WO2022222856A1 - Composé cyclique benzocondensé, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation - Google Patents

Composé cyclique benzocondensé, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation Download PDF

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WO2022222856A1
WO2022222856A1 PCT/CN2022/087060 CN2022087060W WO2022222856A1 WO 2022222856 A1 WO2022222856 A1 WO 2022222856A1 CN 2022087060 W CN2022087060 W CN 2022087060W WO 2022222856 A1 WO2022222856 A1 WO 2022222856A1
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compound
mmol
alkyl
added
disease
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张贵平
李家鹏
王奎锋
朱荣
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勤浩医药（苏州）有限公司
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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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present application relates to a benzo-fused ring compound, a pharmaceutical composition comprising the same, a preparation method thereof, and use as an HDAC6 inhibitor.
  • Histone deacetylases can catalyze the deacetylation of histones or other proteins, which play important roles in a variety of biological processes mainly through transcriptional repression.
  • HDACs in the human body can be divided into four categories, class I includes HDAC1, HDAC2, HDAC3 and HDAC8; class II includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10; class III includes SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7; class IV includes HDAC11. Class II HDACs are further subdivided into subclass IIa (HDAC4, HDAC5, HDAC7, and HDAC9) and subtype IIb (HDAC6 and HDAC 10).
  • HDAC6 mainly catalyzes the deacetylation of non-histone substrates, such as ⁇ -tubulin and Hsp90. HDAC6 is involved in the pathological process of a variety of diseases, including cancer, neurological diseases, infections, cardiovascular diseases, immune and inflammation-related diseases.
  • HDAC inhibitors are broad-spectrum inhibitors and are not selective for HDAC subtypes.
  • the side effects of broad-spectrum inhibitors of the HDAC family are closely related to their inhibition of class I subtypes (especially inhibition of HDAC1 and HDAC2).
  • the present application provides benzo-fused ring compounds that can be used as HDAC6 inhibitors to prevent or treat HDAC6-related diseases.
  • the compounds of the present application are highly selective for HDAC6, thus avoiding the side effects of broad-spectrum HDAC inhibitors.
  • the compounds of the present invention also have better physicochemical properties (eg solubility, physical and/or chemical stability), improved pharmacokinetic properties (eg improved bioavailability, improved metabolic stability, suitable Half-life and duration of action), improved safety (lower toxicity (eg, reduced cardiotoxicity) and/or fewer side effects), less susceptibility to drug resistance, etc. superior properties.
  • One aspect of the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein
  • the compound has the structure of formula (I):
  • Z and W are each independently CR or N;
  • R a and R b at each occurrence are each independently selected from H, C 1-6 alkyl, C 3-10 cyclohydrocarbyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • n is an integer of 0, 1, 2, 3 or 4;
  • n is an integer of 0, 1 or 2;
  • t is an integer of 0, 1 or 2;
  • R 5 and R 6 at each occurrence are each independently selected from H, C 1-6 alkyl, C 3-10 cyclohydrocarbyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl.
  • compositions comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite thereof , an isotope-labeled compound or prodrug and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid formulation, a liquid formulation or a transdermal formulation.
  • Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Use of the prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating HDAC6-related diseases.
  • Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or
  • the prodrug or the pharmaceutical composition of the present invention is used for preventing or treating HDAC6-related diseases.
  • Another aspect of the present invention provides a method of preventing or treating an HDAC6-related disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer thereof , tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs or pharmaceutical compositions of the invention.
  • Another aspect of the present invention provides methods of preparing the compounds of the present invention.
  • Figure 1 shows the expression level of AC- ⁇ -tubulin in A375 cells treated with Compound 5.
  • alkylene refers to a saturated divalent hydrocarbon radical, preferably a saturated divalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6, carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) group, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the radical group is referred to as "haloalkyl”) ( eg , CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl , or -CH2CH
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2-6 carbon atoms (“C 2-6 alkenyl”).
  • alkynyl refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg ethynyl, 2-propynyl, 2 -butynyl, 1,3-butadiynyl, etc.
  • the alkynyl group is optionally substituted with one or more, such as 1 to 3, the same or different substituents.
