seems to have a role in protecting the intestine against neoplastic transformation and the development of polyps, and its transition to adenocarcinoma in the intestine. Similar to the situation, the absence in the intestine of FXR leads to a strong increase in the formation of hepatocellular cacrcinoma (HCC), the most prominent form of liver cancer. Considering that a functional FXR prevents the formation of colon adenocarcinoma and hepatocellular carcinoma, the activation of FXR induces liver regeneration after hepatectomy. [00113] The combined hepatoprotective hepatic and antineoplastic regenerative effects associated with FXR activation can be exploited therapeutically for the use of FXR agonists in the treatment of severe liver diseases. In one embodiment, the compounds according to the description and pharmaceutical compositions comprising said compounds are used in the treatment of liver diseases, such as HCC, stimulation of liver regrowth and improvement of the side effects associated with major liver excision, liver cirrhosis independent of etiology and prevention or treatment of liver ischemia during liver transplantation or major liver surgery. [00114] Since the discovery of the first synthetic FXR agonist and its administration to rodents, it has become evident that FXR is a key regulator of serum triglycerides. In the past six years, more and more evidence Petition 870180126569, of September 4, 2018, p. 44/98 38/91 have been published that the activation of FXR by synthetic agonists leads to a significant reduction in serum triglycerides, mainly in the form of reduced VLDL, but also to reduce total serum cholesterol. [00115] But the reduction of triglycerides in serum is not an autonomous effect. Treatment of db / db or ob / ob mice with synthetic FXR agonist GW4064 resulted in a marked and combined reduction in serum triglycerides, total cholesterol, free fatty acids and ketone bodies, such as 3-OH-butyrate. In addition, FXR activation is related to the intracellular insulin signaling pathway in hepatocytes, resulting in reduced glucose production from hepatic gluconeogenesis, but a concomitant increase in hepatic glycogen. Insulin sensitivity, as well as glucose tolerance, were positively impacted by treatment with FXR. An effect on reducing body weight has also recently been observed in mice fed excessively on a high-lipid diet. This weight loss effect may result from the induction of FGF-19 FXR, a fibroblast growth factor that is known to lead to weight loss and athletic phenotype. The effect of the FXR agonist on reducing body weight has been demonstrated. [00116] Taken together, these pharmacological effects of FXR agonists can be explored in different therapeutic forms: compounds that bind to FXR are considered to be good candidates for the treatment of type II diabetes because of their sensitizing effects insulin, gluconeogenic and lipid-lowering. [00117] In one embodiment, the compounds according to the description and the pharmaceutical compositions comprising said compounds are used in the prophylaxis and / or treatment of type II diabetes, which can be overcome by FXR-mediated suppression of systemic insulin sensitivity and signaling of intracellular insulin in the liver, greater peripheral glucose uptake and metabolism, greater glycogen storage in the Petition 870180126569, of September 4, 2018, p. 45/98 39/91 liver and decreased glucose production in the serum of gluconeogenesis that occurs in the liver. [00118] In an additional embodiment, said compounds and pharmaceutical compositions are used for the prophylaxis and / or treatment of chronic intrahepatic cholestasis, such as PBC, PSC, progressive family cholestasis (PFIC), alcohol-induced cirrhosis and associated cholestasis , and some forms of extrahepatic cholestatic conditions or liver fibrosis. [00119] The description also refers to a compound of formula (I) or a pharmaceutical composition comprising said compound for the prophylaxis and / or treatment of gastrointestinal conditions with reduced uptake of dietary fats and dietary vitamins fat-soluble, which can be overcome by increasing intestinal levels of bile acids and phospholipids. [00120] In an additional embodiment, said compound or pharmaceutical composition is used to prevent and / or treat a disease selected from the group consisting of lipid and lipoprotein disorders, such as hypercholesterolemia, hypertriglyceridemia and atheriosclerosis as a clinically manifest condition that can be mitigated by the beneficial effect of FXR in reducing total plasma cholesterol, reducing serum triglycerides, increasing the conversion of hepatic cholesterol to bile acids and increasing the clearance and metabolic conversion of VLDL and other lipoproteins in the liver. [00121] In another additional modality, said composition and pharmaceutical composition are used for the prophylaxis and / or treatment of diseases where the combined effects of reducing the lipid, anti-cholestatic and anti-fibrotic content of drugs directed to the FXR can be exploited for the treatment of hepatic steatosis and associated syndromes, such as non-alcoholic steatohepatitis (NASH) or for the treatment of Petition 870180126569, of September 4, 2018, p. 46/98 40/91 cholestatic and fibrotic effects that are associated with alcohol-induced cirrhosis, or with forms of viral origin of hepatitis. [00122] Along with the hypobpidemic effects, it has also been shown that loss of functional FXR leads to increased atheriosclerosis in mice with ApoE deactivated genes. Therefore, FXR agonists may have clinical utility as anti-atherosclerotic and cardioprotective drugs. The lack of regulation of endotebna-1 in cells of the bso vascular muscle can also contribute to such beneficial therapeutic effects. [00123] The description also refers to a compound according to formula (I) or to a pharmaceutical composition comprising said compound for the preventive and post-traumatic treatment of a cardiovascular disorder, such as acute myocardial infarction, stroke acute cerebral palsy or thrombosis, which occur as an outcome of chronic obstructive atheriosclerosis. [00124] In addition to controlling intestinal and colon powder formation, FXR appears to be expressed in breast cancer cell tissue and tissue, but not in healthy breast tissue, and appears to interact with the estrogen receptor on breast cancer cells positive for breast cancer. ER. [00125] This would allow FXR to also be considered as a potential target for the treatment of probferative diseases, especially for the forms of cancer that cause metastasis that matter of forms of cancer that express a responsive form of small molecules of FXR. [00126] In an additional embodiment, said compounds and pharmaceutical compositions are used for the prophylaxis and / or treatment of malignant hyperprobferative disorders, such as different forms of cancer, specifically certain forms of breast, liver or colon cancer, where interference with an FXR binder it will have a beneficial impact. [00127] Finally, FXR also appears to be involved in the control of antibacterial defense in the intestine, although an exact mechanism is not Petition 870180126569, of September 4, 2018, p. 47/98 41/91 provided. From these published data, however, it can be concluded that treatment with FXR agonists may have a beneficial impact on the therapy of inflammatory bowel disorders (IBD), in particular, those forms where the upper (ileal) part of the intestine is affected (eg Crohrris ileus disease) because it appears to occur at the site of action of the FXR control on bacterial growth. In IBD, desensitization of the adaptive immune response is impaired in some way in the intestinal immune system. Bacterial overgrowth may be the trigger that causes the establishment of a chronic inflammatory response. Therefore, the retardation of bacterial growth by mechanisms derived from FXR may be a key mechanism for preventing acute inflammatory episodes. [00128] Thus, the description also refers to a compound according to formula (I) or a pharmaceutical composition comprising said compound to prevent and / or treat a disease related to inflammatory bowel disease, such as Crohrris disease or ulcerative colitis. FXR-mediated restoration of intestinal barrier function and reduction of non-commensal bacterial load is believed to be useful in reducing the exposure of bacterial antigens to the intestinal immune system and, therefore, can reduce inflammatory responses. [00129] The description additionally refers to a compound or pharmaceutical composition for the prophylaxis and / or treatment of obesity and associated disorders, such as the metabolic syndrome (combined conditions of dyslipidemia, diabetes and abnormally high body mass index) that can be overcome by the FXR-mediated reduction of serum triglycerides and blood glucose, and by the increased insulin sensitivity and FXR-mediated weight loss. [00130] In an additional embodiment, the compounds or pharmaceutical composition of the present description are useful in the prevention and / or treatment of the clinical complications of type I and type II diabetes. Examples of such Petition 870180126569, of September 4, 2018, p. 48/98 42/91 complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy or peripheral arterial obstructive disease (PAOD). Other clinical complications of diabetes are also encompassed by the present description. [00131] In addition, the conditions and diseases that result from chronic grease and fibrotic degeneration of the organs due to the forced accumulation of lipids and, specifically, triglycerides, and the subsequent activation of the profibrotic pathways, can also be avoided and / or treated by administering the compounds or pharmaceutical composition of the present description. Such conditions and diseases include NASH and chronic cholestatic conditions in the liver, glomerulosclerosis and diabetic kidney nephropathy, macular degeneration and diabetic retinopathy in the eye and neurodegenerative disorders, such as Alzheimer's disease in the brain or diabetic neuropathy in the peripheral nervous system. Dosage [00132] The effective dosage of the active ingredient used can vary depending on the specific compound used, the mode of administration, the condition being treated and the severity of the condition being treated. This dosage can be readily determined by a person skilled in the art. [00133] When treating or preventing FXR-mediated conditions for which the compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered in a daily dose of about 0.01 milligram to about 100 milligrams per kilogram of the animal's body weight. In some embodiments, the compounds of the present description are administered as a single daily dose or in divided doses, two to six times a day, or in a sustained release form. For most large mammals, the total daily dose is about 1 milligram to about 1000 Petition 870180126569, of September 4, 2018, p. 49/98 43/91 milligrams, or about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be about 7 milligrams to about 350 milligrams. This dosage regimen can be adjusted to provide the optimal therapeutic response. In some modalities, the total daily dose is from about 1 milligram to about 900 milligrams, from about 10 milligrams to about 800 milligrams, from about 20 milligrams to about 700 milligrams, from about 30 milligrams to about 600 milligrams, from about 40 milligrams to about 550 milligrams or from about 50 milligrams to about 400 milligrams. [00134] The compounds of the present application or the compositions thereof can be administered once, twice, three or four times a day, using any appropriate method described above. Likewise, administration or treatment with the compounds can be maintained for several days; for example, commonly, treatment could continue for at least 7 days, 14 days or 28 days, for one treatment cycle. Treatment cycles are well known in cancer chemotherapy, and are often alternated with rest periods of about 1 to 28 days, usually about 7 days or about 14 days between cycles. Treatment cycles, in other modalities, can also be continuous. [00135] In a particular embodiment, the methods provided in this document comprise