WO2020114307A1 - Dérivé d'isoxazole, son procédé de préparation et son utilisation - Google Patents

Dérivé d'isoxazole, son procédé de préparation et son utilisation Download PDF

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WO2020114307A1
WO2020114307A1 PCT/CN2019/121534 CN2019121534W WO2020114307A1 WO 2020114307 A1 WO2020114307 A1 WO 2020114307A1 CN 2019121534 W CN2019121534 W CN 2019121534W WO 2020114307 A1 WO2020114307 A1 WO 2020114307A1
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compound
pharmaceutically acceptable
pharmaceutical composition
metabolites
stereoisomers
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PCT/CN2019/121534
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English (en)
Chinese (zh)
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刘金明
蔡家强
吴勇勇
崔洪
王超磊
田强
宋宏梅
薛彤彤
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN201980066095.8A priority Critical patent/CN112805279B/zh
Publication of WO2020114307A1 publication Critical patent/WO2020114307A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates generally to compounds for the treatment of diseases or conditions mediated by farnesoid X receptor (FXR), and more specifically to FXR agonist compounds, as well as their stereoisomers, tautomers, polymorphs Crystal forms, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, and chemically protected forms and prodrugs thereof.
  • FXR farnesoid X receptor
  • the invention also relates to preparation methods, intermediates, pharmaceutical compositions and kits containing the compounds, and their therapeutic uses.
  • Farnesoid X receptor (FXR, NR1H4) is expressed in the liver, the entire gastrointestinal tract including the esophagus, stomach, duodenum, small intestine, and colon (Kuipers, F. et al., The Farnesoid X Receptor (FXR) as Modulator of Bile Acid Metabolism, Rev. Endocrine Metab. Disorders, 2004, 5: 319-326).
  • FXR is a member of a transcription factor known to be a ligand-activated nuclear receptor.
  • Bile acids such as chenodeoxycholic acid (CDCA) or its taurine or glycine amide conjugates are endogenous ligands of FXR.
  • the bile acid binds to FXR and activates FXR. It controls the expression of various genes through heterodimer complex with retinol X receptor (RXR), including the involvement of bile acid, cholesterol, triglyceride in liver and circulatory system.
  • RXR retinol X receptor
  • Gene expression of acid glyceride and lipoprotein homeostasis (Kalaany, NY; Mangelsdorf, DJ; LXRS and FXR: the yin and yang of cholesterol and fat metabolism, Annu. Rev. Physiol., 2006, 68, 159-191; Calkin , AC; Tontonoz, P.; Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR, Nat. Rev. Mol.
  • FXR also appears to be involved in paracrine and endocrine signaling by up-regulating fibroblast growth factor 15 (rodent) or fibroblast growth factor 19 (monkey, human) (T. Inagaki et al., Fibroblast growth factor 15 functions) aserohepatic signaling Regulated acid homeostasis. Cell Metab., 2005, 2(4), 217-225).
  • Bile acids are amphiphilic molecules that form micelles and emulsify the lipids in the diet. If the bile acid concentration is too high, cytotoxicity will also occur, so physiologically there is a mechanism to strictly control the bile acid concentration. FXR plays a key role in controlling the bile acid to maintain a stable state in the body (Makishima, M.; Nuclear Receptors as Targets for Drug Development: Regulation of Cholesterol and Bile Acid Metabolism by Nuclear Receptors, J. Pharmacol. Sci., 2005, 97 : 177-183).
  • FXR has been shown to regulate complex biological processes beyond metabolism, such as liver regeneration or the integrity of the intestinal barrier. FXR also controls the immune system of the intestine and liver and has a certain anti-inflammatory effect (Modica, S.; Gadaleta, RM; Moschetta, A.; Deciphering the nuclear acceptor FXR paradigm, Nucl. Recept. Signal., 2010 , 8, e005).
  • Obeticholic acid (6-Et CDCA) is an FXR receptor agonist that is more active than the endogenous ligand CDCA and has been shown in a phase IIa clinical study of non-alcoholic fatty liver disease (NAFLD) Significant improvement in insulin sensitivity and other beneficial effects on metabolism disease, Gastroenterology, 2013, 145, 574-582).
  • a phase IIb study of obeticholic acid showed that 72-week treatment is also beneficial for the improvement of histopathology of non-alcoholic hepatitis (NASH).
  • NASH non-alcoholic hepatitis
  • WO2012087519 discloses an agonist or partial agonist of FXR for the treatment of conditions mediated by FXR.
  • the FXR agonist compounds disclosed in the prior art still have defects in pharmacodynamics or pharmacokinetic properties.
  • the present invention relates generally to compounds of general formula (I) or their stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, their chemically protected forms or prodrugs,
  • X is CH or N
  • R is selected from hydrogen, halogen, C 1-6 alkyl and C 1-6 haloalkyl.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the general formula (I) or its stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceuticals Acceptable salts, esters, metabolites, N-oxides, their chemically protected forms or prodrugs, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition may further comprise one or more other therapeutic agents suitable for preventing or treating diseases or conditions mediated by FXR.
  • the present invention also includes a method of preventing or treating a disease or condition mediated by FXR, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of general formula (I) or its stereoisomer, Tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, their chemically protected forms or prodrugs, or the pharmaceutical composition .
  • the present invention also includes a kit for preventing or treating a disease or condition mediated by FXR, which includes:
  • a) a first container which contains as a first therapeutic agent at least one compound of the general formula (I) or its stereoisomers, tautomers, polymorphs, solvates (eg hydrated) Substances), pharmaceutically acceptable salts, esters, metabolites, N-oxides, their chemically protected forms or prodrugs, or the pharmaceutical composition as the first pharmaceutical composition;
  • the present invention also includes the compound of the general formula (I) or its stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites , N-oxide, its chemically protected form or prodrug, or the pharmaceutical composition, which is used to prevent or treat a disease or condition mediated by FXR.
  • the present invention also includes the compound of the general formula (I) or its stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites , N-oxide, its chemically protected form or prodrug, or the use of the pharmaceutical composition in the preparation of a medicament for the prevention or treatment of a disease or disorder mediated by FXR.
