WO2022222856A1 - Benzo-condensed ring compound, pharmaceutical composition comprising same, preparation method therefor and use thereof - Google Patents

Benzo-condensed ring compound, pharmaceutical composition comprising same, preparation method therefor and use thereof 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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PCT/CN2022/087060
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Chinese (zh)
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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.

Abstract

A benzo-condensed ring compound of formula (I), a pharmaceutical composition comprising same, a preparation method therefor and a use thereof as an HDAC6 inhibitor.

Description

苯并稠环化合物、包含其的药物组合物及其制备方法和用途Benzo-fused ring compound, pharmaceutical composition containing same, preparation method and use thereof 技术领域technical field
本申请涉及苯并稠环化合物、包含其的药物组合物及其制备方法和作为HDAC6抑制剂的用途。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.
背景技术Background technique
组蛋白去乙酰化酶(HDAC)可以催化组蛋白或其他蛋白的去乙酰化，其主要通过转录抑制作用在多种生物学过程中发挥重要作用。人体内的HDAC可以分为四类，I类包括HDAC1、HDAC2、HDAC3和HDAC8；II类包括HDAC4、HDAC5、HDAC6、HDAC7、HDAC9和HDAC10；III类包括SIRT1、SIRT2、SIRT3、SIRT4、SIRT5、SIRT6和SIRT7；IV类包括HDAC11。II类HDAC又可分为IIa亚类(HDAC4、HDAC5、HDAC7和HDAC9)和IIb亚型(HDAC6和HDAC 10)。Histone deacetylases (HDACs) 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主要催化非组蛋白底物的去乙酰化，如α-微管蛋白和Hsp90等。HDAC6参与多种疾病的病理过程，包括癌症、神经***疾病、感染、心血管疾病、免疫以及炎症相关疾病。HDAC6 mainly catalyzes the deacetylation of non-histone substrates, such as α-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.
在肿瘤治疗领域，多数的HDAC抑制剂为广谱抑制剂，对HDAC亚型不具有选择性。HDAC家族广谱抑制剂的副作用与其对I类亚型的抑制(特别是HDAC1和HDAC2的抑制)密切相关。In the field of tumor therapy, most 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).
发明内容SUMMARY OF THE INVENTION
本申请提供苯并稠环化合物，其可用作HDAC6抑制剂来预防或治疗HDAC6相关性疾病。本申请的化合物对HDAC6有高选择性，因此避免了HDAC广谱抑制剂的副作用。此外，本发明的化合物还具有更好的物理化学性质(例如溶解度、物理和/或化学稳定性)、改善的药物代谢动力学性质(例如改善的生物利用度、改善的代谢稳定性、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性(例如降低的心脏毒性)和/或较少的副作用)、较不易产生耐药性等更优异的性质。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. In addition, 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.
本发明的一个方面提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)的结构：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):
Figure PCTCN2022087060-appb-000001
Figure PCTCN2022087060-appb-000001
X在每次出现时各自独立地选自-CR 3R 3’-、-C(＝O)-、-C(＝N-OR)-、-NR-、-O-、-S-、-S(＝O)-和-S(＝O) 2-； Each occurrence of X is independently selected from -CR3R3'- , -C( = O)-, -C(=N-OR)-, -NR-, -O-, -S-, - S(=O)- and -S(=O) 2 -;
Y选自-CR 4R 4’-、-C 2-6亚烯基-、-C(＝O)-、-C(＝N-OR)-、-NR-、-O-、-S-、-S(＝O)-和-S(＝O) 2-； Y is selected from -CR 4 R 4' -, -C 2-6 alkenylene-, -C(=O)-, -C(=N-OR)-, -NR-, -O-, -S- , -S(=O)- and -S(=O) 2 -;
Z和W各自独立地为CR或N；Z and W are each independently CR or N;
L选自直接键、-C(＝O)-、-NR-、-O-、-S-、-S(＝O)-、-S(＝O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-和-C 2-6亚炔基-； L is selected from direct bond, -C(=O)-, -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -, -C 1-6 alkylene base-, -C 2-6 alkenylene- and -C 2-6 alkynylene-;
R在每次出现时各自独立地选自H、卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述环烃基和杂环基中至多2个环成员为C(＝O)； R at each occurrence is independently selected from H, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 ring Hydrocarbyl, saturated or partially unsaturated 3-10-membered heterocyclic group, C6-10 -membered aryl group, 5-14-membered heteroaryl group and C6-12 aralkyl group, of which at most 2 A ring member is C (=O);
R 1和R 2在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； R 1 and R 2 are each independently selected at each occurrence from halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, C 3-6 cyclic hydrocarbon group, 3-10-membered heterocyclic group, C 6-10 aryl group, 5-14-membered heteroaryl group, C 6-12 aralkyl group, -C(=O)R a , - OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O) R b , -NR a -C(=O) OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene-NR a R b and -OC 1-6 alkylene-NR a R b ;
R 3、R 3’、R 4和R 4’为H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、 -NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； R 3 , R 3' , R 4 and R 4' are H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-6 cyclic hydrocarbon group, 3-10-membered heterocyclic group, C 6-10 -membered aryl, 5-14-membered heteroaryl, C 6-12 aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O ) 2 NRaRb , -NRaRb ,-C( = O) NRaRb , -NRa -C(=O) Rb , -NRa -C ( = O) ORb ,-NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene-NR a R b and -OC 1-6 alkylene-NR a R b ;
R a和R b在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； 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为0、1、2、3或4的整数；n is an integer of 0, 1, 2, 3 or 4;
m为0、1或2的整数；m is an integer of 0, 1 or 2;
t为0、1或2的整数；t is an integer of 0, 1 or 2;
上述烷基、亚烷基、烯基、亚烯基、炔基、亚炔基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5、-OC(＝O)R 5、-C(＝O)OR 5、-OR 5、-SR 5、-S(＝O)R 5、-S(＝O) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 6、-NR 5-C(＝O)R 6、-NR 5-C(＝O)OR 6、-NR 5-S(＝O) 2-R 6、-NR 5-C(＝O)-NR 5R 6、-C 1-6亚烷基-OR 5、-C 1-6亚烷基-NR 5R 6和-O-C 1-6亚烷基-NR 5R 6，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且 Each of the aforementioned alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cyclohydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl groups is optionally or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered Heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O)R 5 , -OC(=O)R 5 , -C(=O )OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O) 2 R 5 , -S(=O) 2 NR 5 R 6 , -NR 5 R 6 , - C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O) 2 -R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1-6 alkylene-OR 5 , -C 1-6 alkylene-NR 5 R 6 and -OC 1-6 alkylene-NR 5 R 6 , the alkyl, cyclohydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, = O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6- 10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; and
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基。 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.
本发明的另一方面提供药物组合物，其包含本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选是固体制剂、液体制剂或透皮制剂。Another aspect of the present invention provides pharmaceutical 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.
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物在制备用于预防或治疗HDAC6相关性疾病的药物中的用途。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.
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物，其用于预防或治疗HDAC6相关性疾病。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.
本发明的另一方面提供预防或治疗HDAC6相关性疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物。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.
本发明的另一方面提供制备本发明的化合物的方法。Another aspect of the present invention provides methods of preparing the compounds of the present invention.
附图说明Description of drawings
图1显示经化合物5处理后的A375细胞中AC-α-微管蛋白的表达水平。Figure 1 shows the expression level of AC-α-tubulin in A375 cells treated with Compound 5.
具体实施方式Detailed ways
定义definition
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including those variations or substitutions of equivalent techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。The terms "comprising", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open ended and do not exclude other unrecited elements or method steps.
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。As used herein, the term "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.
如本文中所使用，术语“烷基”定义为直链或支链饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CF 3、C 2F 5、CHF 2、CH 2F、CH 2CF 3、CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。 As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, eg, 1 to 6, carbon atoms. For example, as used herein, the term "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 -CH2CH2CF3 , etc. ) . The term "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).
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个或多个双键，且具有 2-6个碳原子(“C 2-6烯基”)。所述烯基为例如-CH＝CH 2、-CH 2CH＝CH 2、-C(CH 3)＝CH 2、-CH 2-CH＝CH-CH 3、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。术语“亚烯基”为相应的二价基团，包括例如“C 2-6亚烯基”、“C 2-4亚烯基”等，其具体实例包括但不限于：-CH＝CH-、-CH 2CH＝CH-、-C(CH 3)＝CH-、亚丁烯基、亚戊烯基、亚己烯基、亚环戊烯基、亚环己烯基等。 As used herein, the term "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"). The alkenyl groups are eg -CH=CH 2 , -CH 2 CH=CH 2 , -C(CH 3 )=CH 2 , -CH 2 -CH=CH-CH 3 , 2-pentenyl, 3-pentenyl Alkenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3- Pentenyl. When a compound of the present invention contains an alkenyl group, the compound may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof. The term "alkenylene" is a corresponding divalent group, including, for example, "C 2-6 alkenylene", "C 2-4 alkenylene" and the like, and specific examples thereof include, but are not limited to: -CH=CH- , -CH 2 CH=CH-, -C(CH 3 )=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, and the like.
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基、2-丙炔基、2-丁炔基、1，3-丁二炔基等。所述炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。术语“亚炔基”为相应的二价基团，包括例如“C 2-8亚炔基”、“C 2-6亚炔基”、“C 2-4亚炔基”等。其实例包括但不限于
Figure PCTCN2022087060-appb-000002
等，所述亚炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。 As used herein, the term "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. The term "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
Figure PCTCN2022087060-appb-000002
etc., the alkynylene group is optionally substituted with one or more, such as 1 to 3, the same or different substituents.
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。As used herein, the terms "cyclohydrocarbylene", "cyclohydrocarbyl" and "hydrocarbon ring" refer 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.
如本文中所使用，术语“环烷基”指饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连***(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C 3-6环烷基”指3至6个成环碳原子的饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。 As used herein, the term "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. Said cycloalkyl has 3 to 15 carbon atoms. For example, the term "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.
如本文中所使用，术语“杂环基”指饱和或不饱和的一价单环或双环基团，其在环中具有2、3、4、5、6、7、8或9个碳原子和一个或多个(例如一个、两个、三个或四个)选自C(＝O)、O、S、S(＝O)、S(＝O) 2和NR a的含杂原子的基团，其中R a表示氢原子或C 1-6烷基或卤代-C 1-6烷基；所述杂环烷基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，3-10元杂环基为在环中具有3-10个碳原子及杂原子的基团，例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。 As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms in the ring and one or more (eg one, two, three or four) heteroatom-containing compounds selected from C(=O), O, S, S(=O), S(=O) 2 and NR a group in which R a represents a hydrogen atom or a C 1-6 alkyl or halo-C 1-6 alkyl; the heterocycloalkyl can be through any of the carbon atoms or a nitrogen atom (if present) ) is attached to the rest of the molecule. In particular, 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.
如本文中所使用，术语“杂环基”涵盖并环结构，所述并环结构与其他基团的连接点可以在并环结构中的任一环上。因此，本发明的杂环基还包括但不限于杂环基并杂环基、杂环基并环烷基、单杂环基并单杂环基、单杂环基并单环烷基，例如3-7元(单)杂环基并3-7元(单)杂环基、3-7元(单)杂环基并(单)环烷基、3-7元(单)杂环基并C 4-6(单)环烷基，其实例包括但不限于吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、哌啶基并吗啉基、
Figure PCTCN2022087060-appb-000003
As used herein, the term "heterocyclyl" encompasses buccal structures whose point of attachment to other groups may be on any ring in the buccal structure. Accordingly, 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, pyrrolidinopyrrolidine group, pyrrolidinopiperidyl, pyrrolidinopiperazinyl, piperidinomorpholinyl,
Figure PCTCN2022087060-appb-000003
如本文中所使用，术语“杂环基”涵盖桥杂环基和螺杂环基。As used herein, the term "heterocyclyl" encompasses bridged heterocyclyl and spiroheterocyclyl.
如本文中所使用，术语“桥杂环”是指两个饱和环共用两个不直接相连的环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子和/或硫原子)的环状结构，包括但不限于7-10元桥杂环、8-10元桥杂环、7-10元含氮桥杂环、7-10元含氧桥杂环、7-10元含硫桥杂环等，例如
Figure PCTCN2022087060-appb-000004
Figure PCTCN2022087060-appb-000005
等。所述“含氮桥杂环”、“含氧桥杂环”、“含硫桥杂环”任选地还含有一个或多个选自氧、氮和硫的其他杂原子。 As used herein, the term "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
Figure PCTCN2022087060-appb-000004
Figure PCTCN2022087060-appb-000005
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.
如本文中所使用，术语“螺杂环”是指由两个或两个以上饱和环共用一个环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子、硫原子)的环状结构，包括但不限于5-10元螺杂环、6-10元螺杂环、6-10元含氮螺杂环、6-10元含氧螺杂环、6-10元含硫螺杂环等，例如
Figure PCTCN2022087060-appb-000006
Figure PCTCN2022087060-appb-000007
Figure PCTCN2022087060-appb-000008
所述“含氮螺杂环”、“含氧螺杂环”、“含硫螺杂环”任选地还含有一个或多个选自氧、氮、硫的其他杂原子。术语“6-10元含氮螺杂环基”是指含有共计6-10个环原子并且其中至少一个环原子为氮原子的螺杂环基。 As used herein, the term "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
Figure PCTCN2022087060-appb-000006
Figure PCTCN2022087060-appb-000007
Figure PCTCN2022087060-appb-000008
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. The term "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.
如本文中所使用，术语“芳基”指具有共轭π电子***的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C 6-14芳基”意指含有6至14个碳原子的芳族基团，诸如苯基或萘基。芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。 As used herein, the term "aryl" refers to an all carbon monocyclic or fused ring polycyclic aromatic group having a conjugated pi electron system. For example, as used herein, the term "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.).
术语“芳烷基”优选表示芳基取代的烷基，其中所述芳基和所述烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。The term "aralkyl" preferably refers to an aryl-substituted alkyl group, wherein said aryl group and said alkyl group are as defined herein. Typically, the aryl group can have 6-14 carbon atoms, and the alkyl group can have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
如本文中所使用，术语“杂芳基”指一价单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等，以及它们的苯并衍生物；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物。As used herein, the term "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. In particular, 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.
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.
如本文中所使用，术语“烷基硫基”意指通过硫原子连接至母体分子部分的如上文所定义的烷基。C 1-6烷基硫基的代表性实例包括但不限于甲硫基、乙硫基、叔丁硫基及己硫基。 As used herein, the term "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.
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O) 2的环成员；所述含氮杂环通过氮原子与分子的其余部分连接。所述含氮杂环优选为饱和含氮单环。特别地，3至14元含氮杂环为在环中具有3-14个碳原子及杂原子(其中至少一个为氮原子)的基团，其包括但不限于三元含氮杂环(如氮丙啶基)、四元含氮杂环(如氮杂环丁烷基)、五元含氮杂环(如吡咯基、吡咯烷基(吡咯烷环)、吡咯啉基、吡咯烷酮基、咪唑基、咪唑烷基、咪唑啉基、吡唑基、吡唑啉基)、六元含氮杂环(如哌啶基(哌啶环)、吗啉基、硫吗啉基、哌嗪基)、七元含氮杂环等。 As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 in the ring , 12 or 13 carbon atoms and at least one nitrogen atom, which may also optionally contain one or more (eg one, two, three or four) selected from N, O, C=O, S, S Ring members of =O and S(=O) 2 ; the nitrogen-containing heterocycle is attached to the rest of the molecule through the nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocycle. In particular, 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.
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。The term "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.
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。If a substituent is described as "optionally substituted," the 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.
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。If substituents are described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。Unless indicated, as used herein, the point of attachment of a substituent can be from any suitable position on the substituent.
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。When the bond of a substituent is shown as a bond connecting two atoms in a ring, such substituent may be bonded to any ring-forming atom in the substitutable ring.
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(D， 2H)、氚(T， 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。 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. Examples of 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). Certain isotopically-labeled compounds of the invention (eg, those incorporating radioisotopes) 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.
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。It will also be appreciated that certain compounds of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, 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.
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、氢溴酸盐/溴化物、氢碘酸盐/碘化物、顺丁烯二酸盐、丙二酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐及其它类似的盐。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.
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、二乙胺盐、赖氨酸盐、镁盐、葡甲胺盐、钾盐及其它类似的盐。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.
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。For a review of suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。As used herein, the term "ester" 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.
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。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. The amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。Also included within the scope of the present invention are 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.
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design，”Pergamon Press，1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier，1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。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. Typically such 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). The 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.
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry，ed.J.F.W.McOmie，Plenum Press，1973；和T.W.Greene & P.G.M.Wuts，Protective Groups in Organic Synthesis， John Wiley&Sons，1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。The present invention also encompasses compounds of the present invention that contain 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.
如本文中所使用，术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。As used herein, the term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.
化合物compound
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)的结构：In some embodiments, 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):
Figure PCTCN2022087060-appb-000009
Figure PCTCN2022087060-appb-000009
X在每次出现时各自独立地选自-CR 3R 3’-、-C(＝O)-、-C(＝N-OR)-、-NR-、-O-、-S-、-S(＝O)-和-S(＝O) 2-； Each occurrence of X is independently selected from -CR3R3'- , -C( = O)-, -C(=N-OR)-, -NR-, -O-, -S-, - S(=O)- and -S(=O) 2 -;
Y选自-CR 4R 4’-、-C 2-6亚烯基-、-C(＝O)-、-C(＝N-OR)-、-NR-、-O-、-S-、-S(＝O)-和-S(＝O) 2-； Y is selected from -CR 4 R 4' -, -C 2-6 alkenylene-, -C(=O)-, -C(=N-OR)-, -NR-, -O-, -S- , -S(=O)- and -S(=O) 2 -;
Z和W各自独立地为CR或N；Z and W are each independently CR or N;
L选自直接键、-C(＝O)-、-NR-、-O-、-S-、-S(＝O)-、-S(＝O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-和-C 2-6亚炔基-； L is selected from direct bond, -C(=O)-, -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -, -C 1-6 alkylene base-, -C 2-6 alkenylene- and -C 2-6 alkynylene-;
R在每次出现时各自独立地选自H、卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述环烃基和杂环基中至多2个环成员为C(＝O)； R at each occurrence is independently selected from H, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 ring Hydrocarbyl, saturated or partially unsaturated 3-10-membered heterocyclic group, C6-10 -membered aryl group, 5-14-membered heteroaryl group and C6-12 aralkyl group, of which at most 2 A ring member is C (=O);
R 1和R 2在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； R 1 and R 2 are each independently selected at each occurrence from halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, C 3-6 cyclic hydrocarbon group, 3-10-membered heterocyclic group, C 6-10 aryl group, 5-14-membered heteroaryl group, C 6-12 aralkyl group, -C(=O)R a , - OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O) R b , -NR a -C(=O) OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene-NR a R b and -OC 1-6 alkylene-NR a R b ;
R 3、R 3’、R 4和R 4’为H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； R 3 , R 3' , R 4 and R 4' are H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-6 cyclic hydrocarbon group, 3-10-membered heterocyclic group, C 6-10 -membered aryl, 5-14-membered heteroaryl, C 6-12 aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O ) 2 NRaRb , -NRaRb ,-C( = O) NRaRb , -NRa -C(=O) Rb , -NRa -C ( = O) ORb ,-NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene-NR a R b and -OC 1-6 alkylene-NR a R b ;
R a和R b在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、 3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； 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为0、1、2、3或4的整数；n is an integer of 0, 1, 2, 3 or 4;
m为0、1或2的整数；m is an integer of 0, 1 or 2;
t为0、1或2的整数；t is an integer of 0, 1 or 2;
上述烷基、亚烷基、烯基、亚烯基、炔基、亚炔基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、 3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5、-OC(＝O)R 5、-C(＝O)OR 5、-OR 5、-SR 5、-S(＝O)R 5、-S(＝O) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 6、-NR 5-C(＝O)R 6、-NR 5-C(＝O)OR 6、-NR 5-S(＝O) 2-R 6、-NR 5-C(＝O)-NR 5R 6、-C 1-6亚烷基-OR 5、-C 1-6亚烷基-NR 5R 6和-O-C 1-6亚烷基-NR 5R 6，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、 3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且 Each of the aforementioned alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cyclohydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl groups is optionally or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered Heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O)R 5 , -OC(=O)R 5 , -C(=O )OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O) 2 R 5 , -S(=O) 2 NR 5 R 6 , -NR 5 R 6 , - C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O) 2 -R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1-6 alkylene-OR 5 , -C 1-6 alkylene-NR 5 R 6 and -OC 1-6 alkylene-NR 5 R 6 , the alkyl, cyclohydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, = O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6- 10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; and
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、 3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基。 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.
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(II)的结构：In some embodiments, 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):
Figure PCTCN2022087060-appb-000010
Figure PCTCN2022087060-appb-000010
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(III)或式(IV)的结构：In some embodiments, 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):
Figure PCTCN2022087060-appb-000011
Figure PCTCN2022087060-appb-000011
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中X在每次出现时各自独立地为-CR 3R 3’-，优选为-CH 2-。 In some embodiments, 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- .
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中Y选自-CR 4R 4’-、-C(＝O)-和-C(＝N-OR)-；优选地，Y选自-CH 2-、-C(CH 3) 2-、-C(＝O)-和-C(＝N-OH)-。 In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- drug, wherein Y is selected from -CR 4 R 4' -, -C(=O)- and -C(=N-OR)-; preferably, Y is selected from -CH 2 -, -C(CH 3 ) 2 -, -C(=O)- and -C(=N-OH)-.
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中Z和W各自独立地为CH、CF或N。In some embodiments, 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.
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中L为-C 1-6亚烷基-，优选为-CH 2-。 In some embodiments, 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 -.
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 1在每次出现时各自独立地选自卤素、-CN、C 1-6烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、-NR aR b、-C(＝O)NR aR b和-NR a-C(＝O)R b，其中所述烷基、杂环基、芳基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、卤代C 1-6烷基、3-10元杂环基、C 6-12芳烷基、-OH和-O-C 1-6烷基；R a和R b在每次出现时各自独立地选自H、C 1-6烷基、卤代C 1-6烷基、C 3-10环烃基和5-14元杂芳基。 In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- drug, wherein R 1 at each occurrence is independently selected from halogen, -CN, C 1-6 alkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, -NR a R b , -C(=O)NR a R b and -NR a -C(=O) R b , wherein each of the alkyl, heterocyclyl, aryl and heteroaryl groups is optionally Substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-10 membered heterocyclyl, C 6-12 aralkyl, -OH and -OC 1-6 alkyl; R a and R b at each occurrence are each independently selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-10 cyclohydrocarbyl, and 5 -14-membered heteroaryl.
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 1在每次出现时各自独立地选自F、Cl、Br、-CN、甲基、乙基、吡咯烷基、苯基、呋喃基、吡唑基、-NR aR b、-C(＝O)NR aR b和-NR a-C(＝O)R b，其中上述甲基、乙基、吡咯烷基、苯基、呋喃基和吡唑基各自任选地被一个或多个独立地选自下列的取代基取代：F、Cl、-CH 3、-CF 3、-CH 2CH 3、哌啶基、叔丁氧羰基取代的哌啶基、苄基、-OH和-OCH 3；R a和R b在每次出现时各自独立地选自H、-CH 3、-CHF 2、环丙基和吡啶基。 In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- drug, wherein R 1 at each occurrence is independently selected from F, Cl, Br, -CN, methyl, ethyl, pyrrolidinyl, phenyl, furyl, pyrazolyl, -NR a R b , -C(=O) NRaRb and -NRa -C(=O )Rb , wherein each of the aforementioned methyl, ethyl, pyrrolidinyl, phenyl, furyl and pyrazolyl groups is optionally replaced by a Substituted with one or more substituents independently selected from the group consisting of F, Cl , -CH3 , -CF3 , -CH2CH3, piperidinyl, t - butoxycarbonyl-substituted piperidinyl, benzyl, -OH and -OCH3 ; Ra and Rb at each occurrence are each independently selected from H, -CH3 , -CHF2 , cyclopropyl and pyridyl.
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 1在每次出现时各自独立地选自F、Cl、Br、-CN、-CH 3、-CF 2CH 3、-CH(OH)CH 3、-NH 2、-NHCH 3、-N(CH 3) 2、-C(＝O)NH 2、-NH-C(＝O)CH 3、-NH-C(＝O)CHF 2、
Figure PCTCN2022087060-appb-000012
Figure PCTCN2022087060-appb-000013
In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or pro- drug, wherein R 1 is independently at each occurrence selected from F, Cl, Br, -CN, -CH 3 , -CF 2 CH 3 , -CH(OH)CH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)NH 2 , -NH-C(=O)CH 3 , -NH-C(=O)CHF 2 ,
Figure PCTCN2022087060-appb-000012
Figure PCTCN2022087060-appb-000013
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 2在每次出现时各自独立地为卤素，优选为F。 In some embodiments, 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.
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 3、R 3’、R 4和R 4’为H或C 1-6烷基，优选为H或甲基。 In some embodiments, 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.
在一些实施方案中，n为0、1或2的整数。In some embodiments, n is an integer of 0, 1, or 2.
在一些实施方案中，m为0或1的整数。In some embodiments, m is an integer of 0 or 1.
在一些实施方案中，t为1或2的整数。In some embodiments, t is an integer of 1 or 2.
本发明涵盖对各个实施方案进行任意组合所得的化合物。The present invention encompasses compounds resulting from any combination of the various embodiments.