administering to an individual an initial daily dose of about 1 to 800 mg of a compound described in the present invention, and increasing the dose in increments until effectiveness is achieved clinic. Increments of about 5, 10, 25, 50 or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice a week, or once a week. [00136] In some embodiments, a compound described herein is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In Petition 870180126569, of September 4, 2018, p. 50/98 44/91 some embodiments, one or more additional therapeutic agents are an (n) ACE inhibitor, Acetyl CoA carboxylase inhibitor, Adenosine A3 receptor agonist, Adiponectin receptor agonist, AKT protein kinase inhibitor, protein AMP-activated kinases (AMPK), Amylin receptor agonist Angiotensin II AT-1 receptor antagonist, autotaxin inhibitors, bioactive lipids, calcitonin agonist, Caspase inhibitor, Caspase-3 stimulator, cathepsin inhibitor, inhibitor Caveolin 1, CCR2 chemokine antagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, chloride channel stimulator, CNR1 cyclin Dl inhibitor, cytochrome 5A1 inhibitor, DGAT1 / 2 inhibitor, IV dipeptidyl inhibitor, modulator endosialin, eotaxin ligand inhibitor, extracellular matrix protein modulator, Famesoid X receptor agonist, fatty acid synthase inhibitors, rec agonist eptor FGF1, fibroblast growth factor (FGF-15, FGF-19, FGF-21), Galectin3 inhibitor, Glucagon receptor agonist, Glucagon type 1 peptide agonist, bile acid receptor 1 agonist coupled to G protein , Hedgehog modulator (Hh), hepatitis C virus NS3 protease inhibitor, hepatocyte factor 4 alpha modulator (HNF4A), hepatocyte growth factor modulator, HMG CoA reductase inhibitor, IL-10 agonist, IL-17, ileal sodium bile acid cotransporter inhibitor, insulin sensitizer, integrin modulator, kinase inhibitor 4 (IRAK4) associated with intereucin-1 receptor, Jak2 tyrosine kinase inhibitor, Klotho beta stimulator, 5 inhibitor -Lipoxygenase, lipoprotein lipase inhibitor, liver X Receptor, LPL gene stimulator, Lysophosphatidate-1 receptor antagonist, Lysyl oxidase homolog 2 inhibitor, matrix metalloproteinase inhibitor (MMPs), M protein kinase inhibitor EKK-5, membrane copper amine oxidase inhibitor (VAP-1), methionine aminopeptidase-2 inhibitor, methyl binding protein modulator Petition 870180126569, of September 4, 2018, p. 51/98 45/91 CpG, MicroRNA-21 (miR-21) inhibitor, mitochondrial uncoupler, myelin basic protein stimulator, PYD NACHT LRR domain 3 (NLRP3) protein inhibitor, N AD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NOX), nicotinic acid receptor 1 agonist, P2Y13 purinoceptor stimulator, PDE3 inhibitor, PDE4 inhibitor, PDE 5 inhibitor, PDGF receptor beta modulator, phosphobpase C inhibitor, PPAR alpha agonist, PPAR agonist delta, PPAR gamma agonist, PPAR gamma modulator, protease-activated receptor-2 antagonist, protein kinase modulator, Rho-associated protein kinase inhibitor, sodium transducer-2 transducer inhibitor, factor inhibitor transcription transcription, STAT-1 inhibitor, Stearoil CoA desaturases-1 inhibitor, Cytokine-1 synabzation stimulator suppressor, Cytokine-3 synabzation stimulator suppressor, Transformation growth factor β (T GF-β), Activated Kinase Transformation Growth Factor 1 (TAK1), Thyroid hormone receptor beta agonist, TLR-4 antagonist, Transglutaminase inhibitor, tyrosine kinase receptor modulator, GPCR modulator, receptor modulator nuclear hormone, WNT modulators or YAP / TAZ modulator. [00137] Non-binding examples of one or more additional therapeutic agents include: ACE inhibitors, such as enalapril; Acetyl CoA carboxylase (ACC) inhibitors, such as DRM-01, gemcabene, PF-05175157 and QLT-091382; Adenosine receptor agonists, such as CF-102, CF101, CF-502 and CGS21680; Adiponectin receptor agonists, such as ADP-355; Amylin / Calcitonin receptor agonists, such as KBP042; Petition 870180126569, of September 4, 2018, p. 52/98 46/91 AMP-activated protein kinase stimulators, such as 0-304; Angiotensin II ATi receptor antagonists, such as irbesartan; Autotaxin inhibitors, such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380 and AM-063; Bioactive lipids, such as DS-102; Cannabinoid receptor type 1 (CNR1) inhibitors, such as namacizumab and GWP-42004; Caspase inhibitors, such as emricasan; Pan cathepsin B inhibitors, such as VBY-376; Pan cathepsin inhibitors, such as VBY-825; CCR2 / CCR5 chemokine antagonists, such as cenicriviroc; CCR2 chemokine antagonists, such as propagermanium; CCR3 chemokine antagonists, such as bertilimumab; Chloride channel stimulators, such as cobiprostone; Diglyceride acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx; Dipeptidyl peptidase IV inhibitors, such as linagliptin; Eotaxin ligand inhibitors, such as bertilimumab; Modulators of extracellular matrix proteins, such as CNX-024; Famesoid X (FXR) receptor agonists, such as AGN242266, AKN-083, EDP-305, GNF-5120, LJN-452, LMB-763, obeticholic acid, Px-102, Px-103, Mx90, M780, M450, M480, PX20606, EYP001 and ΓΝΤ-2228; Agonists of the coupled bile acid receptor (FXR) / GPetition 870180126569, of 09/04/2018, p. 53/98 47/91 proteins coupled to the Famesoid X receptor (TGR5), such as ο ΓΝΤ-767; Fatty acid synthase inhibitors, such as TVB-2640; Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7 inhibitors, such as NGM-282; The fibroblast growth factor 21 (FGF21) ligand, such as BMS-986171, BMS-986036; Fibroblast growth factor 21 (FGF-21) / glucagon bke peptide 1 (GLP-1) agonists, such as YH-25723; Galectin-3 inhibitors, such as GR-MD-02; Agonists of Glucagon-like peptide 1 (GLP1R), such as AC-3174, braglutide, semagglutide; Agonists of the G-protein-coupled bibar acid receptor 1 (TGR5), such as RDX-009, INT-777; Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201; HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin; IL-10 agonists, such as peg-ilodecakin; Ileal sodium bibar acid cotransporter inhibitors, such as A-4250, potassium ethanolate hydrate vobxibat (SHP-262) and GSK2330672; Sensibibzadores de insubna, such as KBP-042, MSDC0602K, Px-102, RG-125 (AZD4076) and WP-100X; beta Klotho (KLB) - FGFlc agonist, such as NGM-313; 5-Lipoxygenase inhibitors, such as tipelukast (MN-001); Bpoprotein bpase inhibitors, such as CAT-2003; Stimulators of LPL genes, such as tiparvovec alipogene; Liver receptor X (LXR) modulators, such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965 and SR-9238; Petition 870180126569, of September 4, 2018, p. 54/98 48/91 Lysophosphatidate-1 receptor antagonists, such as BMT-053011, UD-009. AR [00138] In certain specific embodiments, one or more additional therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogene tiparvovec, aramchol, ARI-3037MO, ASP8232, bertilimumab, anhydrous betaine BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, cenicriviroc, CER-209, CF102, CGS21680, CNX-014, CNX-023, CNX -024, CNX-025, cobiprostone, colesevelam, dapagbflozin, deuterated piogbtazone R-enantiomer, 2,4dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), emricasan, enalaprilz, evogbptin, F-351, GKT-831, GNF-5120, GR-MD-02, hydrochlorothiazide, icosapent ethyl ester, IMM-124-E, ΓΝΤ767, IONIS-DGAT2Rx, ipragliflozina, Irbesarta, propagermanium, IVA-337, JKB- 121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, bnagbptine, braglutide, LJN-452, LMB-763, MBX8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MSDC-0602K, namacizu mab, NC-101, ND-L02-s0201, N GM-282, NGM-313, NGM-386, NGM-395, norursodeoxicobic acid, 0-304, obetichobic acid, 25HC3S, olesoxime, PAT-505, PAT-048 , peg-ilodecakin, piogbtazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX009, remogbflozina etabonate, RG-125 (AZD4076), saroglitazar semagglutide, simtuzumab, sobtromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), TCM-606F, TEV-45478, tipelukast (MN-001), TLY-012, TRX-318, TVX 265 UD-009, ursodeoxychobic acid, VBY-376, VBY-825, VK-2809, vismodegib, potassium ethanolate hydrate vobxibat (SHP-626), VVP-100X, WAV-301, WNT-974 and ZGN-839. EXAMPLES [00139] The following examples are included to demonstrate Petition 870180126569, of September 4, 2018, p. 55/98 49/91 specific modes of description. It should be understood by persons skilled in the art that the techniques described in the examples below are techniques to work well in the practice of the invention and, therefore, they can be considered as constituting preferred modes for their practice. However, people skilled in the art should, in the light of this description, note that many changes can be made in the specific modalities that are described and still obtain an equal or similar result without departing from the spirit and scope of the description. [00140] The compounds of the present description can be prepared according to the procedures of the Schemes and Examples below, using suitable materials and are further exemplified by the following specific examples. In addition, using the procedures described in that document, together with the skills normally common in the art, the additional compounds of the present description claimed in that document can be easily prepared. The compounds illustrated in the examples, however, should not be interpreted as forming the only genre that is considered to be the description. The examples further illustrate details for the preparation of the compounds of the present description. Those skilled in the art will readily understand that known variations in the conditions and processes of the following preparative procedures can be used to prepare these compounds. In order to synthesize the compounds which are the modabilities described in the present description, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally demonstrate the identity of the starting materials required by a simple inspection process, given the examples in the present invention. The present compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described above. In general, the compounds described in the present invention are typically stable and isolable Petition 870180126569, of September 4, 2018, p. 56/98 50/91 at ambient temperature and pressure. [00141] The amine-free bases that correspond to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogen carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, and the extraction of the released amine free base in an organic solvent, followed by evaporation. The amine free base, isolated in this way, can be further converted to another pharmaceutically acceptable salt by dissolving it in an organic solvent, followed by the addition of suitable acid and subsequent evaporation, precipitation or crystallization. The free carboxylic acids that correspond to the isolated salts can be generated by neutralization with a suitable acid, such as aqueous hydrochloric acid, sodium dihydrogen phosphate and the extraction of the free carboxylic acid released in an organic solvent, followed by evaporation. The carboxylic acid isolated in this way can be further converted to another pharmaceutically acceptable salt by dissolving it in an organic solvent, followed by the addition of the appropriate base and subsequent evaporation, precipitation or crystallization. [00142] An illustration of the preparation of the compounds of the present description is shown below. Unless otherwise indicated in the diagrams, the variables have the same meaning as described above. The following examples are intended to illustrate particular embodiments of the description. Starting materials, building blocks and suitable reagents used in the synthesis, as described below, are commercially available from Sigma-Aldrich or Acros Organics, for example, or can be prepared routinely by the procedures described in the literature, for example in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition; John Wiley & Sons or T. Eicher, S. Hauptmann The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Applications, 2nd edition, Wiley-VCH 2003; Fieser et al. “Fiesers Petition 870180126569, of September 4, 2018, p. 57/98 51/91 Reagents for organic Synthesis ”John Wiley & Sons 2000. General Synthetic Scheme [00143] The compounds of Formula (I) in which Y is N can be synthesized according to the following general synthetic scheme. [00144] In the general synthetic