WO2021175079A1 - 对苯二胺类lsd1抑制剂及其制备方法 - Google Patents

对苯二胺类lsd1抑制剂及其制备方法 Download PDF

Info

Publication number
WO2021175079A1
WO2021175079A1 PCT/CN2021/075237 CN2021075237W WO2021175079A1 WO 2021175079 A1 WO2021175079 A1 WO 2021175079A1 CN 2021075237 W CN2021075237 W CN 2021075237W WO 2021175079 A1 WO2021175079 A1 WO 2021175079A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
general formula
stereoisomers
acceptable salts
methyl
Prior art date
Application number
PCT/CN2021/075237
Other languages
English (en)
French (fr)
Inventor
赵冬梅
汪鑫冉
程卯生
张翔宇
闫江坤
王继明
Original Assignee
沈阳药科大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 沈阳药科大学 filed Critical 沈阳药科大学
Publication of WO2021175079A1 publication Critical patent/WO2021175079A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the technical field of chemical synthesis of drugs, and relates to a new type of p-phenylenediamine derivatives and pharmaceutically acceptable salts of the derivatives, their preparation methods and their use as lysine-specific demethylase-1 (LSD1) Use of inhibitors.
  • LSD1 lysine-specific demethylase-1
  • Histone lysine demethylase occupies a very important position in the development of drugs in the field of epigenetics.
  • Shi Yang's research group first discovered histone lysine-specific demethylation Chylase 1, reveals that the process of histone methylation is a reversible and controllable process (Cell 2004,119,941-953.).
  • LSD1 can specifically remove the monomethyl or dimethyl group of histone lysine with the help of the cofactor flavin adenine dinucleotide (FAD).
  • FAD cofactor flavin adenine dinucleotide
  • LSD1 By removing the double methylation modification of H3K4, LSD1 can induce tumor suppressor gene silencing with transcription co-repressor, thereby promoting the growth of tumor cells.
  • researchers have successively reported that LSD1 is used as a tumor treatment target, and the combination of its inhibitors and other drugs (such as kinase inhibitors) can exert better tumor treatment effects. Therefore, the development of LSD1 inhibitors is conducive to the development of anti-tumor drugs, which can be used alone or in combination with other drugs for the treatment of cancer.
  • LSD1 inhibitors There are more than 600 LSD1 inhibitors reported, among which there is no marketed LSD1 inhibitor for tumor treatment. There are currently 11 LSD1 inhibitors in the clinical research stage, which can be divided into two types: irreversible inhibitors and reversible inhibitors. Irreversible inhibitors can form a covalent bond with the cofactor FAD, block FAD from participating in the demethylation cycle, thereby exerting LSD1 inhibitory activity.
  • the representative LSD1 inhibitors ORY-1001, ORY-2001, GSK-2879552, and IMG-7289 currently in the clinical research stage are irreversible inhibitors with trans-phenylcyclopropylamine as the structural core.
  • LSD1 inhibitors At present, most of the research and development of LSD1 inhibitors are carried out with trans-phenylcyclopropylamine compounds, and the development of more new backbone LSD1 inhibitors is the current research hotspot in the field of anti-tumor.
  • LSD1 inhibitors the compound of general formula I of the present invention exhibits better activity at the enzyme level in vitro.
  • the purpose of the present invention is to provide a p-phenylenediamine derivative represented by the general formula I, as well as pharmaceutically acceptable salts and stereoisomers of the derivative, for the preparation of LSD1 inhibitors,
  • R 1 is selected from hydrogen, C1-C3 alkyl, wherein the C1-C3 alkyl may contain 0-4 halogen atoms selected from F, Cl or Br substituted;
  • R 2 is selected from hydrogen, C1-C7 fatty primary amine, C1-C7 fatty secondary amine, C1-C7 fatty tertiary amine, preferably propylamine, N-methylpropylamine, N,N-dimethylpropylamine;
  • R 3 is selected from hydrogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, ethyl, ethoxy, propyl, isopropyl, nitro, cyano, amino, hydroxyl, halogen atom ;
  • n 0, 1, 2 or 3;
  • R 4 selected from halogen atoms, phenyl, naphthyl, C4-C10 aromatic heterocyclic ring; wherein phenyl, naphthyl, C4-C10 aromatic heterocyclic ring may be substituted with one or more substituents R a, C4-C10 aryl and the heterocyclic ring containing 1 ⁇ 3 heteroatoms selected from N, O or S;
  • R a is selected from C1-C3 alkyl, hydroxyl, mercapto, halogen, nitro, amino, cyano, carboxy, hydrazino, amidino, guanidine, amide;
  • n 0, 1, 2 or 3.
  • the purpose of the present invention is to provide a p-phenylenediamine derivative represented by the general formula I, as well as pharmaceutically acceptable salts and stereoisomers of the derivative,
  • R 1 is selected from hydrogen, C1-C3 alkyl, wherein the C1-C3 alkyl may contain 0-4 halogen atoms selected from F, Cl or Br substituted;
  • R 2 is selected from hydrogen, C1-C7 fatty primary amine group, C1-C7 fatty secondary amine group, C1-C7 fatty tertiary amine group; or R 1 and R 2 form a ring together with the nitrogen atom to which they are connected;
  • R 3 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, nitro, cyano, amino, hydroxyl, halogen atom;
  • n 0, 1, 2 or 3;
  • R 4 is selected from a halogen atom, a phenyl group, a naphthyl group, C4-C10 aromatic heterocyclic group; wherein the phenyl, naphthyl, C4-C10 aromatic heterocyclic group optionally substituted by one or more substituents R a, and
  • the C4-C10 aromatic heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;
  • R a is selected from C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, hydroxyl, mercapto, halogen, nitro, amino, cyano, carboxy, Hydrazine, amidino, guanidino, amide;
  • n 0, 1, 2 or 3.
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 1 is preferably hydrogen, methyl, or ethyl.
  • the present invention preferably relates to the p-phenylenediamine derivatives represented by the general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 2 is selected from hydrogen, C1-C7 fatty primary amines, C1-C7 fatty secondary amines and C1-C7 fatty tertiary amines are preferably propylamine, N-methylpropylamine, and N,N-dimethylpropylamine.
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 2 is selected from hydrogen, C1-C7 aliphatic primary amino group Group, C1-C7 fatty secondary amine group, C1-C7 fatty tertiary amine group; or R 1 and R 2 form a ring together with the nitrogen atom to which they are attached.
  • R 2 is selected from hydrogen, C1-C7 aliphatic primary amino group Group, C1-C7 fatty secondary amine group, C1-C7 fatty tertiary amine group; or R 1 and R 2 form a ring together with the nitrogen atom to which they are attached.
  • the present invention preferably relates to the p-phenylenediamine derivatives represented by the general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 2 is selected from hydrogen, C1-C7 primary amino fats Groups (such as alkyl or cycloalkyl), C1-C7 secondary amino aliphatic groups (such as alkyl or cycloalkyl), C1-C7 tertiary amino aliphatic groups (such as alkyl or cycloalkane) Group), C1-C7 nitrogen-containing heterocyclic group, C1-C7 nitrogen-containing heterocyclic group alkyl, wherein the nitrogen-containing heterocyclic group is optionally substituted by an alkyl group (such as methyl or ethyl, preferably methyl )replace.
  • R 2 is selected from hydrogen, C1-C7 primary amino fats Groups (such as alkyl or cycloalkyl), C1-C7 secondary amino aliphatic groups (such as al
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 2 is selected from aminopropyl, methylaminoethyl, Methylaminopropyl, dimethylaminoethyl, dimethylaminopropyl, piperidinyl, N-methylpiperidinyl, piperidinylmethyl.
  • R 2 is selected from aminopropyl, methylaminoethyl, Methylaminopropyl, dimethylaminoethyl, dimethylaminopropyl, piperidinyl, N-methylpiperidinyl, piperidinylmethyl.
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 1 and R 2 are together with the nitrogen atom to which they are attached A five-membered or six-membered ring is formed, such as piperazinyl, N-methylpiperazinyl, aminopiperidinyl, and aminopyrrolidinyl.
  • R 1 and R 2 are together with the nitrogen atom to which they are attached
  • a five-membered or six-membered ring is formed, such as piperazinyl, N-methylpiperazinyl, aminopiperidinyl, and aminopyrrolidinyl.
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 3 is independently selected from hydrogen, C1-C6 alkyl (E.g. C1-C3 alkyl), halo C1-C6 alkyl (e.g. halo C1-C3 alkyl), C1-C6 alkoxy (e.g. C1-C3 alkoxy), halo C1-C6 alkoxy Group (e.g. halogenated C1-C3 alkoxy group), nitro group, cyano group, amino group, hydroxyl group, halogen atom.
  • R 3 is independently selected from hydrogen, C1-C6 alkyl (E.g. C1-C3 alkyl), halo C1-C6 alkyl (e.g. halo C1-C3 alkyl), C1-C6 alkoxy (e.g. C1-C3 al
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 3 is selected from hydrogen, methyl, trifluoromethyl , Methoxy, trifluoromethoxy, ethyl, ethoxy, propyl, isopropyl, nitro, cyano, amino, hydroxyl, halogen atom, preferably amino, hydroxyl, methoxy, trifluoromethyl Oxy.
  • R 3 is selected from hydrogen, methyl, trifluoromethyl , Methoxy, trifluoromethoxy, ethyl, ethoxy, propyl, isopropyl, nitro, cyano, amino, hydroxyl, halogen atom, preferably amino, hydroxyl, methoxy, trifluoromethyl Oxy.
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 3 is independently selected from hydrogen, methyl, trifluoro Methyl, methoxy, nitro, cyano, amino or chlorine.
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2 or 0 or 1.
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 4 is selected from halogen atoms, phenyl groups, naphthyl groups, C4-C10 aromatic heterocyclic group; wherein the phenyl, naphthyl, C4-C10 aromatic heterocyclic group optionally substituted by one or more substituents R a, and the C4-C10 aromatic heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S.
  • R 4 is selected from halogen atoms, phenyl groups, naphthyl groups, C4-C10 aromatic heterocyclic group; wherein the phenyl, naphthyl, C4-C10 aromatic heterocyclic group optionally substituted by one or more substituents R a, and the C4-C10 aromatic heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S.
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 4 is selected from furan, thiophene, pyrrole, oxazole, Isoxazole, pyrazole, imidazole, triazole, phenyl, pyridine, pyrimidine, indole, benzofuran, benzothiophene, benzothiazole, benzoxazole, benzisoxazole, benzimidazole, benzo pyrazole, benzotriazole, naphthalene, quinoline, quinazoline; and the group may be substituted with one or more substituents R a.
  • R 4 is selected from furan, thiophene, pyrrole, oxazole, Isoxazole, pyrazole, imidazole, triazole, phenyl, pyridine, pyrimidine,
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 4 is independently selected from phenyl, naphthyl, furan Group, thienyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, pyridyl, pyrimidinyl, indolyl, benzofuranyl, benzothiophene Group, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzopyrazolyl, benzotriazole, naphthyl, quinolinyl, quinazolinyl; and the group is optionally substituted with one or more substituents R a.
  • R 4 is independently selected from phenyl, naphthyl, furan Group, thieny
  • the present invention preferably relates to the p-phenylenediamine derivatives represented by the general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein Ra is selected from C1-C3 alkyl, hydroxyl, sulfhydryl , Halogen, nitro, amino, cyano, carboxy, hydrazino, amidino, guanidino, amide; preferably methyl, ethyl, fluorine.
  • Ra is selected from C1-C3 alkyl, hydroxyl, sulfhydryl , Halogen, nitro, amino, cyano, carboxy, hydrazino, amidino, guanidino, amide; preferably methyl, ethyl, fluorine.
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein Ra is independently selected from C1-C3 alkyl, C1 ⁇ C3 alkoxy, halogenated C1 ⁇ C3 alkyl, halogenated C1 ⁇ C3 alkoxy, hydroxy, mercapto, halogen, nitro, amino, cyano, carboxy, hydrazino, amidino, guanidino, amide ; Preferably methyl, ethyl, isopropyl, methoxy, trifluoromethoxy, cyano, chlorine or fluorine.
  • R is independently selected from C1-C3 alkyl, C1 ⁇ C3 alkoxy, halogenated C1 ⁇ C3 alkyl, halogenated C1 ⁇ C3 alkoxy, hydroxy, mercapto, halogen, nitro, amino, cyano, carboxy, hydrazin