在优选的实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：In preferred 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:
Figure PCTCN2022087060-appb-000014
Figure PCTCN2022087060-appb-000014
Figure PCTCN2022087060-appb-000015
Figure PCTCN2022087060-appb-000015
Figure PCTCN2022087060-appb-000016
Figure PCTCN2022087060-appb-000016
Figure PCTCN2022087060-appb-000017
Figure PCTCN2022087060-appb-000017
Figure PCTCN2022087060-appb-000018
Figure PCTCN2022087060-appb-000018
Figure PCTCN2022087060-appb-000019
Figure PCTCN2022087060-appb-000019
制备方法Preparation
在一些实施方案中，本发明提供制备式(II)的化合物的方法，其包括以下步骤：In some embodiments, the present invention provides a method of preparing a compound of formula (II) comprising the steps of:
Figure PCTCN2022087060-appb-000020
Figure PCTCN2022087060-appb-000020
其中：in:
Hal为卤素，例如F、Cl、Br或I；Hal is halogen such as F, Cl, Br or I;
R L为离去基团，例如-O-C 1-6烷基，优选-O-CH 3； R L is a leaving group, such as -OC 1-6 alkyl, preferably -O-CH 3 ;
其余各基团如上文所定义；The remaining groups are as defined above;
第一步：使化合物(II)-a与化合物(II)-a-2反应，以得到化合物(II)-b。The first step: reacting compound (II)-a with compound (II)-a-2 to obtain compound (II)-b.
所述反应优选在碱(例如DIPEA、Cs 2CO 3、K 3PO 4、Na 2CO 3、KOAc、NaHCO 3或K 2CO 3等)的存在下进行。所述反应可使用的溶剂例如为THF、1，4-二氧六环、DMF、DMSO或CH 3CN，优选DMF。反应温度为例如室温。 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.
第二步：使化合物(II)-b与羟胺反应，以得到式(II)的化合物。Second step: react compound (II)-b with hydroxylamine to obtain compound of formula (II).
所述反应优选在碱(例如NaOH、Cs 2CO 3、K 3PO 4、Na 2CO 3、KOAc、NaHCO 3或K 2CO 3等)的存在下进行。所述反应可使用的溶剂例如为THF、甲醇、1，4-二氧六环、DMF、DMSO或CH 3CN，或者两种或更多种溶剂的混合溶剂，优选为甲醇和THF的混合溶剂。反应温度为例如0℃至室温。 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.). 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.
药物组合物和治疗方法Pharmaceutical compositions and methods of treatment
在一些实施方案中，本发明提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选是固体制剂、液体制剂或透皮制剂。In some embodiments, 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 Compounds, solvates, metabolites, isotopically-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical compositions are preferably solid formulations, liquid formulations or transdermal formulations.
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物在制备用于预防或治疗HDAC6相关性疾病的药物中的用途。In some embodiments, 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.
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物，其用于预防或治疗HDAC6相关性疾病。In some embodiments, 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.
在一些实施方案中，本发明提供预防或治疗HDAC6相关性疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物。In some embodiments, 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.
所述HDAC6相关性疾病包括但不限于癌症或增生性疾病(例如，肺癌、结肠癌、乳腺癌、***癌、肝癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、***状肾癌、头颈部鳞状细胞癌、白血病、淋巴瘤、骨髓瘤、多发性骨髓瘤和实体肿瘤)；韦尔森氏病(Wilson′s disease)、脊髓小脑型共济失调、朊病毒病、帕金森氏病(Parkinson′s disease)、亨廷顿氏病(Huntington′s disease)、肌萎缩性侧索硬化症、淀粉样变性病、阿尔茨海默氏病(Alzheimer′s disease)、亚历山大氏病(Alexander′s disease)、酒精性肝病、囊性纤维化、皮克氏病(Pick′s Disease)、脊髓性肌肉萎缩症或路易体痴呆(Lewy body dementia)；类风湿性关节炎、骨关节炎；类风湿性脊椎炎；牛皮癣；炎性肠病；慢性炎性肺病、湿疹、哮喘、局部缺血/再灌注损伤、溃疡性结肠炎、急性 呼吸窘迫综合症、牛皮癣性关节炎、感染性关节炎、进行性慢性关节炎、变形性关节炎、骨关节炎、创伤性关节炎、痛风性关节炎、瑞特氏综合症(Reiter′s syndrome)、多软骨炎、急性滑膜炎和脊椎炎、肾小球肾炎、溶血性贫血、再生障碍性贫血、特发性血小板减少性紫癜、中性粒细胞减少症、溃疡性结肠炎、克罗恩氏病(Crohn′s disease)、宿主抗移植物疾病、移植物抗宿主疾病、同种异体移植排斥、慢性甲状腺炎、葛瑞夫兹氏病(Graves′disease)、硬皮病、糖尿病、活动性肝炎、原发性胆汁性肝硬化、重症肌无力、多发性硬化(MS)、***性红斑狼疮、异位性皮炎、接触性皮炎、皮肤晒伤、慢性肾功能不全、史蒂芬斯-强森综合症(Stevens-Johnson syndrome)、特发性脂肪泻、肉状瘤病、格林-巴利综合症(Guillain-Barre syndrome)、葡萄膜炎、结膜炎、角膜结膜炎、中耳炎、牙周病、肺间质纤维化、哮喘、支气管炎、鼻炎、窦炎、尘肺病、肺功能不全综合症、肺气肿、肺纤维化或硅肺病。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. , 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, Infectious Arthritis, Progressive Chronic Arthritis, Deformation Arthritis, Osteoarthritis, Traumatic Arthritis, Gouty Arthritis, Reiter's Reiter's syndrome, polychondritis, acute synovitis and spondylitis, glomerulonephritis, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, neutropenia, Ulcerative colitis, Crohn's disease, host versus graft disease, graft versus host disease, allograft rejection, chronic thyroiditis, Graves' disease, Scleroderma, diabetes, active hepatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis (MS), systemic lupus erythematosus, atopic dermatitis, contact dermatitis, skin sunburn, chronic kidney function Insufficiency, Stevens-Johnson syndrome, idiopathic steatorrhea, sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis, keratoconjunctivitis , otitis media, periodontal disease, pulmonary fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, emphysema, pulmonary fibrosis or silicosis.
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。"Pharmaceutically acceptable carrier" as used herein 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.
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。As used herein, the term "treating", unless otherwise specified, 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.
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。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.).
在另种实施方案中，本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂。In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
实施例Example
以下结合实施例进一步描述本发明，但提供这些实施例并非意在限制本发明的范围。The present invention is further described below in conjunction with the examples, but these examples are not intended to limit the scope of the present invention.
本发明中的缩写具有以下含义：Abbreviations in the present invention have the following meanings:
缩写abbreviation 含义meaning
CDCl 3 CDCl 3 氘代氯仿deuterated chloroform
Cs 2CO 3 Cs 2 CO 3 碳酸铯Cesium carbonate
DASTDAST 二乙氨基三氟化硫Diethylaminosulfur trifluoride
DIPEADIPEA N，N-二异丙基乙胺N,N-Diisopropylethylamine
DMFDMF N，N-二甲基甲酰胺N,N-Dimethylformamide
DMSODMSO 二甲基亚砜dimethyl sulfoxide
LC-MSLC-MS 液相色谱质谱联用liquid chromatography mass spectrometry
m-CPBAm-CPBA 间氯过氧苯甲酸m-chloroperoxybenzoic acid
NMRNMR 核磁共振NMR
Pd 2(dba) 3 Pd 2 (dba) 3 三(二亚苄基丙酮)二钯Tris(dibenzylideneacetone)dipalladium
Pre-HPLCPre-HPLC 制备高效液相色谱法preparative high performance liquid chromatography
TLCTLC 薄层色谱法thin layer chromatography
X-phosX-phos 2-二环己基磷-2’，4’，6’-三异丙基联苯2-Dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl
中间体实施例1：中间体Int.-1的合成Intermediate Example 1: Synthesis of Intermediate Int.-1
Figure PCTCN2022087060-appb-000021
Figure PCTCN2022087060-appb-000021
步骤1step 1
把Int.-1-a(2.0g，13.2mmol)溶于四氯化碳(40mL)中，加入N-溴代丁二酰亚胺(2.5g，14.3mmol)和偶氮异丁腈(200mg，1.2mmol)，80℃反应16小时。TLC监测反应完成后，将反应液旋干，柱色谱法纯化后得无色液体Int.-1(360mg，收率12％)。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.
1H NMR(400MHz，CDCl 3)δ9.14(s，1H)，8.28(dd，J＝8.0，4.0Hz，1H)，7.51(d，J＝8Hz，1H)，4.56(s，2H)，3.94(s，3H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.14 (s, 1H), 8.28 (dd, J=8.0, 4.0 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 4.56 (s, 2H), 3.94(s, 3H).
中间体实施例2：中间体Int.-2的合成Intermediate Example 2: Synthesis of Intermediate Int.-2
Figure PCTCN2022087060-appb-000022
Figure PCTCN2022087060-appb-000022
步骤1step 1
把Int.-2-a(1.0g，6.6mmol)溶于四氯化碳(10mL)中，加入N-溴代丁二酰亚胺(1.23g，6.9mmol)和偶氮二异丁腈(0.43g，2.6mmol)，80℃反应16小时。TLC监测反应完成后，将反应液旋干，柱色谱法纯化后得无色液体Int.-2(0.27g，收率18％)。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.
1H NMR(400MHz，CDCl 3)δ9.29(s，2H)，4.68(s，2H)，4.00(s，3H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.29 (s, 2H), 4.68 (s, 2H), 4.00 (s, 3H).
中间体实施例3：中间体Int.-3的合成Intermediate Example 3: Synthesis of Intermediate Int.-3
Figure PCTCN2022087060-appb-000023
Figure PCTCN2022087060-appb-000023
步骤1step 1
把Int.-3-a(2.0g，11.9mmol)溶于四氯化碳(40mL)中，加入N-溴代丁二酰亚胺(2.5g，14.3mmol)和偶氮二异丁腈(200mg，1.2mmol)，80℃反应16小时。TLC监测反应完成后，将反应液旋干，柱色谱法纯化后得无色液体Int.-3(2.3g，收率78％)。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.
1H NMR(400MHz，DMSO-d 6)δ7.80(dd，J＝8.0，1.2Hz，1H)，7.71(dd，J＝10.2，1.2Hz，1H)，7.46(t，J＝7.6Hz，1H)，4.51(s，2H)，3.92(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.80 (dd, J=8.0, 1.2 Hz, 1H), 7.71 (dd, J=10.2, 1.2 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 4.51(s, 2H), 3.92(s, 3H).
中间体实施例4：中间体Int.-4的合成Intermediate Example 4: Synthesis of Intermediate Int.-4
Figure PCTCN2022087060-appb-000024
Figure PCTCN2022087060-appb-000024
步骤1step 1
把亚硫酸钠(12.5g，43.7mmol)和Int.-4-a(18.0g，90mmol)溶于乙醇(200mL)和水(400mL)中，在100℃下搅拌5h。反应液冷却至室温加入二氯甲烷(600mL)、水(600mL)、四丁基硫酸铵(90mL，94.5mmol)和氢氧化钠(3.6g，90mmol)，室温搅拌30分钟。有机相分离，干燥，浓缩得粗品。将粗品溶于二氯甲烷中(400mL)，冷却至0℃加入三光气(13.4g，45mmol)和DMF(657mg，9.0mmol)，室温反应1小时，TLC监控反应完全。用乙酸乙酯萃取。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩。柱色谱法纯化，得到Int.-4-b(10.0g，产率：50％)。Sodium sulfite (12.5 g, 43.7 mmol) and Int.-4-a (18.0 g, 90 mmol) were dissolved in ethanol (200 mL) and water (400 mL) and stirred at 100 °C for 5 h. The reaction solution was cooled to room temperature and added with dichloromethane (600 mL), water (600 mL), tetrabutylammonium sulfate (90 mL, 94.5 mmol) and sodium hydroxide (3.6 g, 90 mmol), and stirred at room temperature for 30 minutes. The organic phase was separated, dried, and concentrated to give crude product. The crude product was dissolved in dichloromethane (400 mL), cooled to 0°C, added triphosgene (13.4 g, 45 mmol) and DMF (657 mg, 9.0 mmol), and reacted at room temperature for 1 hour. TLC monitored the completion of the reaction. Extract with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography gave Int.-4-b (10.0 g, yield: 50%).
1H NMR(CDCl 3，400MH)δ7.37-7.31(m，2H)，7.28-7.23(m，1H)，7.22-7.15(m，2H)，3.67-3.58(m，2H)，2.84(t，J＝7.2Hz，2H)，2.43-2.31(m，2H). 1 H NMR (CDCl 3 , 400MH) δ 7.37-7.31 (m, 2H), 7.28-7.23 (m, 1H), 7.22-7.15 (m, 2H), 3.67-3.58 (m, 2H), 2.84 (t , J=7.2Hz, 2H), 2.43-2.31(m, 2H).
步骤2Step 2
三乙胺(13.2g，131.1mmol)和甲氧胺(3.6g，43.7mmol)加入二氯甲烷(200mL)，将Int.-4-b(10.0g，43.7mmol)溶于二氯甲烷中的溶液慢慢滴加入反应体系中，室温反应3小时。TLC监测表明反应完 毕。减压浓缩。柱色谱法纯化，得到Int.-4-c(6g，产率：60％)。Triethylamine (13.2 g, 131.1 mmol) and methoxyamine (3.6 g, 43.7 mmol) were added to dichloromethane (200 mL) and Int.-4-b (10.0 g, 43.7 mmol) was dissolved in dichloromethane The solution was slowly added dropwise to the reaction system, and the reaction was carried out at room temperature for 3 hours. TLC monitoring indicated that the reaction was complete. Concentrate under reduced pressure. Purification by column chromatography gave Int.-4-c (6 g, yield: 60%).
步骤3Step 3
将Int.4-c(6g，26.2mmol)、碘苯(530mg，2.6mmol)和间氯过氧苯甲酸(4.1g，24.2mmol)加入三氟乙醇(20mL)，室温反应2小时。TLC监测表明反应完毕。加入碳酸氢钠水溶液和乙酸乙酯，有机相用无水硫酸钠干燥，减压浓缩。柱色谱法纯化，得到Int.4-d(2g，产率：33.6％)。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%).
步骤4Step 4
Int.4-d(2.5g，11.01mmol)溶于四氢呋喃(25mL)中，置换氮气，加入碘化钐(165.2mL，16.52mmol)，室温下搅拌16h。反应完毕减压浓缩，柱色谱法纯化得到产品Int.-4(1.7g，产率：78％)。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%).
1H NMR(DMSO-d 6，400MHz)：δ9.50(s，1H)，7.24-7.10(m，4H)，3.40-3.37(m，2H)，2.91-2.88(m，2H)，2.05-1.99(m，2H). 1 H NMR (DMSO-d 6 , 400MHz): δ 9.50 (s, 1H), 7.24-7.10 (m, 4H), 3.40-3.37 (m, 2H), 2.91-2.88 (m, 2H), 2.05- 1.99(m, 2H).
实施例1：4-((2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物1)的制备Example 1: 4-((2,2-Dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl)-N-hydroxybenzyl Preparation of Amide (Compound 1)
Figure PCTCN2022087060-appb-000025
Figure PCTCN2022087060-appb-000025
步骤1step 1
1-a(110mg，0.60mmol)、4-(溴甲基)苯甲酸甲酯(165mg，0.72mmol)、DMF(2.0mL)和碳酸钾(124mg，0.9mmol)，在室温下反应三个小时，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到1-b(180mg，产率：90％)。1-a (110 mg, 0.60 mmol), methyl 4-(bromomethyl)benzoate (165 mg, 0.72 mmol), DMF (2.0 mL) and potassium carbonate (124 mg, 0.9 mmol) were reacted at room temperature for three hours , water and ethyl acetate were added, the mixture was extracted and separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1-b (180 mg, yield: 90%).
步骤2Step 2
1-b(120mg，0.36mmol)、四氢呋喃(0.5mL)和甲醇(0.5mL)在0℃下搅拌，加入氢氧化钠(57.6mg，1.44mmol)和羟胺水溶液(1mL)，在室温下反应40分钟，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到化合物1(82mg，产率：68％)。1-b (120 mg, 0.36 mmol), tetrahydrofuran (0.5 mL) and methanol (0.5 mL) were stirred at 0 °C, sodium hydroxide (57.6 mg, 1.44 mmol) and hydroxylamine aqueous solution (1 mL) were added, and the reaction was carried out at room temperature for 40 After minutes, water and ethyl acetate were added, and the mixture was extracted and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 1 (82 mg, yield: 68%).
1H NMR(400MHz，CDCl 3)：δ11.17(s，1H)，9.01(s，1H)，7.77-7.66(m，2H)，7.44(d，J＝8.2Hz，2H)，7.24(dd，J＝7.7，1.5Hz，1H)，7.19-7.11(m，1H)，7.01(td，J＝7.5，1.1Hz，1H)，6.82(dd，J＝8.3，1.1Hz，1H)，5.01(s，2H)，3.60(t，J＝6.9Hz，2H)，3.39(t，J＝6.9Hz，2H)。LC-MS m/z[M+H] +：333.3。 1 H NMR (400 MHz, CDCl 3 ): δ 11.17 (s, 1H), 9.01 (s, 1H), 7.77-7.66 (m, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.24 (dd , J=7.7, 1.5Hz, 1H), 7.19-7.11 (m, 1H), 7.01 (td, J=7.5, 1.1Hz, 1H), 6.82 (dd, J=8.3, 1.1Hz, 1H), 5.01 ( s, 2H), 3.60 (t, J=6.9 Hz, 2H), 3.39 (t, J=6.9 Hz, 2H). LC-MS m/z [M+H] + : 333.3.
实施例2：6-((2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基烟酰胺(化合物2)的制备Example 2: 6-((2,2-Dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl)-N-hydroxynicotinamide Preparation of (Compound 2)
Figure PCTCN2022087060-appb-000026
Figure PCTCN2022087060-appb-000026
步骤1step 1
1-a(130mg，0.71mmol)、Int.-1(194mg，0.85mmol)、碳酸钾(147mg，1.06mmol)和DMF(2mL)，在室温下反应过夜，加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到2-b(200mg，产率：85％)。1-a (130 mg, 0.71 mmol), Int.-1 (194 mg, 0.85 mmol), potassium carbonate (147 mg, 1.06 mmol) and DMF (2 mL), react at room temperature overnight, add water and ethyl acetate, and separate the layers After extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain 2-b (200 mg, yield: 85%).
步骤2Step 2
在0℃下，将2-b(200mg，0.6mmol)溶于四氢呋喃(0.5mL)和甲醇(0.5mL)中并搅拌，加入氢氧化钠(96mg，2.4mmol)和羟胺水溶液(1mL)，在室温下反应40分钟，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到化合物2(118mg，产率：59％)。At 0°C, 2-b (200 mg, 0.6 mmol) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) with stirring, sodium hydroxide (96 mg, 2.4 mmol) and aqueous hydroxylamine (1 mL) were added, and The reaction was carried out at room temperature for 40 minutes, water and ethyl acetate were added, and the mixture was extracted and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 2 (118 mg, yield: 59%).
1H NMR(400MHz，DMSO-d 6)δ11.35(s，1H)，9.21(s，1H)，8.84(dd，J＝2.2，0.8Hz，1H)，8.08(dd，J＝8.2，2.2Hz，1H)，7.57-7.41(m，1H)，7.23(dd，J＝7.6，1.5Hz，1H)，7.14(ddd，J＝8.8，7.3，1.6Hz，1H)，7.01(td，J＝7.5，1.1Hz，1H)，6.92(dd，J＝8.3，1.1Hz，1H)，5.09(s，2H)，3.71(t，J＝6.9Hz，2H)，3.40(t，J＝6.9Hz，2H).LC-MS m/z[M+H] +：334.3. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.35 (s, 1H), 9.21 (s, 1H), 8.84 (dd, J=2.2, 0.8 Hz, 1H), 8.08 (dd, J=8.2, 2.2 Hz, 1H), 7.57-7.41 (m, 1H), 7.23 (dd, J=7.6, 1.5Hz, 1H), 7.14 (ddd, J=8.8, 7.3, 1.6Hz, 1H), 7.01 (td, J= 7.5, 1.1Hz, 1H), 6.92 (dd, J=8.3, 1.1Hz, 1H), 5.09 (s, 2H), 3.71 (t, J=6.9Hz, 2H), 3.40 (t, J=6.9Hz, 2H).LC-MS m/z [M+H] + : 334.3.
实施例3：2-((2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基嘧啶-5-甲酰胺(化合物3)的制备Example 3: 2-((2,2-Dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl)-N-hydroxypyrimidine- Preparation of 5-carboxamide (compound 3)
Figure PCTCN2022087060-appb-000027
Figure PCTCN2022087060-appb-000027
步骤1step 1
1-a(130mg，0.71mmol)、Int.-2(194mg，0.85mmol)、碳酸钾(147mg，1.06mmol)和DMF(2mL)，在室温下反应过夜，加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到3-b(200mg，产率：85％)。1-a (130 mg, 0.71 mmol), Int.-2 (194 mg, 0.85 mmol), potassium carbonate (147 mg, 1.06 mmol) and DMF (2 mL), react at room temperature overnight, add water and ethyl acetate, and separate the layers After extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain 3-b (200 mg, yield: 85%).
步骤2Step 2
3-b(200mg，0.6mmol)、四氢呋喃(0.5mL)和甲醇(0.5mL)在0℃下搅拌，加入氢氧化钠(96mg，2.4mmol)和羟胺水溶液(1mL)，在室温下反应40分钟，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到化合物3(107mg，产率：53％)。3-b (200 mg, 0.6 mmol), tetrahydrofuran (0.5 mL) and methanol (0.5 mL) were stirred at 0 °C, sodium hydroxide (96 mg, 2.4 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 added, the mixture was extracted and separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 (107 mg, yield: 53%).
1H NMR(400MHz，DMSO-d 6)δ11.28(s，1H)，9.29(s，1H)，9.00(s，2H)，7.22(dd，J＝7.6，1.5Hz，1H)，7.13(td，J＝7.6，7.0，1.5Hz，1H)，7.07(dd，J＝8.4，1.3Hz，1H)，6.99(td，J＝7.4，1.3Hz，1H)，5.29(s，2H)，3.72(t，J＝6.9Hz，2H)，3.41(t，J＝7.0Hz，2H).LC-MS m/z[M+H] +：335.3. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.28 (s, 1H), 9.29 (s, 1H), 9.00 (s, 2H), 7.22 (dd, J=7.6, 1.5 Hz, 1H), 7.13 ( td, J=7.6, 7.0, 1.5Hz, 1H), 7.07 (dd, J=8.4, 1.3Hz, 1H), 6.99 (td, J=7.4, 1.3Hz, 1H), 5.29 (s, 2H), 3.72 (t, J=6.9 Hz, 2H), 3.41 (t, J=7.0 Hz, 2H). LC-MS m/z[M+H] + : 335.3.
实施例4：4-((2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-3-氟-N-羟基苯甲酰胺(化合物4)的制备Example 4: 4-((2,2-Dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl)-3-fluoro-N - Preparation of hydroxybenzamide (compound 4)
Figure PCTCN2022087060-appb-000028
Figure PCTCN2022087060-appb-000028
步骤1step 1
把Int.-3(160mg，0.65mmol)溶到DMF(1.0mL)中，加入1-a(100mg，0.55mmol)和碳酸钾(229mg，1.65mmol)，在室温下反应16小时。TLC监测反应完成后，用乙酸乙酯萃取。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，柱色谱法纯化，得到4-b(130mg，收率68％)。Int.-3 (160 mg, 0.65 mmol) was dissolved in DMF (1.0 mL), 1-a (100 mg, 0.55 mmol) and potassium carbonate (229 mg, 1.65 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 4-b (130 mg, yield 68%).
步骤2Step 2
在0℃下把4-b(130mg，0.51mmol)溶入四氢呋喃(2mL)和甲醇(2mL)中，加入1mL羟胺水溶液和氢氧化钠(82mg，2.1mmol)，在25℃下搅拌1h。TLC监测反应完成后，用乙酸乙酯萃取。水相浓缩，柱色谱法纯化得到淡黄色固体形式的化合物4(20mg，收率15％)。4-b (130 mg, 0.51 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL) at 0 °C, 1 mL of hydroxylamine aqueous solution and sodium hydroxide (82 mg, 2.1 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 compound 4 (20 mg, 15% yield) as a pale yellow solid.
1H NMR(400MHz，DMSO-d 6)δ11.30(s，1H)，9.16(s，1H)，7.66-7.39(m，3H)，7.32-7.11(m，2H)，7.09-6.97(m，1H)，6.88-6.71(m，1H)，5.02(s，2H)，3.78-3.56(m，2H)，3.48-3.39(m，2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.30 (s, 1H), 9.16 (s, 1H), 7.66-7.39 (m, 3H), 7.32-7.11 (m, 2H), 7.09-6.97 (m , 1H), 6.88-6.71(m, 1H), 5.02(s, 2H), 3.78-3.56(m, 2H), 3.48-3.39(m, 2H).
LC-MS m/z[M+H] +：351.2 LC-MS m/z [M+H] + : 351.2
实施例5：4-((6-氯-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物5)的制备Example 5: 4-((6-Chloro-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl)-N - Preparation of hydroxybenzamide (compound 5)
Figure PCTCN2022087060-appb-000029
Figure PCTCN2022087060-appb-000029
步骤1step 1
使5-a(155mg，0.85mmol)、4-(溴甲基)苯甲酸甲酯(233mg，1.02mmol)、碳酸钾(176mg，1.27mmol)和DMF(2mL)在室温下反应过夜，加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到5-b(250mg，产率：81％)。5-a (155 mg, 0.85 mmol), methyl 4-(bromomethyl)benzoate (233 mg, 1.02 mmol), potassium carbonate (176 mg, 1.27 mmol) and DMF (2 mL) were reacted at room temperature overnight, water was added and ethyl acetate, and subjected to liquid separation extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain 5-b (250 mg, yield: 81%).
