WO2019109415A1 - Composé de dégradation ciblée de hmgcr et son application - Google Patents

Composé de dégradation ciblée de hmgcr et son application Download PDF

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WO2019109415A1
WO2019109415A1 PCT/CN2017/118543 CN2017118543W WO2019109415A1 WO 2019109415 A1 WO2019109415 A1 WO 2019109415A1 CN 2017118543 W CN2017118543 W CN 2017118543W WO 2019109415 A1 WO2019109415 A1 WO 2019109415A1
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alkyl
compound
aryl
group
butyl
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PCT/CN2017/118543
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Chinese (zh)
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饶燏
宋保亮
杨毅庆
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清华大学
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to the field of biomedicine, and in particular to the compounds and their use.
  • HMG-CoA Reductase is the rate-limiting enzyme in the cholesterol synthesis pathway, and its activity is regulated at multiple levels by its synthesized small molecule metabolites.
  • statin inhibits the activity of the enzyme by competitively binding to the substrate, thereby maintaining cholesterol levels within a normal range.
  • traditional inhibitors of HMGCR are ineffective in partially tolerated patients or in patients with severe hyperlipidemia.
  • the present invention utilizes proteolytic cleavage targeting chimera (PROTACs) technology to design a dual function molecule, one end of which binds to a target protein, and the other end of which binds to an E3 ligase, and the two are linked by a linker to form a compound.
  • the compound is capable of ubiquitinating the target protein by E3 and directing the target protein into the degradation pathway, and has a specific degradation effect on the target protein.
  • the invention provides a compound which is a compound of formula I or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate thereof , solvates, metabolites, pharmaceutically acceptable salts or prodrugs:
  • X represents a ligand of a hydroxymethylglutaryl coenzyme A reductase
  • Z represents a ligand of an E3 ligase
  • Y represents a chain linking X and Z.
  • the compound according to the embodiment of the present invention has the effect of specifically degrading HMGCR, has small side effects, and has good cholesterol lowering activity, and can treat or prevent stroke, cardiovascular disease, Alzheimer's disease, obesity or diabetes.
  • the above compound may further include at least one of the following additional technical features:
  • the X is derived from a compound of formula II,
  • Cy is aryl, heteroaryl, fused bicyclic, fused heterobicyclic, cycloalkyl, cycloalkenyl, heterocyclyl, spirobicyclo or spirobicyclo;
  • each R 1a is independently H, ⁇ , C 1-3 alkyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 5-10 alkyl, cyano substituted alkyl, Hydroxy-substituted alkyl, amino-substituted alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero Cyclo or heterocyclylalkyl;
  • R m and R w is independently H, ⁇ , C 1-3 alkyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 5-10 alkyl, cyano substituted alkyl , hydroxy-substituted alkyl, amino-substituted alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, a heterocyclic or heterocyclylalkyl group, or R a , R b and an N atom attached thereto, together form a heterocyclic ring consisting of 3 to 12 atoms;
  • n is independently 0, 1, 2, 3 or 4;
  • Each g is independently 1, 2, 3 or 4;
  • Each p is independently 0, 1 or 2;
  • Each R 2 is independently hydrogen, hydrazine, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, oxo, C 1-3 alkyl, n-butyl, isobutyl, sec.
  • R 6 , R 7 , R 8 , R 9 and R 10 are independently H, anthracene, alkyl, alkenyl or alkynyl;
  • Each of R 11 and R 12 is independently H, anthracene, alkyl, cyano substituted alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic or heterocyclic ring.
  • the Cy is an aryl group, a heteroaryl group, a fused bicyclic group or a fused heterobicyclic group.
  • the Cy is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the substituent R 2 may be substituted at any substitutable position on the monocyclic or fused ring, and the attachment point is attached to L 1 .
  • the R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxy
  • the attachment point is attached to a carbonyl group in the compound of formula II.
  • the L1 is Or -O-.
  • the dotted key represents a single bond Or double bond Among them, the two attachment points are respectively connected to X and Z, and there is no left-right order limitation of the connection direction.
  • the R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, phenyl, halophenyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropane base,
  • R 2a is hydrogen, hydrazine, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, oxo, C 1-3 alkyl, n-butyl, isobutyl, sec-butyl , tert-butyl, C 5-10 alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino,
  • R 6 , R 7 , R 8 , R 9 and R 10 are independently H, anthracene, alkyl, alkenyl or alkynyl;
  • Each of R 11 and R 12 is independently H, anthracene, alkyl, cyano substituted alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic or heterocyclic ring.