  • the present invention preferably relates to p-phenylenediamine derivatives represented by general formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, wherein n is 0, 1, 2 or 3, preferably 0 or 1.
  • the compounds of general formula I of the present invention and their pharmaceutically acceptable salts are preferably the following compounds, but these compounds are not meant to limit the present invention:
  • the compound of formula I in the present invention can form a pharmaceutically acceptable salt with an acid.
  • Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and acid addition salts are particularly preferred acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid.
  • Acid benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • alkyl refers to straight or branched chain alkyl
  • aromatic heterocycle (group) refers to containing one or more selected from N A monocyclic or polycyclic ring system of heteroatoms of, O, and S.
  • the ring system refers to an organic group obtained by removing one or multiple hydrogen atoms at different positions in the ring system and having aromaticity.
  • thiazolyl imidazolyl, pyridyl, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, furyl, thienyl, pyrrolyl, indolyl, Benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, etc.; fatty primary amine (group), fatty secondary amine ( Group), fatty tertiary amine (group) refers to a chain or cyclic system containing one or more nitrogen atoms, such as ethylamine, N-methylethylamine, N,N-dimethylethylamine, propylamine , Butylamine, cyclobutylamine, tetrahydropyrrole, piperazine, piperidine, tetrahydropyrazole,
  • the examples and preparation examples provided below further illustrate and exemplify the compounds of the present invention and the preparation methods thereof. It should be understood that the scope of the following examples and preparation examples does not limit the scope of the present invention in any way.
  • the compound of formula (I) according to the present invention can be prepared according to the method of Route 1 or the method of Route 2.
  • the starting material I and the substituted aliphatic amine undergo a nucleophilic substitution reaction to obtain intermediate II.
  • the reaction condition a is an organic base (such as triethylamine, N,N-diisopropylethylamine, etc.) or an inorganic base (such as: sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, etc.) as the acid binding agent, carried out at room temperature or under heating;
  • the reaction solvent can be methanol, ethanol, propanol, Acetone, N,N-dimethylformamide, dimethylsulfoxide and other polar solvents; preferably potassium carbonate as the acid binding agent, N,N-dimethylformamide as the solvent, and react at 80°C.
  • Reaction condition b can be hydrogenation reduction catalyzed by various palladium catalysts, a combination of reducing metals and inorganic acids (such as iron powder/ammonium chloride, iron powder/hydrochloric acid, zinc Powder/acetic acid, etc.); the reaction solvent can be tetrahydrofuran, methanol, ethanol, dichloromethane, water, etc.
  • the solvent can be a single solvent or a mixed solvent; the catalytic hydrogenation conditions are preferably 10% Pd/C as the catalyst and methanol as the solvent
  • the reaction temperature is preferably room temperature.
  • the reaction condition c is palladium complex catalysis, inorganic base and heating reaction under oxygen-free conditions;
  • the zero-valent palladium complex can be Pd(PPh 3 ) 4 , PdCl 2 , PdCl 2 (dppf), Pd(OAc) 2 and Pd(PPh 3 ) 2 Cl 2 etc., preferably Pd(PPh 3 ) 4 ;
  • the inorganic base can be potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, etc., Sodium carbonate is preferred;
  • the solvent can be ethanol, 1,4-dioxane, tetrahydrofuran, toluene, N,N-dimethylformamide, dimethyl sulfoxide, water, ethylene glycol dimethyl ether, etc., or It is a mixed solvent composed of two solvents, the solvent is preferably a mixed solvent of ethylene glycol dimethyl ether and water (volume ratio is 10:1);
  • the reaction temperature can be 80-
  • the reaction condition d is catalyzed by organic or inorganic acid and heated for 10-48 hours; the organic acid can be benzenesulfonic acid, p-toluenesulfonic acid and acetic acid, etc.
  • the inorganic acid can be dilute sulfuric acid, dilute hydrochloric acid, dilute nitric acid, etc.
  • the amount of acid is a catalytic amount, preferably p-toluenesulfonic acid, dilute hydrochloric acid;
  • the solvent can be methanol, ethanol, isopropanol, N,N-dimethylformamide And dimethyl sulfoxide, etc., preferably ethanol, isopropanol;
  • the reaction temperature can be 60-130°C, preferably 80°C; the reaction time is preferably 24 hours.
  • Intermediate VI and Intermediate VII undergo nucleophilic substitution reaction to obtain Intermediate VIII.
  • Reaction condition e is organic acid or inorganic acid catalyzed by heating for 48-96 hours; organic acid can be benzenesulfonic acid, p-toluenesulfonic acid and acetic acid, etc.
  • the inorganic acid can be dilute sulfuric acid, dilute hydrochloric acid, dilute nitric acid, etc.
  • the amount of acid used is a catalytic amount or a molar amount, preferably p-toluenesulfonic acid, dilute hydrochloric acid;
  • the solvent can be methanol, ethanol, isopropanol, N,N-di Methylformamide and dimethyl sulfoxide, etc., preferably ethanol, isopropanol;
  • the reaction temperature can be 80-150°C, preferably 110°C; the reaction time is preferably 72 hours; according to the reaction process, the tube can be sealed and heated for reaction.
  • the reaction condition f is an organic base (such as triethylamine, N,N-diisopropylethylamine, etc.) or an inorganic base (such as sodium carbonate) , Potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, etc.) as an acid binding agent, proceed at room temperature or under heating;
  • the reaction solvent can be methanol, ethanol, propanol, acetone, N, Polar solvents such as N-dimethylformamide and dimethyl sulfoxide; preferably potassium carbonate is used as the acid binding agent, and N,N-dimethylformamide is used as the solvent for reaction at 80°C.
  • the present invention also provides the p-phenylenediamine derivatives represented by the general formula I, as well as the pharmaceutically acceptable salts and stereoisomers of the derivatives, which are used as a lysine-specific demethylase 1 (LSD1) inhibitor.
  • LSD1 lysine-specific demethylase 1
  • the present invention also provides the use of the p-phenylenediamine derivatives represented by the general formula I and the pharmaceutically acceptable salts and stereoisomers of the derivatives for preparing drugs for the treatment of cancer.
  • the cancer includes, but is not limited to, stomach cancer, breast cancer, prostate cancer, liver cancer, ovarian cancer, colon cancer, kidney cancer, head and neck cancer, melanoma, and leukemia.
  • the p-phenylenediamine derivatives represented by the general formula I of the present invention and the pharmaceutically acceptable salts and stereoisomers of the derivatives as LSD1 inhibitors can be used in combination with other drugs for disease treatment.
  • the present invention also provides the use of the composition for preparing a medicine for the treatment of cancer.
  • the composition comprises a p-phenylenediamine derivative represented by the general formula I and a pharmaceutically acceptable salt and stereo Isomers, and pharmaceutical carriers.
  • the composition may also contain other drugs.
  • Step A-1 Preparation of 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole
  • Step A-2 Preparation of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine
  • Step A-3 N-[2-(Dimethylamino)ethyl]-5-methoxy-N-methyl-N'-[4-(1-methyl-1H-indol-3-yl )-2-pyrimidinyl]-2-nitro-1,4-phenylenediamine synthesis
  • N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (2.0g, 5.1mmol ), N,N,N'-trimethylethylenediamine (0.5g, 5.1mmol) and N,N-diisopropylethylamine (0.7g, 5.1mmol) into 100mL reaction flask, add 4mL N,N -Dimethylformamide, react at 80°C for 12h. The reaction solution was cooled, and the reaction solution was cooled and added to 100 mL of water, extracted with ethyl acetate (10 mL ⁇ 3), and washed with saturated brine (10 mL ⁇ 3).
  • Examples 2-4, 10 and 14 The synthesis of Examples 2-4, 10 and 14 was based on N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indole -3-yl)pyrimidin-2-amine and different fatty amines were obtained according to the same synthesis method as in Example 1.
  • Step A-4 tert-butyl [1-(5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)-2- Preparation of nitrophenyl) piperidin-4-yl) carbamate
  • N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (2.0g, 5.1mmol ), N,N-diisopropylethylamine (0.7g, 5.1mmol) and 4-tert-butoxycarbonylaminopiperidine (1.0g, 5.1mmol) into a 100mL reaction flask, add 4mL N,N-dimethyl Formamide, react at 80°C for 12h.
  • the reaction solution was cooled, and the reaction solution was cooled and added to 100 mL of water, extracted with ethyl acetate (10 mL ⁇ 3), and washed with saturated brine (10 mL ⁇ 3).
  • the ethyl acetate phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purified by silica gel column chromatography to obtain 1.9 g of orange-red solid with a yield of 64.1%
  • Step A-5 N-[4-(4-Aminopiperidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methyl-1H-indole-3 -Yl) pyrimidin-2-amine synthesis
  • Examples 6-9, Examples 11-13, and Examples 15-17 were obtained by using different fatty amine substrates according to the synthesis method of Example 5.
  • Step A-6 Preparation of N-[2-(dimethylamino)ethyl]-N-methyl-2-nitrophenyl-1,4-diamine
  • Step A-7 N-(2-(Dimethylamino)ethyl)-N-methyl-N'-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl ]-2-Nitrobenzene-1,4-Diamine Synthesis
  • Step A-8 Add N-(2-(dimethylamino)ethyl)-N-methyl-N'-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidine Benzyl]-2-nitrobenzene-1,4-diamine (0.5g, 1.1mmol) and 10% palladium on carbon (0.1g) were added to a 50ml reaction flask, and 20ml of methanol was added. Under hydrogen conditions, react at room temperature for 12 hours. After filtration, the filtrate was concentrated to obtain 0.4 g of a light yellow solid with a yield of 89.0%.
  • Step A-10 Preparation of N,N,N'-trimethyl-N'-(4-nitrophenyl)ethane-1,2-diamine
  • step A-6 Using p-fluoronitrobenzene and N,N,N'-trimethylethylenediamine as raw materials, it was prepared according to the operation of step A-6, and the yield was 60.7%.
  • Step A-11 Preparation of N-[2-(dimethylamino)ethyl]-N-methylbenzene-1,4-diamine
  • Step A-12 Synthesis of N-[2-(dimethylamino)ethyl]-N-methyl-N'-(4-phenylpyrimidin-2-yl)phenyl-1,4-diamine
  • the present invention purchases Cayman's 700120 kit to detect the LSD1 inhibitory activity of some compounds, and the specific operation steps are as follows:
  • Test wells and positive control wells sequentially add 120 ⁇ L LSD1 buffer, 10 ⁇ L test compound solution, 20 ⁇ L LSD1 enzyme, 20 ⁇ L LSD1 detection peptide.
  • the microplate reader is excited at a wavelength of 530nM and detects the intensity of the emitted fluorescence of 590nM.
  • Inhibition rate% (100% active hole-sample hole) / 100% active hole * 100
  • the in vitro enzyme level activity test IC 50 is designated as being within the following range:
  • the compound of formula I and its pharmaceutically acceptable salts or prodrugs of the present invention can be administered alone, but are usually administered as a mixture with a pharmaceutical carrier.
  • a pharmaceutical carrier depends on the desired route of administration and standard pharmaceutical practice.
  • the preparation methods of various pharmaceutical dosage forms of this type of compound such as tablets, capsules, injections, aerosols, suppositories, films, dripping pills, topical liniments and ointments, are used to illustrate their applications in the pharmaceutical field. New application.
  • the activated carbon adsorption was carried out, filtered through a 0.65 ⁇ m microporous membrane, and filled into a nitrogen tank to make a water injection preparation. Each pack is 2mL, a total of 100 bottles are filled.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种通式I所示的对苯二胺类衍生物及其药学上可接受的盐、其立体异构体，该通式I的对苯二胺类衍生物及其药学上可接受的盐、其立体异构体可单独或联合用药，作为赖氨酸特异性脱甲基酶-1(LSD1)抑制剂。