步骤2Step 2
5-b(250mg，0.68mmol)、四氢呋喃(0.5mL)和甲醇(0.5mL)在0℃下搅拌，加入氢氧化钠(108mg， 2.7mmol)和羟胺水溶液(1mL)，在室温下反应40分钟，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到化合物5(99mg，产率：40％)。5-b (250 mg, 0.68 mmol), tetrahydrofuran (0.5 mL) and methanol (0.5 mL) were stirred at 0°C, sodium hydroxide (108 mg, 2.7 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 added, the mixture was extracted and separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 5 (99 mg, yield: 40%).
1H NMR(400MHz，DMSO-d 6)δ11.18(s，1H)，9.02(s，1H)，7.78-7.68(m，2H)，7.46-7.34(m，3H)，7.21(dd，J＝8.8，2.5Hz，1H)，6.83(d，J＝8.9Hz，1H)，5.01(s，2H)，3.63(t，J＝6.9Hz，2H)，3.39(t，J＝6.9Hz，2H).LC-MS m/z[M+H] +：367.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 9.02 (s, 1H), 7.78-7.68 (m, 2H), 7.46-7.34 (m, 3H), 7.21 (dd, J =8.8, 2.5Hz, 1H), 6.83(d, J=8.9Hz, 1H), 5.01(s, 2H), 3.63(t, J=6.9Hz, 2H), 3.39(t, J=6.9Hz, 2H) ).LC-MS m/z[M+H] + : 367.1
实施例6：4-((6，8-二氯-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物6)的制备Example 6: 4-((6,8-Dichloro-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl )-N-hydroxybenzamide (compound 6) preparation
Figure PCTCN2022087060-appb-000030
Figure PCTCN2022087060-appb-000030
步骤1step 1
把1-a(200mg，1.1mmol)加入DMF(5mL)中，加入N-氯代丁二酰亚胺(436mg，3.3mmol)加热至80℃，反应1小时，冷却至室温，过夜反应，TLC监测反应完成后，加入水和乙酸乙酯萃取，有机相减压浓缩，柱色谱法纯化后得到6-b(160mg，收率58％)。1-a (200 mg, 1.1 mmol) was added to DMF (5 mL), N-chlorosuccinimide (436 mg, 3.3 mmol) was added, heated to 80°C, reacted for 1 hour, cooled to room temperature, reacted overnight, TLC After monitoring the completion of the reaction, water and ethyl acetate were added for extraction, the organic phase was concentrated under reduced pressure, and purified by column chromatography to obtain 6-b (160 mg, yield 58%).
步骤2Step 2
把6-b(160mg，0.64mmol)溶于DMF(1.0mL)中，加入4-(溴甲基)苯甲酸甲酯(174mg，0.76mmol)和碳酸钾(262mg，1.89mmol)，在室温下反应16小时。TLC监测反应完成后，加入水和乙酸乙酯萃取，有机相减压浓缩，柱色谱法纯化后得到6-c(150mg，收率59％)。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%).
1H NMR(400MHz，DMSO-d 6)δ7.92(d，J＝8.0Hz，2H)，7.67(d，J＝2.4Hz，1H)，7.43(dd，J＝5.4，2.4Hz，3H)，4.79(s，2H)，3.84(s，3H)，3.45(t，J＝7.2Hz，2H)，3.19(t，J＝7.2Hz，2H).LC-MS m/z[M+H] +：400.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.92 (d, J=8.0 Hz, 2H), 7.67 (d, J=2.4 Hz, 1H), 7.43 (dd, J=5.4, 2.4 Hz, 3H) , 4.79(s, 2H), 3.84(s, 3H), 3.45(t, J=7.2Hz, 2H), 3.19(t, J=7.2Hz, 2H).LC-MS m/z[M+H] + : 400.0.
步骤3Step 3
把6-c(150mg，0.38mmol)溶于四氢呋喃(1.0mL)和甲醇(1.0mL)中，加入羟胺水溶液(0.5mL)和氢氧化钠(61mg，1.52mmol)，在室温下反应2小时。TLC监测反应完成后，反应减压浓缩，柱色谱法纯化后得到化合物6(60mg，收率39％)。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%).
1H NMR(400MHz，DMSO-d 6)δ11.20(s，1H)，9.05(s，1H)，7.70(t，J＝5.6Hz，3H)，7.43(d，J＝2.4Hz，1H)，7.32(d，J＝8.0Hz，2H)，4.77(s，2H)，3.40(t，J＝7.2Hz，2H)，3.16(t，J＝7.2Hz，2H).LC-MS m/z[M+H] +：401.0. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 9.05 (s, 1H), 7.70 (t, J=5.6Hz, 3H), 7.43 (d, J=2.4Hz, 1H) , 7.32(d, J=8.0Hz, 2H), 4.77(s, 2H), 3.40(t, J=7.2Hz, 2H), 3.16(t, J=7.2Hz, 2H).LC-MS m/z [M+H] + : 401.0.
实施例7：4-((6-溴-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物7)的制备Example 7: 4-((6-Bromo-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl)-N - Preparation of hydroxybenzamide (compound 7)
Figure PCTCN2022087060-appb-000031
Figure PCTCN2022087060-appb-000031
步骤1step 1
1-b(1.0g，3.02mmol)、N-溴代丁二酰亚胺(0.64g，3.6mmol)和DMF(20mL)在60℃下反应4个小时，加入饱和食盐水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到7-b(1.12g，产率：91％)1-b (1.0 g, 3.02 mmol), N-bromosuccinimide (0.64 g, 3.6 mmol) and DMF (20 mL) were reacted at 60°C for 4 hours, and saturated brine and ethyl acetate were added, Extraction and separation, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 7-b (1.12 g, yield: 91%)
步骤2Step 2
7-b(30mg，0.07mmol)、四氢呋喃(0.2mL)和甲醇(0.2mL)在0℃下搅拌，加入氢氧化钠(11mg，0.28mmol)和羟胺水溶液(0.3mL)，在室温下反应40分钟，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到7(9mg，产率：30％)。7-b (30 mg, 0.07 mmol), tetrahydrofuran (0.2 mL) and methanol (0.2 mL) were stirred at 0 °C, sodium hydroxide (11 mg, 0.28 mmol) and hydroxylamine aqueous solution (0.3 mL) were added, and the reaction was carried out at room temperature for 40 After minutes, water and ethyl acetate were added, and the mixture was extracted and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 7 (9 mg, yield: 30%).
1H NMR(400MHz，DMSO-d 6)δ11.18(s，1H)，9.04(s，1H)，7.72(d，J＝8.2Hz，2H)，7.57-7.21(m，4H)，6.76(d，J＝8.9Hz，1H)，5.00(s，2H)，3.63(t，J＝6.9Hz，2H)，3.39(t，J＝6.9Hz，2H).LC-MS m/z[M+H] +：411.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 9.04 (s, 1H), 7.72 (d, J=8.2Hz, 2H), 7.57-7.21 (m, 4H), 6.76 ( d, J=8.9Hz, 1H), 5.00 (s, 2H), 3.63 (t, J=6.9Hz, 2H), 3.39 (t, J=6.9Hz, 2H). LC-MS m/z[M+ H] + : 411.0.
实施例8：4-((6-氰基-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物8)的制备Example 8: 4-((6-Cyano-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl)- Preparation of N-hydroxybenzamide (compound 8)
Figure PCTCN2022087060-appb-000032
Figure PCTCN2022087060-appb-000032
步骤1step 1
将7-b(870mg，2.12mmol)、DMF(10mL)、DIPEA(410mg，3.18mmol)、氰化锌(496mg，4.24mmol)、x-phose(606mg，1.27mmol)和双(二亚苄基丙酮)钯(577mg，0.63mmol)装入反应瓶中，用氮气置换三次，110℃反应过夜，加入饱和食盐水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到8-b(680mg，产率：90％)。7-b (870 mg, 2.12 mmol), DMF (10 mL), DIPEA (410 mg, 3.18 mmol), zinc cyanide (496 mg, 4.24 mmol), x-phose (606 mg, 1.27 mmol) and bis(dibenzylidene) Acetone) palladium (577 mg, 0.63 mmol) was put into a reaction flask, replaced with nitrogen three times, reacted at 110 °C overnight, added with saturated brine and ethyl acetate, extracted and separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure , and purified by column chromatography to obtain 8-b (680 mg, yield: 90%).
步骤2Step 2
将8-b(150mg，0.42mmol)、四氢呋喃(0.5mL)和甲醇(0.5mL)在0℃下搅拌，加入氢氧化钠(33mg，0.84mmol)和羟胺水溶液(0.5mL)，0℃反应40分钟，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到化合物8(41mg，产率：27％)。8-b (150 mg, 0.42 mmol), tetrahydrofuran (0.5 mL) and methanol (0.5 mL) were stirred at 0 °C, sodium hydroxide (33 mg, 0.84 mmol) and hydroxylamine aqueous solution (0.5 mL) were added, and the reaction was carried out at 0 °C for 40 After minutes, water and ethyl acetate were added, and the mixture was extracted and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 8 (41 mg, yield: 27%).
1H NMR(400MHz，DMSO-d 6)δ11.19(s，1H)，9.02(s，1H)，7.81-7.68(m，3H)，7.61(dd，J＝8.7，2.0Hz，1H)，7.44(d，J＝8.1Hz，2H)，6.91(d，J＝8.7Hz，1H)，5.11(s，2H)，3.78(t，J＝6.9Hz，2H)，3.46(t，J＝6.9Hz，2H).LC-MS m/z[M+H] +：358.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.19 (s, 1H), 9.02 (s, 1H), 7.81-7.68 (m, 3H), 7.61 (dd, J=8.7, 2.0 Hz, 1H), 7.44(d, J=8.1Hz, 2H), 6.91(d, J=8.7Hz, 1H), 5.11(s, 2H), 3.78(t, J=6.9Hz, 2H), 3.46(t, J=6.9 Hz, 2H).LC-MS m/z[M+H] + : 358.1.
实施例9：1-(4-(羟基氨甲酰基)苄基)-3，4-二氢-1H-苯并[c][1，2]噻嗪-6-甲酰胺2，2-二氧化物(化合物9)的制备Example 9: 1-(4-(Hydroxycarbamoyl)benzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-6-carboxamide 2,2-di Preparation of oxide (compound 9)
Figure PCTCN2022087060-appb-000033
Figure PCTCN2022087060-appb-000033
步骤1step 1
在0℃下，向8-b(100mg，0.28mmol)、碳酸钾(19mg，0.14mmol)和二甲基亚砜(1.5mL)的混合物中加入五滴过氧化氢水溶液，在室温下反应过夜，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到9-b(200mg粗品)，无需纯化直接用于下一步反应。Five drops of aqueous hydrogen peroxide were added to a mixture of 8-b (100 mg, 0.28 mmol), potassium carbonate (19 mg, 0.14 mmol) and dimethyl sulfoxide (1.5 mL) at 0°C, and the reaction was carried out at room temperature overnight. , water and ethyl acetate were added, and the mixture was extracted and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 9-b (200 mg crude product), which was directly used in the next reaction without purification.
步骤2Step 2
9-b(100mg，0.26mmol)、四氢呋喃(0.5mL)和甲醇(0.5mL)在0℃下搅拌，加入氢氧化钠(41mg，1.04mmol)和羟胺水溶液(0.5mL)，在室温下反应40分钟，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到9(24mg，产率：24％)。9-b (100 mg, 0.26 mmol), tetrahydrofuran (0.5 mL) and methanol (0.5 mL) were stirred at 0 °C, sodium hydroxide (41 mg, 1.04 mmol) and hydroxylamine aqueous solution (0.5 mL) were added, and the reaction was carried out at room temperature for 40 After minutes, water and ethyl acetate were added, and the mixture was extracted and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 9 (24 mg, yield: 24%).
1H NMR(400MHz，DMSO-d 6)δ11.17(s，1H)，9.02(s，1H)，7.89-7.68(m，4H)，7.63(dd，J＝8.6，2.1Hz，1H)，7.44(d，J＝8.1Hz，2H)，7.26(s，1H)，6.84(d，J＝8.7Hz，1H)，5.08(s，2H)，3.69(t，J＝6.9Hz，2H)，3.44(t，J＝6.9Hz，2H).LC-MS m/z[M+H] +：376.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.17 (s, 1H), 9.02 (s, 1H), 7.89-7.68 (m, 4H), 7.63 (dd, J=8.6, 2.1 Hz, 1H), 7.44(d, J=8.1Hz, 2H), 7.26(s, 1H), 6.84(d, J=8.7Hz, 1H), 5.08(s, 2H), 3.69(t, J=6.9Hz, 2H), 3.44 (t, J=6.9 Hz, 2H). LC-MS m/z [M+H] + : 376.1.
实施例10：4-((6-氨基-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物10)的制备Example 10: 4-((6-Amino-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl)-N - Preparation of hydroxybenzamide (compound 10)
Figure PCTCN2022087060-appb-000034
Figure PCTCN2022087060-appb-000034
步骤1step 1
把1-b(600mg，1.8mmol)溶于乙酸酐(5.0mL)中，加入硝酸(1.0mL)，在室温下反应3小时。TLC监测反应完成后，加入水和乙酸乙酯萃取，有机相减压浓缩，柱色谱法纯化后得到10-a(450mg，收率66％)。1-b (600 mg, 1.8 mmol) was dissolved in acetic anhydride (5.0 mL), nitric acid (1.0 mL) was added, and the reaction was carried out at room temperature for 3 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 10-a (450 mg, yield 66%).
1H NMR(400MHz，CDCl 3)δ8.17-7.97(m，4H)，7.47(d，J＝8.2Hz，2H)，6.84(d，J＝9.2Hz，1H)，5.19(s，2H)，3.95(s，3H)，3.67(d，J＝6.8Hz，2H)，3.52(t，J＝6.8Hz，2H).LC-MS m/z[M+H] +：377.1. 1 H NMR (400MHz, CDCl 3 ) δ 8.17-7.97 (m, 4H), 7.47 (d, J=8.2Hz, 2H), 6.84 (d, J=9.2Hz, 1H), 5.19 (s, 2H) , 3.95 (s, 3H), 3.67 (d, J=6.8Hz, 2H), 3.52 (t, J=6.8Hz, 2H). LC-MS m/z [M+H] + : 377.1.
步骤2Step 2
把10-a(400mg，1.2mmol)溶于四氢呋喃(5.0mL)中，加入钯碳(50mg，10％wt)，在室温下反应16小时。TLC监测反应完成后，过滤，柱色谱法纯化后得到10-b(200mg，收率48％)。LC-MS m/z[M+H] +：347.1. 10-a (400 mg, 1.2 mmol) was dissolved in tetrahydrofuran (5.0 mL), palladium on carbon (50 mg, 10% wt) was added, and the reaction was carried out at room temperature for 16 hours. After completion of the reaction monitored by TLC, 10-b (200 mg, yield 48%) was obtained after filtration and purification by column chromatography. LC-MS m/z [M+H] + : 347.1.
步骤3Step 3
把10-b(100mg，0.29mmol)溶于四氢呋喃(1.0mL)/甲醇(1.0mL)中，加入羟胺水溶液(0.5mL)和氢氧化钠(46mg，1.16mmol)，在室温下反应1小时。TLC监测反应完成后，过滤，柱色谱法纯化后得到10(30mg，收率30％)。10-b (100 mg, 0.29 mmol) was dissolved in tetrahydrofuran (1.0 mL)/methanol (1.0 mL), hydroxylamine aqueous solution (0.5 mL) and sodium hydroxide (46 mg, 1.16 mmol) were added, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction monitored by TLC, 10 was obtained after filtration and purification by column chromatography (30 mg, 30% yield).
1H NMR(400MHz，DMSO-d 6)δ11.18(s，1H)，9.02(s，1H)，7.71(d，J＝8.1Hz，2H)，7.37(d，J＝8.1Hz，2H)，6.63-6.48(m，1H)，6.44-6.31(m，J＝5.5Hz，2H)，4.96(s，2H)，4.80(s，2H)，3.39-3.34(m，J＝6.9Hz，2H)，3.19-3.11(m，2H).LC-MS m/z[M+H] +：348.2. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 9.02 (s, 1H), 7.71 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 6.63-6.48(m, 1H), 6.44-6.31(m, J=5.5Hz, 2H), 4.96(s, 2H), 4.80(s, 2H), 3.39-3.34(m, J=6.9Hz, 2H) , 3.19-3.11 (m, 2H). LC-MS m/z [M+H] + : 348.2.
实施例11：4-((6-乙酰氨基-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物11)的制备Example 11: 4-((6-Acetylamino-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl)- Preparation of N-hydroxybenzamide (compound 11)
Figure PCTCN2022087060-appb-000035
Figure PCTCN2022087060-appb-000035
步骤1step 1
10-b(150mg，0.43mmol)溶于二氯甲烷(6mL)中，加入三乙胺(131mg，1.29mmol)，在0℃下滴加乙酰氯(41mg，0.52mmol)。反应2小时，将反应液直接浓缩，柱色谱法纯化，得到产品11-a(150mg，产率：89％)。10-b (150 mg, 0.43 mmol) was dissolved in dichloromethane (6 mL), triethylamine (131 mg, 1.29 mmol) was added, and acetyl chloride (41 mg, 0.52 mmol) was added dropwise at 0°C. After reacting for 2 hours, the reaction solution was directly concentrated and purified by column chromatography to obtain the product 11-a (150 mg, yield: 89%).
1H NMR(400MHz，DMSO-d 6)δ9.88(s，1H)，7.94(d，J＝8.4Hz，2H)，7.53-7.46(m，3H)，7.27(dd，J＝8.8，2.4Hz，1H)，6.77(d，J＝8.8Hz，1H)，4.98(s，2H)，3.84(s，3H)，3.54(t，J＝6.8Hz，2H)，3.32(d，J＝7.6Hz，2H)，1.99(s，3H).MS m/z[M+H] +：389.2 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.53-7.46 (m, 3H), 7.27 (dd, J=8.8, 2.4 Hz, 1H), 6.77(d, J=8.8Hz, 1H), 4.98(s, 2H), 3.84(s, 3H), 3.54(t, J=6.8Hz, 2H), 3.32(d, J=7.6 Hz, 2H), 1.99 (s, 3H). MS m/z[M+H] + : 389.2
步骤2Step 2
将11-a(120mg，0.31mmol)加入四氢呋喃(3mL)/甲醇(3mL)中，然后加入氢氧化钠(48mg，1.24mmol)和羟胺水溶液(0.4mL)。在室温下搅拌半小时，用稀盐酸将溶液pH调至9，浓缩，柱色谱法纯 化，再制备得到淡红色固体产品化合物11(23mg，产率：19％)。11-a (120 mg, 0.31 mmol) was added to tetrahydrofuran (3 mL)/methanol (3 mL), followed by sodium hydroxide (48 mg, 1.24 mmol) and aqueous hydroxylamine (0.4 mL). After stirring at room temperature for half an hour, the pH of the solution was adjusted to 9 with dilute hydrochloric acid, concentrated, and purified by column chromatography to obtain compound 11 as a pale red solid product (23 mg, yield: 19%).
1H NMR(400MHz，DMSO-d 6)δ11.18(s，1H)，9.89(s，1H)，7.72(d，J＝8.2Hz，2H)，7.49(d，J＝2.2Hz，1H)，7.41(d，J＝8.2Hz，2H)，7.28(dd，J＝8.8，2.2Hz，1H)，6.79(d，J＝8.8Hz，1H)，4.95(s，2H)，3.53(t，J＝6.8Hz，2H)，3.32(t，J＝6.8Hz，2H)，1.99(s，3H).MS m/z[M+H] +：390.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 9.89 (s, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.49 (d, J=2.2 Hz, 1H) , 7.41(d, J=8.2Hz, 2H), 7.28(dd, J=8.8, 2.2Hz, 1H), 6.79(d, J=8.8Hz, 1H), 4.95(s, 2H), 3.53(t, J=6.8Hz, 2H), 3.32 (t, J=6.8Hz, 2H), 1.99 (s, 3H). MS m/z[M+H] + : 390.1
实施例12：4-((2，2-二氧化-6-(吡咯烷-1-基)-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物12)的制备Example 12: 4-((2,2-Dioxy-6-(pyrrolidin-1-yl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-1- Preparation of methyl)-N-hydroxybenzamide (compound 12)
Figure PCTCN2022087060-appb-000036
Figure PCTCN2022087060-appb-000036
步骤1step 1
向7-b(0.052g，0.126mmol)和吡咯烷(0.011g，0.151mmol)在1，4-二氧六环(2.0mL)中的溶液加入Pd 2(dba) 3(0.0116g，0.0126mmol)、xphose(0.012g，0.0252mmol)和Cs 2CO 3(0.082g，0.252mmol)，用氮气置换，并在封口瓶中于80℃下加热过夜。将反应混合物在减压下蒸发，并通过柱色谱法(石油醚中0-30％乙酸乙酯)纯化，得到黄色固体形式的化合物12-b(0.0.03g，57％)。 To a solution of 7-b (0.052 g, 0.126 mmol) and pyrrolidine (0.011 g, 0.151 mmol) in 1,4-dioxane (2.0 mL) was added Pd2(dba) 3 (0.0116 g, 0.0126 mmol ) ), xphose (0.012 g, 0.0252 mmol) and Cs 2 CO 3 (0.082 g, 0.252 mmol), replaced with nitrogen and heated at 80 °C overnight in a sealed vial. The reaction mixture was evaporated under reduced pressure and purified by column chromatography (0-30% ethyl acetate in petroleum ether) to give compound 12-b (0.0.03 g, 57%) as a yellow solid.
1H NMR(400MHz，DMSO-d 6)δ7.98(d，J＝8.2Hz，2H)，7.51(d，J＝8.2Hz，2H)，6.74(d，J＝8.5Hz，1H)，6.50-6.34(m，2H)，4.92(s，2H)，3.88(s，3H)，3.46(t，J＝6.9Hz，2H)，3.29(t，J＝6.9Hz，2H)，3.19(t，J＝6.4Hz，4H)，1.95(t，J＝6.4Hz，4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.98 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 6.74 (d, J=8.5 Hz, 1H), 6.50 -6.34(m, 2H), 4.92(s, 2H), 3.88(s, 3H), 3.46(t, J=6.9Hz, 2H), 3.29(t, J=6.9Hz, 2H), 3.19(t, J=6.4Hz, 4H), 1.95(t, J=6.4Hz, 4H).
步骤2Step 2
在0℃下，向NaOH(40mg，1.0mmol)的水溶液(1.0mL)中加入50％W/W的NH 2OH水溶液(1.0mL)。在0℃下滴加7-b在THF/MeOH(1∶1，4mL)中的溶液。加入完成后，移除冰浴，并将反应混合物在室温下搅拌1h。反应完成后，将pH用1N HCl调节至7-8。将有机溶剂在减压下蒸发。将固体过滤，用水洗涤，干燥，并通过Pre-HPLC纯化，以得到白色固体形式的化合物12(28mg，27.9％) To a solution of NaOH (40 mg, 1.0 mmol) in water (1.0 mL) was added 50% W/W aqueous NH2OH (1.0 mL) at 0 °C. A solution of 7-b in THF/MeOH (1:1, 4 mL) was added dropwise at 0°C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the pH was adjusted to 7-8 with 1N HCl. The organic solvent was evaporated under reduced pressure. The solid was filtered, washed with water, dried, and purified by Pre-HPLC to give compound 12 as a white solid (28 mg, 27.9%)
1H NMR(400MHZ，DMSO-d 6)δ11.23(s，1H)，9.08(s，1H)，7.75(d，J＝7.5Hz，2H)，7.42(d，J＝7.3Hz，2H)，6.76(d，J＝8.9Hz，1H)，6.47-6.35(m，2H)，4.88(s，2H)，3.51-3.44(m，2H)，3.30-3.24(m，2H)，3.24-3.13(m，4H)，2.01-1.88(m，4H).LC-MS m/z[M+H] +＝402.2. 1 H NMR (400MHZ, DMSO-d 6 ) δ 11.23 (s, 1H), 9.08 (s, 1H), 7.75 (d, J=7.5Hz, 2H), 7.42 (d, J=7.3Hz, 2H) , 6.76(d, J=8.9Hz, 1H), 6.47-6.35(m, 2H), 4.88(s, 2H), 3.51-3.44(m, 2H), 3.30-3.24(m, 2H), 3.24-3.13 (m, 4H), 2.01-1.88 (m, 4H). LC-MS m/z [M+H] + =402.2.
实施例13：4-((6-(2-氯-4-氟苯基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物13)的制备Example 13: 4-((6-(2-Chloro-4-fluorophenyl)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazine Preparation of -1-yl)methyl)-N-hydroxybenzamide (compound 13)
Figure PCTCN2022087060-appb-000037
Figure PCTCN2022087060-appb-000037
步骤1step 1
向13-a(50mg，0.29mmol)、7-b(118mg，0.29mmol)、1，1′-双二苯基膦二茂铁二氯化钯(21mg，0.03mmol)和碳酸钾(99mg，0.72mmol)的混合物中加入1，4-二氧六环(0.5mL)和水(0.1mL)，80℃下搅 拌2小时。反应液浓缩后，通过柱色谱法纯化得到13-b(108mg，产率：82％)。MS m/z[2M+NH 4] +：935.8。 To 13-a (50 mg, 0.29 mmol), 7-b (118 mg, 0.29 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (21 mg, 0.03 mmol) and potassium carbonate (99 mg, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added to the mixture of 0.72 mmol), and the mixture was stirred at 80°C for 2 hours. After the reaction solution was concentrated, it was purified by column chromatography to obtain 13-b (108 mg, yield: 82%). MS m/z [2M+ NH4 ] + : 935.8.