scheme above, X is an output group, PG is a protection group, and the remaining variables are as provided here. A compound of formula (C) can be prepared by reacting a compound of formula (A) with a compound of formula (B) in the presence of a base to form a compound of formula (C). A compound of formula (D) is formed from a compound of formula (C) under appropriate deprotection conditions. A compound of formula (D) can be combined with a compound of formula (E) in the presence of a base to give a compound of Formula (I). [00145] The appropriate compounds of structure (A) and (B) can be prepared according to the specific methods described in the following Examples or by methods known in the art. In some embodiments, X is halo. In some embodiments, PG is BOC. General overview 1 Petition 870180126569, of September 4, 2018, p. 58/98 52/91 Step 1: 2- (3-hydroxyazetidin-1-yl) isonicotinonitrile (la) [00146] Potassium carbonate (4.6 g, 33 mmol) was added to 2-chloro-4-pyridinocarbonitrile (2.0 g, 14.4 mmol) and 3-hydroxyazetidine hydrochloride (1.7 g, 16 mmol) in NMP (12 mL) at room temperature, and the mixture was heated at 80 ° C for 2 hours in a closed tube. The mixture was cooled to room temperature, treated with H2O and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated. Purification by chromatography (24 g ISCO silica column) using a 1: 1 gradient of hexanes / EtOAc - 100% EtOAc produced 2- (3-hydroxyazetidin-1-yl) isonicotinonitrile (la). Step 2: 2- (3-oxoazetidin-1-yl) isonicotinonitrile (lb) [00147] N-methylmorpholine (1.9 g, 16 mmol), and then tetrapropylammonium perutenate (190 mg, 0.5 mmol) 2- (3hydroxyazetidin-1-yl) isonicotinonitrile (1.9 g, 10.7 mmol) in CH2 Cl2 (200 mL) was added with molecular sieves (1 g, powdered, 4 Â) at room temperature. After 20 minutes, with vigorous stirring, the mixture was filtered through a pad of Celite and was concentrated. Purification by chromatography (24 g ISCO silica column) using a 100% gradient Petition 870180126569, of September 4, 2018, p. 59/98 53/91 hexanes - 1: 3 hexanes / EtOAc produced 2- (3-oxoazetidin-lil) isonicotinonitrile (lb). Synthesis of lc: (4-bromo-3-chlorophenoxy) (tert-butyl) dimethylsilane (lc) [00148] To the solution of 4-bromo-3-chlorophenol (250 g, 1.21 mol) and TBSC1 (272 g, 1.81 mol) in DMF (2.0 L) imidazole (164 g, 2.41 mol) was added. Then, the reaction was stirred at 30 ° C for 12 h. The reaction mixture was poured into H2O (3 L) and extracted with EtOAc (2 L) twice. The combined organic layers were washed with H2O (1 L) and brine (1 L), dried over Na2SO4, filtered and concentrated in vacuo. Purification by chromatography on silica gel eluted with petroleum ether produced (4-bromo-3-chlorophenoxy) (tert-butyl) dimethylsilane (lc). Step 3: 2- (3- (4 - ((tert-butyldimethylsilyl) oxy) -2-chlorophenyl) -3hydroxyazetidin-l-yl) isonicotinonitrile (ld) [00149] Isopropylmagnesium chloride and lithium chloride complex (1, 3 mL, 1.7 mmol, 1.5 M in THF) was added dropwise to (4bromo-3-chlorophenoxy) (tert-butyl) dimethylsilane (lc, 370 mg, 1.15 mmol) in THF (0.9 ml) at room temperature. After 3 h, the reaction was cooled to 0 ° C and treated with 2- (3-oxoazetidin-1-yl) isonicotinonitrile (199 mg, 1.15 mmol) in one portion as a solid. After 1 h, the reaction was quenched with H2O and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by chromatography (4 g ISCO silica column) using a gradient of 100% hexanes - 1: 3 hexanes / EtOAc yielded 2- (3- (4 - ((tert-butyldimethylsilyl) oxy) -2-chlorophenyl) -3-hydroxyazetidin-1 yl) isonicotinonitrile (ld). Step 4: 2- (3- (2-chloro-4-hydroxyphenyl) -3-hydroxyazetidin-1-yl) isonicotinonitrile (le) [00150] To a solution of 2- (3- (4 - ((tert-butyldimethylsilyl ) oxy) -2chlorophenyl) -3-hydroxyazetidin-l-yl) isonicotinonitrile (ld) (180 mg, 0.43 mmol) in 2-MeTHF (4 mL) a solution of 1 M TBAF in THF (0.6 Petition 870180126569, of September 4, 2018, p. 60/98 54/91 mL, 0.59 mmol) at room temperature. After 30 minutes, the mixture was removed with water and extracted with EtOAc. The organic phase was washed with brine (10 ml), dried with Na2SC> 4 and concentrated to produce 2- (3- (2chloro-4-hydroxyphenyl) -3-hydroxyazetidin-1-yl) isonicotinonitrile (le), which was used without further purification. General overview 2 Step 1: 2,6-dichloro-4-fluorbenzaldehyde oxime (2b) [00151] A suspension of 2,6-dichloro-4-fluorobenzaldehyde (6.0 g, 31.2 mmol), NH2OH.HCI (4.3 g, 62.4 mmol), Na2CC> 3 (8.3 g, 78.7 mmol) in ethanol-water (50 ml, 5: 1) was stirred at room temperature for 3 h. The reaction was condensed in vacuo and the residue was treated with water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SC> 4 and concentrated to produce 2,6-dichloro-4fluorbenzaldehyde oxime (2b). Step 2: 2,6-dichloro-4-fluorine-N-hydroxybenzimidoyl chloride (2c) [00152] To a solution of 2,6-dichloro-4-fluorbenzaldehyde oxime (2b, 5.5 g, 26.7 mmol ) in DMF (10 mL) was added to N-chlorosuccinimide (4.3 g, 32.0 mmol). The reaction was stirred at room temperature for 1 h. The mixture was suppressed with H2O and extracted with EtOac. The combined organic layers were washed with brine, dried over anhydrous Na2SC> 4, filtered and concentrated to produce 2,6-dichloro-4-fluorine-N chloride 870180126569, from 04/09/2018, p. 61/98 55/91 hydroxybenzimidoyl (2c) which was used without further purification in the next step. Step 3: Ethyl 5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol-4-carboxylate (2d) [00153] To a solution of 3-cyclopropyl-3oxopropionic acid ethyl ester (5.0 g, 32.0 mmol) in 30 mL of THF was added Et 3 N (10.8 g, 107.2 mmol), the reaction was stirred at room temperature for 30 min and then the reaction mixture from the previous step (2,6dichloro-4-fluorine-N-hydroxybenzimidoyl chloride (2c)) was added by dripping. The resulting mixture was stirred for 2 h at room temperature. The solvent was removed and the residue was partitioned with 100 ml of water and 50 ml of EtOAc. The organic layer was washed with brine, dried, filtered, concentrated and purified by a silica gel column (PE / EA = 10/1) to produce 5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazole- Ethyl 4-carboxylate (2d). Step 4: (5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol-4-yl) methanol (2e) [00154] The solution of 5-cyclopropyl-3- (2,6-dichloro- Ethyl 4-fluorophenyl) isoxazol-4-carboxylate (2d, 3.4 g, 9.3 mmol) in THF (30 mL) was added L1AIH4 (11.1 mL, 11.1 mmol, 1 M in hexanes) per dripping at 0 ° C. The reaction was stirred for 30 min. 1.0 ml of water was added, then 2.0 g of 10% NaOH and 3.0 ml of water were added. The mixture was filtered and concentrated. The crude material was purified by a silica gel column (PE / EA = 2/1) to produce (5-cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4-yl) methanol (2e). LCMS (ESI): m / z 302.0 (M + 1) + . NMR Ή (500 MHz, CDCI3): δ 7.22-7.20 (d, J = 8.5 Hz, 2H), 4.42-4.41 (d, J = 6.0 Hz, 2H), 2, 19-2.16 (m, 1H), 1.41-l, 39 (m, 1H), 1.29-l, 26 (m, 2H), l, 16-l, 13 (m, 2H). General overview 3 Petition 870180126569, of September 4, 2018, p. 62/98 56/91 ο 3c 3d Step 1: Methyl 5-fluorine-6- (3-hydroxyazetidin-1-yl) nicotinate (3a) [00155] A mixture of azetidin-3-ol hydrochloride (2.8 g, 26 mmol), 6-bromine -5-methyl fluomycotinate (5.0 g, 21 mmol) and potassium carbonate (7.4 g, 53 mmol) in DMF (100 mL) was heated to 65 ° C for 19 hours. The mixture was purified by flash chromatography (silica gel) to produce the desired product. LCMS-ESL (m / z): [M + H] + calc, for C10H12FN2O3: 227.1; found: 227.0. Step 2: Methyl 5-fluorine-6- (3-oxoazetidin-1-yl) nicotinate (3b) [00156] A solution of methyl 5-fluorine-6- (3-hydroxyazetidin-1-yl) nicotinate (4 , 7 g, 21 mmol) in dichloromethane (270 mL) was treated with Dess-Martin periodinane (9.7 g, 23 mmol). After 6 hours of stirring at room temperature, an additional portion of Dess-Martin periodinane (1.5 g) was added, and the mixture was kept under stirring overnight at room temperature. After stirring overnight, the mixture was treated with aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified twice by flash chromatography (silica gel) to produce the desired material. LCMS-ESI + (m / z): [M + H2O + H] + calcd. for C10H12FN2O4: 243.1; found: 243.0. Step 3: Methyl 6- (3- (4 - ((tert-butyldimethylsilyl) oxy) -2-chlorophenyl) -3hydroxyazetidin-1-yl) -5-fluoricotinate (3c) Petition 870180126569, of September 4, 2018, p. 63/98 57/91 [00157] A solution of (4-bromo-3-chlorophenoxy) (tert-butyl) dimethylsilane (4.5 g, 14 mmol) in 2-methyltetrahydrofuran (14 mL) was treated with a chloride solution lithium and isopropylmagnesium chloride (Aldrich, 1.3 M, 11 mL, 15 mmol), by drip, using a syringe. The resulting mixture was stirred for about an hour, and then it was cooled in an ice / water bath. Methyl 5-fluorine-6- (3-oxoazetidin-1-yl) nicotinate (2.0 g, 8.9 mmol) was added in portions over 2 hours. The mixture was left to stand overnight at room temperature. The mixture was suppressed with 10% aqueous citric acid solution. The aqueous phase was extracted three times with ethyl acetate. The combined organic materials were washed once with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to produce the crude desired product, which was then used without further purification. LCMS-ESI + (m / z): [M + H] + calc, for C22H29CIFN2O4SÍ: 467.2; found: 467.1. Step 4: 6- (3- (2-chloro-4-hydroxyfeml) -3-hydroxyazetidin-l-yl) -5-methyl fluoricotinate (3d) [00158] 6- (3- (4 - ((terc-butildimethilsihl) oxy) -2-chlorophenyl) -3hydroxyzetidin-1-yl) -5-crude methyl fluomycotinate (about 10 mmol) was resuspended in tetrahydrofuran (70 mL) and treated with tetra-n-butylammonium fluoride solution ( Aldrich, 1.0 M in THF, 18 mL, 18 mmol). The mixture was left to stand at room temperature until considered complete by LC / MS, and then it was purified by flash chromatography (silica gel) to produce the intermediate 3d. LCMS-ESU (m / z): [M + H] + calc, for C16H15CIFN2O4: 353.1; found: 353.0. Example 1: 5 - (((4-bromo-3-chlorophenoxy) methyl) -4-cyclopropyl-1- (2,6dichlorophenyl) -1H-pyrazole Step 1: 2,4-difluorbenzaldehyde oxime Petition 870180126569, of September 4, 2018, p. 64/98 58/91 HO F [00159] This compound was synthesized according to the procedure described in general synthesis 2, step 1, from 2,4-difluorbenzaldehyde (10 g, 70 mmol). Step 2: 2,4-difluoro-N-hydroxybenzimidoyl chloride F [00160] This compound was synthesized according to the procedure described in general synthesis 2, step 2, from 2,4-difluorbenzaldehyde oxime (9 g, 57 mmol). Step 3: Ethyl 5-cyclopropyl-3- (2,4-difluorphenyl) isoxazol-4-carboxylate [00161] This compound was synthesized according to the procedure described in general synthesis 2, step 3, from 2,4-difluoro-N-hydroxybenzimidoyl chloride (11 g, 57 mmol). Step 4: (5-cyclopropyl-3- (2,4-difluorfenyl) isoxazol-4-yl) methanol [00162] This compound was synthesized according to the procedure Petition 870180126569, dc 09/04/2018, p. 65/98 59/91 as described in general synthesis 2, step 4, from ethyl 5-cyclopropyl-3- (2,4difluorphenyl) isoxazol-4-carboxylate (2.2 g, 8 mmol). Step 5: 4- (chloromethyl) -5-cyclopropyl-3- (2,4-difluorphenyl) isoxazole [00163] To a solution of (5-cyclopropyl-3- (2,4-difluorfenyl) isoxazol4-yl) methanol (113 mg, 0.45 mmol) in CH2 Cl2 (2.3 mL) was added thionyl chloride (164 pL, 2.3 mmol) at 0 ° C. The mixture was heated to reflux for 15 minutes and cooled to room temperature. The mixture was concentrated in vacuo. More CH2 Cl2 (5 ml) was added and the mixture was concentrated again. This process was repeated a third time to remove excess thionyl chloride. The crude residue was used in the next step without further purification. Step 6: 2- (3- (2-chloro-4 - (((5-cyclopropyl-3- (2,4-difluorphenyl) isoxazol-4yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) isonicotinonitrile [00164] 4- (chloromethyl) -5-cyclopropyl-3- (2,4-difluorfenyl) isoxazole (113 mg, 0.45 mmol), 2- (3- (2-chloro-4-hydroxyphenyl) -3- hydroxyazetidin-lil) isonicotinonitrile (intermediate le) (149 mg, 0.5 mmol) and K2CO3 (124 mg, 0.9 mmol) were combined in anhydrous DMF (2.3 mL) at room temperature. The mixture was heated to 65 ° C under nitrogen. After 2 h, the solution was cooled