  • the X is derived from atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin sodium, rosuvastatin or simvastatin Statins,
  • the X is
  • attachment point can be attached to Y at different alternative positions of the ring in a variety of ways.
  • the Z is derived from a compound of formula III,
  • Q is N or CR 2 ;
  • M, S, K are each independently C(R m R w ), N(R 1a ), O or S.
  • R 2 may be substituted at any substitutable position on the ring of the monocyclic or fused ring.
  • the Z is derived from a compound of the formulae IV (1) to IV (4),
  • R 2b is hydrogen, hydrazine, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , COOH, oxo, C 1-3 alkyl, n-butyl, isobutyl, sec-butyl , tert-butyl, C 5-10 alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aryloxy, heteroaryloxy, heterocyclyloxy , arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, amino, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, cycloalkylamino, alkylthio, haloalkyl, haloalkoxy , hydroxy substituted alkyl, hydroxy substituted alkylamino, cyano substituted alkyl, cyano substituted alkoxy, cyano substituted alkylamin
  • R 6 , R 7 , R 8 , R 9 and R 10 are independently H, anthracene, alkyl, alkenyl or alkynyl;
  • Each of R 11 and R 12 is independently H, anthracene, alkyl, cyano substituted alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic or heterocyclic ring.
  • the Z is derived from lenalidomide, pomamide or thalidomide
  • the Z is Wherein, the attachment point can be attached to Y at different replaceable positions of the benzene ring in a variety of ways.
  • the Y is a group having 1 to 30 atoms, and the atom includes at least one selected from the group consisting of a carbon atom, a sulfur atom, an oxygen atom, a nitrogen atom, and a selenium atom.
  • the atoms are not limited to the listed carbon atoms, sulfur atoms, oxygen atoms, nitrogen atoms, and selenium atoms.
  • the number of each atom may be, for example, 10, 15, 20 or 25, and the number of each atom may be the same or different.
  • Y is optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, fused bicyclic, fused heterobicyclo, cycloalkyl, cycloalkenyl, Heterocyclyl, spirobicyclo or spirobicyclo.
  • the Y is Wherein x 1 -x 23 are each independently a key, Alkynyl, alkenyl, aryl, heteroaryl, fused bicyclic, fused heterobicyclic, cycloalkyl, cycloalkenyl, heterocyclyl, spirobicyclo or spirobicyclo.
  • the Y is Where r is an integer between 0 and 4, and s is an integer between 0 and 7, and each x is independently
  • the Y is
  • r is an integer between 1 and 4
  • s is an integer between 1 and 7
  • x is
  • Y can be connected to X and Z respectively at different alternative positions of the benzene ring where the attachment point is located by means of attachment points in various ways.
  • r is an integer between 0 and 4
  • s is an integer between 0 and 7.
  • r is an integer between 1 and 4
  • s is an integer between 1 and 7
  • x is
  • the invention provides a compound which is a compound of any one of formulas 1 to 18, or a stereoisomer, geometric isomer, tautomer, oxynitride, a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
  • the invention proposes a pharmaceutical composition.
  • the pharmaceutical composition comprises the above compound.
  • the above composition may further include at least one of the following additional technical features:
  • the pharmaceutical composition further comprises an adjuvant.
  • the pharmaceutical composition further comprises other drugs for treating or preventing stroke, cardiovascular disease, Alzheimer's disease, obesity or diabetes.
  • the other medicament for treating or preventing stroke, cardiovascular disease, Alzheimer's disease, obesity or diabetes comprises a substance selected from the group consisting of Repatha, insulin, metformin, glipizide, gliclazide. At least one of glibenclamide, glibenclamide, glimepiride, gliclazide, and acarbose voglibose.
  • the invention provides the use of a compound as described above for the manufacture of a medicament for the degradation of hydroxymethylglutaryl coenzyme A reductase.
  • the invention provides the use of the above pharmaceutical composition for the preparation of a medicament for the degradation of hydroxymethylglutaryl coenzyme A reductase.