步骤2Step 2
将13-b(108mg，0.24mmol)加入甲醇(1mL)和四氢呋喃(1mL)中，在-5℃下搅拌，-5℃下加入氢氧化钠(37mg，0.93mmol)和50％羟胺溶液(1mL)，-5℃下搅拌10分钟，自然升至室温，搅拌50分钟。TLC监测显示反应完成后，降温到-5℃搅拌，滴加稀盐酸，将pH调至8，乙酸乙酯萃取3次，有机相合并后，用食盐水洗，无水硫酸钠干燥，浓缩后柱色谱法纯化得到13(29.1mg，产率：29％)，纯度98％。13-b (108 mg, 0.24 mmol) was added to methanol (1 mL) and tetrahydrofuran (1 mL), stirred at -5 °C, sodium hydroxide (37 mg, 0.93 mmol) and 50% hydroxylamine solution (1 mL) were added at -5 °C ), stirred at -5°C for 10 minutes, naturally warmed to room temperature, and stirred for 50 minutes. After TLC monitoring showed that the reaction was completed, the temperature was lowered to -5°C and stirred, diluted hydrochloric acid was added dropwise, the pH was adjusted to 8, and the pH was adjusted to 8. After extraction with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by chromatography gave 13 (29.1 mg, yield: 29%) in 98% purity.
1H NMR(400MHz，DMSO-d 6)δ11.20(s，1H)，9.04(s，1H)，7.75(d，J＝8.3Hz，2H)，7.57-7.38(m，4H)，7.34-7.16(m，3H)，6.87(d，J＝8.6Hz，1H)，5.06(s，2H)3.70(t，J＝6.9Hz，2H)，3.46(t，J＝6.8Hz，2H).LC-MS m/z[M+H] +＝461.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 9.04 (s, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.57-7.38 (m, 4H), 7.34- 7.16(m, 3H), 6.87(d, J=8.6Hz, 1H), 5.06(s, 2H) 3.70(t, J=6.9Hz, 2H), 3.46(t, J=6.8Hz, 2H).LC -MS m/z[M+H] + =461.1
实施例14：N-羟基-4-((6-(2-甲氧基苯基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)苯甲酰胺(化合物14)的制备Example 14: N-Hydroxy-4-((6-(2-methoxyphenyl)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2] Preparation of Thiazin-1-yl)methyl)benzamide (Compound 14)
Figure PCTCN2022087060-appb-000038
Figure PCTCN2022087060-appb-000038
步骤1step 1
向14-a(50mg，0.33mmol)、7-b(134mg，0.33mmol)、1，1′-双二苯基膦二茂铁二氯化钯(24mg，0.03mmol)和碳酸钾(113mg，0.82mmol)的混合物中加入1，4-二氧六环(0.5mL)和水(0.1mL)，在80℃下搅拌2小时。反应液浓缩后，通过柱色谱法纯化得到14-b(123mg，产率：86％)。MS m/z[M+NH 4] +：455.3。 To 14-a (50 mg, 0.33 mmol), 7-b (134 mg, 0.33 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (24 mg, 0.03 mmol) and potassium carbonate (113 mg, 1,4-dioxane (0.5 mL) and water (0.1 mL) were added to the mixture of 0.82 mmol), and the mixture was stirred at 80°C for 2 hours. After the reaction solution was concentrated, it was purified by column chromatography to obtain 14-b (123 mg, yield: 86%). MS m/z [M+ NH4 ] + : 455.3.
步骤2Step 2
14-b(123mg，0.28mmol)加入甲醇(1mL)和四氢呋喃(1mL)中，-5℃下搅拌，-5℃下加入氢氧化钠(45mg，1.13mmol)和50％羟胺溶液(1mL)，-5℃下搅拌10分钟，自然升至室温，搅拌50分钟。TLC监测显示反应完成后，降温到-5℃搅拌，滴加稀盐酸，将pH调至8，乙酸乙酯萃取3次，有机相合并后，用食盐水洗，无水硫酸钠干燥，浓缩后柱色谱法纯化得到14(21.1mg，产率：17％)，纯度98％。14-b (123 mg, 0.28 mmol) was added to methanol (1 mL) and tetrahydrofuran (1 mL), stirred at -5 °C, sodium hydroxide (45 mg, 1.13 mmol) and 50% hydroxylamine solution (1 mL) were added at -5 °C, Stir at -5°C for 10 minutes, naturally warm to room temperature, and stir for 50 minutes. After TLC monitoring showed that the reaction was completed, the temperature was lowered to -5°C and stirred, diluted hydrochloric acid was added dropwise, the pH was adjusted to 8, and the pH was adjusted to 8. After extraction with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by chromatography gave 14 (21.1 mg, yield: 17%) in 98% purity.
1H NMR(400MHZ，DMSO-d 6)δ11.20(s，1H)，9.05(s，1H)，7.75(d，J＝8.3Hz，2H)，7.49(d，J＝8.2Hz，2H)，7.35-7.18(m，4H)，7.10-6.92(m，2H)，6.82(d，J＝8.6Hz，1H)，5.04(s，2H)，3.73(s，3H)，3.66(d，J＝6.7Hz，2H)，3.47-3.40(m，2H).LC-MS m/z[M+H] +＝439.1 1 H NMR (400MHZ, DMSO-d 6 ) δ 11.20 (s, 1H), 9.05 (s, 1H), 7.75 (d, J=8.3Hz, 2H), 7.49 (d, J=8.2Hz, 2H) , 7.35-7.18(m, 4H), 7.10-6.92(m, 2H), 6.82(d, J=8.6Hz, 1H), 5.04(s, 2H), 3.73(s, 3H), 3.66(d, J =6.7Hz, 2H), 3.47-3.40 (m, 2H).LC-MS m/z[M+H] + =439.1
实施例15：4-((2，2-二氧化-6-(4-(三氟甲基)苯基)-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物15)的制备Example 15: 4-((2,2-Dioxy-6-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[c][1,2]thiazide Preparation of oxazin-1-yl)methyl)-N-hydroxybenzamide (compound 15)
Figure PCTCN2022087060-appb-000039
Figure PCTCN2022087060-appb-000039
步骤1step 1
将7-b(1()()mg，0.24mmol)、15-a(51mg，0.27mmol)、碳酸钾(83mg，0.6mmol)和1，1′-双二苯基膦二茂铁二氯化钯(22mg，0.03mmol)加入至1，4-二氧六环(2mL)和水(0.4mL)中，氮气保护下80℃下反应5个小时。加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到15-b(93mg，产率：80％)。Combine 7-b (1()() mg, 0.24 mmol), 15-a (51 mg, 0.27 mmol), potassium carbonate (83 mg, 0.6 mmol) and 1,1'-bisdiphenylphosphinoferrocene dichloride Palladium (22 mg, 0.03 mmol) was added to 1,4-dioxane (2 mL) and water (0.4 mL), and the reaction was carried out at 80° C. for 5 hours under nitrogen protection. Water and ethyl acetate were added, followed by liquid separation extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain 15-b (93 mg, yield: 80%).
步骤2Step 2
将15-b(93mg，0.19mmol)加入甲醇(1mL)、四氢呋喃(1mL)和水(0.5mL)中，0℃下加入氢氧化钠(30mg，0.76mmol)和羟胺水溶液(1mL)，搅拌10分钟后升温至室温反应50分钟。反应液用稀盐酸调pH为7到8，加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到15(40mg，产率：43％)。15-b (93 mg, 0.19 mmol) was added to methanol (1 mL), tetrahydrofuran (1 mL) and water (0.5 mL), sodium hydroxide (30 mg, 0.76 mmol) and hydroxylamine aqueous solution (1 mL) were added at 0°C, and stirred for 10 After 50 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, and the liquid was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain 15 (40 mg, yield: 43%) .
1H NMR(400MHz，DMSO-d 6)δ11.20(s，1H)，9.04(s，1H)，7.85(d，J＝8.2Hz，2H)，7.76(dd，J＝15.1，8.3Hz，4H)，7.69(s，1H)，7.55(dd，J＝8.6，1.9Hz，1H)，7.48(d，J＝8.2Hz，2H)，6.92(d，J＝8.6Hz，1H)，5.08(s，2H)，3.71(t，J＝6.8Hz，2H)，3.50(t，J＝6.8Hz，2H).LC-MS m/z[M+H] +：477.1。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 9.04 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.76 (dd, J=15.1, 8.3 Hz, 4H), 7.69(s, 1H), 7.55(dd, J=8.6, 1.9Hz, 1H), 7.48(d, J=8.2Hz, 2H), 6.92(d, J=8.6Hz, 1H), 5.08( s, 2H), 3.71 (t, J=6.8 Hz, 2H), 3.50 (t, J=6.8 Hz, 2H). LC-MS m/z [M+H] + : 477.1.
实施例16和实施例17：4-((2，2-二氧化-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物16)和4-(4-(1-(4-(羟基氨甲酰基)苄基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(化合物17)的制备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)
Figure PCTCN2022087060-appb-000040
Figure PCTCN2022087060-appb-000040
步骤1step 1
将16-a(100mg，0.26mmol)、7-b(108mg，0.26mmol)、1，1′-双二苯基膦二茂铁二氯化钯(19mg，0.03mmol)和碳酸钾(92mg，0.67mmol)加入1，4-二氧六环(1.0mL)和水(0.2mL)中，氮气保护下，80℃ 下搅拌2小时。反应液浓缩后，通过柱色谱法纯化得到16-b(90mg，产率：65％)。Combine 16-a (100 mg, 0.26 mmol), 7-b (108 mg, 0.26 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (19 mg, 0.03 mmol) and potassium carbonate (92 mg, 0.67 mmol) was added to 1,4-dioxane (1.0 mL) and water (0.2 mL), and the mixture was stirred at 80° C. for 2 hours under nitrogen protection. After the reaction solution was concentrated, it was purified by column chromatography to obtain 16-b (90 mg, yield: 65%).
步骤2Step 2
将16-b(90mg，0.16mmol)加入甲醇(1mL)和四氢呋喃(1mL)中，-5℃下加入氢氧化钠(25mg，0.63mmol)和50％羟胺溶液(1mL)，-5℃下搅拌10分钟，自然升至室温，搅拌50分钟。TLC监测显示反应完成后，降温到-5℃搅拌，滴加稀盐酸，将pH调至8，乙酸乙酯萃取3次，有机相合并后，用食盐水洗，无水硫酸钠干燥，浓缩后柱色谱法纯化得到化合物17(87.5mg产率：97％)，纯度98％。16-b (90 mg, 0.16 mmol) was added to methanol (1 mL) and tetrahydrofuran (1 mL), sodium hydroxide (25 mg, 0.63 mmol) and 50% hydroxylamine solution (1 mL) were added at -5 °C, and stirred at -5 °C For 10 minutes, it was naturally warmed to room temperature and stirred for 50 minutes. After TLC monitoring showed that the reaction was completed, the temperature was lowered to -5°C and stirred, diluted hydrochloric acid was added dropwise, the pH was adjusted to 8, and the pH was adjusted to 8. After extraction with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Chromatographic purification afforded compound 17 (87.5 mg yield: 97%) with 98% purity.
1H NMR(400MHz，DMSO-d 6)δ11.18(s，1H)，9.04(s，1H)，8.18(s，1H)，7.81(s，1H)，7.72(d，2H)，7.47-7.43(m，3H)，7.35(d，J＝8.8Hz，1H)，6.82(d，1H)，5.01(s，2H)，4.33(m，1H)，4.02(m，2H)，3.60(m，4H)，2.90(s，2H)，2.01(m，2H)，1.84-1.69(m，2H)，1.41(s，9H).LC-MS m/z[M+H] +：582.2 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18(s, 1H), 9.04(s, 1H), 8.18(s, 1H), 7.81(s, 1H), 7.72(d, 2H), 7.47- 7.43(m, 3H), 7.35(d, J=8.8Hz, 1H), 6.82(d, 1H), 5.01(s, 2H), 4.33(m, 1H), 4.02(m, 2H), 3.60(m , 4H), 2.90 (s, 2H), 2.01 (m, 2H), 1.84-1.69 (m, 2H), 1.41 (s, 9H). LC-MS m/z [M+H] + : 582.2
步骤3Step 3
17(60mg，0.10mmol)加入二氯甲烷(0.9mL)中，0℃下搅拌，0℃下滴加三氟乙酸(0.3mL)，自然升至室温，搅拌60分钟。TLC监测显示反应完成后，浓缩旋干，加二氯甲烷溶解，加碳酸氢钠饱和溶液洗，二氯甲烷萃取3次，有机相合并后，用食盐水洗，无水硫酸钠干燥，浓缩后柱色谱法纯化得到化合物16(17.6mg产率：35.4％)，纯度98％。17 (60 mg, 0.10 mmol) was added to dichloromethane (0.9 mL), stirred at 0°C, trifluoroacetic acid (0.3 mL) was added dropwise at 0°C, naturally warmed to room temperature, and stirred for 60 minutes. TLC monitoring showed that the reaction was completed, concentrated and spin-dried, dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, extracted with dichloromethane 3 times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated after column Purification by chromatography gave compound 16 (17.6 mg yield: 35.4%) with 98% purity.
1H NMR(400MHz，DMSO-d 6)δ11.19(s，1H)，9.04(m，1H)，8.81-8.44(m，1H)，8.16(s，1H)，7.88(s，1H)，7.73(d，2H)，7.49(s，1H)，7.45(d，2H)，7.38(d，1H)，6.83(d，1H)，5.02(s，2H)，4.47(m，1H)，3.61(m，2H)，3.45-3.39(m，4H)，3.09(m，2H)，2.33-2.06(m，4H).LC-MS m/z[M+H] +：482.2 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.19 (s, 1H), 9.04 (m, 1H), 8.81-8.44 (m, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.73(d, 2H), 7.49(s, 1H), 7.45(d, 2H), 7.38(d, 1H), 6.83(d, 1H), 5.02(s, 2H), 4.47(m, 1H), 3.61 (m, 2H), 3.45-3.39 (m, 4H), 3.09 (m, 2H), 2.33-2.06 (m, 4H). LC-MS m/z [M+H] + : 482.2
实施例18：4-((2，2-二氧化-6-(1H-吡唑-4-基)-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物18)的制备Example 18: 4-((2,2-Dioxy-6-(1H-pyrazol-4-yl)-3,4-dihydro-1H-benzo[c][1,2]thiazine- Preparation of 1-yl)methyl)-N-hydroxybenzamide (Compound 18)
Figure PCTCN2022087060-appb-000041
Figure PCTCN2022087060-appb-000041
步骤1step 1
将18-a(50mg，0.26mmol)、7-b(105mg，0.26mmol)、1，1′-双二苯基膦二茂铁二氯化钯(19mg，0.03mmol)、碳酸钾(89mg，0.65mmol)加入1，4-二氧六环(1.0mL)和水(0.2mL)中，氮气保护，95℃下搅拌2小时。反应液浓缩后，通过柱色谱法纯化得到18-b(68mg，产率：67％)。18-a (50 mg, 0.26 mmol), 7-b (105 mg, 0.26 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (19 mg, 0.03 mmol), potassium carbonate (89 mg, 0.65 mmol) was added to 1,4-dioxane (1.0 mL) and water (0.2 mL), under nitrogen protection, and stirred at 95° C. for 2 hours. After the reaction solution was concentrated, it was purified by column chromatography to obtain 18-b (68 mg, yield: 67%).
步骤2Step 2
将18-b(68mg，0.17mmol)加入甲醇(1mL)和四氢呋喃(1mL)中，-5℃加入氢氧化钠(27mg，0.68mmol)和50％羟胺溶液(1mL)，-5℃下搅拌10分钟，自然升至室温，搅拌50分钟。TLC监测显示反应完成后，降温到-5℃搅拌，滴加稀盐酸，将pH调至8，乙酸乙酯萃取3次，有机相合并后，用食盐水洗，无水硫酸钠干燥，浓缩后柱色谱法纯化得到18(3.0mg，产率：4％)，纯度91％。Add 18-b (68 mg, 0.17 mmol) to methanol (1 mL) and tetrahydrofuran (1 mL), add sodium hydroxide (27 mg, 0.68 mmol) and 50% hydroxylamine solution (1 mL) at -5 °C, and stir at -5 °C for 10 minutes, naturally warmed to room temperature, and stirred for 50 minutes. After TLC monitoring showed that the reaction was completed, the temperature was lowered to -5°C and stirred, diluted hydrochloric acid was added dropwise, the pH was adjusted to 8, and the pH was adjusted to 8. After extraction with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Chromatographic purification gave 18 (3.0 mg, yield: 4%) in 91% purity.
1H NMR(400MHz，CD 3OD)δ7.92(s，2H)，7.74(d，J＝8.1Hz，2H)，7.54-7.43(m，3H)，7.35(t，J＝11.5Hz，1H)，6.85(t，J＝11.4Hz，1H)，5.07(s，2H)，3.48(d，J＝5.6Hz，2H)，3.43(d，J＝5.7Hz，2H).LC-MS m/z[M+H] +：399.1 1 H NMR (400 MHz, CD 3 OD) δ 7.92 (s, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.54-7.43 (m, 3H), 7.35 (t, J=11.5 Hz, 1H) ), 6.85(t, J=11.4Hz, 1H), 5.07(s, 2H), 3.48(d, J=5.6Hz, 2H), 3.43(d, J=5.7Hz, 2H).LC-MS m/ z[M+H] + : 399.1
实施例19：4-((2，2-二氧化-4-氧代-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物19)的制备Example 19: 4-((2,2-Dioxy-4-oxo-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl)methyl)- Preparation of N-hydroxybenzamide (compound 19)
Figure PCTCN2022087060-appb-000042
Figure PCTCN2022087060-appb-000042
步骤1step 1
将19-a(2.0g，21.5mmol)在二氯甲烷(20mL)中溶解，然后依次加入三乙胺(4.3g，43mmol)和(氯磺酰基)乙酸乙酯(4.2g，21.5mmol)。反应在室温下搅拌2小时，加入水(200mL)，二氯甲烷萃取，干燥，浓缩，柱色谱法纯化，得到产品19-b(2.6g，产率：49％)。19-a (2.0 g, 21.5 mmol) was dissolved in dichloromethane (20 mL), then triethylamine (4.3 g, 43 mmol) and (chlorosulfonyl)ethyl acetate (4.2 g, 21.5 mmol) were added sequentially. The reaction was stirred at room temperature for 2 hours, water (200 mL) was added, extracted with dichloromethane, dried, concentrated, and purified by column chromatography to give the product 19-b (2.6 g, yield: 49%).
1H NMR(400MHz，DMSO-d 6)δ10.16(s，1H)，7.37-7.31(m，2H)，7.24-7.21(m，2H)，7.15-7.11(m，1H)，4.19(s，2H)，4.08(q，J＝7.2Hz，2H)，1.15(t，J＝7.2Hz，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 7.37-7.31 (m, 2H), 7.24-7.21 (m, 2H), 7.15-7.11 (m, 1H), 4.19 (s) , 2H), 4.08 (q, J=7.2Hz, 2H), 1.15 (t, J=7.2Hz, 3H).
步骤2Step 2
19-b(2.6g，10.7mmol)溶于水(20mL)和四氢呋喃(40mL)中，加入氢氧化钠(1.7g，42.8mmol)，将混合物室温搅拌过夜，加入稀盐酸将pH调至2，乙酸乙酯(200mL)萃取，干燥，浓缩，得到产物19-c(2.3g，产率：100％)。19-b (2.6 g, 10.7 mmol) was dissolved in water (20 mL) and tetrahydrofuran (40 mL), sodium hydroxide (1.7 g, 42.8 mmol) was added, the mixture was stirred at room temperature overnight, and diluted hydrochloric acid was added to adjust the pH to 2, Extraction with ethyl acetate (200 mL), drying, and concentration gave the product 19-c (2.3 g, yield: 100%).
1H NMR(400MHz，DMSO-d 6)δ13.26(s，1H)，10.05(s，1H)，7.35-7.31(m，2H)，7.25-7.20(m，2H)，7.15-7.10(m，1H)，4.07(s，2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.26 (s, 1H), 10.05 (s, 1H), 7.35-7.31 (m, 2H), 7.25-7.20 (m, 2H), 7.15-7.10 (m , 1H), 4.07(s, 2H).
步骤3Step 3
19-c(2.3g，10.7mmol)溶于二氯甲烷(30mL)，加入草酰氯(2.03g，7.13mmol)和催化量的DMF两滴。反应2小时，直接浓缩干，得到产品19-d(2.5g，产率：100％)，直接进行下一步反应。19-c (2.3 g, 10.7 mmol) was dissolved in dichloromethane (30 mL), oxalyl chloride (2.03 g, 7.13 mmol) and two drops of catalytic DMF were added. After reacting for 2 hours, it was directly concentrated to dryness to obtain the product 19-d (2.5 g, yield: 100%), and the next reaction was carried out directly.
步骤4Step 4
19-d(2.5g，10.7mmol)在二氯甲烷(30mL)中溶解，加入三氯化铝(7.1g，53.5mmol)，在室温下搅拌过夜。加入稀盐酸，用二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，柱色谱法纯化得到产品19-e(1.7g，产率：81％)。19-d (2.5 g, 10.7 mmol) was dissolved in dichloromethane (30 mL), aluminum trichloride (7.1 g, 53.5 mmol) was added, and the mixture was stirred at room temperature overnight. Dilute hydrochloric acid was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the product 19-e (1.7 g, yield: 81%).
1H NMR(400MHz，DMSO-d 6)δ11.48(s，1H)，7.90(dd，J＝8.0，1.6Hz，1H)，7.69-7.64(m，1H)，7.21-7.16(m，1H)，7.10(d，J＝8.0Hz，1H)，4.79(s，2H).MS m/z[M-H] -：196.2 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.48 (s, 1H), 7.90 (dd, J=8.0, 1.6 Hz, 1H), 7.69-7.64 (m, 1H), 7.21-7.16 (m, 1H) ), 7.10 (d, J=8.0 Hz, 1H), 4.79 (s, 2H). MS m/z [MH] − : 196.2
步骤5Step 5
将19-e(100mg，51mmol)、4-(溴甲基)苯甲酸甲酯(116mg，51mmol)和DIPEA(196mg，153mmol)分别加入二氯甲烷(4mL)中，在室温下搅拌2小时，直接浓缩，柱色谱法纯化，得到产品19-f(110mg，产率：63％)。19-e (100 mg, 51 mmol), methyl 4-(bromomethyl)benzoate (116 mg, 51 mmol) and DIPEA (196 mg, 153 mmol) were added to dichloromethane (4 mL), respectively, and stirred at room temperature for 2 hours, Direct concentration and purification by column chromatography gave the product 19-f (110 mg, yield: 63%).
1H NMR(400MHz，DMSO-d 6)δ8.02(dd，J＝8.0，1.6Hz，1H)，7.97(d，J＝8.4Hz，2H)，7.67-7.62(m，1H)，7.60(d，J＝8.4Hz，2H)，7.26(t，J＝7.2Hz，1H)，7.11(d，J＝8.4Hz，1H)，5.27(s，2H)，5.13(s，2H)，3.84(s，3H).MS m/z[M-H] -：344.0 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (dd, J=8.0, 1.6 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.67-7.62 (m, 1H), 7.60 ( d, J=8.4Hz, 2H), 7.26(t, J=7.2Hz, 1H), 7.11(d, J=8.4Hz, 1H), 5.27(s, 2H), 5.13(s, 2H), 3.84( s, 3H).MS m/z[MH] - : 344.0
步骤6Step 6
19-f(110mg，0.32mmol)在四氢呋喃(2mL)和甲醇(2mL)中溶解，然后加入氢氧化钠(51mg，1.28mmol)和羟胺水溶液(0.3mL)。在室温下搅拌半小时，用稀盐酸将溶液pH调至9，浓缩，柱色谱法纯化，得到淡红色固体产品19(14mg，产率：13％)。19-f (110 mg, 0.32 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), then sodium hydroxide (51 mg, 1.28 mmol) and aqueous hydroxylamine (0.3 mL) were added. After stirring at room temperature for half an hour, the pH of the solution was adjusted to 9 with dilute hydrochloric acid, concentrated, and purified by column chromatography to obtain the product 19 as a pale red solid (14 mg, yield: 13%).
1H NMR(400MHz，DMSO-d 6)δ11.20(s，1H)，9.05(s，1H)，7.99(s，1H)，7.74(d，J＝8.0Hz，2H)，7.64(s，1H)，7.51(d，J＝7.0Hz，2H)，7.24(t，J＝4.0Hz，1H)，7.13(d，J＝8.4Hz，1H)，5.23(s，2H)，5.13(s，2H).MS m/z[M+H] +：347.4 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 9.05 (s, 1H), 7.99 (s, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.64 (s, 1H), 7.51(d, J=7.0Hz, 2H), 7.24(t, J=4.0Hz, 1H), 7.13(d, J=8.4Hz, 1H), 5.23(s, 2H), 5.13(s, 2H).MS m/z[M+H] + : 347.4
实施例20：4-((6-(1，1-二氟乙基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯 甲酰胺(化合物20)的制备Example 20: 4-((6-(1,1-difluoroethyl)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazine- Preparation of 1-yl)methyl)-N-hydroxybenzamide (compound 20)
Figure PCTCN2022087060-appb-000043
Figure PCTCN2022087060-appb-000043
步骤1step 1
在二氯甲烷(15mL)中依次加入三氯化铝(4.4g，33mmol)和乙酸酐(1.65mL)，搅拌20分钟后加入1-a(1.0g，5.5mmol)。反应在室温下搅拌过夜，反应完后加入水，用二氯甲烷萃取，干燥，浓缩，柱色谱法纯化得到产品白色固体20-b(900mg，产率：73％)。Aluminum trichloride (4.4 g, 33 mmol) and acetic anhydride (1.65 mL) were sequentially added to dichloromethane (15 mL), and after stirring for 20 minutes, 1-a (1.0 g, 5.5 mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, water was added, extracted with dichloromethane, dried, concentrated, and purified by column chromatography to obtain the product 20-b as a white solid (900 mg, yield: 73%).