  • the invention also includes methods and corresponding intermediates for preparing the compounds of the invention.
  • the compound of the general formula (I) of the present invention has excellent in vivo or in vitro pharmacodynamics or pharmacokinetic properties, shows good FXR activation activity and activation, and excellent liver microsomal stability, and thus has good Drug activity and metabolic advantages.
  • Figure 1 shows the effect of administering compound C3 in a mouse fatty liver model, where a represents p ⁇ 0.05 compared to the control group; b represents p ⁇ 0.05 compared to the model group.
  • alkyl refers to a saturated linear or branched hydrocarbon group having 1 to 6 carbon atoms (C 1-6 ), wherein the alkyl group may be optionally substituted by one or more (eg, 1 , 2, 3, or 4) suitable substituents.
  • the alkyl group has 1 to 6 carbon atoms (C 1-6 ).
  • the alkyl group has 1 to 4 carbon atoms (C 1-4 ), especially 1 to 3 carbon atoms (C 1-3 ) or 1 to 2 carbon atoms (C 1-2 ) .
  • alkyl groups include, but are not limited to: methyl (Me), ethyl (Et), 1-propyl (n-Pr), 2-propyl (i-Pr or isopropyl), 1-butyl ( n-Bu or n-butyl), 2-methyl-1-propyl (i-Bu or isobutyl), 2-butyl (s-Bu or sec-butyl), 2-methyl-2-propyl (T-Bu or tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl , 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl
  • halo or halogen as used herein includes F, Cl, Br or I.
  • Halo includes but is not limited to mono-, di- or tri-substitution, and the halogen atoms used for substitution may be the same or different.
  • haloalkyl as used herein includes fluoroalkyl, chloroalkyl, bromoalkyl, or iodoalkyl.
  • chiral refers to molecules that have non-superimposability of mirror image pairs
  • achiral refers to molecules that can overlap on their mirror image pairs
  • stereoisomer refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups.
  • Diastereomer refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The mixture of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.
  • Enantiomer refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.
  • the stereochemical definitions and rules used in this article generally follow SPParker, Ed., McGraw-Hill Dictionary of Chemicals (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry” of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to their diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to constitute the invention a part of.
  • optically active compounds that is, they have the ability to rotate the plane of plane polarized light.
  • the prefixes D and L, or R and S are used to indicate the absolute configuration of the chiral center of the molecule.
  • the prefixes d and l or (+) and (-) are used to indicate the sign that the compound rotates plane polarized light, where (-) or l means that the compound is levorotatory.
  • Compounds with the prefix (+) or d are right-handed. For a specific chemical structure, these stereoisomers are the same, but they are mirror images of each other.
  • a specific stereoisomer can also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can occur in a chemical reaction or process without stereoselectivity or stereospecificity.
  • the terms "racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers, which is not optically active.
  • the stereoisomers of the invention may exist in a predominant form, for example, greater than 50%ee (enantiomeric excess), greater than 80%ee, greater than 90%ee, greater than 95%ee, or greater than 99% ee.
  • the method for preparing the compound of the present invention produces a mixture of stereoisomers
  • these isomers can be separated by conventional techniques such as preparative chromatography.
  • the compound can be prepared in racemic form, or a single enantiomer can be prepared by selective synthesis of enantiomers or by resolution.
  • diastereoisomers are formed by standard techniques, for example by forming salts with optically active acids such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid Pairs, followed by step crystallization and free base regeneration, the compounds can be resolved into their enantiomeric components.
  • the compounds can also be resolved by forming diastereomeric esters or amides, followed by chromatographic purification and removal of chiral auxiliaries. Alternatively, the compound can be resolved using a chiral HPLC column.
  • tautomer or “tautomeric form” refers to structural isomers of different energies that can be interconverted by a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compound of general formula (I), which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, esters, solvates, metabolites, N-oxides, and chemically protected forms and prodrugs. After administration to an individual in need, the compound of the present invention or its metabolite or residue can be provided directly or indirectly.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention.
  • Exemplary salts include but are not limited to isonicotinate, salicylate, acid citrate, oleate, tannate, pantothenate, gluconate, glucuronate, glucuronic acid Salts and parabens (ie 1,1'-methylene-bis(2-hydroxy-3-naphthoate)), etc.
  • the pharmaceutically acceptable salt may include the inclusion of another molecule of counter ion.
  • the counter ion can be any organic or inorganic ion that stabilizes the charge on the parent compound.
  • pharmaceutically acceptable salts may have more than one charged atom in their structure. Where multiple charged atoms are part of a pharmaceutically acceptable salt, there may be multiple counter ions.
  • a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ions.
  • the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, with an inorganic acid or with an organic acid such as salicylic acid, pyranosidic acid such as glucose
  • an inorganic acid or with an organic acid such as salicylic acid, pyranosidic acid such as glucose
  • pyranosidic acid such as glucose
  • the free base is treated with uronic acid or galacturonic acid, ⁇ -hydroxy acid amino acid, aromatic acid, etc.
  • the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, using an inorganic or organic base such as an amine (primary, secondary, or tertiary amine), alkali metal hydroxide, or Alkaline earth metal hydroxides, etc. treat free acids.
  • an inorganic or organic base such as an amine (primary, secondary, or tertiary amine), alkali metal hydroxide, or Alkaline earth metal hydroxides, etc. treat free acids.
  • suitable salts include, but are not limited to, organic salts derived from amino acids and cyclic amines, and inorganic salts.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other components making up the formulation and/or the mammal treated with it.
  • ester means an ester derived from a compound of general formula (I), including physiologically hydrolyzable esters, which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the general formula of the present invention ( I) Compound.
  • the compound of the general formula (I) of the present invention may itself be an ester.
  • the compound of the present invention may exist in the form of a solvate (such as a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol, or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol, or ethanol.
  • the amount of polar solvents, especially water can be present in stoichiometric or non-stoichiometric ratios.
