WO2023020416A1 - Composé tricyclique, composition pharmaceutique le comprenant et son utilisation - Google Patents

Composé tricyclique, composition pharmaceutique le comprenant et son utilisation Download PDF

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WO2023020416A1
WO2023020416A1 PCT/CN2022/112425 CN2022112425W WO2023020416A1 WO 2023020416 A1 WO2023020416 A1 WO 2023020416A1 CN 2022112425 W CN2022112425 W CN 2022112425W WO 2023020416 A1 WO2023020416 A1 WO 2023020416A1
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alkylene
compound
cycloalkyl
alkyl
aryl
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PCT/CN2022/112425
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Chinese (zh)
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李家鹏
王奎锋
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勤浩医药（苏州）有限公司
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Publication of WO2023020416A1 publication Critical patent/WO2023020416A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application relates to tricyclic compounds, pharmaceutical compositions comprising them and their use as HDAC6 inhibitors.
  • Histone deacetylase can catalyze the deacetylation of histone or other proteins, and it plays an important role in various biological processes mainly through transcriptional repression.
  • HDAC in the human body can be divided into four types, 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 can be further divided into subclasses IIa (HDAC4, HDAC5, HDAC7, and HDAC9) and IIb subtypes (HDAC6 and HDAC10).
  • HDAC6 mainly catalyzes the deacetylation of non-histone substrates, such as ⁇ -tubulin and Hsp90. HDAC6 is involved in the pathological process of various diseases, including cancer, neurological diseases, infection, cardiovascular disease, immunity and inflammation-related diseases.
  • HDAC inhibitors are broad-spectrum inhibitors, which 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 the inhibition of HDAC1 and HDAC2).
  • the present application provides tricyclic compounds, which can be used as HDAC6 inhibitors to prevent or treat HDAC6-related diseases.
  • the compounds of the present application have high selectivity to HDAC6, thus avoiding the side effects of HDAC broad-spectrum inhibitors.
  • the compounds of the present invention also have good physicochemical properties (such as solubility, physical and/or chemical stability), good pharmacokinetic properties (such as good bioavailability, good metabolic stability, suitable half-life and duration of action), good safety (lower toxicity (such as reduced cardiotoxicity) and/or fewer side effects), less likely to develop drug resistance and other properties.
  • One aspect of the 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):
  • Ring A and Ring B are each independently a 6-membered aromatic ring (ie, a benzene ring) or a 5-14-membered heteroaromatic ring (preferably a 6-membered heteroaromatic ring, more preferably a pyridine ring);
  • V is -NR 1 -;
  • Z and W are each independently CR 2' or N;
  • R a and R b 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 or 2;
  • p and q are each independently an integer of 0, 1, 2, 3 or 4;
  • R 5 and R 6 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.
  • compositions comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite thereof , isotope-labeled compound or prodrug and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.
  • 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 medicaments 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 for preventing or treating HDAC6-related diseases, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer thereof to an individual in need thereof , tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs or pharmaceutical compositions of the invention.
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group 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 (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group group is referred to as "haloalkyl” ) ( eg CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl or -CH2CH2
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. 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 (“ C2-6 alkenyl”).
  • alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, for example ethynyl, 2-propynyl, 2 -butynyl, 1,3-butadiynyl and the like.
  • the alkynyl group is optionally substituted with one or more (such as 1 to 3) same or different substituents.
  • alkynylene is a 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) same or different substituents.
  • cycloalkylene means ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms of saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings, which Including but not limited to (ylidene)cyclopropyl (ring), (ylidene)cyclobutyl (ring), ((ylidene)cyclopentyl (ring), ((ylidene)cyclohexyl (ring), (ylidene)cycloheptyl ( (ring), (sub)cyclooctyl (ring), (sub)cyclononyl (ring), (sub)cyclohexenyl (ring), etc.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, cyclononyl, or bicyclic, including spiro, 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, decahydronaphthyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, cyclononyl
  • the cycloalkyl has 3 to 15 carbon atoms
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclo hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • a 3-10 membered heterocyclic group is a group with 3-10 carbon atoms and heteroatoms in the ring, such as but not limited to oxiranyl, aziridinyl, azetidinyl ( azetidinyl), oxetanyl (oxetanyl), tetrahydrofuryl, dioxolinyl (dioxolinyl), pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyrrolidinyl pyryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • heterocyclyl encompasses an amalgamated ring structure, and the connection point of the amalgamated ring structure to other groups may be on any ring in the amalgamated ring structure. Therefore, the heterocyclyl group of the present invention also includes, but is not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, for example 3-7 membered (single) heterocyclic group and 3-7 membered (single) heterocyclic group, 3-7 membered (single) heterocyclic group and (single) cycloalkyl group, 3-7 membered (single) heterocyclic group C 4-6 (mono)cycloalkyl, examples of which include, but are not limited to, pyrrolidinocyclopropyl, cyclopentylaziridine, pyrrolidinocyclo
  • heterocyclyl encompasses both bridged and spiroheterocyclyls.
