Classifications

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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • 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
  • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• the present application relates to oxadiazole compounds, pharmaceutical compositions containing them and their use as HDAC6 inhibitors.
• Histone deacetylase can catalyze the deacetylation of histones or other proteins, and plays an important role in various biological processes mainly through transcriptional repression.
• HDACs in the human body can be divided into four categories.
• Category I includes HDAC1, HDAC2, HDAC3, and HDAC8;
• category II includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10;
• category III includes SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, and SIRT6. and SIRT7; class IV includes HDAC11.
• Class II HDACs can be divided into subtype IIa (HDAC4, HDAC5, HDAC7 and HDAC9) and subtype IIb (HDAC6 and HDAC10).
• 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 the inhibition of HDAC1 and HDAC2).
• L is selected from direct bond, -C 1-6 alkylene-, -C 2-6 alkenylene- and -C 2-6 alkynylene-;
• X is CR 6 or N
• Y is CR 4 or N
• Z is CR 5 or N
• R a and R b is 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;
• Another aspect of the invention provides a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Prodrugs or pharmaceutical compositions of the present invention, which are used to prevent or treat HDAC6-related diseases.
• Another aspect of the invention provides a method for preventing or treating HDAC6-related diseases, the method comprising administering an effective amount of a compound of the 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.
• alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon.
• an alkyl group has 1 to 12, such as 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 base, 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 called a "haloalkyl”) (eg CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 Cl or -CH 2 CH 2 CF 3 , etc.
• halogen in which case the group group is called a "haloalkyl
• 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).
• alkynyl means a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2 -Butynyl, 1,3-butadiynyl, etc.
• the alkynyl group is optionally substituted with one or more (such as 1 to 3) substituents that may be the same or different.
• alkynylene refers to 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 by one or more (such as 1 to 3) the same or different substituents.
• cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cycloctyl, cyclononyl, or bicyclo, 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, decalinyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
• monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cycloctyl, cyclononyl, or bicyclo
• heterocyclyl encompasses fused ring structures whose point of attachment to other groups can be on any ring in the fused ring structure. Accordingly, heterocyclyl groups of the present invention also include, but are not limited to, heterocyclyl-heterocyclyl, heterocyclyl-cycloalkyl, mono-heterocyclyl-monoheterocyclyl, mono-heterocyclyl-monocycloalkyl, e.g.
• spiroheterocycle refers to a ring containing one or more (eg, 1, 2, 3, or 4) heteroatoms formed from two or more saturated rings sharing one ring atom. (such as oxygen atoms, nitrogen atoms, sulfur atoms), including but not limited to 5-10-membered spiroheterocycles, 6-10-membered spiroheterocycles, 6-10-membered nitrogen-containing spiroheterocycles, 6-10-membered spiroheterocycles, Oxygen-containing spiroheterocycles, 6-10-membered sulfur-containing spiroheterocycles, etc.
• 5-10-membered spiroheterocycles 6-10-membered spiroheterocycles, 6-10-membered nitrogen-containing spiroheterocycles, 6-10-membered spiroheterocycles, Oxygen-containing spiroheterocycle
• aralkyl preferably means an aryl-substituted alkyl group, wherein said aryl and said alkyl are as defined herein.
• the aryl group may have 6 to 14 carbon atoms
• the alkyl group may have 1 to 6 carbon atoms.
• Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
• Each of the "nitrogen-containing heteroaryl", “oxygen-containing heteroaryl” and “sulfur-containing heteroaryl” optionally contains one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
• Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl , thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., as well as 5-10 membered ring groups containing these groups.
• 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 include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
• 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 in the case of normal valence and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
• substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the substituent lists, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Optional substituent substitutions of choice. If the nitrogen of a substituent is described as optionally substituted with one or more of the substituents listed, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected as 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 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 are substituted with 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 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. , 11 C, 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g.
• positron emitting isotopes eg 11 C, 18 F, 15 O and 13 N
• PTT positron emission tomography
• Isotopically labeled compounds of the invention may be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using appropriate isotopically labeled reagents in place of the previously employed non-labeled reagents.
• Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O , acetone- d6 or DMSO- d6 .
• compositions of the present invention may exist in free form for therapeutic use, 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 that can be directly administered to a patient in need thereof. Or indirectly provide the compound of the invention or its metabolites or residues. Therefore, when reference is made herein to "a compound of the invention", it is also intended to encompass the various derivative forms of the compound described above.
• Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
• esters means esters derived from compounds of each general formula herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the present invention). compound).
• the compounds of the present invention may themselves be esters.
• metabolites of the compounds of the invention ie substances formed in the body upon administration of the compounds of the invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc. of the administered compound.
• the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce metabolites thereof.
• the present invention further includes within its scope prodrugs of the compounds of the invention which may themselves have less pharmacological activity or be drug-free.
• Certain derivatives of physiologically active compounds of the invention can be converted to compounds of the invention having the desired activity when administered into or onto the body, for example by hydrolytic cleavage.
• prodrugs will be functional group 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," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EB Roche, American Pharmaceutical Association).
• prodrugs of the present invention may be prepared, 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 invention.
• the invention also encompasses compounds of the invention containing protecting groups.
• protecting groups In any process for preparing the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming chemically protected forms of the compounds of the invention. This can be achieved by conventional protecting groups, for example, 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.
• the protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
• the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or pro- Medicine, wherein said compound has the structure of formula (I):
• L is selected from direct bond, -C 1-6 alkylene-, -C 2-6 alkenylene- and -C 2-6 alkynylene-;
• Y is CR 4 or N
• Z is CR 5 or N
• alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally replaced by one at each occurrence.
• the present invention provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds thereof, or Prodrugs, wherein the compound has the structure of formula (II) or formula (III):
• L' is -C 1-6 alkylene-, the alkylene group is optionally substituted by one or more substituents independently selected from the following: -OH, C 3-6 cyclic hydrocarbon group, 3-10 membered Heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl; preferably, the alkylene is optionally substituted by one or more substituents independently selected from the following: -OH, cyclopropyl and phenyl optionally substituted by one or more halogens;
• the invention provides compounds of Formula (I), Formula (II) or Formula (III), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs thereof compound, solvate, metabolite, isotopically labeled compound or prodrug, wherein L is a direct bond or -C 1-6 alkylene-, wherein said alkylene is optionally selected from one or more independently Substituted from the following substituents: -OH, -OCH 3 , C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl , the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are further optionally substituted by one or more halogens or C 1-6 alkyl groups.
• L is a direct bond, methylene or ethylene, wherein said methylene and ethylene are optionally substituted with one or more substituents independently selected from: -OH , -OCH 3 , methyl, cyclopropyl, phenyl, pyrazolyl, pyridyl, pyrimidinyl and pyridazinyl, the above groups are optionally further substituted by one or more halogens and/or methyl;
• L is a direct bond, -CH2- , -CH 2 CH 2 -,
• the invention provides compounds of Formula (I), Formula (II) or Formula (III), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs thereof compounds, solvates, metabolites, isotopically labeled compounds or prodrugs, where X, Y and Z are each independently CH, CF or N.
• the invention provides compounds of Formula (I), Formula (II) or Formula (III), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs thereof Compounds, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl;
• C 1-6 alkyl e.g. methyl group
• halo C 1-6 alkyl e.g. trifluoromethyl
• -OC 1-6 alkyl e.g. methoxy
• -O-halo C 1-6 alkyl e.g. trifluoromethoxy base
• the invention provides compounds of Formula (I), Formula (II) or Formula (III), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs thereof compounds, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein R c and R d are each independently selected at each occurrence from H, C 1-6 alkyl (e.g., methyl, ethyl, tert.
• C 3-10 cycloalkyl such as cyclopropyl
• 3-10 membered heterocyclyl such as pyrrolidinyl, morpholinyl or piperidinyl optionally substituted by F
• C 6-10 Aryl phenyl optionally substituted by F
• 5-14 membered heteroaryl such as pyridyl
• the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are further optionally Substituted with one or more substituents independently selected from the group consisting of: halogen (e.g., F), -OH, halogenated C 1-6 alkyl (e.g., trifluoromethyl), and C 3-6 cycloalkyl (e.g., cyclopropyl) ).