  • a “metabolite” is a product produced by metabolism of a specific compound or its salt in the body. Metabolites of compounds can be identified using conventional techniques known in the art and tests such as those described herein can be used to determine their activity. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method including contacting a compound of the general formula (I) of the present invention with a mammal for a period of time sufficient to produce its metabolite.
  • Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (m-CPBA), hydrogen peroxide, Alkyl hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyl dioxirane oxidize heterocycles and tertiary amines.
  • peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (m-CPBA)
  • hydrogen peroxide Alkyl hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyl dioxirane oxidize heterocycles and tertiary amines.
  • any process for preparing the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming a chemically protected form of the compounds of the present invention.
  • This can be achieved through conventional protecting groups, for example, as described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & PGMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Those protecting groups, these references are incorporated herein by reference.
  • the protecting group can be removed at an appropriate subsequent stage.
  • the invention further includes within its scope prodrugs of the compounds of the invention.
  • a prodrug will be a functional group derivative of the compound, which is easily converted into the desired therapeutically active compound in vivo. Therefore, in these cases, the term "administration" used in the treatment method of the present invention should include the treatment of various diseases or conditions with one or more prodrug forms of the claimed compounds, but After the individual is administered, the prodrug form is converted into the above compound in vivo.
  • “Design of Prodrug” ed. H. Bundgaard, Elsevier, 1985, a conventional method for selecting and preparing suitable prodrug derivatives is described.
  • any general formula or structure shown herein, including the compound of general formula (I), is also intended to represent the unlabeled form and the isotopically labeled form of the compound.
  • Isotope-labeled compounds have the structure shown in the molecular formula given herein, except that one or more atoms are replaced with atoms having a selected atomic mass or mass number.
  • isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • isotope-labeled compounds of the present invention for example, those containing radioisotopes such as 3 H, 13 C, and 14 C.
  • isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission tomography (SPECT), including drug or substrate tissue distribution Determination, or used for radiotherapy of patients.
  • PET positron emission tomography
  • SPECT single photon emission tomography
  • the deuterium-labeled or substituted therapeutic compounds of the invention may have improved DMPK (pharmacokinetic and pharmacokinetic) properties related to distribution, metabolism and excretion (ADME).
  • substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, for example, increased half-life in the body, or reduced dose requirements.
  • 18 F labeled compounds can be used for PET or SPECT studies.
  • the isotopically-labeled compounds and prodrugs of the present invention can generally be prepared by replacing the non-isotopically-labeled reagents with readily available isotopically-labeled reagents by the methods disclosed in the implementation route or examples and the following preparation methods.
  • substitution with heavier isotopes, especially deuterium (ie, 2 H or D) may provide certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or reduced dose requirements or improved therapeutic index.
  • deuterium is regarded as a substituent in the compound of formula (I).
  • concentration of such heavier isotopes, especially deuterium can be defined by the isotope enrichment factor.
  • any atom not specifically designated as a specific isotope is intended to mean any stable isotope of that atom.
  • any atom clearly deuterium (D) is intended to represent deuterium.
  • composition includes products containing a therapeutically effective amount of a compound of formula (I) of the present invention, as well as any product produced directly or indirectly from a combination of compounds of formula (I) of the present invention.
  • the present invention provides compounds of general formula (I) or their stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters , Metabolites, N-oxides, their chemically protected forms or prodrugs,
  • X is CH or N
  • R is selected from hydrogen, halogen, C 1-6 alkyl and C 1-6 haloalkyl.
  • the present invention provides compounds or their stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N- Oxides, their chemically protected forms or prodrugs, where R is selected from hydrogen, fluorine, methyl and trifluoromethyl.
  • the present invention provides compounds or their stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N- Oxides, their chemically protected forms or prodrugs, where X is CH; and R is selected from hydrogen, fluorine, methyl and trifluoromethyl.
  • the present invention provides compounds or their stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N- Oxides, their chemically protected forms or prodrugs, where X is N; and R is hydrogen.
  • the present invention provides compounds or their stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N- Oxides, their chemically protected forms or prodrugs, wherein the compound is selected from:
  • the compound of the general formula (I) of the present invention may contain an asymmetric center or a chiral center, and thus may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to their diastereomers, enantiomers, and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to constitute the present invention portion.
  • the present invention covers all diastereomers, including cis-trans (geometric) isomers and conformational isomers.
  • cis-trans geometric isomers
  • conformational isomers for example, if the compound of general formula (I) contains a double bond or a fused ring, the cis and trans forms and mixtures thereof are covered within the scope of the present invention.
  • the stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, then the stereoisomer is so designated and defined.
  • the compounds of the present invention can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the present invention is intended to encompass both solvated and unsolvated forms.
  • the compounds of the invention can also exist in different tautomeric forms, and all such forms are encompassed within the scope of the invention.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the general formula (I) of the present invention as described above or a stereoisomer, tautomer, polymorph, or solvate thereof (Eg hydrate), pharmaceutically acceptable salts, esters, metabolites, N-oxides, their chemically protected forms or prodrugs, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition may further include one or more other therapeutic agents, such as other therapeutic agents suitable for preventing or treating diseases or conditions mediated by FXR.
  • “Pharmaceutically acceptable carrier” in the present invention refers to diluents, adjuvants, excipients or vehicles administered together with the active ingredient, and it is suitable for contact with humans and/or others within the scope of reasonable medical judgment Animal tissue without excessive toxicity, irritation, allergic reactions or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil , Sesame oil, etc.
  • sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil , Sesame oil, etc.
  • water is an exemplary carrier.
  • Physiological saline and aqueous solutions of glucose and glycerin can also be used as liquid carriers, especially for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol, etc.
  • the composition may also contain small amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral preparations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceuticals (1990).
  • the pharmaceutical composition of the present invention can act systemically and/or locally.
  • they can be administered by suitable routes, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.
  • the pharmaceutical composition of the present invention can be administered in a suitable dosage form.
  • the dosage form includes but is not limited to tablets, capsules, lozenges, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, ointment, aqueous suspension , Injectable solutions, elixirs, syrups.