to room temperature, suppressed with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC> 4, filtered and concentrated. Purification by Petition 870180126569, of September 4, 2018, p. 66/98 60/91 chromatography: ISCO (12 g silica column) using a gradient of 100% CH2CI2 - 3: 1 CfLCL / premixed with 60: 35: 5 CH2Cl2: Et2O: MeOH gave the title compound. Step 7: 2- (3- (2-chloro-4 - (((5-cyclopropyl-3- (2,4-difluorphenyl) isoxazol4-yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) isonicotinic acid ( Example 1) [00165] 10 M aqueous sodium hydroxide solution (0.67 mL) was added to 2- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,4-difluorphenyl) isoxazol-4il ) methoxy) phenyl) -3-hydroxyazetidin-1-yl) isonicotinonitrile (210 mg, 0.39 mmol) in ethanol (2 mL) and H2O (2 mL) at room temperature, and the mixture was heated to 60 ° C for 90 minutes in a closed tube. The mixture was cooled to room temperature and the pH was adjusted to about 5 with 1 M HCl, which caused a precipitate to come out of the solution. The solution was filtered and the solid was washed with Et2Ü and dried under vacuum to produce the acid 2- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,4-difluorfenyl) isoxazol-4-yl) methoxy) phenyl) 3-hydroxyazetidin-1-yl) isonicotinic (example 1) . NMR Ή (300 MHz, DMSO-d6) NMR Ή (300 MHz, DMSO-d 6 ) δ 13.41 (s, 1H), 8.19 (dd, J = 5.2, 0.8 Hz, 1H) , 7.59 (td, J = 8.5, 6.5 Hz, 1H), 7.49 - 7.34 (m, 2H), 7.28 - 7.15 (m, 1H), 7.05 - 6.96 (m, 2H), 6.88 - 6.74 (m, 2H), 6.20 (s, 1H), 5.00 (s, 2H), 4.47 (d, J = 9 , 3 Hz, 2H), 4.18 (d, J = 9.2 Hz, 2H), 2.40 (tt, J = 8.3, 5.3 Hz, 1H), 1.20 - 1.00 (m, 4H). MS (ESI + ) (m / z) 554.0 (Μ + H). Example 2: 2- (3- (2-Chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-l- acid il) isonicotinic Petition 870180126569, dc 09/04/2018, p. 67/98 61/91 Synthesis of intermediate A: [00166] To a solution of (4-bromo-3-chlorophenoxy) (tertbutyl) dimethylsilane (lc, 60 g, 187 mmol) in THF (500 mL) was added, by dripping, n-BuLi (2.5 M, 75 mL) at -78 ° C under N2. The reaction was stirred at -78 ° C for 1h. Then, a solution of tert-butyl 3-oxoazetidine-carboxylate (27 g, 155 mmol) in THF (500 mL) was dropped into the mixture at -78 ° C. Then, the reaction was stirred at 20 ° C for 3 h. The reaction mixture was poured into H2O (1 L) and extracted with EtOAc (2 L) three times. The combined organic layers were washed with water (1 L), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by gel chromatography eluting with 10: 1 petroleum ether: EtOAc to yield 3- (4 - ((tert-butyldimethylsilyl) oxy) -2-chlorophenyl) azetidin-3-ol (intermediate A) . Step 1: tert-Butyl 3- (2-chloro-4-hydroxyphenyl) -3-hydroxyazetidine-1-carboxylate Petition 870180126569, of September 4, 2018, p. 68/98 62/91 [00167] To a solution of tert-butyl 3- (4 - ((tert-butyldimethylsilyl) oxy) -2-chlorophenyl) -3-hydroxyazetidine-1-carboxylate (intermediate A, 1.27 g, 3.07 mmol) in THF (50.0 mL) at -10 ° C 1 M TBAF in THF (3.68 mL, 3.68 mmol) was added by dropping. The reaction was stirred for 2 hours and concentrated to yield tert-butyl 3- (2-chloro-4-hydroxyphenyl) -3hydroxyazetidine-1-carboxylate, which was used without further purification. Step 2: 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazole [00168] A solution of (5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) ) isoxazol-4-yl) methanol (2e); 845 mg, 2.80 mmol) in DCM (28.0 mL) was cooled to 0 ° C. Thionyl chloride (1.02 mL, 14.0 mmol) was added and the solution was heated to 45 ° C for 1 hour. The reaction was concentrated to dryness and was used without purification in the next step. Step 3: tert- 3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol4-yl) methoxy) phenyl) -3-hydroxyazetidine-1-carboxylate butyl [00169] A solution of tert-butyl 3- (2-chloro-4-hydroxyphenyl) -3-hydroxyazetidino1-carboxylate (922 mg, 3.07 mmol) in DMF (28.0 mL) was added to 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) crude isoxazole, followed by the addition of potassium carbonate (773 mg, 5.60 mmol). The mixture was heated to 60 ° C for 8 hours. The reaction was concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography on silica gel (DCM / Et2O / MeOH) to yield 3- (2-chloro-4 - ((5-cyclopropyl-3 (2,6-dichloro-4-fluorophenyl) isoxazole-4- il) methoxy) tert-butyl-3-hydroxyzetidine-lcarboxylate. LCMS-ESI + (ra / z): [(M + H) -BOC] + calc. 483.04; found 483.04. Step 4: 3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol4-yl) methoxy) phenyl) azetidin-3-ol Petition 870180126569, of September 4, 2018, p. 69/98 63/91 [00170] To a solution of 3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro4-fluorophenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidine Tert-Butyl -1-carboxylate (1.52 g, 2.60 mmol) in DCM (130 mL) 4 N HCl in 1,4-dioxane (26.0 mL, 104 mmol) was added. The solution was stirred at room temperature for 2.5 hours and was concentrated to dryness to yield 3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazole-4il) methoxy) phenyl) azetidin-3-ol as the hydrochloride salt, which was used without further purification. LCMS-ESI + (m / z): [M + H] + calc. 483.04; found 483.03. Step 5: 2- (3- (2-chloro-4 - (((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-1 -yl) methyl isonicotinate [00171] A mixture of methyl 2-bromopyridine-4-carboxylate (0.466 g, 2.16 mmol), 3- (2-chloro-4 - (((5-cyclopropyl-3- (2 , 6-dichloro-4fluorfenyl) isoxazol-4-yl) methoxy) phenyl) azetidin-3-ol as the hydrochloride salt (1.02 g, 1.96 mmol), cesium carbonate (2.56 g, 7, 85 mmol), (±) -BINAP (0.244 g, 0.392 mmol), palladium acetate trimer (88.0 mg, 0.131 mmol) and 1,4-dioxane (40.0 mL) was heated to 85 ° C for 18 hours. The reaction was cooled to room temperature, filtered through cebte and purified by silica gel chromatography (acetone / hexanes) to yield 2- (3- (2-chloro-4 ((5-cyclopropyl-3- (2,6- methyl dichloro-4-fluorophenyl) isoxazol-4-yl) methoxy) phenyl) -3hydroxyazetidin-1-yl) isonicotinate. LCMS-ESU (m / z): [M + H] + scale. 618.08; found 618.20. Step 6: 2- (3- (2-Chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol-4-yl) methoxy) -methyl) -3-hydroxyazetidin- 1-yl) isonicotinic (Example 2). [00172] To a solution of 2- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6dichloro-4-fluorophenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin -1 yl) isonicotinate (617 mg, 0.997 mmol) in THF / water (1: 1, 10 mL) lithium hydroxide monohydrate (83.6 mg, 1.99 mmol) was added. THE Petition 870180126569, of September 4, 2018, p. 70/98 64/91 solution was stirred for 90 minutes, concentrated to remove THF and diluted with water. Acetic acid (0.23 mL, 3.99 mmol) was added with stirring, resulting in the precipitation of solids. The solids were filtered, washed with water, IPA and ether, and dried in vacuo to produce 2- (3 (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) ) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) isonicotinic (example 2). LCMS-ESI + (m / z): [M + H] + calc. 604.06; found 604.15. NMR Ή (300 MHz, DMSO-J 6 ) δ 13.47 (br s, 1H), 8.18 (dd, J = 5.3, 0.8 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.02 (dd, J = 5.3, 1.4 Hz, 1H), 6.93 (d, J = 2.6 Hz, 1H), 6.86 (br s, 1H), 6.75 (dd, J = 8.6, 2.6 Hz, 1H), 6.20 (s, 1H), 4 , 91 (s, 2H), 4.49 (d, J = 9.3 Hz, 2H), 4.19 (d, J = 9.3 Hz, 2H), 2.46 - 2.37 (m, 1H), 1.23 - 1.04 (m, 4H). Example 3: 6- (3- (2-Chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-l- acid il) -5fluornicotinic Petition 870180126569, of September 4, 2018, p. 71/98 65/91 [00173] Steps 1 to 4 were as described for the synthesis of example 2. Step 5: 6- (3- (2-chloro-4 - (((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-1 -yl) -5-methyl fluoricotinate [00174] A mixture of methyl-6-chloro-5-fluorpyridine (235 mg, 1.24 mmol), 3- (2-chloro-4 - ((5-cyclopropyl-3 - (2,6-dichloro-4-fluorophenyl) isoxazol-4yl) methoxy) phenyl) azetidin-3-ol as the hydrochloride salt (495 mg, 0.952 mmol) and potassium carbonate (1.05 g, 7.61 mmol) in DMF (30.0 mL) was heated to 60 ° C for 1 hour. The reaction was concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel (DCM / Et2O / MeOH) to yield 6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol-4-yl) Petition 870180126569, of September 4, 2018, p. 72/98 66/91 methoxy) phenyl) -3-hydroxyazetidin-1-yl) -5-methyl fluoricotinate. LCMS-ESL (zw / z): [M + H] + calc. 636.07; found 635.96. Step 6: 6- (3- (2-Chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin- acid l-yl) -5-fluoricotinic [00175] To a solution of 6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6dichloro-4-fluorophenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) -5 methyl fluoricotinate (364 mg, 0.571 mmol) in THF / water (1: 1, 20.0 mL) lithium hydroxide monohydrate (41, 3 mg, 0.984 mmol). The solution was stirred for 18 hours, concentrated to remove THF and diluted with water (10.0 ml). The pH was adjusted to 3 using HCI IN. The solids were filtered, washed with water, dissolved in ACN / water and lyophilized to produce 6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazole -4-yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) -5-fluoricotinic (Example 3). LCMS-ESL (m / z): [M + H] + calc. 622.05; found 622.12. NMR Ή (400 MHz, DMSO-d 6 ) δ 12.84 (bs, 1H), 8.44 (t, J = 1.7 Hz, 1H), 7.79 - 7.63 (m, 3H), 7.39 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.77 (dd, J = 8.6, 2.6 Hz, 1H ), 6.28 (s, 1H), 4.93 (s, 2H), 4.70 (d, J = 9.8 Hz, 2H), 4.34 (d, J = 9.5 Hz, 2H ), 2.50-2.43 (m, 1H), 1.22 - 1.08 (m, 4H). Intermediate 4: (3- (2,6-dichloro-4-fluorophenyl) -5-methylisoxazol-4-yl) methanol [00176] According to general synthesis 2, starting with 2,6-dichloro-4fluorbenzaldehyde in step 1 and using ethyl acetoacetate in step 3, (3 (2,6-dichloro-4-fluorphenyl) -5-methylisoxazole- 4-yl) methanol (intermediate 4) was synthesized. LCMS-ESL (m / z) - [M + H] + calc. 276.00; found 276.05. Example 4: Preparation of 6- (3- (2-chloro-4 - ((3- (2,6-dichloro-4fluorfeniI) -5-methylisoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-1 acid -il) -5Ption 870180126569, of 09/04/2018, p. 73/98 67/91 fluoricotinic [00177] According to the general procedure described for example 3, using intermediate 4, 6- (3- (2-chloro-4 - ((3- (2,6-dichloro-4fluorfenyl) -5-methylisoxazole -4-yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) -5 fluoricotinic was synthesized. LCMS-ESI + (m / z): [M + H] + calc. 596.04; found, 596.12. NMR Ή (400 MHz, DMSO-d 6 ) δ 12.82 (bs, 1H), 8.44 (t, J = 1.6 Hz, 1H), 7.74 - 7.66 (m, 3H), 7.39 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 6.75 (dd, J = 8.7, 2.6 Hz, 1H), 6.26 (s, 1H), 4.87 (s, 2H), 4.69 ( d, J = 9.8 Hz, 2H), 4.34 (d, J = 9.8 Hz, 2H), 2.57 (s, 3H). z Example 5: 6- (3- (2-Chloro-4 - ((4-cyclopropyl-1- (2,6-dichloro-4fluorfenyl) -1H-pyrazol-5-yl) methoxy) phenyl) -3-hydroxyzetidin acid -l-il) -5fluornicotinic Petition 870180126569, of September 4, 2018, p. 74/98 68/91 F Example 5 Step 1: (2,6-dichloro-4-fluorophenyl) hydrazine hydrochloride [00178] To a -5 ° C solution (internal temperature, crushed ice / acetone bath) of 2,6-dichloro-4-fluoranibna ( 3.0 g, 17 mmol) in 37% hydrochloric acid (30 mL) and trifluoroacetic acid (20 mL), an aqueous sodium nitrite solution (1.4 g, 20 mmol, 6 mL of Water). The reaction was stirred for 90 minutes and then a solution of stannous chloride dihydrate (5.6 g, 25 mmol) in 37% hydrochloric acid (16 mL) was added over 15 minutes, maintaining the internal temperature < 2 ° C. The mixture was stirred overnight at room temperature. The mixture was filtered and the collected solid was washed with isopropyl alcohol and dried under vacuum to produce the title compound. LCMS-ESI + (m / z): [M + H] + calc, for C6H6CI2FN2: 195.0; found: 194.9. Petition 870180126569, of September 4, 2018, p. 75/98 69/91 Step 2: Ethyl 4-cyclopropyl-1- (2,6-dichloro-4-fluorphenyl) -1H-pyrazol-5carboxylate [00179] Ν, Ν-dimethylformamide dimethylacetal (2.7 mL, 20 mmol) -ethyl cyclopropyl-2-oxopropanoate (Synnovator, 1.6 g, 10 mmol) and stirred overnight at room temperature. The mixture was then concentrated to dryness under reduced pressure. To the residue, successively, ethanol (40 ml), (2,6-dichloro-4fluorfenyl) hydrazine hydrochloride (2.6 g, 11 mmol) and 37% hydrochloric acid (150 pL) were added. The reaction was stirred at room temperature for four hours, followed by 2 days of heating under reflux. The cooled mixture was purified by flash chromatography (silica gel) to produce the title compound. LCMS-ESI + (m / z): [M + H] + calc, for C15H14CI2FN2O2: 343.0; found: 343.1. Step 3: (4-chlorocyclopropyl-1- (2,6-dichloro-4-fluorophenyl) -1H-pyrazol-5yl) methanol [00180] A solution of 4-cyclopropyl-1- (2,6-dichloro-4- fluorophenyl) -1Hpyrazol-5-carboxylate (1.5 g, 4.4 mmol) in tetrahydrofuran (50 mL) was cooled to between -12 and -10 ° C. A solution of lithium and aluminum hydride (Aldrich, 2 M in tetrahydrofuran, 2.6 mL, 5.2 mmol) was added by dripping. The mixture was kept under stirring for 35 minutes. The mixture was suppressed (Fieser procedure) and purified by flash chromatography (silica gel) to produce the title compound. LCMS-ESI + (m / z): [M + H] + calc, for C13H12CI2FN2O: 301.0; found: 301.1. Step 4: 5- (chloromethyl) -4-cyclopropyl-1- (2,6-dichloro-4-fluorophenyl) -1Hpyrazol [00181] Thionyl chloride (110 pL, 1.5 mmol) was added to a solution of ( 4-cyclopropyl-1- (2,6-dichloro-4-fluorophenyl) -1H-pyrazol-5-yl) methanol (0.15 g, 0.51 mmol) in dichloromethane (2.5 mL). The mixture was heated at 60 ° C for 40 minutes and then concentrated under reduced pressure to produce the crude desired product, which was then used without Petition 870180126569, of September 4, 2018, p. 76/98 70/91 additional purification. LCMS-ESI + (m / z): [M + H] + calc. for C13H11CI3FN2: 319.0; found: 319.1. Step 5: 6- (3- (2-chloro-4 - ((4-cyclopropyl-1- (2,6-dichloro-4-fluorophenyl) -1Hpyrazol-5-yl) methoxy) phenyl) -3-hydroxyazetidin- methyl l-yl) -5-fluoricotinate [00182] A solution of 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazole (0.16 g, 0.51 mmol) in DMF (3 mL) was treated with methyl 6- (3 (2-chloro-4-hydroxyphenyl) -3-hydroxyazetidin-1-yl) -5-fluomycotinate (0.20 g, 0.56 mmol), iodide sodium (0.13 g, 0.86 mmol) and potassium carbonate (0.14 g, 1.0 mmol). The mixture was heated to 65 ° C overnight and then it was purified by flash chromatography (silica gel) to produce the desired material. LCMS-ESI + (m / z): [M + H] + calc. for C29H24CI3F2N4O4: 635.1; found: 635.2. Step 6: 6- (3- (2-Chloro-4 - ((4-cyclopropyl-1- (2,6-dichloro-4-fluorophenyl) 1H-pyrazol-5-yl) methoxy) phenyl) -3- acid hydroxyazetidin-1-yl) -5-fluoricotinic (Example 5) [00183] A mixture of 6- (3- (2-chloro-4 - ((4-cyclopropyl-l- (2,6-dichloro-4-fluorophenyl) - 1 H-pyrazol-5-yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) -5 methyl fluomycotinate (0.35 g, 0.39 mmol) and lithium hydroxide monohydrate (49 mg, 1.2 mmol) were resuspended in 1: 1 aqueous tetrahydrofuran (6 mL) and the mixture was stirred at room temperature. After completion, the mixture was acidified with glacial acetic acid and concentrated. The residue was purified by flash chromatography (silica gel) to produce 6- (3- (2-chloro-4 - ((4-cyclopropyl-1 - (2,6-dichloro-4-fluorophenyl) -1H-pyrazole acid) - yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) -5-fluomycotin (Example 5). LCMS-ESI + (m / z): [M + H] + calc. for C28H22CI3F2N4O4: 621.1; found: 621.2. NMR Ή (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.44 (t, J = 1.6 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H ), 7.70 (dd, J = 12.7, 1.7 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.80 (dd, J = 8.7, 2.6 Hz, Petition 870180126569, of September 4, 2018, p. 77/98 71/91 1Η), 6.28 (s, 1H), 5.01 (s, 2H), 4.69 (d, J = 9.8 Hz, 2H), 4.34 (d, J = 9.6 Hz, 2H), 1.89 (tt, J = 8.4, 5.1 Hz, 1H), 0.93 (m, 2H), 0.65 (m, 2H). Example 6: 5 - ((1S, 3S) -3- (2-chloropropyl-3- ((5-cyclopropyl-3- (2,6-dichloro-4fluorphenyl) isoxazol-4-yl) methoxy) phenyl acid) - 3-hydroxycyclobutyl) -6methoxyynicotinic Μβ ° 2 ° γ> ΧΖ ο N OMe Intermediate 5 Steps 1 -9 Cl Step 10 » Step 11 Synthesis of the intermediate 5 Step 1: (5-bromo-6-methoxypyridin-3-yl) methanol Br ^ 5x / C ° 2 Me Br / ^ / CH 2 OH 00 [00184] To a solution of methyl 5-bromo-6-methoxyinicotinate (52.8 g, 215.0 mmol) in THF (500 mL) was added DIBAL-H (1.0 M in toluene) (344 mL , 344 mmol) at -20 ° C. Then, the mixture was stirred at room temperature for 2 h. The mixture was suppressed with saturated NH4 Cl solution and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and purified by flash chromatography on silica gel (PE / EtOAc = 4/1) to produce the title compound. Step 2: 3-bromo-5 - ((((tert-butyldimethylsilyl) oxy) methyl) -2-methoxypyridine Petition 870180126569, of September 4, 2018, p. 78/98 Τ2! 9 I'i CH2OH Br TBDSCI TBDMSO NNO [00185] To a solution of (5-bromo-6-methoxypyridin-3-yl) methanol (42.2 g, 194 mmol) and tert-butyldimethylsilyl chloride (35.0 g, 232 mmol) in CH2Cl2 (500 ml) imidazole (19.8 g, 291 mmol) was added. The mixture was stirred at room temperature for 8 h. The mixture was suppressed with water and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and purified by flash chromatography on silica gel (ΡΕ / EtOAc = 10/1) to produce the title compound. Step 3: 3- (benzyloxy) -l- (5 - ((((tert-butyldimethylsilyl) oxy) methyl) -2methoxypyridin-3-yl) cicIobutan-l-ol [00186] 3-bromo-5 - ((((tert-butyldimethylsilyl) oxy) methyl) -2-methoxypyridine (61.2 g, 184 mmol) was dissolved in absolute THF (500 mL) under argon), a solution 1, 6 M of n-butyl lithium (138 mL, 221 mmol) in THF was dropped at -78 ° C. The mixture was stirred for 30 min at the same temperature. A solution of 3- (benzyloxy) cyclobutan-l-one (35.7 g, 202 mmol) in THF (100 mL) was then added at -78 ° C, and the mixture was subsequently stirred at this temperature for 30 minutes. min. Saturated aqueous ammonium chloride solution was subsequently added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and then with saturated sodium chloride solution, dried over magnesium sulfate and filtered. After removing the solvent in a rotary evaporator, the residue was purified by flash chromatography on silica gel (ΡΕ / EtOAc = 2/1) to produce the title compound. Step 4: 3- (benzyloxy) -1- (5- (hydroxymethyl) -2-methoxypyridin-3-yl) cyclobutanl-ol Petition 870180126569, of September 4, 2018, p. 79/98 73/91 ΟΒη [00187] To a solution of 3- (benzyloxy) -1- (5 - ((((tert-butyldimethylsilyl) oxy) methyl) -2-methoxypyridin-3-yl) cyclobutan-l-ol (31.6 g, 73 , 6 mmol) in THF (300 mL) TBAF (88 mL, 1 mol / L) was added. The mixture was stirred at room temperature for 6 hours, and then it was poured into water and extracted with ethyl acetate. The organic phase was washed with water and then with saturated sodium chloride solution, dried over magnesium sulfate and filtered. The organic phase was concentrated to produce the title compound. z Step 5: 5- (3- (Benzyloxy) -l-hydroxycyclobutyl) -6-methoxyynicotinic acid [00188] To a solution of 3- (benzyloxy) -1- (5- (hydroxymethyl) -2methoxypyridin-3-yl) cyclobutan-1-ol (23.2 g, 73.6 mmol) in MeCN (300 mL) and H2O (100 ml) iodobenzene diacetate (64.4 g, 200 mmol) and TEMPO (7.86 g, 50 mmol) were added, and the solution was stirred at room temperature for 2 hours. The mixture was suppressed with saturated sodium bicarbonate solution and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate and filtered; the organic phase was concentrated to produce the title compound. Step 6: Methyl 5- (3- (benzyloxy) -l-hydroxycyclobutyl) -6-methoxyynicotinate [00189] To a solution of 5- (3- (benzyloxy) -1-hydroxycyclobutyl) 6-methoxyynicotinic acid (17.5 g, crude) in THF / MeOH (200/50 ml) was added TMSN2CH3 (50 ml, 20 ml mol / L) at 0 ° C. The mixture was stirred Petition 870180126569, of September 4, 2018, p. 80/98 74/91 at room temperature for 3 hours, and then it was poured into water and extracted with ethyl acetate. The organic phase was washed with water and then with saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel (PE / EA = 10.1) to produce the title compound. Step 7: Methyl 5- (3- (benzyloxy) -l-fluordclobutyl) -6-methoxyynicotinate [00190] To a cooled solution of methyl 5- (3- (benzyloxy) -hydroxycyclobutyl) -6-methoxyynicotinate (15.2 g, 44.3 mmol) in DCM (200 mL) was added DAST (8.0 mL ) at -78 ° C by drip using a syringe. After stirring for 5 minutes at -78 ° C, the reaction was allowed to warm to -20 ° C and was stirred for 75 minutes, then it was removed with H2O (100 ml), diluted with EtOAc and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 brine, and then it was dried over MgSÜ4, filtered and concentrated. The crude product was purified by chromatography (PE: EtOAc = 4: 1) to produce the title compound. Step 8: Methyl 5- (3-hydroxycyclobutyl) -6-methoxyynicotinate [00191] To a solution of methyl 5- (3- (benzyloxy) -l-fluorocyclobutyl) -6methoxyynicotinate (12.7 g, 3.68 mmol) in MeOH (200 mL) and formic acid (10 mL) was added Black powder (3.0 g). The reaction was stirred vigorously under N2. After about 1.5 hours, more black Pd (1.5 g) was added and the reaction was stirred overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in EtOAc and Petition 870180126569, of September 4, 2018, p. 81/98 75/91 washed with saturated Na2C0.3 solution. The organic phase was dried over MgSO4, filtered and concentrated to an oily residue. The residue was purified by chromatography (MeOfkCI-LCb = 1:20) to produce the title compound. Step 9: Methyl 6-methoxy- 5- (3-oxocyclobutyl) nicotinate (intermediate 5) [00192] To a solution of methyl 5- (3-hydroxycyclobutyl) -6-methoxyynicotinate (4.0 g, 16.9 mmol) in MeCN (100 mL) and H2O (30 mL) was added iodobenzene diacetate (16 , 1 g, 50 mmol) and TEMPO (2.92 g, 18.6 mmol), and the solution was stirred at room temperature for 2 hours. The mixture was suppressed with saturated Na2CÜ3 solution and then it was diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated and purified by chromatography (PE: EA = 5: 1) to produce intermediate 5. Step 10: 4 - ((4- bromo-3-chlorophenoxy) methyl) -5-cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazole [00193] Lima solution of 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichloro- Crude 4fluorfenyl) isoxazole (prepared as described in example 2, step 2; 0.42 g, 1.3 mmol) in Ν, Ν-dimethylformamide (DMF, 6 mL) was treated with 4bromop-3-chlorophenol (0.27 g , 1.3 mmol), sodium iodide (0.34 g, 2.2 mmol) and potassium carbonate (0.37 g, 2.6 mmol). The mixture was heated to 60 ° C for 35 minutes before being cooled and was purified by flash chromatography (silica gel) to produce the desired material. LCMS-ESI + (m / z): [M + H] + calc. for CioHisBrCLFNCL: 491.9; found: 492.0. Step 11: 5- (3- (2-chloro-4 - (((5-cidopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxycyclobutyl) - Methyl 6-methoxyynicotinate Petition 870180126569, dc 09/04/2018, p. 82/98 76/91 [00194] Under an argon atmosphere, a solution of 4 - ((4-bromo-3-chlorophenoxy) methyl) -5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazole (0.83 g, 1.7 mmol) in 2-methyltetrahydrofuran (2 mL) was treated with a solution of lithium chloride and isopropylmagnesium chloride (Aldrich, 1.3 M in tetrahydrofuran, 1.3 mL, 1.7 mmol) by drip using a syringe. After four hours had passed, an additional volume of lithium chloride and isopropylmagnesium chloride solution (1.3 mL) was added. In a separate container, under an argon atmosphere, a solution of methyl 6-methoxy-5- (3oxyclobutyl) nicotinate (intermediate 5), 0.21 g, 0.90 mmol) in tetrahydrofuran (5 mL) with lanthanum chloride (111) / 2 lithium chloride solution (Aldrich, 0.6 M in tetrahydrofuran, 1.5 mL, 0.9 mmol). This mixture was stirred for one hour at room temperature before being cooled in a crushed ice / acetone bath at -8 ° C. The Grignard solution above was added by dripping to the ketone solution using a syringe. The reaction mixture was stirred overnight under an argon atmosphere. The mixture was suppressed with saturated aqueous ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate. The combined organic materials were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to produce the title compound. LCMS-ESI + (m / z): [M + H] + calc, for C31H27CI3FN2O6: 647.1; found: 647.1. Step 12: 5 - ((1S3S) -3- (2-chloro-4 - (((5-cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4-yl) methoxy) phenyl) -3- acid