• halogen e.g., F
• -OH halogenated C 1-6 alkyl
• C 3-6 cycloalkyl e.g., cyclopropyl
• the invention provides compounds of Formula (I), Formula (II) or Formula (III), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs thereof substance, solvate, metabolite, isotopically labeled compound or prodrug, wherein R 1 is selected from methyl, cyclopropyl, cyclohexyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidyl, morpholinyl , phenyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and imidazopyridyl; each of said groups is optionally substituted by one or more substituents independently selected from the following: -F, - Cl, -OH, -CN, -NH 2 , -CH 3 , -CF 3 , -CH 2 CF 2 CF 3 , -NHCH 2 CF 3 ,
• the invention provides compounds of Formula (I), Formula (II) or Formula (III), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs thereof substance, solvate, metabolite, isotopically labeled compound or prodrug, wherein R1 has the following structure:
• U and V are each independently CR 8e R 8f , NR 8g or O;
• the invention provides compounds of Formula (I), Formula (II) or Formula (III), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs thereof compounds, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein R 1 is selected from methyl,
• the present invention provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds thereof, or Prodrug, wherein said compound is selected from:
• compositions and methods of treatment are provided.
• the invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof Compounds, solvates, metabolites, isotopically 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 invention provides a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled
• a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled Use of compounds or prodrugs or pharmaceutical compositions of the present invention in the preparation of medicaments for preventing or treating HDAC6-related diseases.
• the invention provides a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled Compounds or prodrugs or pharmaceutical compositions of the invention for preventing or treating HDAC6-related diseases.
• the invention provides methods for preventing or treating HDAC6-related diseases, the methods comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomeric compound thereof.
• the HDAC6-related 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 cancer, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, multiple myeloma, and solid tumors); Wilson's disease Wilson's disease, spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease Alzheimer's disease, Alexander's disease, alcoholic liver disease, cystic fibrosis, Pick's disease, spinal muscular atrophy or Lewy body dementia; similar Rheumatoid arthritis, osteoarthritis; rheumatoi
• pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle that is administered with a therapeutic agent and is suitable for contact with humans and/or within the scope of reasonable medical judgment. Tissues 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, or preventing the progression of one or more symptoms of the disorder or condition to which such term applies.
• compounds of the present application are synthesized via the following reaction scheme:
• R is halogen and each remaining group is as defined herein.
• PG is an amino protecting group
• Step 2 to Step 5 (Compound 6)
• Example 18 (Compound 70i-A, 70i-B, 70i-BA, 70i-BB)
• Compound 70i-B (240mg, 0.49mmol) was subjected to chiral separation (column: IC, mobile phase: Hex/EtOH/TFA 50/50/0.3, flow rate: 25mL/min, detection wavelength: 254nM) to obtain white solid compound 70i- B-A (retention time: 21.264 minutes, 50 mg, 21%) and compound 70i-B-B (retention time: 29.823 minutes, 50 mg, 21%) are both chiral pure compounds.
• Example 21 (Compound 84j-A, 84j-B, 84j-AA, 84j-AB)
• Example 22 (Compound 88j-A, 88j-B, 88j-AA, 88j-AB)
• Example 28 (Compound 103j-A, 103j-B, 103j-C, 103j-D)
• 118a was used to replace 84a, and 118c was used to replace 84c, to obtain 118.
• reaction solution was purified through a silica gel column (dichloromethane/ethyl acetate: 50-90%) to obtain an off-white product 63e (400 mg, yield: 36.53%). MS m/z[M+H] + :500.3.
• Pentafluoropropionic acid (20 mg, 0.12 mmol), N,N-diisopropylethylamine (30 mg, 0.23 mmol), HATU (44 mg, 0.12 mmol) and DMF (2 mL) were added to the reaction flask. After stirring at room temperature for half an hour, compound 63j (30 mg, 0.078 mmol) was added, and the mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction solution was purified through a reversed-phase column (acetonitrile/0.05% formic acid aqueous solution: 50-70%) to obtain white solid product 145 (2 mg, yield: 4.83%). MS m/z[MH] + :530.2.
• reaction solution was purified through a silica gel column (dichloromethane/ethyl acetate: 50-90%) to obtain an off-white product 159b (50 mg, yield: 44.16%). MS m/z[M+H] + :371.2.
• HDAC6 (Abcam), test compounds and 20 ⁇ M substrate solution (Ac-GAK(Ac)-AMC) were added to the 384-well plate respectively, and incubated 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 455 nm was detected, and the inhibition rate at each concentration was calculated. IC 50 was obtained by fitting with GraphPadPrism 7.0 software.