Description

对苯二胺类LSD1抑制剂及其制备方法 技术领域
本发明属于化学合成药物技术领域，涉及一类新型对苯二胺类衍生物以及所述衍生物的药学可接受的盐、它们的制备方法及其作为赖氨酸特异性去甲基酶-1(LSD1)抑制剂的用途。
背景技术
组蛋白赖氨酸去甲基化酶在开发表观遗传学领域的药物中占据着非常重要的地位，直到2004年，Shi Yang课题组第一次发现了组蛋白赖氨酸特异性去甲基化酶1，揭示了组蛋白甲基化过程是一个可逆、可控的过程(Cell 2004,119,941–953.)。研究发现LSD1在辅因子黄素腺嘌呤二核苷酸(FAD)的辅助下可以特异性地去除组蛋白赖氨酸的单甲基或双甲基，通过作用于甲基化的赖氨酸可以分别发挥基因转录激活和转录抑制的作用。进而调控下游信号通路，发挥调节作用。通过去除H3K4的双甲基化修饰，LSD1可以与转录共阻遏物诱导抑癌基因的沉默，从而促进肿瘤细胞的生长。研究者相继报道了LSD1作为肿瘤治疗靶标，其抑制剂与其他药物(如激酶抑制剂)联合用药可发挥更好的肿瘤治疗效果。因此，LSD1抑制剂的开发有利于抗肿瘤药物的研发，可以单独或者与其他药物组合用于癌症的治疗。
已报道的LSD1抑制剂有六百多个，其中尚无用于肿瘤治疗的上市LSD1抑制剂。目前处于临床研究阶段的LSD1抑制剂共有11个，可分为不可逆性抑制剂和可逆性抑制剂两类。不可逆性抑制剂可以与辅因子FAD形成共价结合，阻断FAD参与去甲基的循环，从而发挥LSD1抑制活性。目前处于临床研究阶段的代表性LSD1抑制剂ORY-1001、ORY-2001、GSK-2879552、IMG-7289均以反苯基环丙胺为结构母核的不可逆抑制剂。目前已公布结构的抑制剂中只有Utah大学原研、Salarius制药公司推进临床试验的Seclidemstat mesylate和Celgene制药公司开发的CC-90011作 为可逆性LSD1抑制剂处于临床研究阶段，适应症均为肿瘤。
目前对于LSD1抑制剂的研发多数以反苯基环丙胺类化合物展开，开发更多新骨架LSD1抑制剂是目前抗肿瘤领域的研究热点。本发明所述通式I化合物作为LSD1抑制剂，在体外酶水平表现出较好的活性。
发明内容
本发明的目的在于提供一种通式I所示的对苯二胺类衍生物，以及所述衍生物的药学可接受的盐和立体异构体，用于制备LSD1抑制剂，
Figure PCTCN2021075237-appb-000001
其中：
R 1选自氢、C1-C3烷基，其中，所述C1-C3烷基可含有0-4个选自F、Cl或Br的卤原子取代；
R 2选自氢、C1～C7脂肪伯胺、C1～C7脂肪仲胺、C1～C7脂肪叔胺，优选为丙胺、N-甲基丙胺、N,N-二甲基丙胺；
R 3选自氢、甲基、三氟甲基、甲氧基、三氟甲氧基、乙基、乙氧基、丙基、异丙基、硝基、氰基、氨基、羟基、卤原子；
m为0、1、2或3；
X＝C或N；
R 4选自卤原子、苯、萘、C4-C10芳杂环；其中苯、萘、C4-C10芳杂环可被一个或多个R a取代，且所述C4-C10芳杂环含有1～3个选自N、O或S的杂原子；
R a选自C1～C3烷基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、酰胺；
n为0、1、2或3。
本发明的目的在于提供一种通式I所示的对苯二胺类衍生物，以及所述衍生物的药学可接受的盐和立体异构体，
Figure PCTCN2021075237-appb-000002
其中：
R 1选自氢、C1-C3烷基，其中，所述C1-C3烷基可含有0-4个选自F、Cl或Br的卤原子取代；
R 2选自氢、C1～C7脂肪伯胺基团、C1～C7脂肪仲胺基团、C1～C7脂肪叔胺基团；或者R 1和R 2与它们所连接的氮原子一起形成环；
R 3选自氢、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、硝基、氰基、氨基、羟基、卤原子；
m为0、1、2或3；
X＝C或N；
R 4选自卤原子、苯基、萘基、C4-C10芳杂环基团；其中苯基、萘基、C4-C10芳杂环基团任选地被一个或多个R a取代，且所述C4-C10芳杂环基团含有1～3个选自N、O或S的杂原子；
R a选自C1～C3烷基、C1～C3烷氧基、卤代C1～C3烷基、卤代C1～C3烷氧基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、酰胺基；
n为0、1、2或3。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 1优选为氢、甲基、乙基。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 2选自氢、C1～C7脂肪伯胺、C1～C7脂肪仲胺、C1～C7脂肪叔胺，优选为丙胺、N-甲基丙胺、N,N-二甲基丙胺。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 2选自氢、C1～C7脂肪伯胺基团、C1～C7脂肪仲胺基团、C1～C7脂肪叔胺基团；或者R 1和R 2与它们所连接的氮原 子一起形成环。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 2选自氢、C1～C7的伯氨基脂肪族基团(例如烷基或环烷基)、C1～C7的仲氨基脂肪族基团(例如烷基或环烷基)、C1～C7的叔氨基脂肪族基团(例如烷基或环烷基)、C1～C7的含氮杂环基、C1～C7的含氮杂环基烷基，其中所述含氮杂环基任选地被烷基(例如甲基或乙基，优选甲基)取代。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 2选自氨基丙基、甲氨基乙基、甲氨基丙基、二甲氨基乙基、二甲氨基丙基、哌啶基、N-甲基哌啶基、哌啶基甲基。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 1和R 2与它们所连接的氮原子一起形成五元环或六元环，例如哌嗪基、N-甲基哌嗪基、氨基哌啶基、氨基吡咯烷基。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 3独立地选自氢、C1-C6烷基(例如C1-C3烷基)、卤代C1-C6烷基(例如卤代C1-C3烷基)、C1-C6烷氧基(例如C1-C3烷氧基)、卤代C1-C6烷氧基(例如卤代C1-C3烷氧基)、硝基、氰基、氨基、羟基、卤原子。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 3选自氢、甲基、三氟甲基、甲氧基、三氟甲氧基、乙基、乙氧基、丙基、异丙基、硝基、氰基、氨基、羟基、卤原子，优选氨基、羟基、甲氧基、三氟甲氧基。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 3独立地选自氢、甲基、三氟甲基、甲氧基、硝基、氰基、氨基或氯。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，m为0、1、2或3，优选0、1或2或者0或1。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，X＝C或N，优选N。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 4选自卤原子、苯基、萘基、C4-C10芳杂环基团；其中苯基、萘基、C4-C10芳杂环基团任选地被一个或多个R a取代，且所述C4-C10芳杂环基团含有1～3个选自N、O或S的杂原子。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 4选自呋喃、噻吩、吡咯、噁唑、异噁唑、吡唑、咪唑、三氮唑、苯基、吡啶、嘧啶、吲哚、苯并呋喃、苯并噻吩、苯并噻唑、苯并噁唑、苯并异噁唑、苯并咪唑、苯并吡唑、苯并三氮唑、萘、喹啉、喹唑啉；且所述基团可被一个或多个R a取代。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R 4独立地选自苯基、萘基、呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、吡唑基、咪唑基、三氮唑基、苯基、吡啶基、嘧啶基、吲哚基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并吡唑基、苯并三氮唑基、萘基、喹啉基、喹唑啉基；且所述基团任选地被一个或多个R a取代。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R a选自C1～C3烷基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、酰胺；优选甲基、乙基、氟。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，R a独立地选自C1～C3烷基、C1～C3烷氧基、卤代C1～C3烷基、卤代C1～C3烷氧基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、酰胺基；优选甲基、乙基、异丙基、甲氧基、三氟甲氧基、氰基、氯或氟。
进一步地，本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体，其中，n为0、1、2或3，优选0或1。
本发明通式I化合物及其药学上可接受的盐优选以下化合物，但这些化合物并不意味着对本发明的任何限制：
N-[2-(二甲氨基)乙基]-5-甲氧基-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基-1,4-苯二胺
2-甲氧基-N’-甲基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-N’-[2-(甲氨基)乙基]-5-硝基-1,4-苯二胺
N-[2-甲氧基-5-硝基-4-(哌嗪-1-基)苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
N-[2-甲氧基-4-(4-甲基哌嗪-1-基)-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