  • the invention provides the use of a compound as described above for the manufacture of a medicament for lowering cholesterol or for treating or preventing stroke, cardiovascular disease, Alzheimer's disease, obesity or diabetes.
  • the invention provides the use of the above pharmaceutical composition for the preparation of a medicament for lowering cholesterol or for treating or preventing stroke, cardiovascular disease, Alzheimer's disease, obesity or diabetes.
  • the invention provides a method for degrading a hydroxymethylglutaryl coenzyme A reductase, the method comprising: comprising a hydroxymethylglutaryl coenzyme A reductase with the above compound or the above The pharmaceutical composition is in contact.
  • the invention provides a method for lowering cholesterol or treating or preventing stroke, cardiovascular disease, Alzheimer's disease, obesity or diabetes, the method comprising administering to a patient the above compound or the above pharmaceutical composition .
  • the small molecule compound or pharmaceutical composition according to an embodiment of the present invention can degrade HMGCR, has cholesterol lowering activity, and can be used for treating or preventing stroke, cardiovascular disease, Alzheimer's disease, obesity or diabetes, compared with the conventional HMGCR inhibitor. Equivalent or stronger activity that activates the lipid metabolism-associated SREBP pathway.
  • PROTAC means “proteolytic cleavage targeting chimera”
  • Target Protein means “target protein”
  • Ub means “ubiquitin”
  • Linker means “chain”
  • Ligand means “ligand”
  • Recognition domain means “recognition region”
  • Proteasome means “proteasome”.
  • the small molecule compound of the formula VI can be formed by the click chemistry between the Pomalidomide terminal derivative and the Atorvastatin terminal derivative, as shown in Fig.
  • FIG. 1 is a schematic diagram of a basic technical route of PROTACs according to an embodiment of the present invention
  • FIG. 2 is a schematic diagram of constructing a small molecule compound of the present invention by click chemistry according to an embodiment of the present invention
  • Figure 3 is a schematic diagram showing the synthetic route of an Atorvastatin derivative according to an embodiment of the present invention.
  • FIG. 4 is a schematic diagram showing the degradation of HMGCR by the compounds of Formulas 1 and 2 according to an embodiment of the present invention
  • FIG. 5 is a schematic illustration of the degradation of HMGCR by compounds of Formulas 3 and 4, in accordance with an embodiment of the present invention
  • FIG. 6 is a schematic illustration of the degradation of HMGCR by the compounds of Formulas 5 and 6 in accordance with an embodiment of the present invention
  • FIG. 7 is a schematic illustration of the degradation of HMGCR by the compounds of Formulas 7 and 8 in accordance with an embodiment of the present invention
  • Figure 8 is a schematic illustration of the degradation of HMGCR by a compound of Formula 9 according to an embodiment of the present invention.
  • Figure 9 is a schematic diagram showing the degradation of HMGCR by the compound of Formula 10 according to an embodiment of the present invention.
  • Figure 10 is a schematic illustration of the degradation of HMGCR by a compound of Formula 11 according to an embodiment of the present invention.
  • Figure 11 is a schematic illustration of the degradation of HMGCR by a compound of Formula 12-Form 18, in accordance with an embodiment of the present invention
  • Figure 12 is a graphical representation of the effect of a compound of Formula 4 and Atorvastatin on the low density lipoprotein receptor (LDLR) in the SREBP pathway, in accordance with an embodiment of the present invention.
  • LDLR low density lipoprotein receptor
  • the term "administered to a patient as described above, or a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable, is pharmaceutically acceptable.
  • the salt or prodrug or the pharmaceutical composition described above means that a predetermined amount of the substance is introduced into the patient by some suitable means.
  • the drug or pharmaceutical composition can be administered by any conventional route as long as it can reach the intended tissue.
  • Various modes of administration are contemplated, including peritoneal, venous, muscular, subcutaneous, cortical, oral, topical, nasal, pulmonary, and rectal, but the invention is not limited to these exemplary modes of administration.
  • the frequency and dosage of the pharmaceutical composition of the present invention can be determined by a number of relevant factors including the type of disease to be treated, the route of administration, the age, sex, weight and severity of the disease as well as the active ingredient. Type of drug.
  • therapeutically effective amount refers to an amount of a compound that is sufficient to significantly ameliorate certain symptoms associated with a disease or condition, that is, an amount that provides a therapeutic effect for a given condition and dosage regimen.