1H NMR(400MHz，DMSO-d 6)δ10.75(s，1H)，7.85(d，J＝1.8Hz，1H)，7.77(dd，J＝8.4，2.0Hz，1H)，6.83(d，J＝8.4Hz，1H)，3.46-3.42(m，2H)，3.38(d，J＝6.0Hz，2H)，2.51(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.77 (dd, J=8.4, 2.0 Hz, 1H), 6.83 (d, J=8.4Hz, 1H), 3.46-3.42 (m, 2H), 3.38 (d, J=6.0Hz, 2H), 2.51 (s, 3H).
MS m/z[M-H] -：224.3 MS m/z[MH] - : 224.3
步骤2Step 2
将20-b(400mg，1.7mmol)、4-(溴甲基)苯甲酸甲酯(610mg，2.6mmol)和碳酸钾(736mg，5.2mmol)分别加入DMF(10mL)中，在室温下搅拌16小时，加入水，乙酸乙酯萃取，干燥，浓缩，柱色谱法纯化，得到白色固体产品20-c(600mg，产率：90％)。20-b (400 mg, 1.7 mmol), methyl 4-(bromomethyl)benzoate (610 mg, 2.6 mmol) and potassium carbonate (736 mg, 5.2 mmol) were added to DMF (10 mL), respectively, and stirred at room temperature for 16 After 1 hour, water was added, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to obtain the product 20-c as a white solid (600 mg, yield: 90%).
1H NMR(400MHz，DMSO-d 6)δ7.95(d，J＝8.4Hz，2H)，7.88(d，J＝1.8Hz，1H)，7.72(dd，J＝8.8，2.0Hz，1H)，7.53(d，J＝8.4Hz，2H)，6.86(d，J＝8.8Hz，1H)，5.15(s，2H)，3.83(s，3H)，3.76(t，J＝6.8Hz，2H)，3.50(t，J＝6.8Hz，2H)，2.49(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.95 (d, J=8.4 Hz, 2H), 7.88 (d, J=1.8 Hz, 1H), 7.72 (dd, J=8.8, 2.0 Hz, 1H) , 7.53(d, J=8.4Hz, 2H), 6.86(d, J=8.8Hz, 1H), 5.15(s, 2H), 3.83(s, 3H), 3.76(t, J=6.8Hz, 2H) , 3.50(t, J=6.8Hz, 2H), 2.49(s, 3H).
步骤3Step 3
20-c(600mg，1.6mmol)溶于纯DAST(8mL)中，45℃加热，搅拌24小时，反应液倒入冰的碳酸氢钠溶液中，并用二氯甲烷萃取，干燥，浓缩，柱色谱法纯化，得到产品20-d(270mg，产率：42％)。20-c (600 mg, 1.6 mmol) was dissolved in pure DAST (8 mL), heated at 45°C, stirred for 24 hours, the reaction solution was poured into ice-sodium bicarbonate solution, extracted with dichloromethane, dried, concentrated, and subjected to column chromatography method to obtain the product 20-d (270 mg, yield: 42%).
1H NMR(400MHz，DMSO-d 6)δ7.95(d，J＝8.4Hz，2H)，7.53(d，J＝8.4Hz，2H)，7.48(s，1H)，7.33(d，J＝8.6Hz，1H)，6.85(d，J＝8.8Hz，1H)，5.10(s，2H)，3.84(s，3H)，3.70(t，J＝6.8Hz，2H)，3.46(t，J＝6.8Hz，2H)，1.91(t，J＝18.8Hz，3H).MS m/z[M-H] -：394.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.95 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.48 (s, 1H), 7.33 (d, J= 8.6Hz, 1H), 6.85(d, J=8.8Hz, 1H), 5.10(s, 2H), 3.84(s, 3H), 3.70(t, J=6.8Hz, 2H), 3.46(t, J= 6.8Hz, 2H), 1.91 (t, J=18.8Hz, 3H). MS m/z [MH] - : 394.1.
步骤4Step 4
20-d(270mg，0.68mmol)在四氢呋喃(6mL)和甲醇(6mL)中溶解，然后加入氢氧化钠(174mg，27.2mmol)和羟胺水溶液(0.5mL)。在室温下搅拌半小时，用稀盐酸将溶液pH调至9，浓缩，柱色谱法纯化，再制备得到红棕色固体产品20(115mg，产率：42％)。MS m/z[M-H] -：395.2 20-d (270 mg, 0.68 mmol) was dissolved in tetrahydrofuran (6 mL) and methanol (6 mL), then sodium hydroxide (174 mg, 27.2 mmol) and aqueous hydroxylamine (0.5 mL) were added. After stirring at room temperature for half an hour, the pH of the solution was adjusted to 9 with dilute hydrochloric acid, concentrated, and purified by column chromatography to obtain a reddish-brown solid product 20 (115 mg, yield: 42%). MS m/z[MH] - : 395.2
实施例22：4-((7-(1，1-二氟乙基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物22)的制备Example 22: 4-((7-(1,1-difluoroethyl)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazine- Preparation of 1-yl)methyl)-N-hydroxybenzamide (compound 22)
Figure PCTCN2022087060-appb-000044
Figure PCTCN2022087060-appb-000044
步骤1step 1
无水亚硫酸钠(610mg，4.8mmol)溶于水(20mL)和乙醇(10mL)，加入22-a(1g，4.4mmol)，将溶液升温至100℃。搅拌5小时。冷却到室温，加入二氯甲烷(30mL)和水(30mL)。将四丁基硫酸氢铵(1.57g，4.6mmol)和氢氧化钠(176mg，4.4mmol)加入到溶液中搅拌半小时。分离有机相，干燥，浓缩。残留物溶于二氯甲烷(50mL)，冷却到0℃，慢慢加入三光气(654mg，2.2mmol)和DMF(32mg，0.44mmol)。混合物室温搅拌1小时，浓缩，柱色谱法纯化，得到产品22-b(800mg，产率：74％)。Anhydrous sodium sulfite (610 mg, 4.8 mmol) was dissolved in water (20 mL) and ethanol (10 mL), 22-a (1 g, 4.4 mmol) was added, and the solution was warmed to 100°C. Stir for 5 hours. Cool to room temperature and add dichloromethane (30 mL) and water (30 mL). Tetrabutylammonium hydrogen sulfate (1.57 g, 4.6 mmol) and sodium hydroxide (176 mg, 4.4 mmol) were added to the solution and stirred for half an hour. The organic phase was separated, dried and concentrated. The residue was dissolved in dichloromethane (50 mL), cooled to 0°C, and triphosgene (654 mg, 2.2 mmol) and DMF (32 mg, 0.44 mmol) were added slowly. The mixture was stirred at room temperature for 1 hour, concentrated, and purified by column chromatography to obtain the product 22-b (800 mg, yield: 74%).
1H NMR(400MHz，CDCl 3)δ7.96(d，J＝8.3Hz，2H)，7.36(d，J＝8.2Hz，2H)，3.97-3.90(m，2H)，3.43-3.38(m，2H)，2.61(s，3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 3.97-3.90 (m, 2H), 3.43-3.38 (m, 2H), 2.61(s, 3H).
步骤2Step 2
22-b-R(410mg，4.88mmol)溶于水(10mL)和四氢呋喃(30mL)中，加入碳酸钾(1.35g，9.23mmol)。22-b(800mg，3.25mmol)溶于四氢呋喃(10mL)中，然后慢慢滴加到溶液中。室温搅拌2小时，加入水，乙酸乙酯萃取，干燥，浓缩，经柱色谱法纯化后得22-c(430mg，产率：52％)。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%).
1H NMR(400MHz，CDCl 3)δ7.97(d，J＝7.8Hz，2H)，7.39(d，J＝7.7Hz，2H)，3.84(s，3H)，3.58-3.51(m，2H)，3.27-3.19(m，2H)，2.64(s，3H).LC-MS m/z[M+H] +：258.1. 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J=7.8 Hz, 2H), 7.39 (d, J=7.7 Hz, 2H), 3.84 (s, 3H), 3.58-3.51 (m, 2H) , 3.27-3.19 (m, 2H), 2.64 (s, 3H). LC-MS m/z [M+H] + : 258.1.
步骤3Step 3
22-c(430mg，1.7mmol)溶于三氟乙醇(20mL)中，加入碘苯(34mg，0.17mmol)，m-CPBA(318mg，1.84mmol)。溶液在室温搅拌3小时后，反应液加入到饱和亚硫酸钠水溶液和饱和碳酸氢钠水溶液中，乙酸乙酯萃取，用饱和食盐水洗涤一次，无水硫酸钠干燥，浓缩，柱色谱法纯化得到产品22-d(150mg，产率：35％)。22-c (430 mg, 1.7 mmol) was dissolved in trifluoroethanol (20 mL), iodobenzene (34 mg, 0.17 mmol), m-CPBA (318 mg, 1.84 mmol) were added. After the solution was stirred at room temperature for 3 hours, the reaction solution was added to saturated aqueous sodium sulfite solution and saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain product 22 -d (150 mg, yield: 35%).
步骤4Step 4
将22-d(950mg，3.73mmol)溶于无水四氢呋喃(10mL)，置换氮气后，常温下滴加碘化钐(45mL，4.5mmol)。在室温下搅拌反应1小时，反应完成后，浓缩，经柱色谱法纯化得22-e(250mg，产率：30％)。22-d (950 mg, 3.73 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), nitrogen was replaced, and samarium iodide (45 mL, 4.5 mmol) was added dropwise at room temperature. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated and purified by column chromatography to give 22-e (250 mg, yield: 30%).
1H NMR(400MHz，CDCl 3)δ7.56(dd，J＝8.0，1.6Hz，1H)，7.34(d，J＝1.5Hz，1H)，7.27(d，J＝8.0Hz，1H)，3.52(t，J＝6.8Hz，2H)，3.31(t，J＝6.8Hz，2H)，2.58(s，3H).LC-MS m/z[M-H] -：224.2. 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (dd, J=8.0, 1.6 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 3.52 (t, J=6.8Hz, 2H), 3.31 (t, J=6.8Hz, 2H), 2.58 (s, 3H). LC-MS m/z [MH] − : 224.2.
步骤5Step 5
将22-e(140mg，0.62mmol)、4-(溴甲基)苯甲酸甲酯(170mg，0.74mmol)和碳酸钾(256mg，1.86mmol)溶于DMF(2mL)。在室温下搅拌反应1小时，反应完成后，加入乙酸乙酯稀释，饱和碳酸氢钠水溶液洗涤，饱和食盐水洗涤。将有机相干燥，浓缩，残余物经柱色谱法纯化得22-f(125mg，产率：54％)。22-e (140 mg, 0.62 mmol), methyl 4-(bromomethyl)benzoate (170 mg, 0.74 mmol) and potassium carbonate (256 mg, 1.86 mmol) were dissolved in DMF (2 mL). The reaction was stirred at room temperature for 1 hour, and after completion of the reaction, ethyl acetate was added to dilute, and the mixture was washed with saturated aqueous sodium bicarbonate solution and saturated brine. The organic phase was dried, concentrated, and the residue was purified by column chromatography to give 22-f (125 mg, yield: 54%).
1H NMR(400MHz，DMSO-d 6)δ7.99(d，J＝8.3Hz，2H)，7.63(dd，J＝7.9，1.5Hz，1H)，7.58(d，J＝8.3Hz，2H)，7.44(d，J＝8.0Hz，1H)，7.33(d，J＝1.4Hz，1H)，5.15(s，2H)，3.86(s，3H)，3.71(t，J＝6.9Hz，2H)，3.50(t，J＝6.8Hz，2H)，2.45(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.99 (d, J=8.3 Hz, 2H), 7.63 (dd, J=7.9, 1.5 Hz, 1H), 7.58 (d, J=8.3 Hz, 2H) , 7.44(d, J=8.0Hz, 1H), 7.33(d, J=1.4Hz, 1H), 5.15(s, 2H), 3.86(s, 3H), 3.71(t, J=6.9Hz, 2H) , 3.50(t, J=6.8Hz, 2H), 2.45(s, 3H).
步骤6Step 6
将22-f(130mg，0.35mmol)溶于DAST(3mL)，45℃搅拌反应72小时，反应完成后，加入水(10mL)淬灭，乙酸乙酯(50mL)萃取，乙酸乙酯相饱和食盐水洗涤，干燥，浓缩，经制备色谱法纯化得22-g(100mg，产率：72％)。22-f (130 mg, 0.35 mmol) was dissolved in DAST (3 mL), and the reaction was stirred at 45° C. for 72 hours. After the reaction was completed, water (10 mL) was added to quench, and ethyl acetate (50 mL) was used for extraction. The ethyl acetate phase was saturated with common salt. Washed with water, dried, concentrated, and purified by preparative chromatography to give 22-g (100 mg, yield: 72%).
1H NMR(400MHz，DMSO-d 6)δ7.96(d，J＝8.3Hz，2H)，7.53(d，J＝8.2Hz，2H)，7.37(d，J＝8.0 Hz，1H)，7.19(d，J＝7.9Hz，1H)，6.93(s，1H)，5.11(s，2H)，3.84(s，3H)，3.67(t，J＝6.9Hz，2H)，3.43(t，J＝6.9Hz，2H)，1.81(t，J＝18.8Hz，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.96 (d, J=8.3 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.19 (d, J=7.9Hz, 1H), 6.93 (s, 1H), 5.11 (s, 2H), 3.84 (s, 3H), 3.67 (t, J=6.9Hz, 2H), 3.43 (t, J= 6.9Hz, 2H), 1.81(t, J=18.8Hz, 3H).
步骤7Step 7
将22-g(100mg，0.25mmol)溶于四氢呋喃/甲醇(1mL/1mL)中得混合溶液，加入氢氧化钠(41mg，1mmol)和羟胺水溶液(0.5mL)。在室温下搅拌反应1小时。反应完成后，Pre-HPLC纯化得化合物22(70mg，71％)。22-g (100 mg, 0.25 mmol) was dissolved in tetrahydrofuran/methanol (1 mL/1 mL) to obtain a mixed solution, and sodium hydroxide (41 mg, 1 mmol) and hydroxylamine aqueous solution (0.5 mL) were added. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, Pre-HPLC purification gave compound 22 (70 mg, 71%).
1H NMR(400MHz，DMSO-d 6)δ7.72(d，J＝8.3Hz，2H)，7.43(d，J＝8.2Hz，2H)，7.36(d，J＝8.0Hz，1H)，7.19(d，J＝7.9Hz，1H)，6.97(s，1H)，5.06(s，2H)，3.64(t，J＝6.9Hz，2H)，3.42(t，J＝6.7Hz，2H)，1.82(t，J＝18.8Hz，3H).LC-MS m/z[M-H] -：395.4. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.72 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.19 (d, J=7.9Hz, 1H), 6.97 (s, 1H), 5.06 (s, 2H), 3.64 (t, J=6.9Hz, 2H), 3.42 (t, J=6.7Hz, 2H), 1.82 (t, J=18.8 Hz, 3H). LC-MS m/z [MH] − : 395.4.
实施例25：N-(1-(4-(羟基氨甲酰基)苄基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-6-基)烟酰胺(化合物25)的制备Example 25: N-(1-(4-(Hydroxycarbamoyl)benzyl)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazine Preparation of -6-yl)nicotinamide (compound 25)
Figure PCTCN2022087060-appb-000045
Figure PCTCN2022087060-appb-000045
步骤1step 1
10-b(100mg，0.29mmol)溶入吡啶(10mL)中，加入烟酸酰氯盐酸盐(63mg，0.35mmol)，在室温下搅拌16h。减压浓缩，柱色谱法纯化后得到白色固体25-b(120mg，收率92％)。10-b (100 mg, 0.29 mmol) was dissolved in pyridine (10 mL), nicotinic acid chloride hydrochloride (63 mg, 0.35 mmol) was added, and the mixture was stirred at room temperature for 16 h. It was concentrated under reduced pressure and purified by column chromatography to obtain 25-b as a white solid (120 mg, yield 92%).
LC-MS m/z[M+H] +：452.1. LC-MS m/z[M+H] + : 452.1.
步骤2Step 2
25-b(120mg，0.27mmol)溶入四氢呋喃/甲醇(2mL/2mL)中，加入氢氧化钠(42mg，1.06mmol)和羟胺溶液(1.0mL)，在室温下搅拌1h。减压浓缩，柱色谱法纯化后得到白色固体25(90mg，收率75％)。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%).
1H NMR(DMSO-d 6，400MHz)：δ11.22(s，1H)，10.44(s，1H)，9.11(s，1H)，9.10(s，1H)，8.78(d，J＝8.0Hz，1H)，8.29(d，J＝8.0Hz，2H)，7.76(d，J＝4.0Hz，2H)，7.71(s，1H)，7.61-7.58(m，1H)，7.55-7.52(m，1H)，7.46(d，J＝8.0Hz，2H)，5.03(s，2H)，3.61(t，J＝8.0Hz，2H)，3.41(t，J＝8.0Hz，2H).LC-MS m/z[M+H] +：453.1. 1 H NMR (DMSO-d 6 , 400MHz): δ 11.22 (s, 1H), 10.44 (s, 1H), 9.11 (s, 1H), 9.10 (s, 1H), 8.78 (d, J=8.0Hz , 1H), 8.29(d, J=8.0Hz, 2H), 7.76(d, J=4.0Hz, 2H), 7.71(s, 1H), 7.61-7.58(m, 1H), 7.55-7.52(m, 1H), 7.46(d, J=8.0Hz, 2H), 5.03(s, 2H), 3.61(t, J=8.0Hz, 2H), 3.41(t, J=8.0Hz, 2H).LC-MS m /z[M+H] + : 453.1.
实施例27：4-((6-(环丙基甲酰氨基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物27)的制备Example 27: 4-((6-(Cyclopropylcarboxamido)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazine-1- Preparation of methyl)-N-hydroxybenzamide (compound 27)
Figure PCTCN2022087060-appb-000046
Figure PCTCN2022087060-appb-000046
步骤1step 1
把10-b(100mg，0.29mmol)溶于二氯甲烷(5.0mL)中，加入环丙基甲酰氯(60mg，0.58mmol)和碳酸钾(121mg，0.87mmol)，在室温下反应3小时。TLC监测反应完成后，加入水和乙酸乙酯萃取，有机相减压浓缩，柱色谱法纯化后得到27-b(80mg，收率67％)。10-b (100 mg, 0.29 mmol) was dissolved in dichloromethane (5.0 mL), cyclopropylcarbonyl chloride (60 mg, 0.58 mmol) and potassium carbonate (121 mg, 0.87 mmol) were added, and the mixture was reacted at room temperature for 3 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 27-b (80 mg, yield 67%).
1H NMR(400MHz，DMSO-d 6)δ8.0(d，J＝8.0Hz，2H)，7.57(s，1H)，7.41-7.39(m，3H)，7.07(dd，J＝8Hz，1H)，6.72(d，J＝8Hz，1H)，5.00(s，2H)，3.90(s，3H)，3.41(t，J＝8.0Hz，2H)，3.26(t，J＝8.0Hz，2H)，1.50-1.45(m，1H)，1.08-1.04(m，2H)，0.88-0.82(m，2H).LC-MS m/z[M+H] +：415.1 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.0 (d, J=8.0 Hz, 2H), 7.57 (s, 1H), 7.41-7.39 (m, 3H), 7.07 (dd, J=8 Hz, 1H) ), 6.72(d, J=8Hz, 1H), 5.00(s, 2H), 3.90(s, 3H), 3.41(t, J=8.0Hz, 2H), 3.26(t, J=8.0Hz, 2H) , 1.50-1.45 (m, 1H), 1.08-1.04 (m, 2H), 0.88-0.82 (m, 2H). LC-MS m/z [M+H] + : 415.1
步骤2Step 2
把27-b(80mg，0.19mmol)溶于四氢呋喃(1.0mL)和甲醇(1.0mL)中，加入羟胺水溶液(0.5mL)和氢氧化钠(30mg，0.76mmol)，在室温下反应2小时。TLC监测反应完成后，反应减压浓缩，柱色谱法纯化后得到27(50mg，收率63％)。27-b (80 mg, 0.19 mmol) was dissolved in tetrahydrofuran (1.0 mL) and methanol (1.0 mL), hydroxylamine aqueous solution (0.5 mL) and sodium hydroxide (30 mg, 0.76 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 27 (50 mg, yield 63%).
1H NMR(400MHz，DMSO-d 6)δ10.19(s，1H)，7.74(d，2H)，7.54(s，1H)，7.41(d，J＝8Hz，2H)，7.32(d，J＝8Hz，1H)，6.83(d，J＝8Hz，1H)，5.0(s，2H)，3.54(m，2H)，3.38(m，2H)，1.75(m，1H)，0.79 (m，4H).LC-MS m/z[M+H] +：416.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.19 (s, 1H), 7.74 (d, 2H), 7.54 (s, 1H), 7.41 (d, J=8Hz, 2H), 7.32 (d, J =8Hz, 1H), 6.83(d, J=8Hz, 1H), 5.0(s, 2H), 3.54(m, 2H), 3.38(m, 2H), 1.75(m, 1H), 0.79(m, 4H ).LC-MS m/z[M+H] + : 416.1.
实施例29和实施例30：4-((6-(二甲基氨基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物29)和N-羟基-4-((6-(甲基氨基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)苯甲酰胺(化合物30)的制备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)
Figure PCTCN2022087060-appb-000047
Figure PCTCN2022087060-appb-000047
步骤1step 1
将1-b(700mg，2.11mmol)、乙酸酐(15mL)和浓硝酸(300mg，3.16mmol)加入反应瓶中，40℃反应过夜。加入饱和碳酸氢钠水溶液和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到29-b(600mg，产率：75％)。1-b (700 mg, 2.11 mmol), acetic anhydride (15 mL) and concentrated nitric acid (300 mg, 3.16 mmol) were added to the reaction flask and reacted at 40°C overnight. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added, and the mixture was extracted by liquid separation. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain 29-b (600 mg, yield: 75%).
步骤2Step 2
29-b(600mg，0.68mmol)、四氢呋喃(20mL)和氢气在室温下反应16小时，过滤得滤液，将滤液减压浓缩得到29-c(525mg，产率：95％)。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%).
步骤3Step 3
29-c(200mg，0.58mmol)、碳酸钾(240mg，1.74mmol)、DMF(5mL)和碘甲烷(180mg，1.27mmol)加入反应瓶中，在室温下反应过夜，加入饱和食盐水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到29-d1(70mg，产率：34％)和29-d2(70mg，产率：33％)29-c (200 mg, 0.58 mmol), potassium carbonate (240 mg, 1.74 mmol), DMF (5 mL) and methyl iodide (180 mg, 1.27 mmol) were added to the reaction flask, and the reaction was carried out at room temperature overnight, and saturated brine and ethyl acetate were added. The ester was extracted and separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 29-d1 (70 mg, yield: 34%) and 29-d2 (70 mg, yield: 33%)
步骤4Step 4
29-d1(70mg，0.07mmol)、四氢呋喃(1mL)和甲醇(1mL)在0℃下搅拌，加入氢氧化钠(11mg，0.28mmol)和羟胺水溶液(1mL)，在室温下反应40分钟，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到30(38mg，产率：54％)。29-d1 (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 30 (38 mg, yield: 54%).
1H NMR(400MHz，DMSO-d 6)δ11.18(s，1H)，9.03(s，1H)，7.71(d，J＝8.2Hz，2H)，7.38(d，J＝8.1Hz，2H)，6.66(d，J＝8.6Hz，1H)，6.40-6.31(m，2H)，5.53(d，J＝5.0Hz，1H)，4.82(s，2H)，3.38(t，J＝6.1Hz，2H)，3.20(t，J＝7.0Hz，2H)，2.61(d，J＝4.5Hz，3H).LC-MS m/z[M+H] +：362。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 9.03 (s, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H) , 6.66(d, J=8.6Hz, 1H), 6.40-6.31(m, 2H), 5.53(d, J=5.0Hz, 1H), 4.82(s, 2H), 3.38(t, J=6.1Hz, 2H), 3.20 (t, J=7.0 Hz, 2H), 2.61 (d, J=4.5 Hz, 3H). LC-MS m/z [M+H] + : 362.
29-d2(70mg，0.07mmol)、四氢呋喃(1mL)和甲醇(1mL)在0℃下搅拌，加入氢氧化钠(11mg，0.28mmol)和羟胺水溶液(1mL)，在室温下反应40分钟，加入水和乙酸乙酯，萃取分液，有机相用无水硫酸钠干燥，减压浓缩，柱色谱法纯化得到29(41mg，产率：58％)。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%).
1H NMR(400MHz，DMSO-d 6)δ11.18(s，1H)，9.03(s，1H)，7.71(d，J＝8.2Hz，2H)，7.39(d，J＝8.2Hz，2H)，6.71(d，J＝9.3Hz，1H)，6.57(d，J＝7.7Hz，2H)，4.86(s，2H)，3.44(t，J＝6.9Hz，2H)，3.27(t，J＝6.8Hz，2H)，2.81(s，6H).LC-MS m/z[M+H] +：376。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 9.03 (s, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H) , 6.71(d, J=9.3Hz, 1H), 6.57(d, J=7.7Hz, 2H), 4.86(s, 2H), 3.44(t, J=6.9Hz, 2H), 3.27(t, J= 6.8 Hz, 2H), 2.81 (s, 6H). LC-MS m/z [M+H] + : 376.