N-[4-(4-氨基哌啶-1-基)-2-甲氧基-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
2-甲氧基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-5-硝基-N’-(哌啶-4-甲基)-1,4-苯二胺
(S)-N-[4-(3-氨基哌啶-1-基)-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
(R)-N-[4-(3-氨基哌啶-1-基)-2-甲氧基-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
N-(4-氨基环己基)-5-甲氧基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
2-甲氧基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-N’-(1-甲基哌啶-4-基)-5-硝基苯-1,4-二胺
2-甲氧基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-5-硝基-N’-(哌啶-3-基)-1,4-苯二胺
N-[4-(3-氨基吡咯啉-1-基)-2-甲氧基-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
N-(3-氨基丙基)-5-甲氧基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
2-甲氧基-N’-甲基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-N’-[3-(甲氨基)丙基]-5-硝基苯-1,4-二胺
N-(2-氨基乙基)-5-甲氧基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
N-(4-氨基丁基)-5-甲氧基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
N-(5-氨基戊基)-5-甲氧基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
N-(2-(二甲氨基)乙基)-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,2,4-三胺
N’-[2-(二甲氨基)乙基]-2-甲氧基-N’-甲基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N,2-二甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,4-二胺
N’-[2-(二甲氨基)乙基]-N’,2-二甲基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,4-二胺
2-氯-N’-[2-(二甲氨基)乙基]-N’-甲基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,4-二胺
2-氯-N-[2-(二甲氨基)乙基]-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-(三氟甲基)苯基-1,4-二胺
2-[(2-(二甲氨基)乙基)(甲基)氨基]-5-[(4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基)氨基]苯腈
N-[2-(二甲氨基)乙基]-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-(三氟甲基)苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-(4-苯基嘧啶-2-基)苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-(5-苯基嘧啶-2-基)苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-[5-(萘乙酰胺-2-基)-2-嘧啶基]苯基-1,4-二胺
N-[5-(苯并呋喃-3-基)-2-嘧啶基]-N’-[2-(二甲氨基)乙基]-N’-甲基苯基-1,4-二胺
N-[5-(苯并[b]噻吩-3-基)-2-嘧啶基]-N’-[2-(二甲氨基)乙基]-N’-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-[5-(噻吩-3-基)-2-嘧啶基]苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-(5-(呋喃-3-基)-2-嘧啶基)-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-(5-(3-甲氧基苯基)-2-嘧啶基)-N-甲基苯基-1,4-二胺
N-[5-(3-氯苯基)-2-嘧啶基]-N’-[2-(二甲氨基)乙基]-N’-甲基苯基-1,4-二胺
3-[2-((4-((2-(二甲氨基)乙基)(甲基)氨基)苯基)氨基)-5-嘧啶基]苯腈
N-[2-(二甲氨基)乙基]-N-甲基-N’-[5-(3-(三氟甲氧基)苯基)-2-嘧啶基]苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(3-氟苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(3,5-二甲基苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(4-氟-3-甲基苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(3-氟-4-甲氧基苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-[5-(甲苯基)-2-嘧啶基]苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(2-氟苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(4-氟苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[5-(3,4-二甲氧基苯基)-2-嘧啶基]-N’-[2-(二甲氨基)乙基]-N’-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-(5-(5-异丙基-2-甲氧基苯基)-2-嘧啶基)-N- 甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-(4-(2-氟-4-甲基苯基)-2-吡啶基)-N-甲基苯基-1,4-二胺
而且，按照本发明所属领域的一些通常方法，本发明中通式I的化合物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与酸加成的盐是特别优选的酸为：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸。
本发明中“卤素”是指氟、氯、溴或碘；“烷基”是指直链或支链的烷基；“芳杂环(基团)”是指含有一个或多个选自N、O、S的杂原子的单环或多环的环状体系，该环状体系是指具有芳香性的，并且除去环状体系中的一个或不同位置的多个氢原子而得到的有机基团，如噻唑基，咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基，吲哚基，苯并噻唑基，噁唑基，异噁唑基，萘基，喹啉基，异喹啉基，苯并咪唑基，苯并噁唑基等；脂肪伯胺(基团)、脂肪仲胺(基团)、脂肪叔胺(基团)是指含有一个或多个氮原子的链状或环状体系，如乙胺、N-甲基乙胺、N,N-二甲基乙胺、丙胺、丁胺、环丁胺、四氢吡咯、哌嗪、哌啶、四氢吡唑烷、四氢咪唑、N-甲基哌啶等，并且除去链状或环状体系中的一个或不同位置的氢原子而得到的有机基团。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实例和制备例的范围并不以任何方式限制本发明的范围。按照本发明的式(I)化合物，可按照路线1的方法或路线2方法制备得来。
Figure PCTCN2021075237-appb-000003
如路线1所示，其中应用的全部可变因数如权利要求中的定义。
起始原料I与取代的脂肪胺发生亲核取代反应得到中间体II，反应条件a为一种有机碱(如：三乙胺、N,N-二异丙基乙胺等)或无机碱(如：碳酸钠、碳酸钾、碳酸铯、磷酸钠、氢氧化钠、氢氧化钾等)做缚酸剂的情况下，于室温或加热条件下进行；反应溶剂可以是甲醇、乙醇、丙醇、丙酮、N,N-二甲基甲酰胺、二甲基亚砜等极性溶剂；优选碳酸钾做缚酸剂，N,N-二甲基甲酰胺做溶剂，80℃反应。中间体II经还原反应得中间体III，反应条件b可以为各种钯类催化剂催化下的氢化还原、还原性金属与无机酸组合(如：铁粉/氯化铵、铁粉/盐酸、锌粉/醋酸，等)；反应溶剂可以是四氢呋喃、甲醇、乙醇、二氯甲烷、水等，溶剂可以是单一溶剂也可以是混合溶剂；催化氢化条件优选10％Pd/C做催化剂、甲醇做溶剂、反应温度优选室温。还原性金属与无机酸组合进行还原时，优选铁粉/氯化铵体系，水和乙醇的混合溶剂作为反应溶剂，温度为60-80℃。中间体IV与取代的芳基硼酸经铃木反应得中间体V，反应条件c为钯配合物催化、无机碱和无氧条件下加热反应；零价钯配合物可以为Pd(PPh 3) 4、PdCl 2、PdCl 2(dppf)、Pd(OAc) 2和Pd(PPh 3) 2Cl 2等，优选Pd(PPh 3) 4；无机碱可以为碳酸钾、碳酸钠、碳酸锂、碳酸铯等，优选碳酸钠；溶剂可以为乙醇、1,4-二氧六环、四氢呋喃、甲苯、N,N-二甲基甲酰胺、二甲基亚砜、水和乙二醇二甲醚等，也可以是两种溶剂组成的混合溶剂，溶剂优选乙二醇二甲醚和水(体积比为10:1)的混合溶剂；反应温度可以为80-140℃，优选110℃。中间体III和中间体V发生亲核取代反应得到目标产物，反应条件d为有机酸或无机酸催化下，加热10-48小时；有机酸可以为苯磺酸、 对甲苯磺酸和乙酸等，无机酸可以是稀硫酸、稀盐酸、稀硝酸等，酸的用量为催化量，优选对甲苯磺酸、稀盐酸；溶剂可以为甲醇、乙醇、异丙醇、N,N-二甲基甲酰胺和二甲基亚砜等，优选乙醇、异丙醇；反应温度可以为60-130℃，优选80℃；反应时间优选24小时。