  • alkynylene is the corresponding divalent group including, for example, “C 2-8 alkynylene", “C 2-6 alkynylene", “C 2-4 alkynylene” and the like. Examples include but are not limited to etc., the alkynylene group is optionally substituted with one or more, such as 1 to 3, the same or different substituents.
  • cyclohydrocarbylene refers to rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atomically saturated (ie, “cycloalkylene” and “cycloalkyl”) or unsaturated (ie, having one or more double and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon rings, which Including but not limited to ()cyclopropylidene (ring), ()cyclobutylidene (ring), ()cyclopentylidene (ring), ()cyclohexylene (ring), ()cycloheptidene ( cyclo), () cyclooctyl (ring), () cyclononyl (ring), () cyclohexenyl (ring), and the like.
  • cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic rings, including spirocyclic, fused, or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[ 3.2.1] octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooc
  • Said cycloalkyl has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • a 3-10 membered heterocyclyl group is a group having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl ( azetidinyl), oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyridine Alanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • heterocyclyl encompasses buccal structures whose point of attachment to other groups may be on any ring in the buccal structure.
  • heterocyclyl groups of the present invention also include, but are not limited to, heterocyclylnoheterocyclyl, heterocyclylnocycloalkyl, monoheterocyclylmonoheterocyclyl, monoheterocyclylmonocycloalkyl, such as 3-7-membered (mono)heterocyclyl and 3-7-membered (mono)heterocyclyl, 3-7-membered (mono)heterocyclyl and (mono)cycloalkyl, 3-7-membered (mono)heterocyclyl C 4-6 (mono)cycloalkyl, examples of which include, but are not limited to, pyrrolidinocyclopropyl, cyclopentazacyclopropyl, pyrrolidinocyclobutyl
  • heterocyclyl encompasses bridged heterocyclyl and spiroheterocyclyl.
  • bridged heterocycle refers to two saturated rings formed by sharing two non-directly connected ring atoms containing one or more (eg 1, 2, 3 or 4) heteroatoms (eg oxygen, nitrogen and/or sulfur) cyclic structures including, but not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7- 10-membered oxygen-containing bridged heterocycle, 7-10-membered sulfur-containing bridged heterocycle, etc., for example Wait.
  • the "nitrogen-bridged heterocycle”, “oxygen-bridged heterocycle”, and “sulfur-bridged heterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • spiroheterocycle refers to a ring formed by two or more saturated rings sharing a ring atom containing one or more (eg, 1, 2, 3, or 4) heteroatoms (eg oxygen atom, nitrogen atom, sulfur atom) cyclic structure, including but not limited to 5-10 membered spiroheterocycle, 6-10 membered spiroheterocycle, 6-10 membered nitrogen-containing spiroheterocycle, 6-10 membered spiroheterocycle Oxygen-containing spiroheterocycle, 6-10 membered sulfur-containing spiroheterocycle, etc., for example
  • the "nitrogen-containing spiroheterocycle", “oxygen-containing spiroheterocycle” and “sulfur-containing spiroheterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • 6-10 membered nitrogen-containing spiroheterocyclyl refers to a spiroheterocyclyl group containing a total of 6-10 ring atoms and wherein at least one of the ring atoms is a nitrogen atom.
  • aryl refers to an all carbon monocyclic or fused ring polycyclic aromatic group having a conjugated pi electron system.
  • C 6-14 aryl means an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl.
  • the aryl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO2 , C1-6 alkyl, etc.).
  • aralkyl preferably refers to an aryl-substituted alkyl group, wherein said aryl group and said alkyl group are as defined herein.
  • the aryl group can have 6-14 carbon atoms
  • the alkyl group can have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • heteroaryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, In particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which comprise at least one heteroatom which may be the same or different (the heteroatom being eg oxygen, nitrogen or sulphur) and, in addition, In each case it can be benzo-fused.
  • heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • alkylthio means an alkyl group, as defined above, attached to the parent molecular moiety through a sulfur atom.
  • Representative examples of C 1-6 alkylthio groups include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • the nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocycle.