实施例32：N-羟基-4-((6-甲基-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)苯甲酰胺(化合物32)的制备Example 32: N-Hydroxy-4-((6-methyl-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl) Preparation of methyl)benzamide (compound 32)
Figure PCTCN2022087060-appb-000048
Figure PCTCN2022087060-appb-000048
步骤1step 1
7-b(200mg，0.49mmol)、甲基硼酸(59mg，0.98mmol)、磷酸钾(311mg，1.47mmol)、醋酸钯(11mg，0.049mmol)和三环己基膦(27mg，0.098mmol)加入到甲苯(10mL)和水(1mL)中，氮气保护，100℃加热16小时。加入水和乙酸乙酯萃取，干燥，浓缩，柱色谱法纯化，得到产品32-b(130mg，产率：77％)。7-b (200 mg, 0.49 mmol), methylboronic acid (59 mg, 0.98 mmol), potassium phosphate (311 mg, 1.47 mmol), palladium acetate (11 mg, 0.049 mmol) and tricyclohexylphosphine (27 mg, 0.098 mmol) were added to Toluene (10 mL) and water (1 mL), under nitrogen, heated at 100°C for 16 hours. Water and ethyl acetate were added for extraction, dried, concentrated, and purified by column chromatography to obtain the product 32-b (130 mg, yield: 77%).
1H NMR(400MHz，DMSO-d 6)δ7.94(d，J＝8.2Hz，2H)，7.50(d，J＝8.2Hz，2H)，7.05(s，1H)，6.95(d，J＝8.2Hz，1H)，6.70(d，J＝8.4Hz，1H)，5.00(s，2H)，3.84(s，3H)，3.56(t，J＝6.8Hz，2H)，3.32(d，J＝8.4Hz，2H)，2.20(s，3H).LC-MS m/z[M+H] +：346.3 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.94 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.05 (s, 1H), 6.95 (d, J= 8.2Hz, 1H), 6.70(d, J=8.4Hz, 1H), 5.00(s, 2H), 3.84(s, 3H), 3.56(t, J=6.8Hz, 2H), 3.32(d, J= 8.4Hz, 2H), 2.20 (s, 3H). LC-MS m/z [M+H] + : 346.3
步骤2Step 2
将32-b(130mg，0.38mmol)加入至四氢呋喃(3mL)和甲醇(3mL)中，然后加入氢氧化钠(60mg，1.12mmol)和羟胺水溶液(0.4mL)，在室温下搅拌0.5小时，浓缩，用Pre-HPLC制备纯化得到白色固体产品32(16mg，产率：12.3％).32-b (130 mg, 0.38 mmol) was added to tetrahydrofuran (3 mL) and methanol (3 mL), then sodium hydroxide (60 mg, 1.12 mmol) and hydroxylamine aqueous solution (0.4 mL) were added, stirred at room temperature for 0.5 h, and concentrated , and purified by Pre-HPLC to obtain 32 as a white solid product (16 mg, yield: 12.3%).
1H NMR(400MHz，DMSO-d 6)δ11.19(s，1H)，9.04(s，1H)，7.71(d，J＝8.2Hz，2H)，7.41(d，J＝8.2Hz，2H)，7.05(s，1H)，6.96(d，J＝8.4Hz，1H)，6.72(d，J＝8.4Hz，1H)，4.96(s，2H)，3.55(t，J＝6.8Hz，2H)，3.32(d，J＝7.0Hz，2H)，2.20(s，3H).LC-MS m/z[M+H] +：347.1。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.19 (s, 1H), 9.04 (s, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H) , 7.05(s, 1H), 6.96(d, J=8.4Hz, 1H), 6.72(d, J=8.4Hz, 1H), 4.96(s, 2H), 3.55(t, J=6.8Hz, 2H) , 3.32 (d, J=7.0 Hz, 2H), 2.20 (s, 3H). LC-MS m/z [M+H] + : 347.1.
实施例33：N-羟基-4-((7-甲基-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)苯甲酰胺(化合物33)的制备Example 33: N-Hydroxy-4-((7-methyl-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazin-1-yl) Preparation of methyl)benzamide (compound 33)
Figure PCTCN2022087060-appb-000049
Figure PCTCN2022087060-appb-000049
步骤1step 1
33-a(1.8g，16.08mmol)、氯磺酰基乙酸乙酯(2.5g，13.40mmol)和三乙胺(3.8mL，26.80mmol)在二氯甲烷(20mL)中溶解，室温下搅拌2h。TLC监测表明反应完成后，用1N盐酸洗去多余间甲基苯胺和三乙胺，减压浓缩得到粗品33-b。33-a (1.8 g, 16.08 mmol), ethyl chlorosulfonyl acetate (2.5 g, 13.40 mmol) and triethylamine (3.8 mL, 26.80 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 2 h. After TLC monitoring indicated that the reaction was completed, excess m-toluidine and triethylamine were washed off with 1N hydrochloric acid, and concentrated under reduced pressure to obtain crude product 33-b.
1H NMR(CDCl 3，400MHz)：δ7.31-7.27(m，1H)，7.18-7.15(m，2H)，6.93(s，1H)，4.33-4.29(m，2H)，4.04(m，2H)，2.40(s，3H)，1.38-1.35(m，3H).[M+H] +：258.1 1 H NMR (CDCl 3 , 400 MHz): δ 7.31-7.27 (m, 1H), 7.18-7.15 (m, 2H), 6.93 (s, 1H), 4.33-4.29 (m, 2H), 4.04 (m, 2H), 2.40 (s, 3H), 1.38-1.35 (m, 3H). [M+H] + : 258.1
步骤2Step 2
33-b(4.8g粗品，18.66mmol)和氢氧化钠(3.7g，93.30mmol)溶入甲醇和水(40mL/20mL)中，室温下搅拌16h。TLC监测表明反应完成后，3N盐酸调节pH＝4，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，减压浓缩，得到粗品33-c。33-b (4.8 g crude product, 18.66 mmol) and sodium hydroxide (3.7 g, 93.30 mmol) were dissolved in methanol and water (40 mL/20 mL) and stirred at room temperature for 16 h. After TLC monitoring showed that the reaction was completed, 3N hydrochloric acid was adjusted to pH=4, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 33-c.
1H NMR(CDCl 3，400MHz)：δ7.31-7.27(m，1H)，7.18-7.10(m，3H)，3.97(s，2H)，2.40(s，2H)，1.37(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz): δ 7.31-7.27 (m, 1H), 7.18-7.10 (m, 3H), 3.97 (s, 2H), 2.40 (s, 2H), 1.37 (t, J= 8.0Hz, 3H).
步骤3Step 3
33-c(2.0g，8.74mmol)溶解到二氯甲烷(20mL)中，在0℃下加入草酰氯(1.12mL，13.10mmol)和10滴DMF，室温搅拌2h。TLC监测表明反应完成后，将反应物减压浓缩得到粗品33-d。33-c (2.0 g, 8.74 mmol) was dissolved in dichloromethane (20 mL), oxalyl chloride (1.12 mL, 13.10 mmol) and 10 drops of DMF were added at 0°C, and the mixture was stirred at room temperature for 2 h. After TLC monitoring indicated that the reaction was complete, the reaction was concentrated under reduced pressure to obtain crude 33-d.
步骤4Step 4
33-d(2.0g，8.74mmol)溶解到二氯甲烷(20mL)中，在0℃下加入氯化铝(5.83g，43.70mmol)，室温搅拌16h。TLC监测表明反应完成后，1N盐酸淬灭反应，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得到粗品33-e。33-d (2.0 g, 8.74 mmol) was dissolved in dichloromethane (20 mL), aluminum chloride (5.83 g, 43.70 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 16 h. After TLC monitoring indicated that the reaction was completed, the reaction was quenched with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 33-e.
1H NMR(DMSO-d 6，400MHz)：δ11.40(s，1H)，7.83(d，J＝8.0Hz，1H)，7.05(d，J＝8.0Hz，1H)，6.91(s，1H)，4.76(s，2H)，2.38(s，3H). 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.40 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.91 (s, 1H) ), 4.76(s, 2H), 2.38(s, 3H).
步骤5Step 5
33-e(1.0g，4.74mmol)溶解到甲醇(10mL)中，在0℃下加入硼氢化钠(540mg，14.22mmol)，室温搅拌2h。TLC监测表明反应完成后，加水淬灭反应，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得到粗品33-f。33-e (1.0 g, 4.74 mmol) was dissolved in methanol (10 mL), sodium borohydride (540 mg, 14.22 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 h. After TLC monitoring showed that the reaction was completed, the reaction was quenched by adding water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 33-f.
步骤6Step 6
33-f(1.0g，4.74mmol)溶入三氟醋酸(10mL)中，加入三乙基硅烷(5.5g，47.40mmol)，在50℃下搅拌2h。减压浓缩。柱色谱法纯化后得到白色固体33-g(420mg，收率45％)。33-f (1.0 g, 4.74 mmol) was dissolved in trifluoroacetic acid (10 mL), triethylsilane (5.5 g, 47.40 mmol) was added, and the mixture was stirred at 50° C. for 2 h. Concentrate under reduced pressure. After purification by column chromatography, 33-g (420 mg, 45% yield) was obtained as a white solid.
步骤7Step 7
33-g(420mg，2.13mmol)溶入甲醇(5mL)中，加入钯碳(50mg，10％wt)，置换氢气，在室温下搅拌16h。过滤，减压浓缩，得到白色固体33-h(420mg，收率100％)。33-g (420 mg, 2.13 mmol) was dissolved in methanol (5 mL), palladium on carbon (50 mg, 10% wt) was added, hydrogen was replaced, and the mixture was stirred at room temperature for 16 h. Filtration and concentration under reduced pressure gave 33-h as a white solid (420 mg, 100% yield).
1H NMR(DMSO-d 6，400MHz)：δ10.03(s，1H)，7.10(d，J＝4.0Hz，1H)，6.81(d，J＝4.0Hz，1H)，6.58(s，1H)，3.38-3.26(m，4H)，2.24(s，3H). 1 H NMR (DMSO-d 6 , 400 MHz): δ 10.03 (s, 1H), 7.10 (d, J=4.0 Hz, 1H), 6.81 (d, J=4.0 Hz, 1H), 6.58 (s, 1H) ), 3.38-3.26(m, 4H), 2.24(s, 3H).
步骤8Step 8
33-h(100mg，0.50mmol)溶入DMF(10mL)中，加入碳酸钾(138mg，1.0mmol)和4-(溴甲基)苯甲酸甲酯(138mg，0.60mmol)，在室温下搅拌16h。乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩。柱色谱法纯化后得到白色固体33-i(140mg，收率80％)。33-h (100 mg, 0.50 mmol) was dissolved in DMF (10 mL), potassium carbonate (138 mg, 1.0 mmol) and methyl 4-(bromomethyl)benzoate (138 mg, 0.60 mmol) were added, and the mixture was stirred at room temperature for 16 h . It was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification by column chromatography, 33-i (140 mg, 80% yield) was obtained as a white solid.
1H NMR(DMSO-d 6，400MHz)：δ8.05(d，J＝4.0Hz，2H)，8.08(d，J＝8.0Hz，2H)，7.09(d，J＝8.0Hz，1H)，6.88(d，J＝4.0Hz，1H)，6.64(s，1H)，5.07(s，2H)，3.95(s，3H)，3.47-3.45(m，2H)，3.33-3.29(m，2H)，2.24(s，3H). 1 H NMR (DMSO-d 6 , 400 MHz): δ 8.05 (d, J=4.0 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 1H), 6.88(d, J=4.0Hz, 1H), 6.64(s, 1H), 5.07(s, 2H), 3.95(s, 3H), 3.47-3.45(m, 2H), 3.33-3.29(m, 2H) , 2.24(s, 3H).
步骤9Step 9
33-i(140mg，0.41mmol)溶入四氢呋喃/甲醇(5mL/5mL)中，加入氢氧化钠(65mg，1.62mmol)和羟胺溶液(1.0mL)，在室温下搅拌1h。减压浓缩。柱色谱法纯化后得到白色固体形式的化合物33(100mg，收率70％)。33-i (140 mg, 0.41 mmol) was dissolved in tetrahydrofuran/methanol (5 mL/5 mL), sodium hydroxide (65 mg, 1.62 mmol) and hydroxylamine solution (1.0 mL) were added, and the mixture was stirred at room temperature for 1 h. Concentrate under reduced pressure. After purification by column chromatography, compound 33 (100 mg, 70% yield) was obtained as a white solid.
1H NMR(DMSO-d 6，400MHz)：δ11.25(s，1H)，9.07(s，1H)，7.75(d，J＝8.0Hz，2H)，7.45(d，J＝8.0Hz，2H)，7.13(d，J＝8.0Hz，1H)，6.87(d，J＝8.0Hz，1H)，6.70(s，1H)，5.02(s，2H)，3.59-3.56(m，2H)，3.38-3.33(m，2H)，2.18(s，3H).LC-MS m/z[M+H] +：347.2. 1 H NMR (DMSO-d 6 , 400 MHz): δ 11.25 (s, 1H), 9.07 (s, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H) ), 7.13(d, J=8.0Hz, 1H), 6.87(d, J=8.0Hz, 1H), 6.70(s, 1H), 5.02(s, 2H), 3.59-3.56(m, 2H), 3.38 -3.33 (m, 2H), 2.18 (s, 3H). LC-MS m/z [M+H] + : 347.2.
实施例34：(Z)-N-羟基-4-((4-(肟基)-7-甲基-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)苯甲酰胺(化合物34)的制备Example 34: (Z)-N-Hydroxy-4-((4-(oximino)-7-methyl-2,2-dioxy-3,4-dihydro-1H-benzo[c][ Preparation of 1,2]thiazin-1-yl)methyl)benzamide (compound 34)
Figure PCTCN2022087060-appb-000050
Figure PCTCN2022087060-appb-000050
步骤1step 1
33-e(100mg，0.47mmol)溶入二氯甲烷(10mL)中，加入DIPEA(120mg，0.95mmol)和4-(溴甲基) 苯甲酸甲酯(118mg，0.51mmol)，在室温下搅拌16h。减压浓缩，柱色谱法纯化后得到白色固体(140mg，收率80％)。33-e (100 mg, 0.47 mmol) was dissolved in dichloromethane (10 mL), DIPEA (120 mg, 0.95 mmol) and methyl 4-(bromomethyl)benzoate (118 mg, 0.51 mmol) were added, and the mixture was stirred at room temperature 16h. It was concentrated under reduced pressure and purified by column chromatography to obtain a white solid (140 mg, 80% yield).
1H NMR(CDCl 3，400MHz)：δ8.09-8.06(m，3H)，7.47(d，J＝8.0Hz，2H)，7.09(d，J＝8.0Hz，1H)，6.86(s，1H)，5.24(s，2H)，4.31(s，2H)，3.96(s，3H)，2.36(s，3H). 1 H NMR (CDCl 3 , 400 MHz): δ 8.09-8.06 (m, 3H), 7.47 (d, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 1H), 6.86 (s, 1H) ), 5.24(s, 2H), 4.31(s, 2H), 3.96(s, 3H), 2.36(s, 3H).
步骤2Step 2
34-b(140mg，0.41mmol)溶入四氢呋喃/甲醇(5mL/5mL)中，加入氢氧化钠(65mg，1.62mmol)和羟胺溶液(1.0mL)，在室温下搅拌1h。减压浓缩，柱色谱法纯化后得到白色固体(100mg，收率70％)。34-b (140 mg, 0.41 mmol) was dissolved in tetrahydrofuran/methanol (5 mL/5 mL), sodium hydroxide (65 mg, 1.62 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 obtain a white solid (100 mg, yield 70%).
1H NMR(CD 3OD，400MHz)：δ7.96(d，J＝8.0Hz，1H)，7.76(d，J＝8.0Hz，2H)，7.47(d，J＝4.0Hz，2H)，7.01(d，J＝8.0Hz，1H)，6.92(s，1H)，5.10(s，2H)，4.49(s，2H)，2.29(s，3H).LC-MS m/z[M+H] +：376.2. 1 H NMR (CD 3 OD, 400 MHz): δ 7.96 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.47 (d, J=4.0 Hz, 2H), 7.01 (d, J=8.0Hz, 1H), 6.92(s, 1H), 5.10(s, 2H), 4.49(s, 2H), 2.29(s, 3H). LC-MS m/z[M+H] + : 376.2.
实施例35：N-羟基-4-((6-(1-甲基-1H-吡唑-4-基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)苯甲酰胺(化合物35)的制备Example 35: N-Hydroxy-4-((6-(1-methyl-1H-pyrazol-4-yl)-2,2-dioxy-3,4-dihydro-1H-benzo[c Preparation of ][1,2]thiazin-1-yl)methyl)benzamide (compound 35)
Figure PCTCN2022087060-appb-000051
Figure PCTCN2022087060-appb-000051
步骤1step 1
将7-b(100mg，0.24mmol)、35-a(56mg，0.27mmol)、碳酸钾(83mg，0.6mmol)、1，1′-双二苯基膦二茂铁二氯化钯(22mg，0.03mmol)加入至1，4-二氧六环(2mL)和水(0.4mL)中，氮气保护下80℃反应五个小时，加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到35-b(55mg，产率：55％)。7-b (100 mg, 0.24 mmol), 35-a (56 mg, 0.27 mmol), potassium carbonate (83 mg, 0.6 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (22 mg, 0.03 mmol) was added to 1,4-dioxane (2 mL) and water (0.4 mL), reacted at 80° C. for five hours under nitrogen protection, added water and ethyl acetate, and extracted by liquid separation. Drying over sodium sulfate, concentration, and purification by column chromatography gave 35-b (55 mg, yield: 55%).
步骤2Step 2
35-b(55mg，0.13mmol)加入甲醇(1mL)、四氢呋喃(1mL)和水(0.5mL)，0℃下加入氢氧化钠(21mg，0.52mmol)和羟胺水溶液(1mL)，搅拌10分钟后升温至室温反应50分钟，反应液用稀盐酸调pH为7到8，加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到35(30mg，产率：54％)。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%).
1H NMR(400MHz，DMSO-d 6)δ11.18(s，1H)，9.04(s，1H)，8.04(s，1H)，7.78(s，1H)，7.72(d，J＝8.3Hz，2H)，7.44(d，J＝8.1Hz，3H)，7.33(dd，J＝8.5，1.8Hz，1H)，6.81(d，J＝8.6Hz，1H)，5.01(s，2H)，3.83(s，3H)，3.61(t，J＝6.9Hz，2H)，3.39(t，J＝6.8Hz，2H).LC-MS m/z[M+H] +：413。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 9.04 (s, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 7.72 (d, J=8.3 Hz, 2H), 7.44(d, J=8.1Hz, 3H), 7.33(dd, J=8.5, 1.8Hz, 1H), 6.81(d, J=8.6Hz, 1H), 5.01(s, 2H), 3.83( s, 3H), 3.61 (t, J=6.9 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H). LC-MS m/z [M+H] + : 413.
实施例36：4-((6-(1-乙基-1H-吡唑-4-基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物36)的制备Example 36: 4-((6-(1-Ethyl-1H-pyrazol-4-yl)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1, 2] Preparation of thiazin-1-yl)methyl)-N-hydroxybenzamide (compound 36)
Figure PCTCN2022087060-appb-000052
Figure PCTCN2022087060-appb-000052
步骤1step 1
将7-b(100mg，0.24mmol)、36-a(60mg，0.27mmol)、碳酸钾(83mg，0.6mmol)和1，1′-双二苯基膦二茂铁二氯化钯(22mg，0.03mmol)加入至1，4-二氧六环(2mL)和水(0.4mL)中，氮气保护下80℃反应五个小时，加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到36-b(54mg，产率：52％)。7-b (100 mg, 0.24 mmol), 36-a (60 mg, 0.27 mmol), potassium carbonate (83 mg, 0.6 mmol) and 1,1′-bisdiphenylphosphinoferrocene palladium dichloride (22 mg, 0.03 mmol) was added to 1,4-dioxane (2 mL) and water (0.4 mL), reacted at 80° C. for five hours under nitrogen protection, added water and ethyl acetate, and extracted by liquid separation. Drying over sodium sulfate, concentration, and purification by column chromatography gave 36-b (54 mg, yield: 52%).
步骤2Step 2
36-b(54mg，0.13mmol)加入甲醇(1mL)、四氢呋喃(1mL)和水(0.5mL)，0℃下加入氢氧化钠(21mg，0.52mmol)和羟胺水溶液(1mL)，搅拌10分钟后升温至室温反应50分钟，反应液用稀盐酸调PH为7到8，加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到化合物36(30mg，产率：55％)。36-b (54 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 reaction solution was heated to room temperature 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, and liquid separation was performed. The organic phase was dried with anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain compound 36 ( 30 mg, yield: 55%).
1H NMR(400MHz，DMSO-d 6)δ11.20(s，1H)，9.05(s，1H)，8.10(s，1H)，7.79(s，1H)，7.72(d，J＝8.2Hz，2H)，7.49-7.40(m，3H)，7.34(dd，J＝8.5，1.8Hz，1H)，6.81(d，J＝8.6Hz，1H)，5.01(s，2H)，4.11(q，J＝7.3Hz，2H)，3.60(t，J＝6.9Hz，2H)，3.39(t，J＝6.8Hz，2H)，1.38(t，J＝7.3Hz，3H).LC-MS m/z[M+H] +：427。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 9.05 (s, 1H), 8.10 (s, 1H), 7.79 (s, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.49-7.40(m, 3H), 7.34(dd, J=8.5, 1.8Hz, 1H), 6.81(d, J=8.6Hz, 1H), 5.01(s, 2H), 4.11(q, J =7.3Hz, 2H), 3.60(t, J=6.9Hz, 2H), 3.39(t, J=6.8Hz, 2H), 1.38(t, J=7.3Hz, 3H).LC-MS m/z[ M+H] + : 427.
实施例37：4-((6-(1-苄基-1H-吡唑-4-基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)-N-羟基苯甲酰胺(化合物37)的制备Example 37: 4-((6-(1-Benzyl-1H-pyrazol-4-yl)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1, 2] Preparation of thiazin-1-yl)methyl)-N-hydroxybenzamide (compound 37)
Figure PCTCN2022087060-appb-000053
Figure PCTCN2022087060-appb-000053
步骤1step 1
7-b(100mg，0.24mmol)、37-a(77mg，0.27mmol)、碳酸钾(83mg，0.6mmol)，1，1′-双二苯基膦二茂铁二氯化钯(22mg，0.03mmol)加入至1，4-二氧六环(2mL)和水(0.4mL)中，氮气保护下80℃反应五个小时，加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到37-b(61mg，产率：51％)。7-b (100 mg, 0.24 mmol), 37-a (77 mg, 0.27 mmol), potassium carbonate (83 mg, 0.6 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (22 mg, 0.03 mmol) was added to 1,4-dioxane (2 mL) and water (0.4 mL), reacted at 80 °C for five hours under nitrogen protection, added water and ethyl acetate, and extracted by liquid separation. Drying over sodium, concentration, and purification by column chromatography gave 37-b (61 mg, yield: 51%).
步骤2Step 2
37-b(61mg，0.12mmol)加入至甲醇(1mL)、四氢呋喃(1mL)和水(0.5mL)，0℃下加入氢氧化钠(19mg，0.48mmol)和羟胺水溶液(1mL)，搅拌10分钟后升温至室温反应50分钟，反应液用稀盐酸调pH为7到8，加入水和乙酸乙酯，分液萃取，有机相用无水硫酸钠干燥，浓缩，然后柱色谱法纯化得到37(30mg，产率：41％)。37-b (61 mg, 0.12 mmol) was added to methanol (1 mL), tetrahydrofuran (1 mL) and water (0.5 mL), sodium hydroxide (19 mg, 0.48 mmol) and hydroxylamine aqueous solution (1 mL) were added at 0°C, and stirred for 10 minutes After being warmed up to room temperature and reacting 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 for liquid separation extraction, the organic phase was dried with anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain 37( 30 mg, yield: 41%).
1H NMR(400MHz，DMSO-d 6)δ11.15(s，1H)，9.09(s，1H)，8.20(s，1H)，7.84(s，1H)，7.71(d，J＝8.2Hz，2H)，7.47(s，1H)，7.42(d，J＝8.2Hz，2H)，7.29(m，6H)，6.82(d，J＝8.6Hz，1H)，5.32(s，2H)，5.00(s，2H)，3.59(t，J＝6.9Hz，2H)，3.39(d，J＝6.7Hz，2H).LC-MS m/z[M+H] +：489。 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.15 (s, 1H), 9.09 (s, 1H), 8.20 (s, 1H), 7.84 (s, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.47(s, 1H), 7.42(d, J=8.2Hz, 2H), 7.29(m, 6H), 6.82(d, J=8.6Hz, 1H), 5.32(s, 2H), 5.00( s, 2H), 3.59 (t, J=6.9 Hz, 2H), 3.39 (d, J=6.7 Hz, 2H). LC-MS m/z [M+H] + : 489.
实施例38：N-羟基-4-((7-(1-羟乙基)-2，2-二氧化-3，4-二氢-1H-苯并[c][1，2]噻嗪-1-基)甲基)苯甲酰胺(化合物38)的制备Example 38: N-Hydroxy-4-((7-(1-hydroxyethyl)-2,2-dioxy-3,4-dihydro-1H-benzo[c][1,2]thiazine Preparation of -1-yl)methyl)benzamide (compound 38)
Figure PCTCN2022087060-appb-000054
Figure PCTCN2022087060-appb-000054
步骤1step 1
将22-d(150mg，0.59mmol)溶于甲醇(10mL)，加入湿钯碳(15mg，10％wt)，置换氢气后，在室温下搅拌过夜。反应完成后，过滤，旋干，经柱色谱法纯化得38-a(45mg，产率：34％)。22-d (150 mg, 0.59 mmol) was dissolved in methanol (10 mL), wet palladium on carbon (15 mg, 10% wt) was added, hydrogen was replaced, and the mixture was stirred at room temperature overnight. After the reaction was completed, it was filtered, spun dry, and purified by column chromatography to obtain 38-a (45 mg, yield: 34%).