  • a therapeutically effective amount of a drug or compound does not require a cure for the disease or condition, but will provide a treatment for the disease or condition such that the onset of the disease or condition of the individual is delayed, prevented or prevented, or the symptoms of the disease or condition are alleviated, or the disease or The duration of the condition is altered, or for example the disease or condition becomes less severe, or the recovery is accelerated.
  • treatment is used to mean obtaining the desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms, and/or may be therapeutic in terms of partially or completely curing the disease and/or the adverse effects caused by the disease.
  • treatment encompasses the treatment of a disease in a mammal, particularly a human, including: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed; (b) inhibiting the disease; or (c) Relieve diseases, such as alleviating symptoms associated with the disease.
  • treatment encompasses any administration of a medicament or compound to an individual for treating, curing, ameliorating, ameliorating, or inhibiting a disease in an individual, including but not limited to, comprising Formula I to Formula VI or Formula 1 described herein. Administration of a compound or pharmaceutical composition of 18 to an individual in need thereof.
  • the excipients include pharmaceutically acceptable excipients, lubricants, fillers, diluents, disintegrants, stabilizers, preservatives, emulsifiers, solubilizers, colorants well known in the formulation arts. , sweetener, made into tablets, pills, capsules, injections and other different dosage forms.
  • the articles used herein are used to refer to the articles of one or more than one (ie, at least one).
  • a component refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
  • Stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • “Chirality” is a molecule that has properties that cannot overlap with its mirror image; “non-chiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more centers of chirality 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 procedures such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds A class of compounds.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds A class of compounds.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds A class of compounds.
  • the ring system formed by the attachment of a substituent R' to a central ring represents that the substituent R' can be substituted at any substitutable or at any reasonable position on the ring.
  • the formula a represents that any position on the A' ring or B' ring that may be substituted may be substituted by R', as shown in formula b, formula c, formula d, formula e, formula f, formula g, and formula h .
  • Attachment point as described in the present invention It can be attached to the rest of the molecule at any attachable position on the ring.
  • the formula i represents any position on the A' ring or B' ring that may be connected as a point of connection.
  • connection point on the ring D which can be connected to the rest of the molecule, for example, as shown in the formula k, specifically as It is indicated that the attachment point can be attached to the remainder of the molecule at various alternative positions of the ring in a variety of ways.
  • connection methods at both ends can be interchanged.
  • connection methods at both ends can be interchanged.
  • connection at both ends can be interchanged.
  • the attachment point can be attached to the remainder of the molecule at any attachable position on the ring, while the ends of the connection can be interchanged.
  • the formula x represents any position on the ring that may be connected as a point of connection, while the ends of the connection point are interchangeable.
  • C 1 - 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the definition of the Markush group for the variable is "alkyl” or "aryl”
  • the “alkyl” or “aryl” respectively represent the attached An alkylene group or an arylene group.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH) 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH) 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2 -butyl (-C(
  • alkyl and its prefix “alk” are used herein to encompass both straight-chain and branched saturated carbon chains.
  • alkylene is used herein to mean a saturated divalent hydrocarbon radical derived by the elimination of two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene, hypoethyl , isopropyl and so on.
  • alkenyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 15 carbon atoms, wherein there is at least one site of unsaturation, i.e., having a carbon-carbon sp 2 double bond, wherein the alkenyl group
  • the group may be optionally substituted with one or more substituents described herein, including the positioning of "cis” and “tans", or the positioning of "E” and "Z”.
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group comprises 2 - 4 carbon atoms.
  • alkynyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 15 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more of the substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group comprises 2 - 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like. .
  • heteroalkyl denotes the insertion of one or more heteroatoms in the alkyl chain, wherein the alkyl group and heteroatom have the meaning as described herein.
  • a heteroalkyl group contains from 1 to 10 carbon atoms, and in other embodiments, a heteroalkyl group contains from 1 to 8 carbon atoms.
  • a heteroalkyl group contains 1 -6 carbon atoms, in other embodiments, the heteroalkyl group contains 1-4 carbon atoms, and in other embodiments, the heteroalkyl group contains 1-3 carbon atoms.