  • a 3- to 14-membered nitrogen-containing heterocycle is a group having 3-14 carbon atoms and a heteroatom (at least one of which is a nitrogen atom) in the ring, which includes, but is not limited to, three-membered nitrogen-containing heterocycles (such as aziridinyl), four-membered nitrogen-containing heterocycles (such as azetidinyl), five-membered nitrogen-containing heterocycles (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrroline, pyrrolidone, imidazole base, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), six-membered nitrogen-containing heterocycles (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl) , seven-membered nitrogen-containing heterocyclic ring, etc.
  • substituted refers to the replacement of one or more (eg, one, two, three, or four) hydrogens on the designated atom by a selection from the designated group, provided that no more than the designated atom is present at the normal valences in the case and the substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently Selected optional substituents are substituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optional substitution of substituents.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent can be from any suitable position on the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (eg, deuterium (D,2H), tritium (T, 3H )); isotopes of carbon (eg, 11C , 13C ); and 14 C); isotopes of chlorine (eg 36 Cl); isotopes of fluorine (eg 18 F); isotopes of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O, 17 O and 18 O); isotopes of phosphorus (eg 32 P); and isotopes of sulfur (eg 35 S).
  • isotopes of hydrogen eg, deuterium (D,2H), tritium (T, 3H )
  • isotopes of carbon eg, 11C , 13C ); and 14 C
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (eg, assays).
  • the radioisotopes tritium (ie 3 H) and carbon-14 (ie 14 C) are particularly useful for this purpose due to their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes such as11C , 18F , 15O , and13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies.
  • Isotopically-labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically-labeled reagent in place of the previously employed non-labeled reagent.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, D2O , acetone-d6, or DMSO - d6.
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can be directly Or indirectly provide a compound of the invention or a metabolite or residue thereof. Accordingly, references herein to "compounds of the present invention" are also intended to encompass the various derivative forms of the compounds described above.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluoro Phosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methyl sulfate, naphthylate, nicotinate, nitrate , orotate, oxalate, palmitate and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium, and other similar salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release free acid or alcohol forms of the present invention) compound).
  • the compounds of the present invention may themselves also be esters.
  • the compounds of the present invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the present invention comprise a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the present invention ie substances formed in the body upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, and the like, of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity when administered into or onto the body can be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage.
  • prodrugs will be functional derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by E.B. Roche, American Pharmaceutical Association).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as “pro-moiety (eg as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" Prepared by substituting appropriate functional groups present in the compounds of the present invention.
  • the present invention also encompasses compounds of the present invention that contain protecting groups.
  • protecting groups In 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 molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, Plenum Press, 1973; and T.W.Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 protecting groups, these references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10% of the stated value, preferably within ⁇ 5%, more preferably within ⁇ 2%.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- medicine, wherein the compound has the structure of formula (I):
  • Z and W are each independently CR or N;
  • R a and R b at each occurrence are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • n is an integer of 0, 1, 2, 3 or 4;
  • n is an integer of 0, 1 or 2;
  • t is an integer of 0, 1 or 2;
  • R 5 and R 6 at each occurrence are each independently selected from H, C 1-6 alkyl, C 3-10 cyclohydrocarbyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- medicine, wherein the compound has the structure of formula (II):
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- medicine, wherein the compound has the structure of formula (III) or formula (IV):
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- drug wherein each occurrence of X is independently -CR3R3'- , preferably -CH2- .
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- drug, wherein Z and W are each independently CH, CF or N.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- drug, wherein L is -C 1-6 alkylene-, preferably -CH 2 -.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- drug wherein each occurrence of R2 is independently halogen, preferably F.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- drug, wherein R 3 , R 3' , R 4 and R 4' are H or C 1-6 alkyl, preferably H or methyl.
  • n is an integer of 0, 1, or 2.
  • m is an integer of 0 or 1.
  • t is an integer of 1 or 2.
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the present invention provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or A prodrug, wherein the compound is selected from:
  • the present invention provides a method of preparing a compound of formula (II) comprising the steps of:
  • Hal is halogen such as F, Cl, Br or I;
  • R L is a leaving group, such as -OC 1-6 alkyl, preferably -O-CH 3 ;
  • the first step reacting compound (II)-a with compound (II)-a-2 to obtain compound (II)-b.