• HDAC proteins of different subtypes purchased from BPS
• test compounds and substrate solutions purchased from BPS
• a concentration of 2.5-40 ⁇ M were added to the 384-well plate respectively, and incubated at 37°C for 30 min.
• IC 50 is obtained by fitting with GraphPadPrism 7.0 software.
• A375/HCT116/HCC827 cells in the logarithmic growth phase digest them with trypsin cell digestion solution, centrifuge, count, and spread them into a 96-well plate at a suitable cell density (30,000 cells/well), 100 ⁇ L per well, surrounded by Add appropriate amount of PBS for water sealing.
• cells were treated with different concentrations of compounds (initial concentration was 100 ⁇ M, 5-fold dilution, and 9 concentration gradients were set).
• the culture medium was aspirated and washed twice with 100 ⁇ L of PBST.
• the cells were then fixed with 4% paraformaldehyde and incubated at room temperature for 20 min. Discard the fixative and wash the cells with PBST.
• the animal and human liver microsomes used in this test system were purchased from Xenotech, Corning or other qualified suppliers and stored in a refrigerator below -60°C before use.
• test product and the control compound were incubated with animal and human liver microsomes respectively for a certain period of time at 37 ⁇ 1°C.
• the maximum incubation time The interval is 60 minutes, and the sample is taken out at the specified time point, and the reaction is terminated with acetonitrile or other organic solvent containing the internal standard. After centrifugation, the resulting supernatant was analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
• test powder is prepared into a stock solution of a certain concentration using 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 then further diluted with appropriate organic solvents.
• Microsomes of various genera were diluted into 2 ⁇ working solution with 100mM potassium phosphate buffer. The final concentration of microsomes in the reaction system was 0.5 mg/mL.
• NADP nicotinamide adenine dinucleotide phosphate
• ISO isocitrate
• Stop solution is prepared with acetonitrile or other organic solvent containing internal standard (tolbutamide or other suitable compound).
• the prepared stop solution is stored in a refrigerator at 2-8°C.
• Incubation will be done in 96-well plates. Prepare 8 incubation plates, named 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 are added to Blank60 plates, and samples are taken after 60 minutes of incubation. The NCF60 plate was incubated with potassium phosphate buffer instead of NADPH regeneration system solution for 60 minutes. All condition samples were run in triplicate.
• the reaction temperature is 37 ⁇ 1°C
• the final volume of the reaction is 200 ⁇ L
• the reaction system includes 0.5mg/mL microsomes, 1.0 ⁇ M substrate, 1mM NADP, 6mM ISO and 1unit/mL IDH.
• LC-MS/MS liquid chromatography-tandem mass spectrometry
• Semi-quantitative determinations were made using the ratio of the analyte peak area to the internal standard peak area.
• the retention time of analytes and internal standards, chromatogram acquisition, and chromatogram integration were processed using the software Analyst (Sciex, Framingham, Massachusetts, USA).
• the CV of the peak area of the internal standard in each matrix in each analytical batch 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 a residual rate:
• CL int (liver) CL int (mic) ⁇ microsomal protein amount in liver (mg/g) ⁇ liver weight to body weight ratio
• hepatic intrinsic clearance and hepatic clearance can be converted by the following formula.
• mice On the day of administration, the actual body weight of the mice was measured and the administration volume was calculated. There were 3 mice in each group, and each compound was tested in two groups. One group was given a single intravenous injection, and the other group of mice was given a single intragastric administration.
• Whole blood samples were collected at specified times (0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration) by orbital blood collection. After blood samples are collected, they are immediately transferred to labeled commercial sample tubes containing K2-EDTA (0.85-1.15 mg), followed by centrifugation (3200x g, 4°C, 10 minutes) and plasma is collected. Plasma was transferred to pre-chilled centrifuge tubes, flash frozen in dry ice, and subsequently stored in an ultra-low temperature freezer at -60°C or below until LC-MS/MS analysis.
• Plasma concentrations were determined using the LC-MS/MS method.
• WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma drug concentration data of compounds 1 and 2 using a non-compartmental model. Relevant pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method.
• Plasma concentrations were determined using the LC-MS/MS method.
• WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma drug concentration data of the compounds using a non-compartmental model. Relevant pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method.
• mice On the day of administration, the actual body weight of the mice was measured and the administration volume was calculated. There were 9 mice in each group, and the compounds were administered as a single intravenous injection (IV) or intragastric administration (PO).