  • Such examples include, but are not limited to, CH 3 OCH 2 -, CH 3 CH 2 OCH 2 -, CH 3 SCH 2 -, (CH 3 ) 2 NCH 2 -, (CH 3 ) 2 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 CH 2 OCH 2 CH 2 -, and the like.
  • cycloalkyl means monovalent or polyvalent, non-aromatic, saturated or partially unsaturated.
  • the ring and does not contain a hetero atom, including a single ring of 3 to 12 carbon atoms or a bicyclic ring of 7 to 12 carbon atoms.
  • a bicyclic carbocyclic ring having 7 to 12 atoms may be a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and a bicyclic carbocyclic ring having 9 or 10 atoms. It may be a bicyclo[5,6] or [6,6] system.
  • Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl.
  • Examples of the cyclic aliphatic group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1- Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptane Base, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl and the like.
  • heterocycle refers to a monocyclic, bicyclic or tricyclic ring system in which one or more The carbon atoms are independently and optionally substituted by a hetero atom having the meaning as described herein, and the ring may be fully saturated or contain one or more unsaturations, but are by no means aromatic, and There are one or more connection points connected to other parts of the molecule.
  • the hydrogen atoms on one or more of the rings are independently and optionally substituted by one or more substituents described herein.
  • the "heterocycle", “heterocyclyl”, “heteroalicyclic” or “heterocyclic” group is a 3-7 membered ring of a monocyclic ring (1-6 carbon atoms and selected from 1-3 heteroatoms of N, O, P, S, wherein S or P is optionally substituted with one or more oxygen atoms to give a group such as SO, SO 2 , PO, PO 2 when When the ring is a three-membered ring, there is only one hetero atom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, here S Or P is optionally substituted with one or more oxygen atoms to give a group such as SO, SO 2 , PO, PO 2 ).
  • heterocyclic group may be a carbon group or a hetero atom group.
  • Heterocyclyl also includes groups formed by the union of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, thiamethane, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thioheterobutyl , homopiperidinyl, epoxypropyl, azepanyl, oxetanyl, thiety
  • heterocyclic group further include a 1,1-dioxothiomorpholinyl group and wherein two carbon atoms in the ring are substituted with an oxygen atom such as a pyrimidinedione group.
  • heteroatom denotes one or more of the O, S, N, P and Si atoms, including the form of any of the oxidation states of N, S and P; the form of primary, secondary, tertiary and quaternary ammonium salts; a form in which a hydrogen atom on a nitrogen atom is substituted, for example, N (for example, N in 3,4-dihydro-2H-pyrrolyl), NH (for example, NH in pyrrolidinyl) or NR (for example, N-substituted pyrrole) NR in an alkyl group.
  • N for example, N in 3,4-dihydro-2H-pyrrolyl
  • NH for example, NH in pyrrolidinyl
  • NR for example, N-substituted pyrrole
  • aryl may be used alone or as a large part of "aralkyl”, “aralkyloxy” or “aryloxyalkyl”, meaning monocyclic, bicyclic and tertiary containing a 6-14 membered ring.
  • a cyclic carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system comprises a 3-7 membered ring and one or more attachment points are attached to the remainder of the molecule.
  • aryl may be used interchangeably with the term “aromatic ring”, and the aromatic ring may include phenyl, naphthyl and anthracenyl.
  • heteroaryl may be used alone or as a large part of “heteroarylalkyl” or “heteroarylalkoxy”, meaning monocyclic, bicyclic and tricyclic systems which together contain a 5-14 membered ring. Wherein at least one ring system is aromatic and at least one ring system comprises one or more heteroatoms, wherein the heteroatoms have the meanings described herein, wherein each ring system comprises a 3-7 membered ring and has one or Multiple attachment points are attached to the rest of the molecule.
  • heteroaryl can be used interchangeably with the terms “aromatic heterocycle” or “heteroaromatic”.
  • the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazole 5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, Pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg 5-tetrazolyl), triazolyl (eg 2-triazolyl and 5-Triazolyl and
  • C 1-6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • prodrug denotes a compound which is converted in vivo to a compound of formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester.
  • the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3 -Phenylpropionate
  • Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate means that the solvent molecule is an association formed by water.
  • any disease or condition as used in the present invention refers to ameliorating a disease or condition (ie, slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms).
  • “treating” refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • “treating” refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both.