  • the reaction is preferably carried out in the presence of a base such as DIPEA, Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 etc.).
  • Solvents that can be used in the reaction are, for example, THF, 1,4-dioxane, DMF, DMSO or CH 3 CN, preferably DMF.
  • the reaction temperature is, for example, room temperature.
  • Second step react compound (II)-b with hydroxylamine to obtain compound of formula (II).
  • the reaction is preferably carried out in the presence of a base such as NaOH, Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 etc.).
  • a base such as NaOH, Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 etc.
  • the solvent that can be used in the reaction is, for example, THF, methanol, 1,4-dioxane, DMF, DMSO or CH 3 CN, or a mixed solvent of two or more solvents, preferably a mixed solvent of methanol and THF .
  • the reaction temperature is, for example, 0°C to room temperature.
  • compositions and methods of treatment are provided.
  • the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, of the present invention
  • a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof of the present invention
  • Compounds, solvates, metabolites, isotopically-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers are preferably solid formulations, liquid formulations or transdermal formulations.
  • the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically-labeled Use of a compound or a prodrug or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating HDAC6-related diseases.
  • the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically-labeled Compounds or prodrugs or pharmaceutical compositions of the present invention for preventing or treating HDAC6-related diseases.
  • the present invention provides a method of preventing or treating an HDAC6-related disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer thereof Conformers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs or pharmaceutical compositions of the invention.
  • the HDAC6-related diseases include, but are not limited to, cancer or proliferative diseases (eg, lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, pancreatic cancer.
  • cancer or proliferative diseases eg, lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, pancreatic cancer.
  • glioma glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, multiple myeloma, and solid tumors
  • Wilson's Wilson's disease spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloid Degenerative diseases, Alzheimer's disease, Alexander's disease, alcoholic liver disease, cystic fibrosis, Pick's Disease, Spinal Muscular Atrophy disease or Lewy body dementia; rheumatoid arthritis, osteoarthritis; rheumatoid spondylitis; psoriasis; inflammatory bowel disease; chronic inflammatory lung disease, eczema, asthma, ischemia/reperfusion injury , Ulcerative Colitis, Acute Respiratory Distress Syndrome, Psoriatic Arthritis, In
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or tissue from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term is applied or one or more symptoms of such disorder or condition, or preventing such A disorder or condition or one or more symptoms of such a disorder or condition.
  • an “individual” as used herein includes a human or non-human animal.
  • exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein).
  • Non-human animals in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).
  • compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
  • Int.-1-a (2.0 g, 13.2 mmol) was dissolved in carbon tetrachloride (40 mL), N-bromosuccinimide (2.5 g, 14.3 mmol) and azoisobutyronitrile (200 mg) were added , 1.2 mmol), and reacted at 80 °C for 16 hours. After the completion of the reaction monitored by TLC, the reaction solution was spun dry, and purified by column chromatography to obtain Int.-1 (360 mg, yield 12%) as a colorless liquid.
  • Int.-2-a (1.0 g, 6.6 mmol) was dissolved in carbon tetrachloride (10 mL), N-bromosuccinimide (1.23 g, 6.9 mmol) and azobisisobutyronitrile ( 0.43 g, 2.6 mmol), react at 80°C for 16 hours. After the completion of the reaction monitored by TLC, the reaction solution was spun dry and purified by column chromatography to obtain Int.-2 (0.27 g, yield 18%) as a colorless liquid.
  • Int.-3-a (2.0 g, 11.9 mmol) was dissolved in carbon tetrachloride (40 mL), N-bromosuccinimide (2.5 g, 14.3 mmol) and azobisisobutyronitrile ( 200 mg, 1.2 mmol), react at 80°C for 16 hours. After the completion of the reaction monitored by TLC, the reaction solution was spun dry and purified by column chromatography to obtain Int.-3 (2.3 g, yield 78%) as a colorless liquid.
  • Int.4-c (6 g, 26.2 mmol), iodobenzene (530 mg, 2.6 mmol) and m-chloroperoxybenzoic acid (4.1 g, 24.2 mmol) were added to trifluoroethanol (20 mL) and reacted at room temperature for 2 hours. TLC monitoring indicated that the reaction was complete. Aqueous sodium bicarbonate solution and ethyl acetate were added, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography gave Int.4-d (2 g, yield: 33.6%).