  • bridged heterocycle refers to two saturated rings that share two ring atoms that are not directly connected and contain one or more (eg, 1, 2, 3, or 4) heteroatoms. (such as oxygen atom, nitrogen atom and/or sulfur atom) ring structure, including but not limited to 7-10 membered bridged heterocycle, 8-10 membered bridged heterocycle, 7-10 membered nitrogen-containing bridged heterocycle, 7- 10-membered oxygen-containing bridged heterocycle, 7-10-membered sulfur-containing bridged heterocycle, etc., for example wait.
  • the "nitrogen-containing bridged heterocycle", “oxygen-containing bridged heterocycle”, and “sulfur-containing bridged heterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • spiroheterocycle refers to a heterocyclic ring formed by two or more saturated rings sharing one ring atom and containing one or more (for example, 1, 2, 3 or 4) heteroatoms (such as oxygen atom, nitrogen atom, sulfur atom), 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, at least one of which is a nitrogen atom.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-14 aryl means an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl.
  • Aryl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • aralkyl preferably denotes an aryl-substituted alkyl group, wherein said aryl and said alkyl are as defined herein.
  • the aryl group may have 6-14 carbon atoms
  • the alkyl group may 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 contain at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and, in addition May be benzo-fused in each case.
  • heteroaryl is selected from 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 as used herein means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of C1-6 alkylthio include, but are not limited to, methylthio, ethylthio, t-butylthio, and hexylthio.
  • the nitrogen-containing heterocyclic ring is preferably a saturated nitrogen-containing monocyclic ring.
  • a 3- to 14-membered nitrogen-containing heterocycle is a group having 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as Aziridinyl), four-membered nitrogen-containing heterocycle (such as azetidinyl), five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidinyl ring), pyrrolinyl, pyrrolidonyl, imidazole group, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidinyl ring), morpholinyl, thiomorpholinyl, piperazinyl) , Seven-membered nitrogen-containing heterocycle, etc.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present.
  • the normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent may 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 hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
  • each substituent is selected independently of the other. Accordingly, 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 may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g.
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13 N and 15 N
  • phosphorus isotopes such as 32 P
  • sulfur isotopes such as 35 S.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes
  • are useful in drug and/or substrate tissue distribution studies eg, assays).
  • the radioisotopes tritium ( ie3H ) and carbon-14 ( ie14C ) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • 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 non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization 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, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can directly Or indirectly provide a compound of the invention or a metabolite or residue thereof. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the 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, methylsulfate, 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 salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, 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 (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound).
  • the compounds of the invention may also themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • 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 vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 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 (for example as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • 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 may be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10%, preferably within ⁇ 5%, more preferably within ⁇ 2% of the stated numerical value.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or precursor thereof Drug, wherein said compound has the structure of formula (I):
  • Ring A and Ring B are each independently a 6-membered aromatic ring (ie, a benzene ring) or a 5-14-membered heteroaromatic ring (preferably a 6-membered heteroaromatic ring, more preferably a pyridine ring);
  • V is -NR 1 -;
  • Z and W are each independently CR 2' or N;
  • R a and R b 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 or 2;
  • p and q are each independently an integer of 0, 1, 2, 3 or 4;
  • R 5 and R 6 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.
  • the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Prodrugs, wherein the compound has the structure of formula (I'):
  • X is CR 3' or N
  • Y is CR 4' or N
  • V is -NR 1 -;
  • Z and W are each independently CR 2' or N;
  • R a and R b 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 or 2;
  • p' and q' are each independently an integer of 0, 1, 2 or 3;
  • R 5 and R 6 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.
  • the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, Isotopically labeled compounds or prodrugs, wherein X and Y are each independently CH or N.
  • the present invention provides a compound of formula (I) or formula (I'), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate thereof Compounds, metabolites, isotopically labeled compounds or prodrugs, wherein the compound has the structure of formula (II), (III), (IV) or (V):
  • the present invention provides a compound of formula (I), formula (I'), formula (II), (III), (IV) or (V) or a pharmaceutically acceptable salt, ester, stereo Isomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R is H, C 1-6 alkyl or C 3-10 cycloalkyl; Preferably, R is H, methyl or cyclopropyl.
  • the present invention provides a compound of formula (I), formula (I'), formula (II), (III), (IV) or (V) or a pharmaceutically acceptable salt, ester, stereo Isomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein Z and W are each independently CH, CF or N.