  • Another aspect of the invention provides therapeutic uses of the compounds and pharmaceutical compositions.
  • the present invention relates to a method of preventing or treating a disease or disorder mediated by FXR, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one general formula of the present invention ( I)
  • the present invention relates to at least one compound of the general formula (I) of the present invention or its stereoisomers, tautomers, polymorphs, solvates (such as hydrates), Pharmaceutically acceptable salts, esters, metabolites, N-oxides, their chemically protected forms or prodrugs, or the pharmaceutical composition of the invention in the preparation of a medicament for the prevention or treatment of diseases or conditions mediated by FXR the use of.
  • FXR diseases or conditions mediated by FXR include but are not limited to:
  • Inflammatory bowel disease dyslipidemia, atherosclerosis, diabetes and related diseases; lipid and lipoprotein disorders; type II diabetes and clinical complications of type I and type II diabetes, including diabetic nephropathy, diabetic neuropathy , Diabetic retinopathy, and other clinically apparent effects of long-term diabetes; chronic fatty and fibrotic degeneration due to forced lipid accumulation, especially triglycerides, and subsequent activation of pro-fibrotic pathways
  • diseases such as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH); obesity or metabolic syndrome (combined disorders of dyslipidemia, diabetes and abnormally high body mass index);
  • treatment means reversing, alleviating, or inhibiting the indicated disease or disorder or the progression of one or more symptoms of such disease or disorder.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals with a disease (such as the diseases described herein).
  • “non-human animals” include all vertebrates, such as non-mammals (eg birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (eg sheep, dogs) , Cats, cows, pigs, etc.).
  • therapeutically effective amount refers to the amount of the compound that will achieve the above-mentioned therapeutic efficacy after being administered.
  • the dosage regimen can be adjusted to provide the most desired response. For example, a single bolus injection can be administered, several divided doses can be administered over time, or the dosage can be reduced or increased proportionally as indicated by the urgent need for the treatment. It should be noted that the dose value may vary with the type and severity of the condition to be reduced, and may include single or multiple doses. It is to be further understood that for any particular individual, the specific dosing regimen should be adjusted over time based on the individual's needs and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of the compound of the present invention administered will depend on the individual, the severity of the condition or condition being treated, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician.
  • the effective dose is about 0.0001 to about 50 mg per kg of body weight per day, for example about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as about 0.7 mg/day to about 700 mg/day.
  • a dose level not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg and the like.
  • the compound of general formula (I) may be used alone or in combination with one or more other therapeutic agents suitable for preventing or treating diseases or conditions mediated by FXR.
  • the compound of general formula (I) in the pharmaceutical composition or as a dosing regimen for combination therapy, is combined with other therapeutic agents having anti-hyperproliferative efficacy, for example.
  • the other therapeutic agent may be, for example, a chemotherapeutic agent.
  • the pharmaceutical composition or other therapeutic agents of the administration regimen preferably have complementary activities to the compound of general formula (I) so that they do not adversely affect each other. Such compounds are suitably present in combination in amounts effective for the intended purpose.
  • Combination therapy can be administered simultaneously or sequentially. When administered sequentially, the combination can be administered in two or more doses.
  • Combined administration includes simultaneous administration using separate pharmaceutical compositions or a single pharmaceutical composition containing a compound of general formula (I) and other therapeutic agents, and sequential administration in any order, with two (or all) preferably present Active agents simultaneously exert their biological activity for a period of time.
  • Suitable doses of any of the above-mentioned concurrently administered agents are those currently in use, and can be reduced due to the combined (synergistic) effect of the newly identified drug with other therapeutic agents or treatments.
  • Combination therapy can provide "synergy” and prove to be “synergistic", that is, the effects achieved when the active ingredients are used together are greater than the sum of the effects produced when the compounds are used separately.
  • the active ingredient (1) is co-formulated in a combined unit dose formulation and is simultaneously administered or delivered; (2) is delivered as a separate formulation alternately or in parallel; or (3) by some other regimen, Can achieve synergy.
  • a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example by separate injections in separate syringes, by separate pills or capsules, or by separate infusions.
  • an effective dose of each active ingredient is administered sequentially, that is, continuously, while in combination therapy, an effective dose of two or more active ingredients is administered together.
  • the compound of general formula (I) or its stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, Esters, metabolites, N-oxides, their chemically protected forms or prodrugs can be combined with other therapeutic agents such as those described herein, and can also be combined with surgical treatment and radiotherapy. Therefore, the combination therapy of the present invention includes administration of at least one compound of general formula (I) or its stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable Salts, esters, metabolites, N-oxides, their chemically protected forms or prodrugs, and the use of at least one other treatment. In order to achieve the desired combined therapeutic effect, the amount of the compound of general formula (I) and other therapeutic agents and the relative timing of administration are selected.
  • the present invention includes metabolites of the compound of the general formula (I), including compounds prepared by contacting the compound of the present invention with a mammal for a time sufficient to produce its metabolite.
  • Metabolites are usually prepared by preparing a compound labeled with a radioisotope of the present invention (for example, 14 C or 3 H) and administering it to animals such as rats, mice, guinea pigs, and monkeys in a detectable dose (for example, greater than about 0.5 mg/kg) Or human parenteral administration, metabolism for a sufficient period of time (usually about 30 seconds to 30 hours), and then its transformation product is isolated from urine, blood or other biological samples for identification. These products are easy to isolate because they are labeled (others are separated by using antibodies that can bind to the remaining epitopes in the metabolites).
  • the metabolite structure is determined by conventional methods, for example by MS, LC/MS or NMR analysis. The analysis of metabolites is performed in the same way as conventional drug metabolism studies well known to those skilled in the art. Metabolites, as long as they are not found in the body, can be used in diagnostic assays to administer the compounds of the present invention therapeutically.
  • kits containing materials for treating the above diseases or conditions.
  • the kit includes a container containing the compound of general formula (I), its stereoisomers, tautomers, polymorphs, solvates (such as hydrates) as the first therapeutic agent , A pharmaceutically acceptable salt, ester, metabolite, N-oxide, or a chemically protected form or prodrug thereof, or a pharmaceutical composition of the present invention containing the first pharmaceutical composition.