  • Int.4-d (2.5 g, 11.01 mmol) was dissolved in tetrahydrofuran (25 mL), nitrogen was replaced, samarium iodide (165.2 mL, 16.52 mmol) was added, and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain the product Int.-4 (1.7 g, yield: 78%).
  • 6-b 160 mg, 0.64 mmol was dissolved in DMF (1.0 mL), methyl 4-(bromomethyl)benzoate (174 mg, 0.76 mmol) and potassium carbonate (262 mg, 1.89 mmol) were added at room temperature The reaction was carried out for 16 hours. After the completion of the reaction monitored by TLC, water and ethyl acetate were added for extraction, the organic phase was concentrated under reduced pressure, and purified by column chromatography to obtain 6-c (150 mg, yield 59%).
  • 6-c (150 mg, 0.38 mmol) was dissolved in tetrahydrofuran (1.0 mL) and methanol (1.0 mL), hydroxylamine aqueous solution (0.5 mL) and sodium hydroxide (61 mg, 1.52 mmol) were added, and the reaction was carried out at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the reaction was concentrated under reduced pressure, and purified by column chromatography to obtain compound 6 (60 mg, yield 39%).
  • Example 16 and Example 17 4-((2,2-Dioxy-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydro- 1H-Benzo[c][1,2]thiazin-1-yl)methyl)-N-hydroxybenzamide (compound 16) and 4-(4-(1-(4-(hydroxycarbamoyl) )benzyl)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-6-yl)-1H-pyrazol-1-yl)piperidine - Preparation of tert-butyl 1-carboxylate (compound 17)
  • 22-b-R (410 mg, 4.88 mmol) was dissolved in water (10 mL) and tetrahydrofuran (30 mL) and potassium carbonate (1.35 g, 9.23 mmol) was added. 22-b (800 mg, 3.25 mmol) was dissolved in tetrahydrofuran (10 mL) and then slowly added dropwise to the solution. After stirring at room temperature for 2 hours, water was added, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to obtain 22-c (430 mg, yield: 52%).
  • 25-b (120 mg, 0.27 mmol) was dissolved in tetrahydrofuran/methanol (2 mL/2 mL), sodium hydroxide (42 mg, 1.06 mmol) and hydroxylamine solution (1.0 mL) were added, and the mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure and purified by column chromatography to give 25 as a white solid (90 mg, yield 75%).
  • Example 29 and Example 30 4-((6-(Dimethylamino)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazine- 1-yl)methyl)-N-hydroxybenzamide (compound 29) and N-hydroxy-4-((6-(methylamino)-2,2-dioxy-3,4-dihydro-1H - Preparation of benzo[c][1,2]thiazin-1-yl)methyl)benzamide (compound 30)
  • 29-b 600 mg, 0.68 mmol
  • tetrahydrofuran (20 mL) and hydrogen were reacted at room temperature for 16 hours, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain 29-c (525 mg, yield: 95%).
  • 29-d2 (70 mg, 0.07 mmol), tetrahydrofuran (1 mL) and methanol (1 mL) were stirred at 0 °C, sodium hydroxide (11 mg, 0.28 mmol) and hydroxylamine aqueous solution (1 mL) were added, and the reaction was carried out at room temperature for 40 minutes. Water and ethyl acetate were extracted and separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 29 (41 mg, yield: 58%).
  • 35-b (55 mg, 0.13 mmol) was added with methanol (1 mL), tetrahydrofuran (1 mL) and water (0.5 mL), sodium hydroxide (21 mg, 0.52 mmol) and hydroxylamine aqueous solution (1 mL) were added at 0°C, and after stirring for 10 minutes The temperature was raised to room temperature and reacted for 50 minutes. The pH of the reaction solution was adjusted to 7 to 8 with dilute hydrochloric acid. Water and ethyl acetate were added, followed by liquid separation extraction. The organic phase was dried with anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain 35 (30 mg , yield: 54%).