hydroxycyclobutyl) -6methoxyynicotinic (Example 6) [00195] A mixture of 5- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro4-fluorphenyl) isoxazol-4-yl) methoxy ) methyl phenyl) -3-hydroxycyclobutyl) -6methoxyynicotinate (0.26 g, 0.40 mmol) and hydroxide monohydrate Petition 870180126569, of September 4, 2018, p. 83/98 / 91 lithium (33 mg, 0.79 mmol) were resuspended in 1: 1 aqueous tetrahydrofuran (10 mL) and stirred overnight at room temperature. Most of the volatile compounds were removed under reduced pressure. The aqueous mixture was diluted with water and treated by dripping with 10% aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate three times. The combined organic materials were washed with saturated aqueous sodium chloride solution (with a small amount of hydrochloric acid added). The combined organic materials were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified first by flash chromatography (silica gel) and then by preparative HPLC (acetonitrile / water, TFA). The combined fractions were collected by HPLC and were neutrabied with saturated aqueous sodium hydrogen carbonate solution, saturated with sodium chloride and extracted three times with ethyl acetate. The combined organic materials were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was resuspended in ethyl acetate, treated with anhydrous magnesium sulfate, filtered and concentrated. Again, the residue was resuspended in ethyl acetate and filtered through a pad of diatomaceous earth celite. The filtrate was concentrated to produce 5 - ((1S, 3S) 3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol-4yl) methoxy acid) phenyl) -3-hydroxycyclobutyl) -6-methoxyynicotinic (Example 6). LCMSESI + (m / z): [M + H] + calc, for C30H25CI3FN2O6: 633.1; found: 633.1. NMR Ή (400 MHz, DMSO-d6) δ 13.00 (bs, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 2.3, 0, 8 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 2.6 Hz , 1H), 6.79 (dd, J = 8.7, 2.6 Hz, 1H), 4.94 (s, 2H), 3.90 (s, 3H), 3.15 - 3.03 ( m, 2H), 2.91 (p, J = 8.8 Hz, 1H), 2.49 - 2.41 (m, 1H), 2.41 - 2.30 (m, 2H), 1.21 - 1.09 (m, 4H). Example 7: 2- (6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyzetidin acid -l-il) -5Petition 870180126569, of 09/04/2018, page 84/98 78/91 fluornicotinamido) ethane-l-sulfonic A solution of 6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-l- il) -5-fluoricotinic (example 3, 0.11 g, 0.18 mmol) in DMF (4 mL) was treated with HATU [00196] 3-hexafluorophosphate (l- [bis (dimethylamino) methylene] lH-) 1,2,3-triazolo [4,5-b] pyridinium, 0.10 g, 0.27 mmol) followed by taurine (34 mg, 0.27 mmol) and N, N-diisopropylethylamine (90 pL, 0.54 mmol). The mixture was stirred overnight at room temperature and was then purified by preparative HPLC (water / acetonitrile / TFA). The combined fractions were treated with ammonium hydroxide solution and were concentrated to produce 2- (6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6dichloro-4-fluorophenyl) acid isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) -5fluomycotinamido) ethane-1-sulfonic (example 7), as the ammonium salt. LCMS-ESI + (m / z): [M + H] + calc. for C30H26CI3F2N4O7S: 729.1; found: 729.2. NMR Ή (400 MHz, DMSO-d6) δ 8.34 (m, 2H), 7.73 - 7.61 (m, 3H), 7.37 (d, J = 8.6 Hz, 1H), 7 , 29 - 6.95 (m, 4H), 6.92 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.6, 2.5 Hz, 1H), 6, 22 (s, 1H), 4.90 (s, 2H), 4.63 (d, J = 9.6 Hz, 2H), 4.29 (d, J = 9.6 Hz, 2H), 3, 46 (q, J = 6.5 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.45 - 2.38 (m, 1H), 1.16 (dt, J = 8.5, 3.1 Hz, 2H), 1.10 (dt, J = 5.4, 2.9 Hz, 2H). Example 8: (6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-l- il) -5fluornicotinoyl) glycine Petition 870180126569, of September 4, 2018, p. 85/98 79/91 Step 1: 6- (3- (2-chloro-4 - (((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-1 -yl) -5-fluornicotinoyl) methyl glycinate [00197] A solution of 6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6dichloro-4-fluorophenyl) isoxazole-4-acid -yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) -5 fluoricotinic (example 3, 0.12 g, 0.19 mmol) in DMF (4 mL) was treated with HATU [00198] hexafluorophosphate 3-oxide (1- [bis (dimethylamino) methylene] 1H-1,2,3-triazolo [4,5-b] pyridinium, 0.11 g, 0.29 mmol) followed by glycinomethyl ester hydrochloride (36 mg, 0, 29 mmol) and N, N-diisopropylethylamine (100 µL, 0.58 mmol). The mixture was stirred overnight at room temperature and was then suppressed with saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution: saturated aqueous sodium hydrogen carbonate solution 1: 1, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to produce the desired product, which was used at continue without further purification. LCMS-ESF (m / z): [M + H] + calc, for C31H26CI3F2N4O6: 693.1; found: 693.2. Step 2: (6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4-fluorophenyl) isoxazoI-4-yl) methoxy) pheniI) -3-hydroxyazetidin- 1-iI) -5-fluoricotinoi) gicin (Example 8) [00199] A mixture of (6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6dichloro-4-fluorophenyl)) methyl isoxazol-4-yl) methoxy) phenyl) -3-hydroxyazetidin-1-yl) -5fluomycotinyl) glycinate (about 0.19 mmol) and lithium hydroxide Petition 870180126569, of September 4, 2018, p. 86/98 80/91 monohydrate (38 mg, 0.91 mmol) in aqueous tetrahydrofuran (2: 1, 3 mL) was stirred at room temperature for 3.5 hours. The volatile solvent was removed under reduced pressure. The residue was diluted with water and acidified to pH 1 with 10% aqueous hydrochloric acid solution. The acidic aqueous mixture was extracted three times with ethyl acetate. The combined organic extracts were washed once with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel) to produce (6- (3- (2-chloro-4 - ((5-cyclopropyl-3- (2,6-dichloro-4fluorfenyl) isoxazol-4-yl) methoxy ) phenyl) -3-hydroxyazetidin-1-yl) -5-fluomycotinoyl) glycine (Example 8). LCMS-ESI + (m / z): [M + H] + calc, for C30H24CI3F2N4O6: 679.1; found: 679.3. NMR Ή (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.68 (t, J = 5.8 Hz, 1H), 8.44 (t, J = 1.7 Hz, 1H ), 7.80 (dd, J = 13.2, 1.8 Hz, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.7 Hz , 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.77 (dd, J = 8.6, 2.6 Hz, 1H), 6.26 (s, 1H), 4 , 93 (s, 2H), 4.66 (d, J = 9.5 Hz, 2H), 4.32 (d, J = 9.3 Hz, 2H), 3.87 (d, J = 5, 8 Hz, 2H), 2.48 - 2.42 (partially obscured by DMSO, m, 1H), 1.16 (m, 4H). Example 9: FRET activity assay [00200] The determination of the cofactor peptide-mediated interaction of the cofactor to quantify the ligand's binding to the nuclear FXR receptor was re-performed as follows. [00201] Preparation of the human FXR alpha ligand bgation domain: The human LBD alpha FXR was expressed in the E. coli BL21 (DE3) strain as a GST-labeled fusion protein at the N-terminus. The DNA encoding the FXR ligand binding domain was cloned into the vector pDEST15 (Invitrogen). The expression was under the control of an IPTG-inducible T7 promoter. The amino acid boundaries of the ligand binding domain were amino acids 187 to 472 of the record in the database NM_005123 (RefSeq). FXR-LBD expression and purification: a prePetition 870180126569, from 09/04/2018, p. 87/98 81/91 overnight culture of a transformed E. coli strain was diluted 1:20 in LB-ampicillin medium and cultivated at 30 ° C to an optical density of OD = 0.4 to 0.6 . Gene expression was then induced by the addition of 0.5 mM IPTG. The cells were incubated for an additional 6 h at 30 ° C, at 180 rpm. The cells were collected by centrifugation (7000 x g, 7 min, room temperature). Per liter of original cell culture, cells were resuspended in 10 ml of lysis buffer (50 mM glucose, 50 mM tris pH 7.9, 1 mM EDTA and 4 mg / ml lysozyme) and left on ice for 30 min . The cells were then subjected to ultrasound, and the cell fragments were removed by centrifugation (22000 x g, 30 min, 4 ° C). per 10 ml of supernatant 0.5 ml of pre-washed glutathione 4B sepharose slurry (Qiagen) was added, and the suspension was kept under slow stirring for 1 h at 4 ° C. The glutathione 4B sepharose beads were pelleted by centrifugation (2000 x g, 15 sec. At 4 ° C) and washed twice with wash buffer (25 mM Tris, 50 mM KC1, 4 mM MgCh and 1 Na NaCl). The pellet was resuspended in 3 ml of elution buffer per liter of the original culture (elution buffer: 20 mM Tris, 60 mM KC1, 5 mM MgCh and 80 mM glutathione was added immediately before use as a powder). The suspension was kept in rotation for 15 min at 4 ° C, the beads were pelleted and eluted again with half the volume of the elution buffer compared to the first time. The eluates were pooled and dialyzed overnight in 20 mM Hepes buffer (pH 7.5) containing KC160 mM, 5 mM MgCh and 1 mM dithiothreitol, and 10% (v / v) glycerol. The protein was analyzed by SDS-Page. [00202] The method measures the ability of putative ligands to modulate the interaction between the bacterial expressed FXR ligand (LBD) binding domain and a synthetic biotinylated peptide based on residues 676 to 700 of SRC-1 (LCD2, 676 to 700). The sequence of the peptide used was B-CPSSHSSLTERHKILHRLLQEGSPS-COOH (SEQ ID NO: 1), where the NPetition 870180126569, of 04/09/2018, p. 88/98 82/91 terminal was biotinylated (Β). The FXR domain (LBD) domain was expressed as a GST fusion protein in BL-21 cells using the vector pDEST15. The cells were lysed by ultrasound, and the fusion proteins were purified on glutathione sepharose (Pharmacia), according to the manufacturer's instructions. To screen the compounds for their influence on the FXR-peptide interaction, Perkin Elmer's LANCE technology was applied. This method is based on the transfer of energy dependent on donation from a donor to a fluorophore acceptor, dependent on the partner of interest. To facilitate the manipulation and reduction of the background signal of the compound, the LANCE fluorescence technology makes use of the generic fluorophores markers and detection tests with temporal resolution, which were performed in a final volume of 25 pL in a 384-well plate , in a Tris-based buffer (20 mM Tris-HCl, pH 7.5; 5 mM KC160, 5 mM MgCL; 35 ng / pL BSA), containing 20 to 60 ng / well of recombinantly expressed FXRLBD fused to the GST, 200 to 600 nM of biotinylated peptide at the N-terminal, representing amino acids 676 to 700 of SRC1, 200 ng / well of streptavidin-xlAPC conjugate (Prozyme) and 6 to 10 ng / well of Eu W1024 - antiGST (Perkin Elmer). The DMSO content of the samples was maintained at 1%. After generating the assay mixture and diluting the potentially modulating FXR binders, the assay was balanced for 1 h in the dark at room temperature on black FIA plates with 384 wells (Greiner). The LANCE signal was detected by a Perkin Elmer VICTOR2VTM multi-marker counter. The results were visualized graphically representing the ratio between the light emitted at 665 nm and 615 nm. A basal level of formation of FXR-peptide is observed in the absence of the added bant. The binders that promote the formation of the complex induce a concentration-dependent increase in the fluorescent signal with temporal resolution. Compounds that match the monomeric FXR and the FXR-peptide complex would be expected not to Petition 870180126569, of September 4, 2018, p. 89/98 83/91 showed signal variation, whereas it would be expected that the ligands, which preferentially bind to the monomeric receptor, would induce a concentration-dependent decrease in the observed signal. [00203] To assess the agonistic potential of the compounds, the EC50 values were determined, for example, for the compounds and are shown below in Table 2 (EC50 FRET). Example 10: Assay of a mammalian hybrid (M1H) [00204] The determination of a bgg-mediated Gal4 promoter-induced transactivation to quantify the bggg-mediated activation of the FXR banton was performed as follows. [00205] The part of the cDNA encoding the FXR bgation domain was cloned into the pCMV-BD vector (Stratagene) as a fusion to the yeast GAL4 DNA bgation domain under the control of the CMV promoter. The amino acid limits of the bgas domain were amino acids 187 to 472 of the record in the database NM_005123 (RefSeq). Plasmid pFR-Luc (Stratagene) was