  • the kit may also include a label or package insert on or accompanying the container.
  • the term "package insert” refers to the instructions usually included in commercial packages of therapeutic products, which contain information on indications, usage, dosage, administration, contraindications and/or warnings related to the use of the therapeutic product.
  • Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like.
  • the container may be made of various materials such as glass and plastic.
  • the container may contain a compound of general formula (I) or a preparation thereof that is effective for treating a condition, and may have a sterile inlet (for example, the container may be an intravenous solution sachet or have a pierceable by a hypodermic injection needle) Corks).
  • the label or package insert indicates that the composition is used to treat a selected condition, such as cancer.
  • the label or package insert may indicate that the patient to be treated is a patient with a disease or condition such as cirrhosis, hyperproliferative disorder, atherosclerosis, type I diabetes, or the label or package insert may also indicate the composition Can be used to treat other conditions.
  • the kit further includes a second container containing, as a second therapeutic agent, at least one other therapeutic agent suitable for preventing or treating a disease or condition mediated by FXR, or as a second A pharmaceutical composition comprising the other therapeutic agent. Therefore, in some embodiments, the kit may include instructions for administering the first therapeutic agent or first pharmaceutical composition and the second therapeutic agent or second pharmaceutical composition (if present).
  • the kit may also include simultaneous, sequential or Instructions for administering the first pharmaceutical composition and the second pharmaceutical composition separately.
  • the kit may further include a third container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and glucose solution.
  • BWFI bacteriostatic water for injection
  • the kit may also include other materials desirable for commercial and user purposes, including other buffers, diluents, fillers, injection needles, and syringes.
  • the kit is suitable for the delivery of solid oral forms of compounds of general formula (I) such as tablets or capsules.
  • a kit preferably includes multiple unit doses.
  • Such kits may include cards with dosages positioned for their intended use.
  • An example of such a kit is a "blister pack".
  • Blister packaging is well known in the packaging industry and is widely used for packaging pharmaceutical unit dosage forms.
  • memory aids can be provided in the form of numbers, letters, or other indicia or calendar inserts that specify the date of administration in the treatment schedule, for example.
  • the present invention provides a method of preparing a compound of general formula (I) of the present invention, the method comprising the following steps:
  • Hal 1 , Hal 2 and Hal 3 are each independently the same or different halogen, such as F, Cl, Br or I, preferably Cl or Br;
  • PG 1 is an amino protecting group, preferably tert-butoxycarbonyl (Boc);
  • PG 2 is a carboxyl protecting group, preferably C 1-6 alkyl, and more preferably methyl;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or
  • reaction conditions of each step are as follows:
  • Step A reacting compound IN-1 with compound IN-2 to obtain compound IN-3;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from linear or cyclic ethers (such as tetrahydrofuran or diethyl ether), N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, 1, 4-Dioxane, dimethyl sulfoxide and any combination thereof, preferably tetrahydrofuran or N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable base (eg alkali metal alkoxide or carbonate) and/or catalyst.
  • the catalyst may be a catalyst system including a crown ether, and the crown ether may be selected from 15-crown-5 and 18-crown-6; the alkali metal carbonate is, for example, potassium carbonate or cesium carbonate; The alkali metal alkoxide may be selected from sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide.
  • the alkali metal alkoxide and catalyst are a combination of sodium t-butoxide and/or potassium t-butoxide and 15-crown-5 and/or 18-crown-6, preferably sodium t-butoxide and 15 -Combination of crown ether-5 or potassium tert-butoxide and 18-crown-6.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature is preferably room temperature (20-30°C) or 50-100°C (eg 50-80°C).
  • the reaction is preferably carried out for a suitable time, for example 1-24 hours, for example 5-15 hours.
  • Step B Remove the PG 1 group in compound IN-3 to obtain compound IN-4;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from halogenated hydrocarbons (for example, dichloromethane, chloroform, ethyl chloride, dichloroethane, trichloroethane), N,N-dimethylformamide, N,N-di Methylacetamide and any combination thereof are preferably dichloromethane.
  • the reaction can be carried out under acidic conditions, such as 1,4-dioxane in hydrogen chloride; or suitable organic acids (such as carboxylic acids or halogenated acids, including but not limited to formic acid, fluoroacetic acid, difluoro Acetic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid and combinations thereof, preferably trifluoroacetic acid).
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature is preferably room temperature (20-30°C).
  • the reaction is preferably carried out for a suitable time, such as 1-5 hours or 6-15 hours, such as 2 hours, 4 hours or overnight.
  • Step C reacting compound IN-4 with compound IN-a to obtain compound IN-5;
  • compound IN-4 is substituted with compound IN-a to give compound IN-5.
  • the substitution reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, N-methylpyrrolidone, dimethylsulfoxide and any combination thereof, preferably N,N- Dimethylformamide or N,N-dimethylacetamide.
  • the substitution reaction is preferably carried out in the presence of a suitable base.
  • the base is an organic base (eg organic amines such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine or pyridine, preferably triethylamine or N,N-diiso Propylethylamine) or inorganic bases (eg alkali metal salts, preferably potassium carbonate).
  • organic bases eg organic amines such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine or pyridine, preferably triethylamine or N,N-diiso Propylethylamine
  • inorganic bases eg alkali metal salts, preferably potassium carbonate.
  • the substitution reaction is preferably carried out at a suitable temperature.
  • the temperature may be 20-150°C, for example 30-140°C, preferably 25°C, 50°C, 100°C or 130°C, preferably 80°C.
  • the substitution reaction is
  • the compound IN-4 is coupled with the compound IN-a to give compound IN-5.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone) dipalladium, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenyl Phosphorus palladium and palladium acetate, preferably tris(dibenzylideneacetone) dipalladium.
  • the base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably cesium carbonate.
  • the coupling reaction is carried out in the presence of an organophosphorus compound derived from biphenyl, which is selected from BINAP, RuPhos and XPhos, preferably BINAP.