路线2所示，其中应用的全部可变因数如权利要求中的定义。
中间体VI和中间体VII发生亲核取代反应得中间体VIII，反应条件e为有机酸或无机酸催化下，加热48-96小时；有机酸可以为苯磺酸、对甲苯磺酸和乙酸等，无机酸可以是稀硫酸、稀盐酸、稀硝酸等，酸的用量为催化量或摩尔量，优选对甲苯磺酸、稀盐酸；溶剂可以为甲醇、乙醇、异丙醇、N,N-二甲基甲酰胺和二甲基亚砜等，优选乙醇、异丙醇；反应温度可以为80-150℃，优选110℃；反应时间优选72小时；根据反应进程，可以选择封管加热反应。中间体VIII与脂肪胺发生亲核取代反应得到目标产物；反应条件f为一种有机碱(如：三乙胺、N,N-二异丙基乙胺等)或无机碱(如：碳酸钠、碳酸钾、碳酸铯、磷酸钠、氢氧化钠、氢氧化钾等)做缚酸剂的情况下，于室温或加热条件下进行；反应溶剂可以是甲醇、乙醇、丙醇、丙酮、N,N-二甲基甲酰胺、二甲基亚砜等极性溶剂；优选碳酸钾做缚酸剂，N,N-二甲基甲酰胺做溶剂，80℃反应。
本发明还提供了通式I所示的对苯二胺类衍生物，以及所述衍生物的药学可接受的盐和立体异构体，其用作赖氨酸特异性去甲基化酶1(LSD1)抑制剂。
本发明还提供了通式I所示的对苯二胺类衍生物以及所述衍生物的药学可接受的盐和立体异构体用于制备用于治疗癌症的药物的用途。
具体地，所述癌症包括但不限于胃癌、乳腺癌、前列腺癌、肝癌、卵巢癌、结肠癌、肾癌、头颈癌、黑色素瘤、白血病。
本发明的通式I所示的对苯二胺类衍生物以及所述衍生物的药学可接受的盐和立体异构体作为LSD1抑制剂均可与其他药物联合用药用于疾病治疗。本发明还提供了组合物用于制备用于治疗癌症的药物的用途，所述组合物包含通式I所示的对苯二胺类衍生物以及所述衍生物的药学可接受的盐和立体异构体，以及药用载体。特别地，所述组合物还可以包含其他药物。
具体实施方式：
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用Bruker ARX-400测定，质谱用Agilent 1100 LC/MSD测定；所用试剂均为分析纯或化学纯。
表1.实施例结构式、化学名、相对分子质量
Figure PCTCN2021075237-appb-000004
Figure PCTCN2021075237-appb-000005
Figure PCTCN2021075237-appb-000006
Figure PCTCN2021075237-appb-000007
Figure PCTCN2021075237-appb-000008
Figure PCTCN2021075237-appb-000009
Figure PCTCN2021075237-appb-000010
Figure PCTCN2021075237-appb-000011
实施例1：N-[2-(二甲氨基)乙基]-5-甲氧基-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基-1,4-苯二胺的合成
步骤A-1：3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚的制备
Figure PCTCN2021075237-appb-000012
将2,4-二氯嘧啶(3.0g，20.4mmol)和三氯化铝(2.6g，20.4mmol)加入100mL反应瓶中,加入30mL乙二醇二甲醚，室温搅拌5min。将N-甲基吲哚(2.7g，20.4mmol)滴加到反应液中，加毕，升温至80℃继续反应6h。冷却反应液至室温，将反应液减压浓缩，加入50mL乙酸乙酯溶解粗品。乙酸乙酯相依次水洗(10mL×3)、饱和食盐水洗(10mL×3)，无水硫酸钠干燥后浓缩，经硅胶柱层析纯化(石油醚：乙酸乙酯＝4:1)得浅黄色固体3.07g，收率62.0％。 1H NMR(600MHz,DMSO)δ8.53(d,J＝5.4Hz,1H),8.51(s,1H),8.43-8.40(m,1H),7.83(d,J＝5.5Hz,1H),7.58(d,J＝7.9Hz,1H),7.30(dtd,J＝14.8,7.1,1.1Hz,2H),3.90(s,3H)。
步骤A-2：N-(4-氟-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺的制备
Figure PCTCN2021075237-appb-000013
将3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(2.4g，10.0mmol)和对甲苯磺酸(1.7g，10.0mmol)加入100mL反应瓶中，加入无水乙醇40mL，回流反 应30min。加入4-氟-2-甲氧基-5-硝基苯胺(1.9g，10.0mmol)，继续回流反应10h。将反应液减压浓缩后，加入40mL水、40mL乙酸乙酯，剧烈搅拌5min后，用饱和氢氧化钠溶液调节PH＝8。分出乙酸乙酯相，以无水硫酸钠干燥后浓缩得粗品，经硅胶柱层析(石油醚：乙酸乙酯＝8:1)后得橘红色固体2.2g，收率56.1％。 1H NMR(600MHz,DMSO)δ9.12(d,J＝8.5Hz,1H),8.41-8.38(m,2H),8.37(s,1H),8.30(s,1H),7.54(d,J＝8.2Hz,1H),7.37(d,J＝13.3Hz,1H),7.32(d,J＝5.4Hz,1H),7.29-7.24(m,1H),7.15(t,J＝7.1Hz,1H),4.03(s,3H),3.89(s,3H)。
步骤A-3：N-[2-(二甲氨基)乙基]-5-甲氧基-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基-1,4-苯二胺的合成
Figure PCTCN2021075237-appb-000014
将N-(4-氟-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺(2.0g，5.1mmol)、N,N,N'-三甲基乙二胺(0.5g，5.1mmol)和N,N-二异丙基乙胺(0.7g，5.1mmol)加入100mL反应瓶，加入4mL N,N-二甲基甲酰胺，80℃反应12h。冷却反应液，将反应液冷却后加入到100mL水中，乙酸乙酯(10mL×3)萃取，饱和食盐水(10mL×3)洗涤。将乙酸乙酯相用无水硫酸钠干燥，减压浓缩。经硅胶柱层析纯化得橘红色固体1.4g，收率58.5％。 1H NMR(600MHz,DMSO)δ8.63(s,1H),8.35(d,J＝7.8Hz,1H),8.32(d,J＝5.3Hz,2H),8.08(s,1H),7.52(d,J＝8.2Hz,1H),7.27-7.23(m,1H),7.21(dd,J＝5.3,2.8Hz,1H),7.12(t,J＝7.4Hz,1H),6.85(s,1H),3.96(d,J＝2.2Hz,3H),3.88(s,3H),3.27(t,J＝6.9Hz,2H),2.86(s,3H),2.48(d,J＝6.8Hz,2H),2.16(s,6H)。
实施例2-4、实施例10和实施例14的合成，以N-(4-氟-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺和不同的脂肪胺按照实施例1相同的合成方法得到。
实施例5：N-[4-(4-氨基哌啶-1-基)-2-甲氧基-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺的合成
步骤A-4：叔丁基[1-(5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基)氨基)-2-硝基苯基)哌啶-4-基]氨基甲酸酯的制备
Figure PCTCN2021075237-appb-000015
将N-(4-氟-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺(2.0g，5.1mmol)、N,N-二异丙基乙胺(0.7g，5.1mmol)和4-叔丁氧羰基氨基哌啶(1.0g，5.1mmol)加入100mL反应瓶，加入4mL N,N-二甲基甲酰胺，80℃反应12h。冷却反应液，将反应液冷却后加入到100mL水中，乙酸乙酯(10mL×3)萃取，饱和食盐水(10mL×3)洗涤。将乙酸乙酯相用无水硫酸钠干燥，减压浓缩。经硅胶柱层析纯化得橘红色固体1.9g，收率64.1％。
步骤A-5：N-[4-(4-氨基哌啶-1-基)-2-甲氧基-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺的合成
Figure PCTCN2021075237-appb-000016
将叔丁基[1-(5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基)氨基)-2-硝基苯基)哌啶-4-基]氨基甲酸酯(1.2g，2.1mmol)加入5ml 6N HCl/MeOH中，室温搅拌反应2h。减压浓缩溶剂，加入5ml水，用饱和氢氧化钠溶液调节PH＝10。乙酸乙酯(10mL×3)萃取，合并乙酸乙酯并用饱和食盐水(10mL×3)洗涤。将乙酸乙酯相用无水硫酸钠干燥，减压浓缩，得橘红色固体0.86g，收率86.8％。 1H NMR(600MHz,DMSO)δ8.79(s,1H),8.36(d,J＝7.9Hz,1H),8.33(d,J＝4.4Hz,2H),8.11(s,1H),7.52(d,J＝8.2Hz,1H),7.25(dd,J＝16.7,6.6Hz,2H),7.12(t,J＝7.5Hz,1H),6.84 (s,1H),3.98(s,3H),3.88(s,3H),3.24(d,J＝12.1Hz,2H),2.87(t,J＝10.6Hz,2H),2.74(t,J＝9.8Hz,1H),1.82(d,J＝10.3Hz,2H),1.65(s,2H),1.44(td,J＝13.5,3.5Hz,2H)。