used as the reporter plasmid, containing a synthetic promoter with five tandem replications of yeast GAL4 bgation sites, boosting the expression of the Photinus pyrabs luciferase gene (American firefly) as the reporter gene. In order to improve the experimental precision the plasmid pRL-CMV (Promega) was cotransfected. PRL-CMV contains the constitutive CMV promoter, controlling the expression of Renilla reniformis luciferase. All assays with the Gal4 reporter gene were performed on HEK293 cells (obtained from DSMZ, Braunschweig, Germany), cultured in MEM with L-glutamine and Earle BSS supplemented with 10% fetal bovine serum, non-essential amino acids at 0.1 mM, 1 mM sodium pyruvate and 100 units of penicillin / streptavidin per ml at 37 ° C in 5% CO2. The medium and supplements were obtained from Invitrogen. For the assay, 5 x 10 5 cells were plated per well in 96-well plates in 100 pL per well. Petition 870180126569, of September 4, 2018, p. 90/98 84/91 MEM without phenol red and L-glutamine, and with Earle BSS supplemented with 10% FBS treated with charcoal / dextran (HyClone, South Logan, Utah), 0.1 mM non-essential amino acids, 2 mM glutamine, pyruvate of 1 mM sodium and 100 units of penicillin / streptavidin per mL, and incubated at 37 ° C in 5% CO2. The next day, the cells reached> 90% confluence. The medium was removed and the cells were transiently transfected using 20 µl per well of an OptiMEM-polyethylenimine-based transfection reagent (OptiMEM, Invitrogen; polyethylenimin; Cat. No. Aldrich 40, 827-7) including the three plasmids described above . MEM, with the same composition used to plate the cells, was added 2 to 4 h after the addition of the transfection mixture. Then, stocks of the pre-diluted MEM compound were added (final vehicle concentration not greater than 0.1%). The cells were incubated for an additional 16 h before firefly and renyl luciferase activities were measured sequentially in the same cell extract, using a double light luciferase assay system (Dyer et al., Anal. Biochem. 2000, 282, 158-161). All experiments were done in triplicate. [00206] To assess the agonistic potency of the FXR of the exemplary compounds, the potency was determined in the M1H assay and is listed below in table 2 (M50H EC50). Table 2 Example ECso FRET (nM) ECso M1H (nM) 1 263 3000 2 25 831 3 7.4 3.8 4 35 176 5 18 8.6 6 49 353 7 6.9 1696 8 8.1 1264 Example 11: Metabolite ID assay in liver immosomes Petition 870180126569, of September 4, 2018, p. 91/98 85/91 humans [00207] The analysis of the metabolic stability of example 3 and comparative example 1 in microsomes of the human liver was re-performed according to the following procedure. Microsomes of human liver (protein concentration of 35 pL of 20 mg / mL), 350 pL of 100 mM potassium phosphate buffer (pH 7.4), 245 pL of deionized water and 0.7 pL of stock solution of the compound (5 mM) were combined in a 1.5 mL microcentrifuge tube. The tube was closed and gently vortexed for 10 seconds, then it was placed in an Eppendorf ThermoMixer C and preheated to 37 ° C with stirring at 1100 rpm for 5 minutes. [00208] The NADPH solution (70 pL; 10 mM in water) was added with stirring, the mixture was aspirated several times with a pipette and 200 pL were removed into a 1.5 ml microcentrifuge tube containing 200 pL of cold acetonitrile . This aliquot was vortexed at high speed for 10 seconds, and then it was placed on ice. After 30 and 60 minutes, more 200 pL aliquots were removed and transferred to a 1.5 ml microcentrifuge tube on ice containing 200 pL of cold acetonitrile. They were vortexed at high speed for 10 seconds and then placed on ice. [00209] The refrigerated aliquots were centrifuged at 14,300 rpm in a microcentrifuge for 10 minutes at 10 ° C, and then the supernatant was transferred to a 96-well deep well plate (1 ml) and sealed with a layer of silicone. The sample was transferred to the Auto Stack's Cool Stack (temperature set to 10 ° C) and 20 pL was injected into the Thermo Ebte Orbitrap mass spectrometer. Samples of 20 pL were analyzed by UPLC-MS in order to identify and quantify the metabolites (Agilent UPLC binary pump 1290 G4220 from Agilent TCC column oven; Column C18 BEH from UPLC Acquity Petition 870180126569, of September 4, 2018, p. 92/98 86/91 by Waters (pore size 130 µm, particle size 1.7 pm, 2.1 x 50 mm) maintained at 40 ° C; Agilent DAD 1290 G4212 diode array with wavelength from 190 to 400 nm; Elite Orbitrap mass spectrometer from Thermo, in positive FTMS mode). [00210] Final microsomal protein concentration: 1 mg / mL [00211] Final NADPH concentration: 1 mM [00212] Final substrate concentration: 5 μΜ [00213] Time points: 0, 30 and 60 minutes [00214] Volume incubation per time point: 200 pL [00215] Comparative example 1, a direct comparator of example 3 that does not have a 4-fluorophenyl substituent present in the compounds described here, has been metabolised to a diol compound (Ml) under the conditions described above (scheme 1). The incorporation of the 4fluor substituent inhibited the formation of the Ml metabolite under the same conditions. Layout 1 Comparative Example 1 m / z G04.0G1Ü Abundance by UV 23% M1 M / Z 638.0664 Abundance by UV <1% Example 12: Evaluation of Pharmacodynamics In Vivo in Macacocinomolgo Petition 870180126569, of September 4, 2018, p. 93/98 87/91 [00216] The in vivo pharmacodynamics of a representative compound of Formula (I) and a comparative example compound were determined as follows. Test article and formulation [00217] The doses of oral suspension of a representative compound of Formula (I) (Example 3) and Comparative Example 2 (Example 13/9 of US Patent No. 9,139,539) were formulated in concentrations of 2, 6 , 20 and 60 mg / mL in aqueous suspensions of 0.5% sodium carboxymethyl cellulose (Na CMC), 1% ethanol and 98.5% 50 mM Tris buffer, at pH 8. Animals [00218] Each dosing group consisted of three male Cynomolgus monkeys. At the dose, the animals weighed between 2.5 and 4.4 kg. Dosage [00219] The test articles were administered to the monkeys orally at 5 ml / kg. Before removal, the gavage tube was washed with approximately 10 mL of water. Sample collection [00220] Venous blood samples were collected at specified time points after the administration of each animal. Blood samples were collected and transferred to tubes containing potassium EDTA anticoagulant (K2). Determination of Plasma FGF19 Concentrations [00221] The BioFendor ELF FGF19 assay kit (product number RD191107200R) was used to determine FGF19 concentrations in the collected blood samples. Determination of Plasma Drug Concentration [00222] A 50 pL aliquot of each plasma sample from the groups Petition 870180126569, of September 4, 2018, p. 94/98 88/91 dosing 10 and 30 mg / kg and samples t = 0 from groups 100 and 300 mg / kg were treated with 200 pL of internal acetonitrile standard (ACN). An aliquot of 25 pL of the remaining samples in the 100 mg / kg group was combined with 25 pL of blank plasma to perform a 1: 2 dilution and treated with 200 pL of acetonitrile (ACN) containing internal standard. A 10 µl aliquot of the remaining samples from the 300 mg / kg group was combined with 40 µl of blank plasma to make a 1: 5 dilution and treated with 200 µl of acetonitrile (ACN) containing internal standard. The above solutions were centrifuged at 5000 RPM for 10 minutes and 50 pL of supernatant was transferred to a 96-well BMP plate, followed by the addition of 200 pL of water. A 10 pL aliquot was injected into the API 5000 LC / MS / MS system. Samples that exceed the instrument's cabling range were diluted and rescanned. HPLC conditions [00223] A Zorbax Extend Cl8 HPLC column (50 x 2.1 mm, 3.5 p) from Agilent Technologies (Part 735700-902) was used. Mobile phase A contained a 1% aqueous solution of acetonitrile in 10 mM ammonium format adjusted to pH 3.0 with formic acid. Mobile phase B contained and 10% 10 mM ammonium formate in acetonitrile adjusted to pH 5.2 with formic acid. A Thermo Aria multiplexer with two identical binary pumps from the Agilent 1200 series (P / N G1312A pump) was used for elution and separation. The elution program used is set out in the following table 3. Petition 870180126569, of September 4, 2018, p. 95/98 89/91 Table 3 Time (sec) Steps Comment Flow rate(mL / min) Mobile Phase A (%) Mobile Phase B (%) 30 Sample Loading 0.50 85 15 180 Inclination 0.50 50 50 90 Inclination 0.50 99 1 60 Elution 0.50 99 1 120 Rebalancing 0.50 85 15 [00224] An API 5000 triple quadripolar mass spectrometer from AB Sciex, Foster City, CA was used in the multiple reaction monitoring mode to quantify the compounds. The mass spectrometry parameters used are shown in table 4 below. Table 4 Ion source Spray Voltage (V) Gas 1 (Arb) Gas 2 (Arb) Collision Gas (Arb) Drying Temperature (° C) Ion spraying 5500 70 50 6 550 Turbo Results [00225] FGF19 levels were compared after oral administration of increasing doses of Example 3 or Comparative Example 2 (3 to 300 mg / kg). Dose-dependent increases in plasma exposure were observed for both compounds and the maximum AUC achieved with each compound at 300mg / kg was comparable (Figure 1). Example 3 Dose dependent FGF19, reaching a Cmax of 16000 pg / ml at the highest dose (Figure 2). Administration of Comparative Example 2 also caused increases in plasma FGF19, but the maximum level of FGF19 was significantly lower (Cmax 3000 ng / ml) than for Example 3. In addition, the maximum induction of FGF19 by Comparative Example 2 was achieved at 5 mg / kg; the higher doses did not increase further Petition 870180126569, of September 4, 2018, p. 96/98 90/91 due to higher plasma drug exposures (Figure 2). This Example demonstrates that IV or oral administration of Example 3 can induce higher levels of FGF19 than Comparative Example 2. [00226] Unless otherwise defined, all technical and scientific terms used in this document have the same meanings as commonly understood by a person normally versed in the technique, to which this description belongs. [00227] Thus, it should be understood that, although the present description has been specifically described by preferred modalities and optional features, the modification, improvements and variations of the descriptions presented herein and described in the present invention can be invoked by persons skilled in the art, and such modifications, improvements and variations are considered to fall within the scope of this description. The materials, methods and examples provided here are representative of the preferred modalities, are exemplary and are not intended to be limitations on the scope of the description. [00228] The description has been described in general terms and generically in the present invention. Each of the more restricted species and subgeneric groupings that fit the generic description is also part of the description. This includes the generic description of the description, with a negative caveat or limitation removing any such subject matter, regardless of whether the material removed was specifically cited in that document. [00229] In addition, where the characteristics or aspects of the description are described in terms of Markush groups, persons skilled in the art will recognize that the description is thus also described in terms of any individual member or subgroup of the group members Markush. [00230] It should be understood that although the present description has been described in conjunction with the above modabilities, the previous description and examples are intended to illustrate and not to limit the scope of this Petition 870180126569, of September 4, 2018, p. 97/98 91/91 description. Other aspects, advantages and modifications in the scope of the present description will be evident to those skilled in the art, to whom the description belongs. Petition 870180126569, of September 4, 2018, p. 98/98 1/11
权利要求:
Claims (31) [1] 1. 1. Compound, characterized by the fact that it is according to formula (I): (I) where: Q is phenylene or pyridylene, each of which is optionally substituted with one or two substituents independently selected from halogen, methyl, Cm alkoxy, Cm halo alkoxy, -CH2F, -CHF2, and -CF3; Y is N or CH; A is pyridylene or phenylene, each of which is optionally substituted with one or two independently selected groups of halogen, Cm alkoxy, Cm halo-alkoxy, Cm alkyl, and Cm halo-alkyl; Z is isoxazole substituted with R 1 or substituted with R 1 pyrazole; R 1 is C1-4 alkyl or C3.6 cycloalkyl, wherein said Cm alkyl is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxyl, C1-3 alkoxy, and C1.3 fluoro-alkoxy, and said C3.6 cycloalkyl is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxyl, C1.3 alkyl, C1.3 fluoro-alkyl, C1.3 alkoxy, and C1.3 fluoro-alkoxy; R 2 and R 3 are independently selected from hydrogen, halogen, methoxy, -CF3, -CHF2, -CH2F, -OCH2F, -OCHF2, -OCF3, and methyl; R 4 is -CO 2 R 5 or -C (O) NR 5 R 6 ; R 5 is hydrogen, Cm alkyl or Cm halo-alkyl; and Petition 870170039578, dc 06/09/2017, p. 10/92 [2] 11/11 R 6 is hydrogen or C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted by 1 to 6 substituents independently selected from halogen, -SO3H, and -CO2H; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. 2. Compound, characterized by the fact that it is according to formula (Ia): (Ia) where: Q is phenylene or pyridylene, each of which is optionally substituted with one or two substituents independently selected from halogen, methyl, Cm alkoxy, C1-4 halo-alkoxy, -CH2F, -CHF2, and -CF3; Y is N or CH; A is pyridylene or phenylene, each of which is optionally substituted with one or two independently selected groups of halogen, Cm alkoxy, C1-4 halo-alkoxy, C1-4 alkyl, and Cm halo-alkyl! R 1 is C1.4 alkyl or C3-6 cycloalkyl, wherein said C1-4 alkyl is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxyl, C1-3 alkoxy, and C1-3 fluoro-alkoxy, and said C3-6 cycloalkyl is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxyl, C1-3 alkyl, fluorine-C1-3 alkyl, C1-3 alkoxy, and fluorine C1-3 alkoxy; Petition 870170039578, of 06/09/2017, p. 11/92 [3] 3/11 R 2 and R 3 are independently selected from hydrogen, halogen, methoxy, -CF3, -CHF2, -CH2F, -OCH2F, -OCHF2, -OCF3, and methyl; R 4 is -CO2R 5 or -C (O) NR 5 R 6 ; R 5 is hydrogen, C 1-6 alkyl or C 1-6 halo-alkyl; R 6 is hydrogen or C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted by 1 to 6 substituents independently selected from halogen, -SO3H, and -CO2H; or pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. 3. Compound according to claim 2, characterized by the fact that it has the structure of formula (Ia): (Ia) where: Q is phenylene optionally substituted by one or two halogens; Y is N or CH; A is pyridylene optionally substituted by one or two groups independently selected from halogen and C1-4 alkoxy; R 1 is C1.4 alkyl or C3-6 cycloalkyl; R 2 and R 3 are independently selected from hydrogen and halogen; R 4 is -CO2R 5 or -C (O) NR 5 R 6 ; R 5 is hydrogen; and Petition 870170039578, dc 06/09/2017, p. 12/92 [4] 4/11 R 6 is C1-2 alkyl optionally substituted by -CO2H or -SO3H; or pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. A compound according to any one of claims 1 to 3, characterized in that Q is phenylene substituted with a chlorine; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [5] Compound according to any one of claims 1 to 4, characterized in that R 1 is cyclopropyl or methyl; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [6] 6. Compound according to any one of the claims, characterized by the fact that R 2 and R 3 are chlorine; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [7] A compound according to any one of claims 1 to 5, characterized by the fact that one of R 2 and R 3 is fluorine and the other is hydrogen; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [8] 8. Compound according to any one of the claims, characterized by the fact that Y is N; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [9] Compound according to claim 8, characterized in that A is pyridylene substituted with a fluorine; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. Petition 870170039578, of 06/09/2017, p. 13/92 5/11 [10] Compound according to claim 8, characterized in that A is unsubstituted pyridylene; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [11] A compound according to claim 8 or 9, characterized by the fact that R 4 is -CO2R 5 , and R 5 is hydrogen; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [12] 12. Compound according to claim 8 or 9, characterized by the fact that: R 4 is -C (O) NR 5 R 6 ; R 5 is hydrogen; and R 6 is C1-2 alkyl, wherein said C1-2 alkyl is replaced by SO 3 H or -CO2H; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [13] A compound according to any one of claims 1 to 7, characterized in that Y is CH; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [14] Compound according to claim 13, characterized in that A is pyridylene replaced by a methoxy; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [15] 15. A compound according to claim 13 characterized by the fact that R 4 is -CO2R 5 and R 5 is hydrogen; or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. Petition 870170039578, of 06/09/2017, p. 14/92 6/11 [16] 16. A compound according to any one of claims 1 to 7, characterized by the fact that R 4 -A is: F or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [17] 17. Compound according to claim 8, characterized by the fact that R 4 -A is: F or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [18] 18. A compound according to claim 7 or 8, characterized by the fact that R 4 -A is: or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [19] 19. A compound according to claim 13, characterized by the fact that R 4 -A is Petition 870170039578, of 06/09/2017, p. 15/92 7/11 or a pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [20] 20. Compound, characterized by the fact that it is selected from the group consisting of: Petition 870170039578, of 06/09/2017, p. 16/92 8/11 or pharmaceutically acceptable salt, a stereoisomer, a mixture of stereoisomers or a tautomer thereof. [21] 21. Compound, characterized by the fact that it has the following formula: or a pharmaceutically acceptable salt thereof. [22] 22. Compound, characterized by the fact that it has the following formula: [23] 23. Pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable compound or salt thereof as defined in any one of claims 1 to 22 and a pharmaceutically acceptable excipient. [24] 24. Method for treating a patient with an FXR-mediated condition, characterized in that it comprises administering a pharmaceutically acceptable compound or salt thereof as defined in any one of claims 1 to 22 or a pharmaceutical composition Petition 870170039578, of 06/09/2017, p. 17/92 9/11 as defined in claim 23 to a patient in need thereof. [25] 25. Method according to claim 24, characterized by the fact that the condition mediated by FXR is selected from the group consisting of: a chronic intrahepatic condition or some form of an extrahepatic cholestatic condition; hepatic fibrosis; an obstructive inflammatory disorder of the liver; chronic inflammatory liver disorder; hepatical cirrhosis; hepatic steatosis or an associated syndrome; cholestatic or fibrotic effects that are associated with alcohol-induced cirrhosis or viral forms of hepatitis; liver failure or liver ischemia after major liver resection; chemotherapy-associated steatohepatitis (CASH); acute liver failure; and Inflammatory Bowel Disease. [26] 26. Method according to claim 24, characterized by the fact that the condition mediated by FXR is selected from the group consisting of: a lipid and lipoprotein disorder; Type I diabetes; Type II diabetes; clinical complications of Type I and Type II Diabetes selected from the group consisting of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and other observed effects of clinically manifested long-term diabetes; Petition 870170039578, of 06/09/2017, p. 18/92 11/10 Non-alcoholic Fatty Liver Disease (NAFLD); Non-alcoholic steatohepatitis (NASH); obesity; a metabolic syndrome selected from the group consisting of combined conditions of dyslipidemia, diabetes and abnormally high body mass index; acute myocardial infarction; acute stroke; and thrombosis that occurs as an end point of chronic obstructive atherosclerosis. [27] 27. Method according to claim 24, characterized by the fact that the condition mediated by FXR is selected from the group consisting of: a non-malignant hyperproliferative disorder; and a malignant hyperproliferative disorder selected from the group consisting of hepatocellular carcinoma, colon adenoma and polyposis; colon adenocarcinoma; breast cancer; pancreatic adenocarcinoma; Barrett's esophagus; and other forms of neoplastic diseases of the gastrointestinal tract and liver. [28] 28. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, characterized in that it is for use in the treatment of an FXR-mediated condition. [29] 29. A pharmaceutically acceptable salt or compound according to claim 28, characterized in that the condition mediated by FXR is non-alcoholic steatohepatitis (NASH). Petition 870170039578, of 06/09/2017, p. 19/92 11/11 [30] 30. Use of a pharmaceutically acceptable compound or salt thereof according to any one of claims 1 to 22, characterized in that it is for the manufacture of a medicament for the treatment of an FXR-mediated condition. [31] 31. Use according to claim 30, characterized by the fact that the condition mediated by FXR is non-alcoholic steatohepatitis (NASH). Petition 870170039578, of 06/09/2017, p. 20/92 1/2 FGF19 AUC (pg / h / mL) 350000 300000 250000 200000 150000 100000 50000 . . / ♦ ♦ ♦ * 100 With parative Exam ple 2 Example 3 1000 10000 100000 1000000 Drug AUC (nM.h)
类似技术:
公开号 | 公开日 | 专利标题 JP6678779B2|2020-04-08|FXR | modulating compound BR102017012319A2|2018-12-04|compound, pharmaceutical composition, and use of a pharmaceutically acceptable salt or compound thereof or a pharmaceutical composition EP3468977B1|2021-07-21|Fxr | modulating compounds OA20099A|2021-12-13|"FXR | modulating compounds".
同族专利:
公开号 | 公开日 HRP20191561T1|2019-11-29| SV2018005799A|2019-03-19| AU2020202618A1|2020-05-14| CL2018003569A1|2019-03-08| AU2021254625A1|2021-11-18| PE20190329A1|2019-03-05| MX2017007701A|2018-11-09| CA2968836A1|2017-12-13| AU2017284109A1|2018-12-13| UY37280A|2017-10-31| JP2020100671A|2020-07-02| LT3257847T|2019-11-11| US10421730B2|2019-09-24| CR20180585A|2019-03-05| KR102361996B1|2022-02-14| CU20180147A7|2019-07-04| PH12018502488A1|2019-09-23| HK1247924A1|2018-10-05| AU2017284109B2|2020-01-23| US20170355685A1|2017-12-14| DK3257847T3|2019-10-07| CO2018012939A2|2019-01-18| KR20210088748A|2021-07-14| US10981881B2|2021-04-20| JP6683846B2|2020-04-22| UA122528C2|2020-11-25| US20200369632A1|2020-11-26| TW202011960A|2020-04-01| US20200071282A1|2020-03-05| SA117380731B1|2020-12-20| ECSP18090693A|2018-12-31| IL263493D0|2019-01-31| MA41519B1|2019-10-31| EA201892482A1|2019-07-31| TWI731392B|2021-06-21| ES2751898T3|2020-04-02| TW201802086A|2018-01-16| PT3257847T|2019-10-30| JP2021113198A|2021-08-05| EA202190485A1|2021-09-30| CN109476636A|2019-03-15| AU2020202618B2|2021-08-26| US20190308962A1|2019-10-10| EP3257847A1|2017-12-20| EP3257847B1|2019-08-21| JP2019517568A|2019-06-24| IL263493A|2022-02-01| KR20190017028A|2019-02-19| NZ748625A|2020-05-29| SG10201704622YA|2018-01-30| SG10201912439TA|2020-02-27| MA47614A|2020-01-01| HUE045528T2|2020-01-28| PH12020551959A1|2021-10-04| DOP2018000280A|2018-12-31| PL3257847T3|2020-02-28| EP3587412A1|2020-01-01| KR102276042B1|2021-07-14| WO2017218330A1|2017-12-21| TWI722203B|2021-03-21| US10774054B2|2020-09-15| JP6867531B2|2021-04-28| SI3257847T1|2019-11-29| ZA201808158B|2019-09-25| EA037694B1|2021-05-04| AR108709A1|2018-09-19|
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法律状态:
2018-12-04| B03A| Publication of a patent application or of a certificate of addition of invention [chapter 3.1 patent gazette]| 2019-10-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. | 2020-07-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]| 2021-06-01| B06W| Patent application suspended after preliminary examination (for patents with searches from other patent authorities) chapter 6.23 patent gazette]|
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申请号 | 申请日 | 专利标题 US201662349490P| true| 2016-06-13|2016-06-13| US62/349490|2016-06-13| 相关专利
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