  • the present invention provides a compound of formula (I), formula (I'), formula (II), (III), (IV) or (V) or a pharmaceutically acceptable salt, ester, stereo Isomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein R 2 , R 3 and R 4 are independently at each occurrence halogen or C1-6 alkyl, preferably F, C1 or methyl.
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Prodrugs, wherein the compound is selected from:
  • compositions and methods of treatment are provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorphic form thereof Compounds, solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled Use of the compound or prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating HDAC6-related diseases.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled
  • the compound or prodrug or the pharmaceutical composition of the present invention is used for preventing or treating HDAC6-related diseases.
  • the present invention provides a method of preventing or treating HDAC6-related diseases, 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 isomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs or pharmaceutical compositions of the present invention.
  • the HDAC6-associated diseases include, but are not limited to, cancer or proliferative diseases (e.g., lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, gastric 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 disease, Alzheimer's disease, Alexander's disease, alcoholic liver disease, cystic fibrosis, Pick's disease, spinal muscular atrophy Rheumatoid arthritis, osteoarthritis; Rheumatoid spondylitis; Psoriasis;
  • “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response 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 applies 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.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • compositions of the present invention may also comprise one or more additional therapeutic or prophylactic agents.
  • Int.-1-a (2.0g, 13.2mmol) was dissolved in carbon tetrachloride (40mL), N-bromosuccinimide (2.5g, 14.3mmol) and azobisisobutyronitrile ( 200mg, 1.2mmol), react at 80°C for 16 hours. After the reaction was monitored by TLC, the reaction solution was spin-dried and purified by column chromatography to obtain a colorless liquid Int.-1 (360 mg, yield 12%).
  • Int.-2-a (1.0g, 6.6mmol) was dissolved in carbon tetrachloride (10mL), N-bromosuccinimide (1.23g, 6.9mmol) and azobisisobutyronitrile ( 0.43g, 2.6mmol), react at 80°C for 16 hours. After the completion of the reaction was monitored by TLC, the reaction solution was spin-dried and purified by column chromatography to obtain a colorless liquid Int.-2 (0.27 g, yield 18%).
  • Int.-3-a (2.0g, 11.9mmol) was dissolved in carbon tetrachloride (40mL), N-bromosuccinimide (2.5g, 14.3mmol) and azobisisobutyronitrile ( 200mg, 1.2mmol), react at 80°C for 16 hours. After the reaction was monitored by TLC, the reaction solution was spin-dried and purified by column chromatography to obtain a colorless liquid Int.-3 (2.3 g, yield 78%).
  • a yellow solid 4 (104 mg, yield 62%) was prepared in a similar manner to Step 3 of Example 3.
  • a yellow solid 5-e (0.557 g, yield 75%) was prepared by a method similar to that of step 2 of Example 4.
  • a yellow solid 5 (70 mg, yield: 58%) was prepared in a similar manner to Step 3 of Example 3.
  • a yellow solid 6 (80 mg, yield 46%) was prepared in a similar manner to Step 3 of Example 3.
  • a yellow solid 7 (16 mg, yield 3%) was prepared in a similar manner to Step 3 of Example 3.
  • a yellow solid 8-c (1.11 g, yield 7.8%) was prepared by a method similar to Example 4 step 2.
  • a yellow solid 8-d (0.164 g, yield 28%) was prepared by a method similar to Example 6 step 2.
  • a white solid 8 (61 mg, yield 46%) was prepared in a similar manner to Step 3 of Example 3.
  • HDAC6 (Abcam), test compound and 20 ⁇ M substrate solution (Ac-GAK(Ac)-AMC) to 384-well plate, incubate at 37°C for 30 min, add 1 ⁇ M Trypsin and 10 ⁇ M TSA, incubate at room temperature for 15 min, and excite at 360 nm. The fluorescence emission intensity at 455nm was detected, and then the inhibition rate at each concentration was calculated, and the IC 50 was fitted by GraphPadPrism 7.0 software.
  • Enzyme activity test was used to evaluate the inhibitory activity of the compounds in the present application on HDAC1.
  • HDAC1 BPS
  • test compound and 20 ⁇ M substrate solution (Ac-GAK(Ac)-AMC) were added to 384-well plate, incubated at 37°C for 30 min, 1 ⁇ M Trypsin and 10 ⁇ M TSA were added, incubated at room temperature for 15 min, excited at 360 nm, The fluorescence emission intensity at 455nm was detected, and then the inhibition rate at each concentration was calculated, and the IC 50 was fitted by GraphPadPrism 7.0 software.