实施例6-9、实施例11-13和实施例15-17采用不同的脂肪胺底物按照实施例5的合成方法得到。
实施例18：N-(2-(二甲氨基)乙基)-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺的合成
步骤A-6：N-[2-(二甲氨基)乙基]-N-甲基-2-硝基苯基-1,4-二胺的制备
Figure PCTCN2021075237-appb-000017
将4-氟-3-硝基苯胺(1.6g，10.2mmol)、N,N,N'-三甲基乙二胺(1.1g，10.2mmol)和N,N-二异丙基乙胺(1.4g，10.2mmol)加入100mL反应瓶，加入4mL N,N-二甲基甲酰胺，80℃反应12h。冷却反应液，将反应液冷却后加入到100mL水中，乙酸乙酯(10mL×3)萃取，饱和食盐水(10mL×3)洗涤。将乙酸乙酯相用无水硫酸钠干燥，减压浓缩。经硅胶柱层析纯化得黄色固体1.6g，收率66.3％。
步骤A-7：N-(2-(二甲氨基)乙基)-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺的合成
将中间体N-[2-(二甲氨基)乙基]-N-甲基-2-硝基苯基-1,4-二胺和3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚按照步骤A-2的操作方法合成N-(2-(二甲氨基)乙基)-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺。 1H NMR(600MHz,DMSO)δ9.62(s,1H),8.54(d,J＝7.1Hz,1H),8.45(d,J＝2.6Hz,1H),8.36(d,J＝5.4Hz,1H),8.33(s,1H),7.81(dd,J＝9.0,2.5Hz,1H),7.55(d,J＝8.2Hz,1H),7.36(d,J＝9.0Hz,1H),7.31-7.26(m,1H),7.24(d,J＝5.4Hz,1H),7.19(t,J＝7.4Hz,1H),3.89(s,3H),3.15-3.09(m,2H),2.76(s,3H),2.43(t,J＝7.0Hz,2H),2.17(s,6H)。
实施例19：N-[2-(二甲氨基)乙基]-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,2,4-三胺的合成
Figure PCTCN2021075237-appb-000018
步骤A-8：将N-(2-(二甲氨基)乙基)-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺(0.5g，1.1mmol)和10％钯碳(0.1g)加入50ml反应瓶中，加入20ml甲醇。氢气条件下，室温反应12h。过滤，将滤液浓缩得浅黄色固体0.4g，收率89.0％。 1H NMR(600MHz,DMSO)δ9.04(s,1H),8.63(d,J＝7.9Hz,1H),8.30(s,1H),8.27(d,J＝5.3Hz,1H),7.53(d,J＝8.2Hz,1H),7.26(dd,J＝11.6,4.5Hz,1H),7.22-7.16(m,2H),7.13(d,J＝5.3Hz,1H),6.97-6.90(m,2H),3.89(s,3H),3.10(s,4H),2.66(s,6H),2.53(s,3H)。
实施例20-27的合成按照实施例18的合成方法得到。
实施例28：N-[2-(二甲氨基)乙基]-N-甲基-N’-(4-苯基嘧啶-2-基)苯基-1,4-二胺的合成
步骤A-9：2-氯-4-苯基嘧啶的制备
Figure PCTCN2021075237-appb-000019
将苯硼酸(1.2g，10.0mmol)、2-氯-4-溴嘧啶(1.9g，10.0mmol)、碳酸钠(2.1g，20.0mmol)和四三苯基膦钯(0.6g，0.5mmol)加入50ml反应瓶中，加入30ml乙二醇二甲醚，氮气保护下，升温至110℃反应12h。反应液冷却减压浓缩得油状物，用40ml乙酸乙酯溶解油状物，并依次用水和饱和食盐水洗涤。无水硫酸钠干燥后浓缩，经硅胶柱层析纯化得白色固体1.0g，收率50.0％。 1H NMR(600MHz,DMSO)δ9.13(d,J＝1.8Hz,2H),7.87-7.79(m,2H),7.60-7.53(m,2H),7.51(dd,J＝8.1,6.5Hz,1H)。
步骤A-10：N,N,N’-三甲基-N’-(4-硝基苯基)乙烷-1,2-二胺的制备
以对氟硝基苯和N,N,N'-三甲基乙二胺为原料，按照步骤A-6的操作 制备，收率60.7％。
步骤A-11：N-[2-(二甲氨基)乙基]-N-甲基苯-1,4-二胺的制备
以N,N,N’-三甲基-N’-(4-硝基苯基)乙烷-1,2-二胺为原料按照步骤A-8的操作制备得到，收率92.6％。
步骤A-12：N-[2-(二甲氨基)乙基]-N-甲基-N’-(4-苯基嘧啶-2-基)苯基-1,4-二胺的合成
以2-氯-4-苯基嘧啶和N-[2-(二甲氨基)乙基]-N-甲基苯-1,4-二胺为原料按照步骤A-2的操作合成，收率55.3％。 1H NMR(600MHz,DMSO)δ9.39(s,1H),8.73(s,2H),7.68(d,J＝7.5Hz,2H),7.53(d,J＝8.9Hz,2H),7.46(t,J＝7.6Hz,2H),7.35(t,J＝7.3Hz,1H),6.69(d,J＝8.9Hz,2H),3.40(d,J＝7.1Hz,2H),2.87(s,3H),2.47-2.40(m,2H),2.23(s,6H)。
实施例29-48的合成按照实施例28的合成方法得到。
本发明部分产物的体外药理测试
本发明采购Cayman公司的700120试剂盒对部分化合物的LSD1抑制活性进行检测，具体操作步骤如下：
(1)检测设置100％活性孔、背景孔、阳性对照孔和化合物孔。每组设三个复孔。
(2)100％活性孔：依次加入120μL LSD1缓冲液、10μL溶液(与溶解化合物和阳性药相同成分的溶液)、20μL LSD1酶、20μL LSD1检测肽。
(3)测试孔和阳性对照孔：依次加入120μL LSD1缓冲液、10μL待测化合物溶液、20μL LSD1酶、20μL LSD1检测肽。
(4)背景孔：依次加入140μL LSD1缓冲液、10μL溶液(与溶解化合物和阳性药相同成分的溶液)、20μL LSD1酶。
(5)加溶液过程中将96孔板置于冰袋上降温，防止酶促反应的进行。加毕，避光，室温孵育30min。
(6)孵育30min后，依次向每个孔加入20μL辣根过氧化物酶溶液、10μL荧光底物溶液。避光，室温孵育10min。
(7)酶标仪530nM波长下激发，检测590nM的发射荧光的强弱。
抑制率％＝(100％活性孔–样品孔)/100％活性孔*100
表2.实施例核磁氢谱、酶抑制活性数据
Figure PCTCN2021075237-appb-000020
Figure PCTCN2021075237-appb-000021
Figure PCTCN2021075237-appb-000022
Figure PCTCN2021075237-appb-000023
Figure PCTCN2021075237-appb-000024
Figure PCTCN2021075237-appb-000025
Figure PCTCN2021075237-appb-000026
Figure PCTCN2021075237-appb-000027
Figure PCTCN2021075237-appb-000028
Figure PCTCN2021075237-appb-000029
Figure PCTCN2021075237-appb-000030
Figure PCTCN2021075237-appb-000031
注：体外酶水平活性测试IC 50被指定为在以下范围内：
A：<1μΜ
B：>1μΜ至<10μΜ
C：>10μΜ至<50μΜ
D：>50μΜ
本发明中通式I的化合物及其药学上可接受的盐或前药可单独施用，但通常是和药用载体混合物给予，所述药用载体的选择要根据所需用药途径和标准药物实践，下面分别用该类化合物的各种药物剂型，例如片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂和软膏剂的制备方法，说明其在制药领域中的新应用。
实施例49：片剂
用含有权利要求1中化合物的化合物(以实施例1化合物为例)10g，按照药剂学一般压片法加辅料20g混匀后，压制成100片，每片重300mg。
实施例50：胶囊剂
用含有权利要求1中化合物的化合物(以实施例2化合物为例)10g，按照药剂学胶囊剂的要求将辅料20g混匀后，装入空心胶囊，每个胶囊 重300mg。
实施例51：注射剂
用含有权利要求1中化合物的化合物(以实施例3化合物为例)10g，按照药剂学常规方法，进行活性炭吸附，经0.65μm微孔滤膜过滤后，填入氮气罐制成水针制剂，每只装2mL，共灌装100瓶。
实施例52：气雾剂
用含有权利要求1中化合物的化合物(以实施例5化合物为例)10g，用适量丙二醇溶解后，加入蒸馏水及其他辐料后，制成500mL的澄清溶液即得。
实施例53：栓剂
用含有权利要求1中化合物的化合物(以实施例9化合物为例)10g，将之研细加入甘油适量，研匀后加入已熔化的甘油明胶，研磨均匀，倾入已涂润滑剂的模型中，制得栓剂50颗
实施例54：膜剂
用含有权利要求1中化合物的化合物(以实施例23化合物为例)10g，将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解，80目筛网过滤，再将实施例18化合物加入到滤液中搅拌溶解，涂膜机制膜100片。
实施例55：滴丸剂
用含有权利要求1中化合物的化合物(以实施例30化合物为例)10g，与明胶等基质50g加热熔化混匀后，滴入低温液体石蜡中，共制得滴丸1000丸。
实施例56：外用搽剂
用含有权利要求1中化合物的化合物(以实施例35化合物为例)10g，按照常规药剂学方法与乳化剂等辅料2.5g混合研磨，再加蒸馏水至200mL制得。
实施例57：软膏剂
用含有权利要求1中化合物的化合物(以实施例40化合物为例)10g，研细后与凡士林等油性基质500g研匀制得。
尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围。