• IV intravenous injection
• PO intragastric administration
• Whole blood samples were collected at specified times by orbital blood sampling. 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 (3200x g, 4°C, 10 minutes) and plasma was collected. Transfer the plasma to pre-cooled centrifuge tubes, flash freeze in dry ice, and then store in an ultra-low temperature freezer at -60°C or lower. Until LC-MS/MS analysis.
• WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma drug concentration data of the compounds using a noncompartmental model. Relevant pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method.
• Mouse brain-blood drug concentration ratio at the same time point drug concentration in brain tissue/drug concentration in plasma
• HEK293 cells were cultured in DMEM medium containing 10% fetal calf serum and 0.8 mg/mL G418 at a culture temperature of 37°C and a CO2 concentration of 5%.
• the cells were digested with TrypLE TM Express and centrifuged. The cell density was adjusted to 2 ⁇ 10 6 cells/mL.
• the cells were then gently mixed with a room temperature balance shaker for 15-20 minutes, and then put on the machine for patch clamp detection. Replace the culture medium of the prepared cells with extracellular fluid. Draw intracellular and external fluids from the liquid pool and add them to the intracellular liquid pool, cell and test substance pool of the QPlate chip respectively.
• 100mM K-Buffer Mix 9.5mL of stock solution A into 40.5mL of stock solution B, adjust the total volume to 500mL with ultrapure water, and titrate the buffer to pH 7.4 with KOH or H 3 PO 4 .
• test substance powder is prepared into a stock solution of a certain concentration using DMSO or other organic solvents, and then further diluted with a suitable organic solvent.
• liver microsomes for studying CYP450 enzyme metabolic phenotypes is based on prepared liver microsomes supplemented with oxidation-reduction coenzymes, and then adding enzyme-specific selective inhibitors under conditions that simulate physiological temperature and physiological environment. biochemical reactions.
• Solution preparation Prepare 0.05M sodium phosphate and 0.07M NaCl buffer, control compound (the final concentration of warfarin and quinidine in the system are both 1 ⁇ M) and the dosage solution (the final concentration is 1 ⁇ M).
• Dialysis membrane pretreatment first soak in distilled water for 60 minutes; then add 20% (v/v) ethanol solution (diluted with distilled water) and continue soaking for 20 minutes until the test starts. Wash twice with distilled water to remove remaining ethanol before use.
• Plasma pretreatment 1) Thaw human, rat, and mouse plasma at room temperature. After thawing, centrifuge at room temperature at a maximum speed of 2000 ⁇ g for 5 minutes, and retain the supernatant (freezing and thawing of plasma will produce fiber precipitation; plasma The samples were kept at room temperature for the rest of the tests); 2) Detect the plasma pH value and adjust the pH to 7.4 ⁇ 0.02 by adding a small amount of solid powder NaH 2 PO 4 .
• Control group and test group Add 100 ⁇ L of plasma solution containing positive control substance or test compound to the administration end (Donor) of the equilibrium dialysis device, and add 100 ⁇ L of blank buffer to the receiving end (Receiver).
• the plasma protein binding rate of the test compound is calculated according to the following formula:
• Binding rate % 100 ⁇ ([administration end] 5h - [receiving end] 5h) / [administration end] 5h
• test strains used in this mutagenicity test were Salmonella typhimurium auxotrophic strains TA98 and TA100.
• the experiment was conducted using a 6-well culture plate with or without the presence of the S9 metabolic activation system.
• a solvent control group (DMSO) and a positive control group were also set up, and each treatment group had 2 duplicate wells.
• Compounds were presented at five concentrations ranging from 62.5 to 1000.0 ⁇ g/well (concentrations equivalent to 312.5 to 5000.0 ⁇ g/dish in the standard Ames assay).
• the culture plate was incubated at 37°C for 48-72 hours, and then the bacterial toxicity in each well was detected, and the number of mutant colonies in each well was counted.
• the test substance is considered to have positive mutagenicity for the test strain.
• This test uses dimethyl sulfoxide (DMSO) to dissolve the test substance and serves as the negative (solvent) control of this test.
• DMSO dimethyl sulfoxide
• 2-nitrofluorene and sodium azide were used as positive controls for TA98 and TA100 respectively;
• 2-aminofluorene was used as the positive control for TA98 and TA100. things.

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