  • the coupling reaction is carried out in a suitable organic solvent, which may be selected from benzene, toluene and xylene, for example toluene.
  • the coupling reaction is carried out under a suitable protective atmosphere (for example, a nitrogen atmosphere).
  • the coupling reaction is carried out at a suitable temperature, which may be 70-100°C, preferably 80°C.
  • the coupling reaction is carried out for a suitable time, such as 1-3 hours, such as 2 hours.
  • Step D reacting compound IN-5 with compound IN-b to obtain compound IN-6;
  • the compound IN-5 and the compound IN-b undergo a metal-catalyzed coupling reaction to obtain the compound IN-6.
  • the metal-catalyzed coupling reaction is carried out by conventional methods.
  • compound IN-5 and compound IN-b are dissolved in a solvent (such as water, an organic solvent, or a mixed solvent of organic solvent and water), a palladium catalyst and a base are added, optionally under nitrogen protection, at 50°C to
  • the reaction is carried out at a temperature of 120°C (preferably 80°C or 90°C) for 8 to 24 hours (preferably 8 hours or 12 hours).
  • the organic solvent is N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, toluene or DME.
  • the palladium catalyst is tris(dibenzylideneacetone) dipalladium, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine palladium, palladium acetate, preferably [ 1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or tris(dibenzylideneacetone)dipalladium etc.
  • the base is preferably an inorganic base, such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or the like.
  • Step E Remove the PG 2 group in compound IN-6 to obtain the compound of general formula (I);
  • the reaction is preferably in a suitable organic solvent (the organic solvent may be selected from linear or cyclic ethers (such as tetrahydrofuran or diethyl ether, etc.), N-methylpyrrolidone, N,N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane, dimethylsulfoxide and any combination thereof, preferably tetrahydrofuran).
  • the reaction is preferably carried out in the presence of alcohol or water and a base.
  • the alcohol may be, for example, methanol or ethanol.
  • the base may be selected from alkali metal hydroxides, and the alkali metal hydroxide may be selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature may be room temperature to 80°C, for example 25°C or 40-60°C.
  • the reaction is preferably carried out for a suitable time, such as 2-5 hours or 6-15 hours, such as 2, 3 or 4 hours or overnight.
  • the present invention provides compounds of general formula (IN-6) or pharmaceutically acceptable salts thereof,
  • the compound is preferably selected from:
  • suitable means that the choice of a specific compound or condition will depend on the specific synthetic operation to be performed and the characteristics of the molecule or molecules to be converted, but the choice is within the ability of those skilled in the art . All process/method steps described herein are performed under conditions sufficient to provide the product shown. Those skilled in the art will understand that all reaction conditions (including, for example, reaction solvent, reaction time, reaction temperature, and whether the reaction should be carried out under anhydrous or inert atmosphere, etc.) can be modified to optimize the desired product yield, and these Variations are within the capabilities of those skilled in the art.
  • the examples provide exemplary methods for preparing compounds of general formula (I). Those skilled in the art will understand that other synthetic routes can be used to synthesize compounds of general formula (I). Although specific raw materials and reagents are described and discussed in the examples, other raw materials and reagents can be substituted to provide various derivatives and/or reaction conditions. In addition, with reference to the present disclosure, many of the example compounds prepared by the method can be further modified using conventional chemistry well known to those skilled in the art.
  • the structure of the compound is determined by nuclear magnetic resonance ( 1 H-NMR) or mass spectrometry (MS).
  • the 1 H-NMR shift ( ⁇ ) is given in units of parts per million (ppm). Chemical shifts are given in units of 10 -6 (ppm).
  • the MS was measured using an Agilent (ESI) mass spectrometer.
  • Thin layer chromatography silica gel plate uses Merck aluminum plate (20 ⁇ 20cm), and thin layer chromatography separation and purification uses GF 254 (0.4 ⁇ 0.5mm).
  • the reaction is monitored by thin layer chromatography (TLC) or LC-MS.
  • TLC thin layer chromatography
  • the developing system used is: dichloromethane and methanol system, n-hexane and ethyl acetate system or petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent needs to be adjusted, or triethylamine or the like needs to be further added to separate and purify the product.
  • microwave reaction Initiator+ 400W, RT ⁇ 300 °C microwave reactor.
  • Column chromatography generally uses 200-300 mesh silica gel as a carrier.
  • the eluent system includes: dichloromethane and methanol system, n-hexane and ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.
  • reaction temperature of the examples is room temperature (20°C to 30°C).
  • the reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Tebo Chemical Technology Co., Ltd. and so on.
  • T1-a 2-(trifluoromethoxy)benzaldehyde (150g, 788.98mmol) in a mixed solvent of ethanol (1000mL) and water (1000mL), add hydroxylamine hydrochloride (65.79g, 946.77) with mechanical stirring mmol), a white solid precipitated, and continued to add 1M aqueous sodium hydroxide solution (789 mL, 788.98 mmol).
  • reaction was reacted at 25°C for 2 hours, 1M hydrochloric acid (2000 mL) was added to the mixture to adjust the pH of the system to about 5, directly filtered with suction, and dried overnight at 50°C to obtain compound (T1-b) (150g, collected Rate: 92%).
  • Step 3 Preparation of 5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-carboxylic acid methyl ester (T1-d)
  • Step 5 Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (T1-f)
  • Benzotriazole (59.65g, 500.74mmol) was dissolved in dichloromethane, the reaction was stirred at -5 °C, dichlorosulfoxide (59.65g, 501.39mmol) was added dropwise, after stirring at room temperature for half an hour, the compound was added A dichloromethane solution (500 mL) of (T1-e) (100 g, 334.17 mmol) was reacted at room temperature for 6 hours. The reaction solution was filtered with suction, and the filtrate was spin-dried to obtain compound (T1-f) (106 g, yield: 94%).
  • reaction solution was spin-dried, ethyl acetate (1500 mL) and water (1500 mL) were added to the residue.