Claims (12)

  1. 通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体：
    Figure PCTCN2021075237-appb-100001
    其中：
    R 1选自氢、C1-C3烷基，其中，所述C1-C3烷基可含有0-4个选自F、Cl或Br的卤原子取代；
    R 2选自氢、C1～C7脂肪伯胺基团、C1～C7脂肪仲胺基团、C1～C7脂肪叔胺基团；或者R 1和R 2与它们所连接的氮原子一起形成环；
    R 3选自氢、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、硝基、氰基、氨基、羟基、卤原子；
    m为0、1、2或3；
    X＝C或N；
    R 4选自卤原子、苯基、萘基、C4-C10芳杂环基团；其中苯基、萘基、C4-C10芳杂环基团任选地被一个或多个R a取代，且所述C4-C10芳杂环基团含有1～3个选自N、O或S的杂原子；
    R a选自C1～C3烷基、C1～C3烷氧基、卤代C1～C3烷基、卤代C1～C3烷氧基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、酰胺基；
    n为0、1、2或3。
  2. 权利要求1中所述的通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体，
    其中，
    R 1选自氢、甲基或乙基。
  3. 权利要求1或2中所述通式(I)的衍生物，及其药学上可接受的盐、立体异构体，
    其中，
    R 2选自C1～C7的伯氨基脂肪族基团、C1～C7的仲氨基脂肪族基团、C1～C7的叔氨基脂肪族基团、C1～C7的含氮杂环基、C1～C7的含氮杂环基烷基，其中所述含氮杂环基任选地被烷基取代，优选为氨基丙基、甲氨基乙基、甲氨基丙基、二甲氨基乙基、二甲氨基丙基、哌啶基、N-甲基哌啶基、哌啶基甲基；
    或者R 1和R 2与它们所连接的氮原子一起形成五元环或六元环，例如哌嗪基、N-甲基哌嗪基、氨基哌啶基、氨基吡咯烷基。
  4. 权利要求1-3任何一项所述的通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体，
    其中，
    R 3选自氢、甲基、三氟甲基、甲氧基、硝基、氰基、氨基或氯；
  5. 权利要求1-4任何一项所述的通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体，
    其中，
    m为0、1或2；
  6. 权利要求1-5任何一项所述的通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体，
    其中，
    X＝N；
  7. 权利要求1-6任何一项所述的通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体，
    其中，
    R 4选自苯基、萘基、呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、吡唑基、咪唑基、三氮唑基、苯基、吡啶基、嘧啶基、吲哚基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并吡唑基、苯并三氮唑基、萘基、喹啉基、喹唑啉基；且所述基团任选地被一个或多个R a取代；
  8. 权利要求1-7任何一项所述的通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体，
    其中，
    R a选自甲基、乙基、异丙基、甲氧基、三氟甲氧基、氰基、氯或氟；
  9. 权利要求1-8任何一项所述的通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体，
    其中，
    n为0或1；
  10. 权利要求1-9任何一项所述的通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体的制备方法，其路线如下：
    Figure PCTCN2021075237-appb-100002
  11. 权利要求1-9任何一项所述的通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体，其作为赖氨酸特异性去甲基化酶1(LSD1)抑制剂。
  12. 权利要求1-9任何一项所述的通式(I)所示的衍生物，及其药学上可接受的盐、立体异构体用于制备用于治疗癌症的药物的用途。
PCT/CN2021/075237 2020-03-06 2021-02-04 对苯二胺类lsd1抑制剂及其制备方法 WO2021175079A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010150110.1 2020-03-06
CN202010150110.1A CN113354622B (zh) 2020-03-06 2020-03-06 对苯二胺类lsd1抑制剂及其制备方法