  • “treating” refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/ Carbonate, hydrogen sulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, Portuguese Saccharate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, Malay Acid salt, malonate, mandelic acid salt, methanesulfonate, methyl sulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalic acid Salt, palmitate
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid. , ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like.
  • Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. .
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods.
  • such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • the free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • the compounds disclosed in the present invention may also be obtained in the form of their hydrates or in the form of their solvents (e.g., ethanol, DMSO, etc.) for their crystallization.
  • solvents e.g., ethanol, DMSO, etc.
  • the compounds disclosed herein may form solvates either intrinsically or by design with pharmaceutically acceptable solvents, including water; thus, the invention is intended to include both solvated and unsolvated forms.
  • any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched.
  • Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the invention include isotopically enriched compounds of the invention, for example, those in which a radioisotope such as 3 H, 14 C and 18 F is present, or in which a non-radioactive isotope is present, such as 2 H and 13 C.
  • a radioisotope such as 3 H, 14 C and 18 F
  • a non-radioactive isotope such as 2 H and 13 C.
  • isotopically enriched compounds can be used for metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) of substrate tissue distribution assays, or may be used in patient radiation therapy.
  • 18 F enriched compounds are particularly desirable for PET or SPECT studies.
  • Isotopically enriched compounds of Formula I or Formula II can be prepared by conventional techniques familiar to those skilled in the art or by the use of suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the Examples and Preparations of the Invention. .
  • substitution of heavier isotopes may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index.
  • Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium.
  • a substituent of a compound of the invention is designated as hydrazine
  • the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor with at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation).
  • the present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D 2 O, acetone -d 6, DMSO-d 6 solvate of those.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable carrier, an excipient, a diluent, an adjuvant, a vehicle, or a combination thereof.
  • the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray.
  • the Pomalidomide terminal derivative used in the following examples was prepared according to the method disclosed in the literature Chemistry & Biology 22, 755-763 (2015).
  • PROTACs proteolytic cleavage targeting chimeras
  • Figure 1 A dual function molecule is designed, one end of which binds to the target protein and the other end binds to E3 ligase, and two The formation of a polymer, the target protein is ubiquitinated and then degraded by the proteasome, at this time E3 can ubiquitinate the target protein and guide it into the degradation pathway.
  • the Atorvastatin terminal derivative used in the following examples was prepared as follows.
  • the reaction equation is shown in Figure 3: firstly, m-bromophenylacetic acid was prepared into an acid chloride and then reacted with fluorobenzene to form an acetophenone intermediate. A bromine atom is introduced at the alpha position of the carbonyl group, and the bromine atom is substituted with a 1,3-dicarbonyl intermediate in the next step, and the resulting intermediate is condensed with primary ammonia to synthesize an anthracene ring. After that, the C-Br bond is converted to a C-B bond and continues to be converted to a C-O bond.
  • the terminal alkyne required for Click chemistry is linked to the newly formed phenolic hydroxyl group by a substitution reaction, and finally the protective group is removed to obtain an Atorvastatin terminal derivative.
  • the specific preparation process is as follows:
  • the compound of the formula 2 to the formula 18 was prepared according to the above production method.
  • the cells were collected: the treated cells were scraped off in the medium, centrifuged at 1,000 g for 5 minutes, and after washing with PBS, the PBS was discarded.
  • Lysis cells 120 ⁇ l of RIPA buffer was added to each sample and sheared 10 times through a 7-gauge needle. Centrifuge at 10,200 rpm for 10 minutes at 4 °C. Transfer 93 ⁇ l of supernatant to a new 1.5 ml Eppendorf tube. 3 ⁇ l of supernatant was taken for protein quantification. 90 ⁇ l of HMGCR Sol Buffer, 60 ⁇ l of 4 ⁇ Loading Buffer was added to the remaining 90 ⁇ l of protein extract, incubated at 37 ° C for 30 minutes, mixed and stored at -20 ° C or directly used for Western Blot detection.
  • the composition of the RIPA buffer was: final concentration 50 mM Tris-HCl pH 8.0, 150 mM NaCl, 2 mM MgCl 2 , 0.1% SDS, 1.5% Nonidet-P40, 0.5% sodium deoxycholate. Further, Pepstatin A was added at a concentration of 5 ⁇ g/ml, Leupeptin at 10 ⁇ g/ml, MG-132 at 5 ⁇ M, PMSF at 1 mM, DTT at 0.25 mM.