  • Step 8 4-((((1R,3r,5S)-8-(4-bromothiazol-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methan Yl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (T1)
  • Example 1 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)benzoic acid (C1)
  • the first step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)benzoic acid methyl ester (C1-a)
  • compound (T1) (1 g, 1.75 mmol) was dissolved in 1,4-dioxane (20 mL), followed by addition of 4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)benzoic acid methyl ester (532.50mg, 1.93mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride ( 143.16mg, 195.66 ⁇ mol) and potassium carbonate (483.85mg, 3.50mmol), nitrogen substitution 2-3 times. Reaction at 80°C for 8 hours.
  • the second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)benzoic acid (C1)
  • Example 2 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-3-methylbenzoic acid (C2)
  • the first step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-3-methylbenzoic acid methyl ester (C2-a)
  • compound (T1) 500 mg, 876.55 mmol was dissolved in 1,4-dioxane (20 mL), followed by addition of 3-methyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester (266.25 mg, 964.20 ⁇ mol), [1,1′-bis(diphenylphosphino)ferrocene] Palladium dichloride (71.58 mg, 97.83 ⁇ mol) and potassium carbonate (241.93 mg, 1.75 mmol) were replaced with nitrogen gas 2-3 times. Reaction at 80°C for 8 hours.
  • the second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-3-methylbenzoic acid (C2)
  • Example 3 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl]thiazol-4-yl)-3-fluorobenzoic acid (C3)
  • the first step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-3-fluorobenzoic acid methyl ester (C3-a)
  • compound (T1) (650 mg, 1.14 mmol) was dissolved in 1,4-dioxane (20 mL), followed by addition of 3-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)benzoic acid methyl ester (248.13mg, 1.25mmol), [1,1′-bis(diphenylphosphino)ferrocene]di Palladium chloride (93.06 mg, 127.18 ⁇ mol) and potassium carbonate (314.50 mg, 2.28 mmol) were replaced with nitrogen gas 2-3 times. Reaction at 80°C for 8 hours.
  • the second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl]thiazol-4-yl)-3-fluorobenzoic acid (C3)
  • Example 4 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-2-fluorobenzoic acid (C4)
  • the first step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-2-fluorobenzoic acid methyl ester (C4-a)
  • compound (T1) 400 mg, 701.24 ⁇ mol was dissolved in 1,4-dioxane (20 mL), followed by addition of 2-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester (152.70 mg, 771.36 ⁇ mol), [1,1′-bis(diphenylphosphino)ferrocene]di Palladium chloride (57.27 mg, 78.26 ⁇ mol) and potassium carbonate (193.54 mg, 1.40 mmol) were replaced with nitrogen gas 2-3 times. Reaction at 80°C for 8 hours.
  • the second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-2-fluorobenzoic acid (C4)
  • Example 5 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-2-(trifluoromethyl)benzoic acid (C5)
  • the first step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-2-(trifluoromethyl)benzoic acid methyl ester (C5-a)
  • compound (T1) (0.4 g, 701.24 ⁇ mol) was dissolved in 1,4-dioxane (20 mL), followed by addition of 4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborolane-2-yl)-2-(trifluoromethyl)benzoic acid methyl ester (277.78 mg, 841.48 ⁇ mol), [1,1′-bis(diphenylphosphino ) Ferrocene] palladium dichloride (57.27 mg, 70.12 ⁇ mol) and potassium carbonate (193.83 mg, 1.40 mmol), nitrogen substitution 2-3 times. Reaction at 80°C for 8 hours.
  • the second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-2-(trifluoromethyl)benzoic acid (C5)
  • the first step 5-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Preparation of methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)picolinic acid methyl ester (C6-a)
  • compound (T1) 50 mg, 87.65 ⁇ mol was dissolved in 1,4-dioxane (20 mL), followed by addition of 5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)picolinic acid methyl ester (27.67mg, 105.19 ⁇ mol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (7.16 mg, 8.77 ⁇ mol) and potassium carbonate (12.11 mg, 87.65 ⁇ mol), nitrogen substitution 2-3 times. The reaction was carried out at 80°C for 8 hours.
  • reaction solution was filtered with celite, and the filtrate was washed with ethyl acetate (100 mL ⁇ 3).
  • the second step 5-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl ) Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)picolinic acid (C6)
  • Emax and Emin are the upper and lower asymptotic estimates of the fitted curve, respectively, x is the log concentration of the compound, and Hillslope is the slope of the curve.
  • Emax represents the maximum activation effect value of the tested compound of the present invention
  • Emax' represents the maximum activation effect value of CDCA, both of which are calculated by the formula shown above.
  • Table 1 shows that the compounds tested have a lower EC 50 (0.002-0.133 ⁇ M) relative to an EC 50 of chenodeoxycholic acid (CDCA) value of 4.43 ⁇ M, indicating that the compounds of the present invention have a greater effect on FXR Good activation activity.
  • Human embryonic kidney cells HEK293 were cultured in DMEM medium containing 10% FBS. Co-transfect the plasmid to make it highly express FXR and human BSEP luciferase reporter gene. The transfected cells were digested, resuspended, counted, and then seeded in multi-well plates. Add 10 ⁇ L of different concentrations of the test compound to the multi-well plate to make the final concentration of 64 ⁇ M, 16 ⁇ M, 4 ⁇ M, 1 ⁇ M, 0.25 ⁇ M, 0.0625 ⁇ M, 0.0156 ⁇ M, 0.0039 ⁇ M, 0.000975 ⁇ M, 0.000244 ⁇ M, 0 ⁇ M, the final concentration of DMSO is 0.5%.
  • test compound 50 ⁇ L was mixed with various liver microsomes (100 ⁇ L). After pre-incubation at 37°C for 5 minutes, NADPH (50 ⁇ L) was added and incubated for 0, 30, and 60 minutes. The test compound, NADPH and liver microsome enzymes The incubation concentrations are 1 ⁇ M, 1mM and 0.5mg/mL, respectively. After adding ice acetonitrile (200 ⁇ L) to terminate the reaction, an appropriate volume of internal standard (rivaroxaban) was added, and the supernatant was collected by vortexing and centrifugation for detection.