Publications (1)

Publication Number Publication Date
WO2021175079A1 true WO2021175079A1 (zh) 2021-09-10

Family

ID=77523988

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/075237 WO2021175079A1 (zh) 2020-03-06 2021-02-04 对苯二胺类lsd1抑制剂及其制备方法

Country Status (2)

Country Link
CN (1) CN113354622B (zh)
WO (1) WO2021175079A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214303A1 (en) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113387935B (zh) * 2021-07-23 2022-06-10 苏州雅深智慧科技有限公司 抑制三突变表皮生长因子受体酪氨酸激酶的化合物及用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085489A (zh) * 2014-11-05 2015-11-25 上海页岩科技有限公司 嘧啶或吡啶类化合物、其制备方法和医药用途
CN105646454A (zh) * 2016-01-19 2016-06-08 浙江大学 含异羟肟酸片段的2-芳胺基嘧啶类衍生物及制备和应用
CN107793413A (zh) * 2016-09-05 2018-03-13 天津滨江药物研发有限公司 嘧啶杂环化合物及其制备方法和应用
CN108069939A (zh) * 2016-11-16 2018-05-25 中国科学院上海药物研究所 含有共轭联烯酰胺结构的化合物、其制备方法、药物组合物和用途
CN110684016A (zh) * 2019-09-27 2020-01-14 上海应用技术大学 一种含氟的azd9291衍生物及其制备方法和应用
CN110753693A (zh) * 2016-12-23 2020-02-04 阿尔维纳斯运营股份有限公司 Egfr蛋白水解靶向嵌合分子和相关使用方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085489A (zh) * 2014-11-05 2015-11-25 上海页岩科技有限公司 嘧啶或吡啶类化合物、其制备方法和医药用途
CN105646454A (zh) * 2016-01-19 2016-06-08 浙江大学 含异羟肟酸片段的2-芳胺基嘧啶类衍生物及制备和应用
CN107793413A (zh) * 2016-09-05 2018-03-13 天津滨江药物研发有限公司 嘧啶杂环化合物及其制备方法和应用
CN108069939A (zh) * 2016-11-16 2018-05-25 中国科学院上海药物研究所 含有共轭联烯酰胺结构的化合物、其制备方法、药物组合物和用途
CN110753693A (zh) * 2016-12-23 2020-02-04 阿尔维纳斯运营股份有限公司 Egfr蛋白水解靶向嵌合分子和相关使用方法
CN110684016A (zh) * 2019-09-27 2020-01-14 上海应用技术大学 一种含氟的azd9291衍生物及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI ZHONG-RUI; SUO FENG-ZHI; HU BO; GUO YAN-JIA; FU DONG-JUN; YU BIN; ZHENG YI-CHAO; LIU HONG-MIN: "Identification of osimertinib (AZD9291) as a lysine specific demethylase 1 inhibitor", BIOORGANIC CHEMISTRY, ACADEMIC PRESS INC., NEW YORK, NY., US, vol. 84, 1 January 1900 (1900-01-01), US, pages 164 - 169, XP085596246, ISSN: 0045-2068, DOI: 10.1016/j.bioorg.2018.11.018 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214303A1 (en) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors

Also Published As

Publication number Publication date
CN113354622B (zh) 2022-11-01
CN113354622A (zh) 2021-09-07

Similar Documents

Publication Publication Date Title
WO2021175079A1 (zh) 对苯二胺类lsd1抑制剂及其制备方法
CA3003721C (en) Inhibitors of ret to treat cancer
WO2012008564A1 (ja) 含窒素芳香族複素環誘導体
TW200951128A (en) Phenyl and benzodioxinyl substituted indazoles derivatives
CN111051300B (zh) 作为组蛋白脱乙酰基酶1和/或2(hdac1-2)的选择性抑制剂的新杂芳基酰胺衍生物
WO2012139499A1 (zh) 一种脲类化合物、其制备方法、其中间体及其应用
JP2008508217A (ja) Ｈｓｐ９０の阻害剤
JP2021500334A (ja) Ｅｈｍｔ２阻害剤としてのアミン置換複素環化合物、その塩、及びそれらの合成方法
CN109111438A (zh) 用于ido抑制剂的脒类化合物
JP2022528042A (ja) アミド類化合物の調製方法及びその医薬分野の使用
US20190169163A1 (en) Quinoline derivative and use thereof
KR20200015787A (ko) Mek억제제로서의 쿠마린 고리계 화합물 및 이의 용도
CN109761902B (zh) 6-菲啶酮衍生物及其制备方法和用途
AU2015303724A1 (en) Quinazoline derivative
ES2562903T3 (es) Nuevo compuesto que tiene actividad inhibidora de PARP
JP2016540801A (ja) フルオロフェニルピラゾール化合物
CN108299420B (zh) 作为选择性雌激素受体下调剂的五环类化合物及其应用
US9493423B2 (en) Compounds capable of inhibiting voltage gated calcium ion channel, and pharmaceutical compositions comprising the same
CN113248474A (zh) 五元氮唑杂环衍生物及其制备方法和用途
WO2023236820A1 (zh) 芳香六元环并咪唑类衍生物及其制备方法和应用
CN107973788B (zh) Bbi608衍生物及其制备与用途
CN110642837A (zh) 含三氮唑或喹啉酮结构的吡啶酰胺类化合物及其应用
CN115322158A (zh) 作为krasg12c蛋白抑制剂的取代喹唑啉类化合物
CN112979659B (zh) 一类HIF-2α小分子抑制剂的制备及用途
JP2009518364A (ja) 増殖を抑えるピリミジル、縮合ピリミジル、ピリジルヒドラゾン

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21764186

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21764186

Country of ref document: EP

Kind code of ref document: A1