  • 38-b (50 mg, 0.13 mmol) was dissolved in a mixed solution of methanol/tetrahydrofuran (1 mL/1 mL), and sodium hydroxide (22 mg, 0.53 mmol) and an aqueous hydroxylamine solution (0.2 mL) were added. The reaction was stirred at room temperature for 1 hour, and after completion of the reaction, 38 was purified by preparative chromatography (40 mg, yield: 82%).
  • Int.-4 (60 mg, 0.3 mmol) was dissolved in DMF (1.0 mL), Int.-1 (84 mg, 0.36 mmol) and potassium carbonate (126 mg, 0.91 mmol) were added, and the reaction was carried out at room temperature for 16 hours. After completion of the reaction monitored by TLC, it was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 39-a (50 mg, yield 46%).
  • 39-a (50 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), 1 mL of hydroxylamine aqueous solution and sodium hydroxide (23 mg, 58 mmol) were added, and the mixture was stirred at 25° C. for 1 h. After completion of the reaction monitored by TLC, it was extracted with ethyl acetate. The aqueous phase was concentrated and purified by column chromatography to give 39 as a pale yellow solid (28 mg, 56% yield).
  • Int.-4 (100 mg, 0.51 mmol) was dissolved in DMF (1.0 mL), Int.-2 (142 mg, 0.61 mmol) and potassium carbonate (212 mg, 1.53 mmol) were added, and the reaction was carried out at room temperature for 16 hours. After completion of the reaction monitored by TLC, it was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 40-a (100 mg, yield 56%).
  • Int.-4 (60 mg, 0.3 mmol) was dissolved in DMF (1.0 mL), methyl 4-(bromomethyl)benzoate (84 mg, 0.36 mmol) and potassium carbonate (126 mg, 0.91 mmol) were added, and the mixture was kept at room temperature. The reaction was continued for 16 hours. After completion of the reaction monitored by TLC, it was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 41-a (50 mg, yield 46%).
  • 44-a (66 mg, 0.17 mmol) was dissolved in tetrahydrofuran (1.0 mL) and methanol (1.0 mL), hydroxylamine aqueous solution (0.5 mL) and sodium hydroxide (27 mg, 0.68 mmol) were added, and the reaction was carried out at room temperature for 2 hours. After completion of the reaction monitored by TLC, the reaction was concentrated under reduced pressure and purified by column chromatography to give 44 (15 mg, 22% yield).
  • the enzymatic activity assay was used to evaluate the inhibitory activity of the compounds in this application on HDAC6.
  • HDAC6 (Abeam), test compound and 20 ⁇ M substrate solution (Ac-GAK(Ac)-AMC) were added to 384-well plate respectively, incubated at 37°C for 30 min, added 1 ⁇ M Trypsin and 10 ⁇ M TSA, incubated at room temperature for 15 min, excited at 360 nm, The fluorescence emission intensity at 455 nm was detected, and the inhibition rate at each concentration was calculated.
  • IC 50 was obtained by fitting with GraphPad Prism 7.0 software.
  • Enzyme activity assays were used to evaluate the inhibitory activity of the compounds in this application on HDAC1.
  • HDAC1 BPS
  • test compounds and 20 ⁇ M substrate solution (Ac-GAK(Ac)-AMC) were added to 384-well plates respectively, incubated at 37°C for 30 min, added 1 ⁇ M Trypsin and 10 ⁇ M TSA, incubated at room temperature for 15 min, excited at 360 nm, The fluorescence emission intensity at 455 nm was detected, and the inhibition rate at each concentration was calculated.
  • IC 50 was obtained by fitting with GraphPad Prism 7.0 software.
  • the antiproliferative activity of the compounds in the present application on human melanoma cell line A375 and human multiple myeloma cell line RPMI8226 was evaluated by CCK8 and CCL assays.
  • the anti-tumor cell proliferation activities of the compounds are shown in Table 3 and Table 4.
  • A375 cells in logarithmic growth phase were taken, digested with trypsin cell digestion solution, centrifuged, counted, and plated in a 96-well plate at a suitable cell density (30,000 cells/well), 100 ⁇ L per well, surrounded by appropriate amount of PBS for water purification. seal up.