  • rivaroxaban internal standard
  • LC-MS/MS mass spectrometer
  • liquid phase is Shimadzu LC-30AD system.
  • the chromatographic column is Hypersil C18, 1.9 ⁇ m particle size, 50 ⁇ 2.1mm; mobile phase A is water + 0.1% formic acid, phase B is acetonitrile; flow rate is 0.55mL/min, column temperature is 40 °C.
  • the ion source is the positive ion mode of the ESI source, and the scanning mode is multiple reaction monitoring (MRM).
  • the rate constant is obtained by plotting "Ln (% of drug residue)" versus "incubation time”, thereby calculating the half-life and liver clearance of the drug. Evaluate the metabolic stability of the drug in liver microsomes.
  • the compounds of the present invention were administered to male SD rats by intravenous (IV) and intragastric (PO), respectively, to investigate the pharmacokinetic characteristics.
  • IV and PO are 1 mg/kg and 5 mg/kg, respectively, the IV administration vehicle system is 5% DMSO: 5% Solutol: 90% saline, and the PO administration vehicle system is 0.5% MC (methyl cellulose ).
  • IV and PO administration blood was collected at different time points. The blood was anticoagulated with K2-EDTA. After centrifugation, plasma samples were obtained and stored at -80°C. Plasma samples were treated with precipitated proteins and analyzed by LC-MS/MS.
  • WinNonlin 6.3 software was used to calculate the pharmacokinetic parameters using a non-compartmental model. The results are shown in Tables 6 and 7.
  • Table 6 shows that the compounds C3 and C5 of the present invention administered IV at a dose of 1 mg/kg have excellent drug exposure in rats.
  • Table 7 shows that the compounds C3 and C5 of the present invention administered by PO at a dose of 5 mg/kg have excellent drug exposure and bioavailability in rats.
  • the compounds C3 and C5 of the present invention have excellent plasma drug exposure and oral bioavailability in rats by IV and PO administration.
  • Other compounds of the present invention also have better AUC last value, C max value and bioavailability, and have better pharmacokinetic properties in rats.
  • mice Eight to ten-week-old male C57 mice (purchased from Viton Lihua) were used. Animals were randomly divided into 5 groups according to body weight before modeling, which were normal group (group 1), model group (group 2), and C3 compound. Administration group (30mg/kg). The normal group was given normal feed, and the model group and C3 compound-administered group were fed with MCD feed (methionine choline-deficient feed, Research Diets). Simultaneously with the modeling, the C3 compound group was administered by intragastric administration once a day for 28 consecutive days. The normal group and the model group were given 0.5% MC (methyl cellulose). See Table 8 for details.
  • Drug Efficacy Index Animals were dissected after administration on day 28, and liver HE staining was performed for pathological scoring (the scoring criteria refer to "Chinese Non-alcoholic Fatty Liver Disease Diagnosis and Treatment Guide”).
  • Pharmacokinetic indicators 0.5h, 1h, 4h after administration on day 28, blood, liver and small intestine tissue samples were taken from the animals, and the drug concentration was detected using LC-MS/MS.
  • Compound C3 can inhibit liver fat lesions induced by MCD feed, and has a significant improvement relative to the model group.
  • the distribution of compound C3 in the liver is higher than that in plasma, indicating that it is effectively enriched at the target site.

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Abstract

La présente invention concerne un dérivé d'isoxazole, son procédé de préparation et son utilisation. L'invention concerne particulièrement un composé agoniste du récepteur farnésoïde X (FXR) et des stéréoisomères, des tautomères, des polymorphes, des solvates (tels que des hydrates), des sels pharmaceutiquement acceptables, des esters, des métabolites, des N-oxydes, des formes chimiquement protégées et des promédicaments de celui-ci. L'invention concerne en outre un procédé de préparation dudit composé, des intermédiaires, des compositions pharmaceutiques et des kits contenant le composé, et une utilisation de celui-ci dans le traitement de maladies ou d'états pathologiques à médiation par FXR.
PCT/CN2019/121534 2018-12-07 2019-11-28 Dérivé d'isoxazole, son procédé de préparation et son utilisation WO2020114307A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
WO2022068815A1 (fr) * 2020-09-30 2022-04-07 中国科学院上海药物研究所 Agoniste de petites molécules de fxr, son procédé de préparation et son utilisation
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné
EP4245365A1 (fr) * 2022-03-16 2023-09-20 Cascade Pharmaceuticals, Inc. Une petite molécule agoniste du récepteur fxr, sa préparation et son utilisation

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WO2012087521A1 (fr) * 2010-12-20 2012-06-28 Irm Llc Compositions et procédés de modulation des récepteurs farnésoïdes x
WO2018067704A1 (fr) * 2016-10-04 2018-04-12 Enanta Pharmaceuticals, Inc. Analogues de l'isoxazole en tant qu'agonistes de fxr et leurs procédés d'utilisation
WO2019120088A1 (fr) * 2017-12-22 2019-06-27 四川科伦博泰生物医药股份有限公司 Dérivé d'isoxazole, son procédé de préparation et son utilisation

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Publication number Priority date Publication date Assignee Title
WO2012087521A1 (fr) * 2010-12-20 2012-06-28 Irm Llc Compositions et procédés de modulation des récepteurs farnésoïdes x
WO2018067704A1 (fr) * 2016-10-04 2018-04-12 Enanta Pharmaceuticals, Inc. Analogues de l'isoxazole en tant qu'agonistes de fxr et leurs procédés d'utilisation
WO2019120088A1 (fr) * 2017-12-22 2019-06-27 四川科伦博泰生物医药股份有限公司 Dérivé d'isoxazole, son procédé de préparation et son utilisation

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
WO2022068815A1 (fr) * 2020-09-30 2022-04-07 中国科学院上海药物研究所 Agoniste de petites molécules de fxr, son procédé de préparation et son utilisation
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné
EP4245365A1 (fr) * 2022-03-16 2023-09-20 Cascade Pharmaceuticals, Inc. Une petite molécule agoniste du récepteur fxr, sa préparation et son utilisation

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