  • CCK8 and CCL methods were used to evaluate the anti-proliferation activity of the compounds in this application on human melanoma cell line A375 and human multiple myeloma cell line RPMI8226.
  • the anti-tumor cell proliferation activity of the compounds is shown in Table 3 and Table 4.
  • Example A375 (IC 50 / ⁇ M) 1 10 2 20.05 3 12.3 4 17.97 5 9.02 6 13.95 7 20.4 8 21.21 9 16.02 10 0.46 11 11.90 12 0.82
  • Example RPMI8226 ( IC50 / ⁇ M) 1 2.95 2 16.25 3 10.94 4 3.36 5 2.68 6 3.22 7 8.84 8 5.18 9 2.66 10 0.41 11 2.31 12 0.23
  • A375/HCT116/HCC827 cells in the logarithmic growth phase, digest them with trypsin cell digestion solution, centrifuge, count, and spread them in a 96-well plate at a suitable cell density (30,000 cells/well), 100 ⁇ L per well, surround with Appropriate amount of PBS for water seal.
  • the cells were treated with different concentrations of compounds (the initial concentration was 100 ⁇ M, diluted 5 times, and 9 concentration gradients were set), and after 6 hours, the medium was aspirated and washed twice with 100 ⁇ L of PBST. Cells were then fixed with 4% paraformaldehyde and incubated at room temperature for 20 min. Discard the fixative and wash the cells with PBST.
  • 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 before use.
  • test substance and the control compound were incubated with animal and human liver microsomes for a certain period of time at 37 ⁇ 1°C, the longest incubation time being 60 minutes, and the samples were taken out at the specified time points, and were mixed with acetonitrile containing internal standard or other Organic solvents terminate the reaction. After centrifugation, the resulting supernatant was detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • the powder of the test product 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.
  • the reference compounds testosterone, diclofenac and propafenone were prepared as 10 mM stock solutions in DMSO, and then further diluted with appropriate organic solvents.
  • NADP nicotinamide adenine phosphate dinucleotide
  • ISO isocitric acid
  • the stop solution is prepared in acetonitrile or other organic solvents containing an internal standard (tolbutamide or other suitable compound). Store the prepared stop solution in a refrigerator at 2-8°C.
  • Incubation will be done in 96-well plates. Prepare 8 incubation plates and name them T0, T5, T15, T30, T45, T60, Blank60 and NCF60 respectively. The first 6 plates correspond 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. In the NCF60 plate, potassium phosphate buffer was used to replace the NADPH regeneration system solution and incubated for 60 minutes. All conditional samples were run in triplicate.
  • Blank60, T5, T15, T30, T45 and T60 in a 37°C water bath for about 10 minutes except for T0 and NCF60.
  • the temperature of the reaction was 37 ⁇ 1°C, the final volume of the reaction was 200 ⁇ L, and 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 analytical run should be within 20%.
  • the in vitro elimination rate constant ke of the compound is obtained by converting the ratio of the peak area of the compound to the internal standard in the following formula into the residual rate:
  • CL int(liver) CL int(mic) ⁇ amount of microsomal protein in the liver (mg/g) ⁇ liver weight to body weight ratio
  • the intrinsic liver clearance rate and the liver clearance rate can be converted by the following formula.
  • CL (liver) (CL int(liver) *Q h )/(CL int(liver) +Q h )
  • mice On the day of administration, the actual body weight of the mice was weighed and the administration volume was calculated. There are 3 mice in each group, and each compound is tested in two groups, one group is administered by single intravenous bolus injection, and the other group is administered by single intragastric administration.
  • Whole blood samples were collected at specified times (0.25, 0.5, 1, 2, 4, 8, 24 hours after administration) by orbital blood collection. After blood samples were collected, they were immediately transferred to labeled commercial sample tubes containing K2-EDTA (0.85-1.15 mg), followed by centrifugation (3200 x g, 4°C, 10 minutes) to obtain plasma. Plasma was transferred to pre-chilled centrifuge tubes, snap-frozen in dry ice, and then stored in an ultra-low temperature freezer at -60°C or below until LC-MS/MS analysis.
  • Plasma drug concentrations were determined using LC-MS/MS methods. Plasma drug concentration data of compounds were processed with a non-compartmental model using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. Relevant pharmacokinetic parameters were calculated using the linear log trapezoidal method.

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Abstract

L'invention concerne un composé tricyclique de formule (I), une composition pharmaceutique le comprenant, et son utilisation en tant qu'inhibiteur de HDAC6.
PCT/CN2022/112425 2021-08-16 2022-08-15 Composé tricyclique, composition pharmaceutique le comprenant et son utilisation WO2023020416A1 (fr)

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