1H NMR(400MHz，DMSO-d 6)δ10.06(s，1H)，7.14(d，J＝7.9Hz，1H)，6.93(dd，J＝7.9，1.3Hz，1H)，6.79(s，1H)，5.18(d，J＝3.8Hz，1H)，4.66(dd，J＝6.1，3.2Hz，1H)，3.36-3.31(m，2H)，3.30-3.25(m，2H)，1.29(d，J＝6.4Hz，3H).LC-MS m/z[M+H] +：228.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (s, 1H), 7.14 (d, J=7.9 Hz, 1H), 6.93 (dd, J=7.9, 1.3 Hz, 1H), 6.79 (s, 1H), 5.18(d, J=3.8Hz, 1H), 4.66(dd, J=6.1, 3.2Hz, 1H), 3.36-3.31(m, 2H), 3.30-3.25(m, 2H), 1.29(d , J=6.4Hz, 3H).LC-MS m/z[M+H] + : 228.2.
步骤2Step 2
将38-a(40mg，0.18mmol)、4-(溴甲基)苯甲酸甲酯(48mg，0.21mmol)和碳酸钾(73mg，0.53mmol)溶于DMF(2mL)。在室温下搅拌反应1小时，反应完成后，加入乙酸乙酯稀释，饱和碳酸氢钠水溶液洗涤，饱和食盐水洗涤。将有机相干燥，浓缩，残余物经柱色谱法纯化得38-b(50mg，产率：72％)。38-a (40 mg, 0.18 mmol), methyl 4-(bromomethyl)benzoate (48 mg, 0.21 mmol) and potassium carbonate (73 mg, 0.53 mmol) were dissolved in DMF (2 mL). The reaction was stirred at room temperature for 1 hour, and after completion of the reaction, ethyl acetate was added to dilute, and the mixture was washed with saturated aqueous sodium bicarbonate solution and saturated brine. The organic phase was dried, concentrated, and the residue was purified by column chromatography to give 38-b (50 mg, yield: 72%).
1H NMR(400MHz，DMSO-d 6)δ8.01(d，J＝8.2Hz，2H)，7.44(d，J＝8.2Hz，2H)，7.14(d，J＝7.9Hz，1H)，7.02(d，J＝8.0Hz，1H)，6.85(s，1H)，5.07(s，2H)，4.74(dd，J＝6.3，3.2Hz，1H)，3.91(s，3H)，3.46(t，J＝6.9Hz，2H)，3.31(t，J＝7.1Hz，2H)，1.66(d，J＝3.3Hz，1H)，1.34(d，J＝6.4Hz，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.01 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.14 (d, J=7.9 Hz, 1H), 7.02 (d, J=8.0Hz, 1H), 6.85(s, 1H), 5.07(s, 2H), 4.74(dd, J=6.3, 3.2Hz, 1H), 3.91(s, 3H), 3.46(t, J=6.9Hz, 2H), 3.31 (t, J=7.1Hz, 2H), 1.66 (d, J=3.3Hz, 1H), 1.34 (d, J=6.4Hz, 3H).
步骤3Step 3
将38-b(50mg，0.13mmol)溶于甲醇/四氢呋喃(1mL/1mL)的混合溶液，加入氢氧化钠(22mg，0.53mmol)和羟胺水溶液(0.2mL)。在室温下搅拌反应1小时，反应完成后，经制备色谱法纯化得38(40mg，产率：82％)。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%).
1H NMR(400MHz，DMSO-d 6)δ11.19(s，1H)，9.03(s，1H)，7.73(d，J＝8.3Hz，2H)，7.44(d，J＝8.2Hz，2H)，7.16(d，J＝7.9Hz，1H)，6.98(d，J＝7.8Hz，1H)，6.84(s，1H)，5.08(d，J＝4.3Hz，1H)，4.98(s，2H)，4.59-4.52(m，1H)，3.55(t，J＝6.9Hz，2H)，3.34(s，2H)，1.16(d，J＝6.4Hz，3H).LC-MS m/z[M-H]-：375.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.19 (s, 1H), 9.03 (s, 1H), 7.73 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H) , 7.16(d, J=7.9Hz, 1H), 6.98(d, J=7.8Hz, 1H), 6.84(s, 1H), 5.08(d, J=4.3Hz, 1H), 4.98(s, 2H) , 4.59-4.52(m, 1H), 3.55(t, J=6.9Hz, 2H), 3.34(s, 2H), 1.16(d, J=6.4Hz, 3H).LC-MS m/z[MH] -: 375.1.
实施例39：6-((2，2-二氧化-4，5-二氢苯并[c][1，2]硫氮杂
Figure PCTCN2022087060-appb-000055
-1(3H)-基)甲基)-N-羟基烟酰胺(化合物39)的制备 Example 39: 6-((2,2-Dioxy-4,5-dihydrobenzo[c][1,2]thiazepine
Figure PCTCN2022087060-appb-000055
Preparation of -1(3H)-yl)methyl)-N-hydroxynicotinamide (compound 39)
Figure PCTCN2022087060-appb-000056
Figure PCTCN2022087060-appb-000056
步骤1step 1
把Int.-4(60mg，0.3mmol)溶到DMF(1.0mL)中，加入Int.-1(84mg，0.36mmol)和碳酸钾(126mg，0.91mmol)，在室温下反应16小时。TLC监测反应完成后，用乙酸乙酯萃取。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，柱色谱法纯化，得到39-a(50mg，收率46％)。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%).
步骤2Step 2
把39-a(50mg，0.14mmol)溶入四氢呋喃(2mL)和甲醇(2mL)中，加入1mL羟胺水溶液和氢氧化钠(23mg，58mmol)，在25℃下搅拌1h。TLC监测反应完成后，用乙酸乙酯萃取。水相浓缩，柱色谱法纯化得到淡黄色固体39(28mg，收率56％)。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).
1H NMR(400MHz，DMSO-d 6)δ11.33(s，1H)，9.19(s，1H)，8.83(s，1H)，8.30-7.91(m，1H)，7.67-7.45(m，1H)，7.21-7.16(m，4H)，4.92(s，2H)，3.63-3.45(m，2H)，2.91-2.64(m，2H)，2.09-1.86(m，2H).LC-MS m/z[M+H] +：348.4 1 H NMR (400MHz, DMSO-d 6 ) δ 11.33 (s, 1H), 9.19 (s, 1H), 8.83 (s, 1H), 8.30-7.91 (m, 1H), 7.67-7.45 (m, 1H) ), 7.21-7.16(m, 4H), 4.92(s, 2H), 3.63-3.45(m, 2H), 2.91-2.64(m, 2H), 2.09-1.86(m, 2H). LC-MS m/ z[M+H] + : 348.4
实施例40：2-((2，2-二氧化-4，5-二氢苯并[c][1，2]硫氮杂
Figure PCTCN2022087060-appb-000057
-1(3H)-基)甲基)-N-羟基嘧啶-5-甲酰胺(化合物40)的制备 Example 40: 2-((2,2-Dioxy-4,5-dihydrobenzo[c][1,2]thiazepine
Figure PCTCN2022087060-appb-000057
Preparation of -1(3H)-yl)methyl)-N-hydroxypyrimidine-5-carboxamide (Compound 40)
Figure PCTCN2022087060-appb-000058
Figure PCTCN2022087060-appb-000058
步骤1step 1
把Int.-4(100mg，0.51mmol)溶到DMF(1.0mL)中，加入Int.-2(142mg，0.61mmol)和碳酸钾(212mg，1.53mmol)，在室温下反应16小时。TLC监测反应完成后，用乙酸乙酯萃取。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，柱色谱法纯化，得到40-a(100mg，收率56％)。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%).
步骤2Step 2
把40-a(50mg，0.14mmol)溶入四氢呋喃(2mL)和甲醇(2mL)中，加入羟胺水溶液(1mL)和氢氧化钠(23mg，58mmol)，在25℃下搅拌1h。TLC监测反应完成后，用乙酸乙酯萃取。水相浓缩，柱色谱法纯化得到淡黄色固体40(17mg，收率18％)。40-a (50 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), hydroxylamine aqueous solution (1 mL) 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 40 as a pale yellow solid (17 mg, 18% yield).
1H NMR(400MHz，DMSO-d 6)δ11.49(s，1H)，9.37(s，1H)，9.06(s，2H)，7.48(s，1H)，7.30-6.99(m，3H)，5.10(s，2H)，3.69-3.40(m，2H)，3.11-2.72(m，2H)，2.11-1.89(m，2H).LC-MS m/z[M+H] +：349.4 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.49 (s, 1H), 9.37 (s, 1H), 9.06 (s, 2H), 7.48 (s, 1H), 7.30-6.99 (m, 3H), 5.10 (s, 2H), 3.69-3.40 (m, 2H), 3.11-2.72 (m, 2H), 2.11-1.89 (m, 2H). LC-MS m/z [M+H] + : 349.4
实施例41：4-((2，2-二氧化-4，5-二氢苯并[c][1，2]硫氮杂
Figure PCTCN2022087060-appb-000059
-1(3H)-基)甲基)-N-羟基苯甲酰胺(化合物41)的制备 Example 41: 4-((2,2-Dioxy-4,5-dihydrobenzo[c][1,2]thiazepine
Figure PCTCN2022087060-appb-000059
Preparation of -1(3H)-yl)methyl)-N-hydroxybenzamide (compound 41)
Figure PCTCN2022087060-appb-000060
Figure PCTCN2022087060-appb-000060
步骤1step 1
把Int.-4(60mg，0.3mmol)溶到DMF(1.0mL)中，加入4-(溴甲基)苯甲酸甲酯(84mg，0.36mmol)和碳酸钾(126mg，0.91mmol)，在室温下反应16小时。TLC监测反应完成后，用乙酸乙酯萃取。合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，柱色谱法纯化，得到41-a(50mg，收率46％)。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%).
步骤2Step 2
把41-a(50mg，0.14mmol)溶入四氢呋喃(2mL)和甲醇(2mL)中，加入羟胺水溶液(1mL)和氢氧化钠(23mg，58mmol)，在25℃下搅拌1h。TLC监测反应完成后，用乙酸乙酯萃取。水相浓缩，柱色谱法纯化得到淡黄色固体41(28mg，收率58％)。41-a (50 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), hydroxylamine aqueous solution (1 mL) 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 41 as a pale yellow solid (28 mg, 58% yield).
1H NMR(400MHz，DMSO-d 6)δ11.20(s，1H)，9.03(s，1H)，7.74(d，J＝8.0Hz，2H)，7.41(d，J＝8.0 Hz，2H)，7.28-7.19(m，2H)，7.17-7.10(m，1H)，6.95-6.88(m，1H)，4.81(s，2H)，3.62-3.49(m，2H)，2.91-2.77(m，2H)，2.10-1.82(m，2H).LC-MS m/z[M+H] +：347.5 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 9.03 (s, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H) , 7.28-7.19(m, 2H), 7.17-7.10(m, 1H), 6.95-6.88(m, 1H), 4.81(s, 2H), 3.62-3.49(m, 2H), 2.91-2.77(m, 2H), 2.10-1.82 (m, 2H). LC-MS m/z [M+H] + : 347.5
实施例42：2-((7-氯-2，2-二氧化-4，5-二氢苯并[c][1，2]硫氮杂
Figure PCTCN2022087060-appb-000061
-1(3H)-基)甲基)-N-羟基嘧啶-5-甲酰胺(化合物42)的制备 Example 42: 2-((7-Chloro-2,2-dioxy-4,5-dihydrobenzo[c][1,2]thiazepine
Figure PCTCN2022087060-appb-000061
Preparation of -1(3H)-yl)methyl)-N-hydroxypyrimidine-5-carboxamide (Compound 42)
Figure PCTCN2022087060-appb-000062
Figure PCTCN2022087060-appb-000062
步骤1step 1
把Int.-4(200mg，1.1mmol)加入DMF(5mL)中，加入N-氯代丁二酰亚胺(436mg，3.3mmol)，加热至80℃，反应1小时，冷却至室温，过夜反应，TLC监测反应完成后，加入水和乙酸乙酯萃取，有机相减压浓缩，柱色谱法纯化后得到42-a(160mg，收率58％)。Int.-4 (200 mg, 1.1 mmol) was added to DMF (5 mL), N-chlorosuccinimide (436 mg, 3.3 mmol) was added, heated to 80 °C, reacted for 1 hour, cooled to room temperature, and reacted overnight , TLC monitoring after the completion of the reaction, adding water and ethyl acetate extraction, the organic phase was concentrated under reduced pressure, and purified by column chromatography to obtain 42-a (160 mg, yield 58%).
步骤1step 1
把42-a(80mg，0.34mmol)溶于DMF(1.0mL)中，加入Int.-2(120mg，0.52mmol)和碳酸钾(142mg，1.02mmol)，在室温下反应16小时。TLC监测反应完成后，加入水和乙酸乙酯萃取，有机相减压浓缩，柱色谱法纯化后得到42-b(120mg，收率92％)。LC-MS m/z[M+H] +：381.1. 42-a (80 mg, 0.34 mmol) was dissolved in DMF (1.0 mL), Int.-2 (120 mg, 0.52 mmol) and potassium carbonate (142 mg, 1.02 mmol) were added, and the reaction was carried out at room temperature 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 42-b (120 mg, yield 92%). LC-MS m/z[M+H] + : 381.1.
步骤2Step 2
把42-b(120mg，0.31mmol)溶于四氢呋喃(1.0mL)和甲醇(1.0mL)中，加入羟胺水溶液(0.5mL)和氢氧化钠(50mg，1.24mmol)，在室温下反应2小时。TLC监测反应完成后，反应减压浓缩，柱色谱法纯化后得到42(90mg，收率22％)。42-b (120 mg, 0.31 mmol) was dissolved in tetrahydrofuran (1.0 mL) and methanol (1.0 mL), hydroxylamine aqueous solution (0.5 mL) and sodium hydroxide (50 mg, 1.24 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 42 (90 mg, yield 22%).
1H NMR(400MHz，DMSO-d 6)δ8.90(s，2H)，8.43(s，1H)，7.44((d，J＝8.0Hz，1H)，7.27-7.25(m，2H)，4.99(s，2H)，3.56-3.53(m，2H)，2.74-2.72(m，2H)，1.99(m，2H).LC-MS m/z[M+H] +：383.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.90 (s, 2H), 8.43 (s, 1H), 7.44 ((d, J=8.0 Hz, 1H), 7.27-7.25 (m, 2H), 4.99 (s, 2H), 3.56-3.53 (m, 2H), 2.74-2.72 (m, 2H), 1.99 (m, 2H). LC-MS m/z [M+H] + : 383.1.
实施例43：4-((7-氯-2，2-二氧化-4，5-二氢苯并[c][1，2]硫氮杂
Figure PCTCN2022087060-appb-000063
-1(3H)-基)甲基)-N-羟基苯甲酰胺(化合物43)的制备 Example 43: 4-((7-Chloro-2,2-dioxy-4,5-dihydrobenzo[c][1,2]thiazepine
Figure PCTCN2022087060-appb-000063
Preparation of -1(3H)-yl)methyl)-N-hydroxybenzamide (compound 43)
Figure PCTCN2022087060-appb-000064
Figure PCTCN2022087060-appb-000064
步骤1step 1
把42-a(50mg，0.22mmol)溶于DMF(1.0mL)中，加入4-(溴甲基)苯甲酸甲酯(60mg，0.26mmol)和碳酸钾(91mg，0.66mmol)，在室温下反应16小时。TLC监测反应完成后，加入水和乙酸乙酯萃取，有机相减压浓缩，柱色谱法纯化后得到43-a(50mg，收率59％)。Dissolve 42-a (50 mg, 0.22 mmol) in DMF (1.0 mL), add methyl 4-(bromomethyl)benzoate (60 mg, 0.26 mmol) and potassium carbonate (91 mg, 0.66 mmol) 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 43-a (50 mg, yield 59%).
步骤2Step 2
把43-a(50mg，0.13mmol)溶于四氢呋喃(1.0mL)和甲醇(1.0mL)中，加入羟胺水溶液(0.5mL)和氢氧化钠(21mg，0.52mmol)，在室温下反应2小时。TLC监测反应完成后，反应减压浓缩，柱色谱法纯化后得到43(18mg，收率36％)。43-a (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1.0 mL) and methanol (1.0 mL), hydroxylamine aqueous solution (0.5 mL) and sodium hydroxide (21 mg, 0.52 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 give 43 (18 mg, yield 36%).
1H NMR(400MHz，DMSO-d 6)δ11.20(s，1H)，9.04(s，1H)，7.71(d，J＝7.6Hz，2H)，7.45-7.29(m， 3H)，7.18(d，J＝7.6Hz，1H)，6.89(d，J＝8.4Hz，1H)，4.77(s，2H)，3.67-3.48(m，2H)，2.85-2.68(m，2H)，2.11-1.87(m，2H).LC-MS m/z[M+H] +：381.4. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 9.04 (s, 1H), 7.71 (d, J=7.6 Hz, 2H), 7.45-7.29 (m, 3H), 7.18 ( d, J=7.6Hz, 1H), 6.89 (d, J=8.4Hz, 1H), 4.77 (s, 2H), 3.67-3.48 (m, 2H), 2.85-2.68 (m, 2H), 2.11-1.87 (m, 2H). LC-MS m/z [M+H] + : 381.4.
实施例44：6-((7-氯-2，2-二氧化-4，5-二氢苯并[c][1，2]硫氮杂
Figure PCTCN2022087060-appb-000065
-1(3H)-基)甲基)-N-羟基烟酰胺(化合物44)的制备 Example 44: 6-((7-Chloro-2,2-dioxy-4,5-dihydrobenzo[c][1,2]thiazepine
Figure PCTCN2022087060-appb-000065
Preparation of -1(3H)-yl)methyl)-N-hydroxynicotinamide (compound 44)
Figure PCTCN2022087060-appb-000066
Figure PCTCN2022087060-appb-000066
步骤1step 1
把42-a(60mg，0.26mmol)溶于DMF(1.0mL)中，加入Int.-1(70mg，0.30mmol)和碳酸钾(100mg，0.78mmol)，在室温下反应16小时。TLC监测反应完成后，加入水和乙酸乙酯萃取，有机相减压浓缩，柱色谱法纯化后得到44-a(66mg，收率67％)。LC-MS m/z[M+H] +：381.1. 42-a (60 mg, 0.26 mmol) was dissolved in DMF (1.0 mL), Int.-1 (70 mg, 0.30 mmol) and potassium carbonate (100 mg, 0.78 mmol) were added, and the reaction was carried out at room temperature 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 44-a (66 mg, yield 67%). LC-MS m/z[M+H] + : 381.1.
步骤2Step 2
把44-a(66mg，0.17mmol)溶于四氢呋喃(1.0mL)和甲醇(1.0mL)中，加入羟胺水溶液(0.5mL)和氢氧化钠(27mg，0.68mmol)，在室温下反应2小时。TLC监测反应完成后，反应减压浓缩，柱色谱法纯化后得到44(15mg，收率22％)。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).
1H NMR(400MHz，DMSO-d 6)δ11.41(s，1H)，9.25(s，1H)，8.87(d，J＝2.0Hz，1H)，8.12(dd，J＝8.0，2.0Hz，1H)，7.55(d，J＝8.0Hz，1H)，7.35(d，J＝2.4Hz，1H)，7.25(dt，J＝18.0，5.4Hz，2H)，4.95(s，2H)，3.64-3.53(m，2H)，2.84-2.74(m，2H)，2.09-1.94(m，2H).LC-MS m/z[M+H] +：382.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.41 (s, 1H), 9.25 (s, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.12 (dd, J=8.0, 2.0 Hz, 1H), 7.55(d, J=8.0Hz, 1H), 7.35(d, J=2.4Hz, 1H), 7.25(dt, J=18.0, 5.4Hz, 2H), 4.95(s, 2H), 3.64- 3.53 (m, 2H), 2.84-2.74 (m, 2H), 2.09-1.94 (m, 2H). LC-MS m/z [M+H] + : 382.1.
生物学测试biological test
实验例1.Experimental example 1.
采用酶活性实验评价本申请中化合物对HDAC6的抑制活性。The enzymatic activity assay was used to evaluate the inhibitory activity of the compounds in this application on HDAC6.
将HDAC6(Abcam)、测试化合物和20μM底物溶液(Ac-GAK(Ac)-AMC)分别加入到384孔板中，37℃孵育30min，加入1μM Trypsin和10μM TSA，室温孵育15min，360nm激发，检测455nm的荧光发射强度，进而计算各浓度下的抑制率，IC 50由GraphPadPrism 7.0软件拟合得到。 HDAC6 (Abeam), test compound and 20 μM substrate solution (Ac-GAK(Ac)-AMC) were added to 384-well plate respectively, incubated at 37°C for 30 min, added 1 μM Trypsin and 10 μM 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.
获得的实验结果如表1所示。The obtained experimental results are shown in Table 1.
表1Table 1
Figure PCTCN2022087060-appb-000067
Figure PCTCN2022087060-appb-000067
Figure PCTCN2022087060-appb-000068
Figure PCTCN2022087060-appb-000068
实验例2.Experimental example 2.
采用酶活性实验评价本申请中化合物对HDAC1的抑制活性。Enzyme activity assays were used to evaluate the inhibitory activity of the compounds in this application on HDAC1.
将HDAC1(BPS)、测试化合物和20μM底物溶液(Ac-GAK(Ac)-AMC)分别加入到384孔板中，37℃孵育30min，加入1μM Trypsin和10μM TSA，室温孵育15min，360nm激发，检测455nm的荧光发射强度，进而计算各浓度下的抑制率，IC 50由GraphPadPrism 7.0软件拟合得到。 HDAC1 (BPS), test compounds and 20 μM substrate solution (Ac-GAK(Ac)-AMC) were added to 384-well plates respectively, incubated at 37°C for 30 min, added 1 μM Trypsin and 10 μM 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.
获得的实验结果如表2所示。The obtained experimental results are shown in Table 2.
表2Table 2
Figure PCTCN2022087060-appb-000069
Figure PCTCN2022087060-appb-000069
实验例3.抗肿瘤细胞增殖活性测试Experimental example 3. Anti-tumor cell proliferation activity test
采用CCK8和CCL法评价本申请中化合物对人黑色素瘤细胞株A375和人多发性骨髓瘤细胞株RPMI8226的抗增殖活性。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.
取上述生长正常的2株细胞，分别用胰酶细胞消化液进行消化，离心，计数，以适合的细胞密度铺到96孔板中(A375细胞：3000个/孔；RPMI8226细胞：8000个/孔)，每孔100μL，周围用适量PBS进行水封，以防边缘孔内水分蒸发。细胞铺板后第二天进行给药，每孔加不同浓度梯度的化合物，每个浓度点设三个复孔，另外设置相应的DMSO阴性处理对照组。药物处理72h后，将96孔板中的所有液体吸出，每孔重新加入100μL培养基(含10％的CCK8溶液)，37℃孵育一段时间后(空白对照组OD450达到1.0以上)，用酶标仪检测450nm处的吸收。悬浮细胞用CCL试剂盒检测，每孔加入等体积试剂，避光孵育2min，采用化学发光检测，计算抑制率，IC 50值由GraphPad Prism 7.0软件拟合得到。 Take the above two normal growing cells, digest them with trypsin cell digestion solution, centrifuge, count, and plate them into 96-well plates at a suitable cell density (A375 cells: 3000 cells/well; RPMI8226 cells: 8000 cells/well). ), 100 μL per well, and water-sealed with an appropriate amount of PBS around to prevent evaporation of water in the edge wells. Drugs were administered on the second day after the cells were plated, compounds with different concentration gradients were added to each well, three duplicate wells were set for each concentration point, and the corresponding DMSO negative treatment control group was also set. After 72 hours of drug treatment, all the liquid in the 96-well plate was aspirated, and 100 μL of medium (containing 10% CCK8 solution) was added to each well. The instrument detects the absorption at 450 nm. Suspended cells were detected with CCL kit, an equal volume of reagent was added to each well, incubated in the dark for 2 min, and chemiluminescence detection was used to calculate the inhibition rate, and the IC 50 value was fitted by GraphPad Prism 7.0 software.
化合物的抗肿瘤细胞增殖活性如表3和表4所示。The anti-tumor cell proliferation activities of the compounds are shown in Table 3 and Table 4.
