CN114853680A - Aromatic six-membered ring imidazole derivative and preparation method and application thereof - Google Patents
Aromatic six-membered ring imidazole derivative and preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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- 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
- C07D401/02—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 two hetero rings
- C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
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- 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
Abstract
An aromatic six-membered ring benzimidazole derivative, a preparation method and application thereof, belongs to the field of drug synthesis, and particularly relates to an aromatic six-membered ring benzimidazole derivative shown in a general formula (I), a preparation method thereof and application thereof as an LSD1 inhibitor. The compound provided by the invention shows better activity at an in vitro enzyme level, is different from the existing irreversible inhibitor with a core structure of the trans-phenylcyclopropylamine, and provides a new skeleton compound for the research field of LSD1 inhibitors. The raw materials of the synthetic route adopted by the invention are cheap and easily available, the used reagent is a common reagent, the reaction condition is mild, the post-treatment is simple, and the compound can be efficiently prepared. The compounds provided by the invention can be used as lysine specific demethylase-1 inhibitors alone or in combination for the treatment of various tumor diseases.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to novel aromatic six-membered ring imidazole derivatives, a preparation method thereof and application thereof as a lysine specific demethylase 1 inhibitor.
Background
Epigenetics plays a key role in life, controlling gene expression and transcription, and contributes to various cellular processes, including cell differentiation, proliferation, and migration. Among the various epigenetic modifications, histone lysine-specific demethylase 1(LSD1) was the first identified histone demethylase to specifically remove the methyl groups in monomethylated and dimethylated H3K4 and H3K9 by enzymatic oxidation and to facilitate downstream gene transcription. By regulating gene expression, LSD1 is intimately involved in tumorigenesis, stem cell biology, neurodegenerative diseases, viral infections, diabetes, and fibrosis. Meanwhile, a plurality of research results support that the abnormal expression of the LSD1 is closely related to the progress of malignant tumors such as prostate cancer, gastric cancer, breast cancer, lung cancer, blood cancer and the like, and the inhibition of the biological action of the LSD1 can generate an anti-cancer effect, which indicates that the LSD1 is a potential cancer treatment target. Therefore, the development of LSD1 inhibitors is beneficial for the development of antitumor drugs, which can be used alone or in combination with other drugs for the treatment of cancer.
In the past decades, great efforts have been made to develop LSD1 inhibitors having biological activity, which can be classified into two types, irreversible inhibitors and reversible inhibitors, according to their mechanism of action. The irreversible inhibitor can form covalent binding with a cofactor FAD and block the participation of the FAD in demethylation circulation, thereby exerting LSD1 inhibitory activity. To date, no LSD1 inhibitor has been marketed for tumor therapy.
Representative LSD1 inhibitors ORY-1001, ORY-2001, GSK-2879552 and IMG-7289 in clinical research stage are irreversible inhibitors with the structural mother nucleus of trans-phenyl cyclopropylamine. Only the Seclimestat mesylates developed by Salarius pharmaceutical company and CC-90011 developed by Celgene pharmaceutical company, which are originally researched by the university of Utah and advance clinical tests, are the inhibitors of the structure published at present, and the inhibitors are used as reversible LSD1 inhibitors in clinical research stage, and all indications are tumors.
Most of the current research and development on LSD1 inhibitors are carried out by using the compound of the transphenylcyclopropylamine, and the development of more novel skeleton LSD1 inhibitors is a research hotspot in the field of tumor resistance at present.
Disclosure of Invention
The invention aims at providing an aromatic six-membered ring benzimidazole derivative shown in a general formula (I) or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, racemate, metabolite, metabolic precursor or prodrug thereof;
wherein:
w and X are each independently C or N, and when one is C, the other can only be N;
R 1 and R 2 Each independently selected from aryl, heteroaryl, cycloalkyl, alkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl; wherein, the aryl, heteroaryl, cycloalkyl, alkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylAlkyl groups may contain one or more substituents;
R 3 is-CH 2 -, carbonyl or thiocarbonyl;
R 4 is substituted N-heterocyclyl, substituted-N (H) -heterocyclylalkyl, substituted-N (Me) -heterocyclylalkyl or-N (R) 5 ) 2 ；
R 5 Selected from hydrogen, C1-C7 fatty primary amine, C1-C7 fatty secondary amine and C1-C7 fatty tertiary amine, preferably propylamine, N-methylpropylamine or N, N-dimethylpropylamine.