  • the cells were treated with different concentrations of compound 5 (the initial concentration was 6.25 ⁇ M, 4-fold dilution, and 5 concentration gradients were set). After 8 h, the medium was aspirated and washed twice with 100 ⁇ L of PBS. Cells were then fixed with 4% paraformaldehyde and incubated at room temperature for 20 min. Discard the fixative and wash the cells with PBS.
  • the second day was washed twice with 1X PBST, and the secondary antibody (CST) and DRAQ5 (Thermofisher) were diluted to appropriate multiples with 0.033% Triton-100 blocking solution (secondary antibody: 1:2000; DRAQ5: 1:10000) , and added it to a 96-well plate and incubated at room temperature for 2 h.
  • the fluorescence signals at 700 nm and 800 nm were detected by a Li-COR Odyssey two-color near-infrared laser imager, respectively.
  • liver microsomes from CD-1 mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and humans.
  • Animal and human liver microsomes used in this test system were purchased from Xenotech, Coming or other qualified suppliers and stored in a refrigerator below -60°C until use.
  • test article and control compound were incubated with animal and human liver microsomes for a certain period of time at 37 ⁇ 1°C, the longest incubation time was 60 minutes.
  • the organic solvent terminates the reaction. After centrifugation, the resulting supernatant was examined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • the powder to be tested is prepared into a stock solution of a certain concentration with DMSO or other organic solvents, and then further diluted with a suitable organic solvent.
  • Control compounds testosterone, diclofenac, and propafenone were prepared as 10 mM stock solutions in DMSO and further diluted with appropriate organic solvents.
  • Microsomes of various genera were diluted to 2X working solutions in 100 mM potassium phosphate buffer. The final concentration of microsomes in the reaction system was 0.5 mg/mL.
  • NADP nicotinamide adenine phosphate dinucleotide
  • ISO isocitrate
  • Stop solutions are prepared in acetonitrile or other organic solvent containing an internal standard (tolbutamide or other suitable compound). The prepared stop solution was stored in a refrigerator at 2-8°C.
  • Incubation will be done in 96-well plates. Eight incubation plates were prepared, named T0, T5, T15, T30, T45, T60, Blank60, and NCF60. The first 6 plates corresponded to reaction time points of 0, 5, 15, 30, 45 and 60 minutes, respectively. No test or control compounds were added to Blank60 plates and samples were taken after 60 minutes of incubation. The NCF60 plate was incubated with potassium phosphate buffer instead of the NADPH regeneration system solution for 60 minutes. All condition samples are in triplicate.
  • Microsomes and test or control compounds were mixed, then incubation plates Blank60, T5, T15, T30, T45, and T60, except T0 and NCF60, were pre-incubated in a 37°C water bath for approximately 10 minutes. Add the stop solution to the incubation plate T0 first, then add the NADPH regeneration system working solution, and add 98 ⁇ L of potassium phosphate buffer to each sample well of the incubation plate NCF60 to start the reaction. After the pre-incubation of Blank60, T5, T15, T30, T45 and T60 on the incubation plate, 98 ⁇ L of NADPH regeneration system working solution was added to each sample well to start the reaction.
  • the reaction temperature was 37 ⁇ 1°C
  • the final volume of the reaction was 200 ⁇ L
  • the reaction system included 0.5 mg/mL microsomes, 1.0 ⁇ M substrate, 1 mM NADP, 6 mM ISO, and 1 unit/mL IDH.
  • the CV of the internal standard peak area in each matrix in each assay run should be within 20%.
  • the in vitro elimination rate constant ke of the compound was obtained by converting the ratio of the compound to the internal standard peak area to the residual rate in the following formula:
  • CL int(liver) CL int(mic) ⁇ microsomal protein content in liver (mg/g) ⁇ liver weight to body weight ratio
  • hepatic intrinsic clearance and hepatic clearance can be converted by the following formula.

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Abstract

L'invention concerne un composé cyclique benzocondensé de formule (I), une composition pharmaceutique le comprenant, son procédé de préparation et son utilisation en tant qu'inhibiteur d'HDAC6.
PCT/CN2022/087060 2021-04-22 2022-04-15 Composé cyclique benzocondensé, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation WO2022222856A1 (fr)

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