表3table 3
No.No. A375(IC 50/μM) A375( IC50 /μM)
1.1. 4.074.07
4.4. 99
5.5. 7.217.21
7.7. 9.159.15
8.8. 9.839.83
12.12. 9.959.95
14.14. 7.087.08
15.15. 2.242.24
32.32. 4.464.46
33.33. 9.489.48
34.34. 4.774.77
37.37. 4.454.45
40.40. 7.757.75
42.42. 9.319.31
43.43. 9.879.87
表4Table 4
No.No. RPMI8226(IC 50/μM) RPMI8226( IC50 /μM)
1.1. 1.681.68
3.3. 5.825.82
5.5. 4.094.09
7.7. 5.455.45
12.12. 2.892.89
14.14. 7.367.36
15.15. 3.493.49
20.20. 9.369.36
29.29. 0.900.90
30.30. 1.971.97
32.32. 2.832.83
33.33. 0.990.99
34.34. 0.590.59
35.35. 5.725.72
36.36. 6.946.94
37.37. 3.713.71
39.39. 6.546.54
40.40. 1.431.43
41.41. 7.27.2
42.42. 0.470.47
43.43. 8.898.89
44.44. 5.495.49
实验例4.微管蛋白、组蛋白H3和H4乙酰化水平的测试Experimental Example 4. Measurement of Tubulin, Histone H3 and H4 Acetylation Levels
取对数生长期的A375细胞，用胰酶细胞消化液进行消化，离心，计数，以适合的细胞密度铺到96孔板中(30000个/孔)，每孔100μL，周围用适量PBS进行水封。第二天给予不同浓度的化合物5处理细胞(起始浓度为6.25μM，4倍稀释，设置5个浓度梯度)，8h后将培养基吸出，用100μL的PBS洗2次。随后用4％的多聚甲醛固定细胞，室温孵育20min。弃固定液，用PBS清洗细胞。每孔加入150μL专用封闭液(含1％Triton-100)室温封闭2h，PBS洗去多余的封闭液。用含0.033％的Triton-100封闭液以1∶2000的比例稀释anti-AC-α-微管蛋白(CST)、AC-H3(CST)、AC-H4(CST)，将其加入至96孔板中，4℃孵育过夜，同时设置空白对照组。第二天分别用1X PBST洗涤2次，将二抗(CST)和DRAQ5(Thermofisher)用0.033％的Triton-100封闭液稀释至合适的倍数(二抗：1∶2000；DRAQ5：1∶10000)，并将其加入至96孔板中，室温孵育2h。1X PBST洗涤2次，PBS洗1次，分别用Li-COR Odyssey双色近红外激光成像仪检测700nm和800nm的荧光信号。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 μL per well, surrounded by appropriate amount of PBS for water purification. seal up. On the second day, the cells were treated with different concentrations of compound 5 (the initial concentration was 6.25 μM, 4-fold dilution, and 5 concentration gradients were set). After 8 h, the medium was aspirated and washed twice with 100 μL 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. 150 μL of special blocking solution (containing 1% Triton-100) was added to each well for blocking at room temperature for 2 h, and the excess blocking solution was washed with PBS. Anti-AC-α-tubulin (CST), AC-H3 (CST), AC-H4 (CST) were diluted 1:2000 with 0.033% Triton-100 blocking solution and added to 96 wells The plate was incubated at 4°C overnight, and a blank control group was set at the same time. 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. After washing twice with 1X PBST and once with PBS, the fluorescence signals at 700 nm and 800 nm were detected by a Li-COR Odyssey two-color near-infrared laser imager, respectively.
A375细胞经化合物5孵育后，AC-α-微管蛋白的表达水平如图1所示，化合物5在24nM时就可以引起α-微管蛋白的乙酰化，且与空白对照组相比有显著差异。After A375 cells were incubated with compound 5, the expression level of AC-α-tubulin was shown in Figure 1. Compound 5 could induce acetylation of α-tubulin at 24 nM, and compared with the blank control group, the expression level was significantly higher than that of the blank control group. difference.
实验例5.稳定性测试Experimental example 5. Stability test
评定受试化合物在CD-1小鼠、Sprague-Dawley大鼠、比格犬、食蟹猴和人的肝微粒体中的一相代谢稳定性。One-phase metabolic stability of test compounds was assessed in liver microsomes from CD-1 mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and humans.
实验体系：Experimental system:
该测试体系所用到的动物和人肝微粒体购买自Xenotech、Coming或其他有资质的供应商，在 使用前储存在低于-60℃冰箱内。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.
实验简介：Experiment introduction:
供试品和对照化合物在37±1℃条件下，分别与动物和人肝微粒体孵育一定的时间，最长孵育时间为60分钟，在指定的时间点取出样品，用含有内标的乙腈或其他有机溶剂终止反应。离心后，所产生的上清液用液相色谱-串联质谱(LC-MS/MS)方法进行检测。The test article and control compound were incubated with animal and human liver microsomes for a certain period of time at 37±1℃, 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).
实验方法：experimental method:
1.缓冲液的配制1. Buffer preparation
用4000mL的超纯水溶解73.21g三水磷酸氢二钾和10.78g磷酸二氢钾。使用10％磷酸或者1M氢氧化钾调整溶液pH值在7.40±0.10之间，其终浓度为100mM。73.21 g of dipotassium hydrogen phosphate trihydrate and 10.78 g of potassium dihydrogen phosphate were dissolved in 4000 mL of ultrapure water. The pH of the solution was adjusted between 7.40 ± 0.10 using 10% phosphoric acid or 1 M potassium hydroxide to a final concentration of 100 mM.
2.工作液的配制2. Preparation of working solution
供试品粉末用DMSO或其他的有机溶剂配制成一定浓度的储备液，然后用合适的有机溶剂进行进一步的稀释。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.
对照化合物睾酮、双氯芬酸和普罗帕酮用DMSO配制成10mM的储备液，然后用合适的有机溶剂进行进一步的稀释。Control compounds testosterone, diclofenac, and propafenone were prepared as 10 mM stock solutions in DMSO and further diluted with appropriate organic solvents.
3.肝微粒体溶液的配制3. Preparation of Liver Microsome Solution
用100mM磷酸钾盐缓冲液将各种属的微粒体稀释成2×的工作液。在反应体系中微粒体的终浓度为0.5mg/mL。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.
4.还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)再生体系的配制4. Preparation of Reduction System of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Regeneration System
称量适量的烟酰胺腺嘌呤磷酸二核苷酸(NADP)和异柠檬酸(ISO)粉末，溶于氯化镁溶液中，振荡混匀。加入适量的异柠檬酸脱氢酶(IDH)轻轻的上下颠倒混合均匀。在反应体系中终浓度分别为：1mM NADP、1mM氯化镁、6mM ISO和1unit/mL IDH。An appropriate amount of nicotinamide adenine phosphate dinucleotide (NADP) and isocitrate (ISO) powders were weighed, dissolved in a magnesium chloride solution, and mixed by shaking. Add an appropriate amount of isocitrate dehydrogenase (IDH) and mix well by inverting gently. The final concentrations in the reaction system were: 1 mM NADP, 1 mM magnesium chloride, 6 mM ISO and 1 unit/mL IDH.
5.终止液的配制5. Preparation of stop solution
终止液用含有内标(甲苯磺丁脲或其他合适的化合物)的乙腈或其他有机溶剂来配制。配制好的终止液储存于2-8℃冰箱。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.
6.孵育过程6. Incubation process
孵育将在96孔板中完成。准备8块孵育板，分别命名为T0、T5、T15、T30、T45、T60、Blank60和NCF60。前6块板对应反应时间点分别为0、5、15、30、45和60分钟。Blank60板中不加入供试品或对照化合物，并在孵育60分钟后取样。NCF60板中用磷酸钾盐缓冲液代替NADPH再生体系溶液进行孵育60分钟。所有条件样品为三个平行。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.
将微粒体和供试品或对照化合物混合，然后将除T0和NCF60外的孵育板Blank60、T5、T15、T30、T45和T60放置于37℃水浴锅中预孵育大约10分钟。孵育板T0中先加入终止液后再添加NADPH再生体系工作液，孵育板NCF60每个样品孔内添加98μL磷酸钾盐缓冲液以启动反应。孵育板Blank60、T5、T15、T30、T45和T60预孵育结束后，每个样品孔内添加98μL NADPH再生体系工作液以启动反应。反应的温度为37±1℃，反应的最终体积是200μL，反应体系中包括0.5mg/mL的微粒体、1.0μM的底物、1mM NADP、6mM ISO和1unit/mL IDH。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 μL 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 μL 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 μL, and the reaction system included 0.5 mg/mL microsomes, 1.0 μM substrate, 1 mM NADP, 6 mM ISO, and 1 unit/mL IDH.
分别在5、15、30、45和60分钟时，将含有内标的冷的终止液加入到反应板中以终止反应。At 5, 15, 30, 45 and 60 minutes, cold stop solution containing internal standard was added to the reaction plate to stop the reaction.
将终止后的所有反应板摇匀，并在4℃，3220×g，离心20分钟。将上清液稀释一定比例后进行LC-MS/MS分析。All reaction plates after termination were shaken and centrifuged at 3220 x g for 20 minutes at 4°C. The supernatant was diluted to a certain ratio for LC-MS/MS analysis.
样品分析Sample analysis
样品分析采用液相色谱-串联质谱(LC-MS/MS)方法进行，不含标准曲线和质控样品。使用分析物峰面积与内标峰面积的比值进行半定量测定。分析物和内标的保留时间、色谱图采集和色谱图的积分采用软件Analyst(Sciex，Framingham，Massachusetts，USA)进行处理。Sample analysis was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method without standard curve and quality control samples. A semi-quantitative determination was performed using the ratio of the analyte peak area to the internal standard peak area. Retention times for analytes and internal standards, chromatogram acquisition and integration of chromatograms were processed using the software Analyst (Sciex, Framingham, Massachusetts, USA).
每个分析批中每种基质中的内标峰面积的CV应在20％之内。The CV of the internal standard peak area in each matrix in each assay run should be within 20%.
数据分析data analysis
通过下面公式中化合物与内标峰面积的比值转化成剩余率求得化合物的体外消除速率常数ke：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:
Figure PCTCN2022087060-appb-000070
Figure PCTCN2022087060-appb-000070
Figure PCTCN2022087060-appb-000071
Figure PCTCN2022087060-appb-000071
Figure PCTCN2022087060-appb-000072
Figure PCTCN2022087060-appb-000072
Figure PCTCN2022087060-appb-000073
Figure PCTCN2022087060-appb-000073
CL int(mic)＝0.693/T 1/2/微粒体蛋白含量(孵育时微粒体浓度mg/mL) CL int(mic) = 0.693/T 1/2 / microsomal protein content (microsomal concentration mg/mL during incubation)
CL int(liver)＝CL int(mic)×肝脏中微粒体蛋白量(mg/g)×肝重体重比 CL int(liver) = CL int(mic) × microsomal protein content in liver (mg/g) × liver weight to body weight ratio
根据充分搅拌模型(well stirmodel)，肝固有清除率和肝清除率可以通过如下公式换算。According to the well stirring model (well stir model), hepatic intrinsic clearance and hepatic clearance can be converted by the following formula.
CL (liver)＝(CL int(liver)*Q h)/(CL int(liver)+Q h) CL (liver) = (CL int(liver) *Q h )/(CL int(liver) +Q h )
公式中的参数见下表。The parameters in the formula are shown in the table below.
Figure PCTCN2022087060-appb-000074
Figure PCTCN2022087060-appb-000074
[1] Brian Davies and Tim Morris，Physiological Parameters in Laboratory Animals and Human.Pharmaceutical Research，Vol.10 No.7，1993[1] Brian Davies and Tim Morris, Physiological Parameters in Laboratory Animals and Human. Pharmaceutical Research, Vol.10 No.7, 1993
[2]Journal of Pharmacology and Experimental Therapeutics，1997，283(1)：46-58.[2] Journal of Pharmacology and Experimental Therapeutics, 1997, 283(1): 46-58.
实验结果Experimental results
Figure PCTCN2022087060-appb-000075
Figure PCTCN2022087060-appb-000075
*SW-100的结构为
Figure PCTCN2022087060-appb-000076
*The structure of SW-100 is
Figure PCTCN2022087060-appb-000076
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, journal articles, books, and any other publications, is incorporated by reference in its entirety.

Claims (15)

  1. 化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)的结构：A compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the formula ( The structure of I):
    Figure PCTCN2022087060-appb-100001
    Figure PCTCN2022087060-appb-100001
    X在每次出现时各自独立地选自-CR 3R 3’-、-C(＝O)-、-C(＝N-OR)-、-NR-、-O-、-S-、-S(＝O)-和-S(＝O) 2-； Each occurrence of X is independently selected from -CR3R3'- , -C( = O)-, -C(=N-OR)-, -NR-, -O-, -S-, - S(=O)- and -S(=O) 2 -;
    Y选自-CR 4R 4’-、-C 2-6亚烯基-、-C(＝O)-、-C(＝N-OR)-、-NR-、-O-、-S-、-S(＝O)-和-S(＝O) 2-； Y is selected from -CR 4 R 4' -, -C 2-6 alkenylene-, -C(=O)-, -C(=N-OR)-, -NR-, -O-, -S- , -S(=O)- and -S(=O) 2 -;
    Z和W各自独立地为CR或N；Z and W are each independently CR or N;
    L选自直接键、-C(＝O)-、-NR-、-O-、-S-、-S(＝O)-、-S(＝O) 2-、-C 1-6亚烷基-、-C 2-6亚烯基-和-C 2-6亚炔基-； L is selected from direct bond, -C(=O)-, -NR-, -O-, -S-, -S(=O)-, -S(=O) 2 -, -C 1-6 alkylene base-, -C 2-6 alkenylene- and -C 2-6 alkynylene-;
    R在每次出现时各自独立地选自H、卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述环烃基和杂环基中至多2个环成员为C(＝O)； R at each occurrence is independently selected from H, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 ring Hydrocarbyl, saturated or partially unsaturated 3-10-membered heterocyclic group, C6-10 -membered aryl group, 5-14-membered heteroaryl group and C6-12 aralkyl group, of which at most 2 A ring member is C (=O);
    R 1和R 2在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； R 1 and R 2 are each independently selected at each occurrence from halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, C 3-6 cyclic hydrocarbon group, 3-10-membered heterocyclic group, C 6-10 aryl group, 5-14-membered heteroaryl group, C 6-12 aralkyl group, -C(=O)R a , - OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O) R b , -NR a -C(=O) OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene-NR a R b and -OC 1-6 alkylene-NR a R b ;
    R 3、R 3’、R 4和R 4’为H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； R 3 , R 3' , R 4 and R 4' are H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-6 cyclic hydrocarbon group, 3-10-membered heterocyclic group, C 6-10 -membered aryl, 5-14-membered heteroaryl, C 6-12 aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O ) 2 NRaRb , -NRaRb ,-C( = O) NRaRb , -NRa -C(=O) Rb , -NRa -C ( = O) ORb ,-NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene-NR a R b and -OC 1-6 alkylene-NR a R b ;
    R a和R b在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； 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为0、1、2、3或4的整数；n is an integer of 0, 1, 2, 3 or 4;
    m为0、1或2的整数；m is an integer of 0, 1 or 2;
    t为0、1或2的整数；t is an integer of 0, 1 or 2;
    上述烷基、亚烷基、烯基、亚烯基、炔基、亚炔基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5、-OC(＝O)R 5、-C(＝O)OR 5、-OR 5、-SR 5、-S(＝O)R 5、-S(＝O) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 6、-NR 5-C(＝O)R 6、-NR 5-C(＝O)OR 6、-NR 5-S(＝O) 2-R 6、-NR 5-C(＝O)-NR 5R 6、-C 1-6亚烷基-OR 5、-C 1-6亚烷基-NR 5R 6和-O-C 1-6亚烷基-NR 5R 6，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且 Each of the aforementioned alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cyclohydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl groups is optionally or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered Heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O)R 5 , -OC(=O)R 5 , -C(=O )OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O) 2 R 5 , -S(=O) 2 NR 5 R 6 , -NR 5 R 6 , - C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O) 2 -R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1-6 alkylene-OR 5 , -C 1-6 alkylene-NR 5 R 6 and -OC 1-6 alkylene-NR 5 R 6 , the alkyl, cyclohydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, = O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6- 10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; and
    R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基。 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.
  2. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中X在每次出现时各自独立地为-CR 3R 3’-，优选为-CH 2-。 The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein X is Each occurrence is independently -CR3R3'- , preferably -CH2- .
  3. 权利要求1或2的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中Y选自-CR 4R 4’-、-C(＝O)-和-C(＝N-OR)-；优选地，Y选自-CH 2-、-C(CH 3) 2-、-C(＝O)-和-C(＝N-OH)-。 A compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein Y is selected from -CR 4 R 4' -, -C(=O)- and -C(=N-OR)-; preferably, Y is selected from -CH 2 -, -C(CH 3 ) 2 -, - C(=O)- and -C(=N-OH)-.
  4. 权利要求1-3中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中Z和W各自独立地为CH、CF或N。The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or A prodrug, wherein Z and W are each independently CH, CF or N.
  5. 权利要求1-4中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中L为-C 1-6亚烷基-，优选为-CH 2-。 The compound of any one of claims 1-4 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Prodrugs, wherein L is -C 1-6 alkylene-, preferably -CH 2 -.
  6. 权利要求1-5中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 1在每次出现时各自独立地选自卤素、-CN、C 1-6烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、-NR aR b、-C(＝O)NR aR b和-NR a-C(＝O)R b，其中所述烷基、杂环基、芳基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、卤代C 1-6烷基、3-10元杂环基、C 6-12芳烷基、-OH和-O-C 1-6烷基；R a和R b在每次出现时各自独立地选自H、C 1-6烷基、卤代C 1-6烷基、C 3-10环烃基和5-14元杂芳基； The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Prodrugs, wherein each occurrence of R 1 is independently selected from halogen, -CN, C 1-6 alkyl, 3-10 membered heterocyclyl, C 6-10 membered aryl, 5-14 membered heteroaryl , -NR a R b , -C(=O)NR a R b , and -NR a -C(=O) R b , wherein the alkyl, heterocyclyl, aryl and heteroaryl groups are each optionally Substituted by one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-10 membered heterocyclyl, C 6-12 aralkyl, - OH and -OC 1-6 alkyl; R a and R b at each occurrence are each independently selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-10 cyclohydrocarbyl and 5-14-membered heteroaryl;
    优选地，R 1在每次出现时各自独立地选自F、Cl、Br、-CN、甲基、乙基、吡咯烷基、苯基、呋喃基、吡唑基、-NR aR b、-C(＝O)NR aR b和-NR a-C(＝O)R b，其中上述甲基、乙基、吡咯烷基、苯基、呋喃基和吡唑基各自任选地被一个或多个独立地选自下列的取代基取代：F、Cl、-CH 3、-CF 3、-CH 2CH 3、哌啶基、叔丁氧羰基取代的哌啶基、苄基、-OH和-OCH 3；R a和R b在每次出现时各自独立地选自H、-CH 3、-CHF 2、环丙基和吡啶基； Preferably, R 1 at each occurrence is independently selected from F, Cl, Br, -CN, methyl, ethyl, pyrrolidinyl, phenyl, furyl, pyrazolyl, -NR a R b , -C(=O) NRaRb and -NRa -C(=O )Rb , wherein each of the aforementioned methyl, ethyl, pyrrolidinyl, phenyl, furyl and pyrazolyl groups is optionally replaced by a Substituted with one or more substituents independently selected from the group consisting of F, Cl , -CH3 , -CF3 , -CH2CH3, piperidinyl, t - butoxycarbonyl-substituted piperidinyl, benzyl, -OH and -OCH3 ; Ra and Rb are each independently selected at each occurrence from H, -CH3 , -CHF2 , cyclopropyl and pyridyl;
    更优选地，R 1在每次出现时各自独立地选自F、Cl、Br、-CN、-CH 3、-CF 2CH 3、-CH(OH)CH 3、-NH 2、-NHCH 3、-N(CH 3) 2、-C(＝O)NH 2、-NH-C(＝O)CH 3、-NH-C(＝O)CHF 2、
    Figure PCTCN2022087060-appb-100002
    Figure PCTCN2022087060-appb-100003
    More preferably, each occurrence of R 1 is independently selected from F, Cl, Br, -CN, -CH 3 , -CF 2 CH 3 , -CH(OH)CH 3 , -NH 2 , -NHCH 3 at each occurrence , -N(CH 3 ) 2 , -C(=O)NH 2 , -NH-C(=O)CH 3 , -NH-C(=O)CHF 2 ,
    Figure PCTCN2022087060-appb-100002
    Figure PCTCN2022087060-appb-100003
  7. 权利要求1-6中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 2在每次出现时各自独立地为卤素，优选为F。 The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Prodrugs wherein each occurrence of R2 is independently halogen, preferably F.
  8. 权利要求1-7中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 3、R 3’、R 4和R 4’为H或C 1-6烷基，优选为H或甲基。 The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or A prodrug, wherein R3 , R3 ' , R4 and R4 ' are H or C1-6 alkyl, preferably H or methyl.
  9. 权利要求1-8中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(II)的结构：The compound of any one of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or A prodrug, wherein the compound has the structure of formula (II):
    Figure PCTCN2022087060-appb-100004
    Figure PCTCN2022087060-appb-100004
  10. 权利要求1-9中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(III)或式(IV)的结构：The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or A prodrug, wherein the compound has the structure of formula (III) or formula (IV):
    Figure PCTCN2022087060-appb-100005
    Figure PCTCN2022087060-appb-100005
  11. 权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or A prodrug, wherein the compound is selected from:
    Figure PCTCN2022087060-appb-100006
    Figure PCTCN2022087060-appb-100006
    Figure PCTCN2022087060-appb-100007
    Figure PCTCN2022087060-appb-100007
    Figure PCTCN2022087060-appb-100008
    Figure PCTCN2022087060-appb-100008
    Figure PCTCN2022087060-appb-100009
    Figure PCTCN2022087060-appb-100009
    Figure PCTCN2022087060-appb-100010
    Figure PCTCN2022087060-appb-100010
    Figure PCTCN2022087060-appb-100011
    Figure PCTCN2022087060-appb-100011
  12. 药物组合物，其包含权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选是固体制剂、液体制剂或透皮制剂。A pharmaceutical composition comprising a compound of any one of claims 1-11 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.
  13. 权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者权利要求12的药物组合物在制备用于预防或治疗HDAC6相关性疾病的药物中的用途。The compound of any one of claims 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Use of the prodrug or the pharmaceutical composition of claim 12 in the preparation of a medicament for preventing or treating HDAC6-related diseases.
  14. 权利要求13的用途，其中所述HDAC6相关性疾病选自癌症或增生性疾病(例如，肺癌、结肠癌、乳腺癌、***癌、肝癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、***状肾癌、头颈部鳞状细胞癌、白血病、淋巴瘤、骨髓瘤、多发性骨髓瘤和实体肿瘤)；韦尔森氏病、脊髓小脑型共济失调、朊病毒病、帕金森氏病、亨廷顿氏病、肌萎缩性侧索硬化症、淀粉样变性病、阿尔茨海默氏病、亚历山大氏病、酒精性肝病、囊性纤维化、皮克氏病、脊髓性肌肉萎缩症或路易体痴呆；类风湿性关节炎、骨关节炎；类风湿性脊椎炎；牛皮癣；炎性肠病；慢性炎性肺病、湿疹、哮喘、局部缺血/再灌注损伤、溃疡性结肠炎、急性呼吸窘迫综合症、牛皮癣性关节炎、感染性关节炎、进行性慢性关节炎、变形性关节炎、骨关节炎、创伤性关节炎、痛风性关节炎、瑞特氏综合症、多软骨炎、急性滑膜炎和脊椎炎、肾小球肾炎、溶血性贫血、再生障碍性贫血、特发性血小板减少性紫癜、中性粒细胞减少症、溃疡性结肠炎、克罗恩氏病、宿主抗移植物疾病、移植物抗宿主疾病、同种异体移植排斥、慢性甲状腺炎、葛瑞夫兹氏病、硬皮病、糖尿病、活动性肝炎、原发性胆汁性肝硬化、重症肌无力、多发性硬化(MS)、***性红斑狼疮、异位性皮炎、接触性皮炎、皮肤晒伤、慢性肾功能不全、史蒂芬斯-强森综合症、特发性脂肪泻、肉状瘤病、格林-巴利综合症、葡萄膜炎、结膜炎、角膜结膜炎、中耳炎、牙周病、肺间质纤维化、哮喘、支气管炎、鼻炎、窦炎、尘肺病、肺功能不全综合症、肺气肿、肺纤维化或硅肺病。The purposes of claim 13, wherein said HDAC6-related disease is selected from cancer or proliferative disease (for example, 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 disease, spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease, Alexander's disease , alcoholic liver disease, cystic fibrosis, Pick's disease, spinal muscular atrophy or dementia with Lewy bodies; rheumatoid arthritis, osteoarthritis; rheumatoid spondylitis; psoriasis; inflammatory bowel disease; chronic inflammation Lung disease, eczema, asthma, ischemia/reperfusion injury, ulcerative colitis, acute respiratory distress syndrome, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, osteoarthritis , traumatic arthritis, gouty arthritis, Rett syndrome, polychondritis, acute synovitis and spondylitis, glomerulonephritis, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenic purpura , neutropenia, ulcerative colitis, Crohn's disease, host-versus-graft disease, graft-versus-host disease, allograft rejection, chronic thyroiditis, Graves' disease, scleroderma , diabetes, active hepatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis (MS), systemic lupus erythematosus, atopic dermatitis, contact dermatitis, skin sunburn, chronic renal insufficiency, Stephen Johnson-Johnson syndrome, idiopathic steatorrhea, sarcoidosis, Guillain-Barré syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, pulmonary fibrosis, asthma, Bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, emphysema, pulmonary fibrosis or silicosis.
  15. 制备权利要求9的式(II)的化合物的方法，其包括以下步骤：A method of preparing a compound of formula (II) of claim 9, comprising the steps of:
    Figure PCTCN2022087060-appb-100012
    Figure PCTCN2022087060-appb-100012
    其中：in:
    Hal为卤素，例如F、Cl、Br或I；Hal is halogen such as F, Cl, Br or I;
    R L为离去基团，例如-O-C 1-6烷基，优选-O-CH 3； R L is a leaving group, such as -OC 1-6 alkyl, preferably -O-CH 3 ;
    其余各基团如权利要求1-11中任一项所定义；The remaining groups are as defined in any one of claims 1-11;
    第一步：使化合物(II)-a与化合物(II)-a-2反应，以得到化合物(II)-b；以及The first step: reacting compound (II)-a with compound (II)-a-2 to obtain compound (II)-b; and
    第二步：使化合物(II)-b与羟胺反应，以得到式(II)的化合物。Second step: react compound (II)-b with hydroxylamine to obtain compound of formula (II).
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