  • HMGCR Solubilization Buffer was: final concentration of 62.5 mM Tris-HCl pH 6.8, 15% SDS, 8 M urea, 10% glycerol, 100 mM DTT.
  • composition of 4 ⁇ Loading Buffer is: 1% SDS, 6% ⁇ -mercaptoethanol, 30% glycerol, and the right amount of bromophenol blue.
  • Protein samples were prepared according to the experimental requirements, denatured at 95 ° C for 10 minutes or 37 ° C for 30 minutes, centrifuged, mixed and loaded onto SDS-PAGE gel loading wells. The loading volume was adjusted according to the protein quantification results, usually 20 ⁇ l per well.
  • Electrophoresis When the power is turned on, the protein sample has a voltage of 80 volts in the concentrated gel. When the protein sample enters the separation gel, we adjust the voltage to 150 volts to continue the electrophoresis. Electrophoresis was terminated when bromophenol blue almost completely ran out of PAGE gel.
  • the degradation activity of the small molecule compound of the present invention on HMGCR is as follows:
  • the degradation is shown in Figure 6 (the compounds shown in Formula 2 and Formula 3 are positive controls), and the degradation of HMGCR by the compounds of Formulas 7 and 8 is shown in Figure 7 (compounds of Formula 2 and Formula 3)
  • the degradation of HMGCR by the compound of Formula 9 is shown in Figure 8 (the compound shown by Formula 2 is a positive control)
  • the degradation of HMGCR by the compound of Formula 10 is shown in Figure 9.
  • the compound shown in 2 is a positive control
  • the degradation of HMGCR by the compound of Formula 11 is shown in Figure 10 (the compound shown by Formula 2 is a positive control)
  • the degradation of HMGCR by the compound of Formula 12 to Formula 18 is as follows.
  • Figure 11 shows the compound shown in Formula 2 as a positive control.
  • D0 set up 800k Huh7 cells
  • Extraction of cellular RNA discard the medium and wash the cells by adding 1 ml of PBS;
  • RNA was finally set to 1 ⁇ g/ ⁇ l, to be used or stored at -80 °C.
  • Step 3 After the reaction is completed, the reaction tube is quickly transferred from the PCR machine to the ice box for 2 minutes; and the premixed liquid in the step 4) is added;
  • Fig. 12 As a result, as shown in Fig. 12, it can be seen that the effect of the compound represented by the formula 4 and Atorvastatin on the low density lipoprotein receptor (LDLR) in the SREBP pathway is shown in Fig. 12. It can be seen that the compound phase represented by the formula 4 Compared with the traditional HMGCR inhibitor Atorvastatin, it has a stronger activity of activating the lipid metabolism-associated SREBP pathway.
  • LDLR low density lipoprotein receptor

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Abstract

La présente invention concerne un composé qui est un composé représenté par la formule (I) ou son stéréoisomère, isomère géométrique, tautomère, oxyde d'azote, hydrate, solvate, métabolite, sel pharmaceutiquement acceptable ou promédicament : X-Y-Z Formule (I), où X représente un ligand de l'hydroxyméthylglutaryl coenzyme A réductase, Z représente un ligand de E3 ligase, et Y représente un lieur qui connecte X et Z.
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WO2021201577A1 (fr) * 2020-03-30 2021-10-07 Uppthera Composé induisant la dégradation de la hmg-coa réductase
KR20210122708A (ko) * 2020-03-30 2021-10-12 (주) 업테라 HMG-CoA 환원효소 분해 유도 화합물
KR102337040B1 (ko) * 2020-03-30 2021-12-09 (주) 업테라 HMG-CoA 환원효소 분해 유도 화합물
WO2022098108A1 (fr) * 2020-11-04 2022-05-12 (주) 업테라 Composé induisant la dégradation de protéine nlrp3
WO2022119362A1 (fr) * 2020-12-03 2022-06-09 (주) 업테라 Composé induisant la dégradation de la protéine gpx4
CN113248473A (zh) * 2021-05-26 2021-08-13 中国药科大学 靶向GSK3α/β降解剂的制备及其医药用途
CN113248473B (zh) * 2021-05-26 2022-02-18 中国药科大学 靶向GSK3α/β降解剂的制备及其医药用途

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