Further, the aromatic six-membered ring benzimidazole derivative shown in the general formula (I) or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, racemate, metabolite, metabolic precursor or prodrug thereof;
wherein R is 5 Is any one of the following structures:
furthermore, the aromatic six-membered ring benzimidazole derivative shown in the general formula (I) or the pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, racemate, metabolite, metabolic precursor or prodrug thereof is any one of the following 46 compounds:
n- (2-aminoethyl) -2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
4- (5- (3-methylpiperidine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
4- (5- (morpholine-4-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
4- (5- (3-aminopiperidine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
N- (3-aminopropyl) -2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N- (piperidin-4-ylmethyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N- (piperidin-3-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
4- (5- (4-methylpiperazine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
2- (4-cyanophenyl) -N- (piperidin-4-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N- (pyrrolidin-3-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
4- (5- (4-methylpiperidine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
4- (5- (2-methylpiperidine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
2- (4-cyanophenyl) -N, N-dimethyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N- (2- (methylamino) ethyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
(R) -2- (4-cyanophenyl) -N- (pyrrolidin-3-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
(R) -2- (4-cyanophenyl) -N- (piperidin-3-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
(R) -4- (5- (2-methylpiperazine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
(S) -4- (5- (2-methylpiperazine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
4- (5- (2-methylpiperazine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
N- (6-aminohexyl) -2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N-methyl-N- (2- (methylamino) ethyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (4-aminobutyl) -2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (2-aminoethyl) -2- (4-cyanophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
(S) -4- (5- (3-aminopyrrolidine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
(R) -2- (4-cyanophenyl) -N- (pyrrolidin-3-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (2-aminoethyl) -2- (4-fluorophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (2-aminoethyl) -N-methyl-2- (4-nitrophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- ([1,1' -biphenyl ] -4-yl) -N- (2-aminoethyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (2-aminoethyl) -N-methyl-1- (p-tolyl) -2- (4- (trifluoromethyl) phenyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (2-aminoethyl) -N-methyl-2- (4- (methylsulfonyl) phenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
4- (6- (piperazine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
3- (4-cyanophenyl) -N- (piperidin-4-yl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
4- (6- (4-aminopiperidine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
N- (4-aminobutyl) -3- (4-cyanophenyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
N- (2-aminoethyl) -3- (4-cyanophenyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
4- (6- (3-aminopiperidine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
3- (4-cyanophenyl) -N- (piperidin-4-ylmethyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
3- (4-cyanophenyl) -N- (piperidin-3-yl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
(R) -4- (6- (3-aminopyrrolidine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
3- (4-cyanophenyl) -N- (2- (methylamino) ethyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
(R) -4- (6- (2-methylpiperazine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
(S) -4- (6- (2-methylpiperazine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
4- (6- (4-methylpiperidine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
4- (6- (2-methylpiperidine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
3- (4-cyanophenyl) -N-methyl-2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
The pharmaceutically acceptable salt of the compound shown in the general formula (I) in the invention refers to a pharmaceutically acceptable addition salt formed by the aromatic six-membered ring imidazole derivative and acid. The addition salts include inorganic and organic acid addition salts, with preferred inorganic and organic acids being: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, or benzoic acid.
"halogen" in the present invention means fluorine, chlorine, bromine or iodine; "alkyl" in the present invention means a straight or branched chain alkyl group; "alkylene" refers to straight or branched chain alkylene; "aryl" refers to an organic group derived from an aromatic hydrocarbon by removal of two hydrogen atoms at one or different positions, such as phenyl, naphthyl; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, which ring system is aromatic and is an organic group obtained by removing multiple hydrogen atoms at one or different positions in the ring system, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, indolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl; "Heterocycloalkyl" means a monocyclic ring system containing one or more heteroatoms selected from N, O, S, such as tetrahydropyrrolyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyrazolyl, tetrahydroimidazolidyl, and tetrahydrooxazolinyl.
The invention also provides a pharmaceutical composition which is prepared by mixing the aromatic six-membered ring imidazole derivative shown in the general formula (I) or pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier or excipient and preparing into a clinically acceptable dosage form. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field. The aromatic six-membered ring benzimidazole derivatives of the present invention may be used in combination with other active ingredients as long as they do not cause other toxic side effects.
The 46 aromatic six-membered ring benzimidazole derivatives are prepared according to the methods of the route I, the route II and the route III.
Route one: an intermediate A-2 is obtained from an initial raw material A-1 through an esterification reaction, wherein a reaction condition a is that ester is formed under the catalysis of strong acid, or the ester is formed through acylation by using an acylation reagent, or the ester is formed through the catalysis of Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP); the reaction solvent is methanol, ethanol or propanol, preferably methanol; the reaction temperature is 65-85 ℃. And (3) carrying out nucleophilic substitution reaction on the intermediate A-2 and substituted aromatic amine or aliphatic amine to obtain an intermediate A-3, wherein the reaction condition b is carried out under the condition that organic base or inorganic base is used as an acid-binding agent, the organic base comprises triethylamine and N, N-diisopropylethylamine, and the inorganic base comprises sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide and potassium hydroxide. The intermediate A-3 is subjected to reduction reaction to obtain an intermediate A-4, wherein the reaction condition c is hydrogenation reduction under a palladium catalyst, or reduction is carried out by adopting a combination of reducing metal and inorganic acid, and the combination of reducing metal and inorganic acid comprises iron powder/ammonium chloride, iron powder/hydrochloric acid and zinc powder/acetic acid; the reaction solvent is one or a mixture of more than two of tetrahydrofuran, methanol, ethanol, dichloromethane and water; the catalytic hydrogenation conditions are preferably 10 percent Pd/C as a catalyst and methanol as a solvent, the reaction temperature is room temperature, when the reducing metal and the inorganic acid are combined for reduction, an iron powder/ammonium chloride system is preferred, a mixed solvent of water and ethanol is preferably used as a reaction solvent, and the reaction temperature is 60-80 ℃. The intermediate A-4 and substituted aromatic aldehyde or aliphatic aldehyde are subjected to nucleophilic addition dehydration reaction to obtain an intermediate A-5, and the reaction condition d is carried out under the catalysis of acetic acid, p-toluenesulfonic acid or Lewis acid; the reaction solvent is tetrahydrofuran, methanol, ethanol, dichloromethane or toluene, preferably ethanol; the reaction temperature is 80-100 ℃. The intermediate A-5 is subjected to cyclization reaction under the catalysis of iodine to obtain an intermediate A-6, and the reaction condition e is carried out under the catalysis of iodine, N-iodosuccinimide (NIS) or iodine chloride; the reaction solvent is methanol, ethanol, propanol, trifluoroethanol, acetone, N-dimethylformamide or dimethyl sulfoxide; the preferable reaction condition is that N-iodosuccinimide is used as a catalyst, trifluoroethanol is used as a solvent, and the reaction is carried out at the temperature of 25-60 ℃. The intermediate A-6 is subjected to ester hydrolysis reaction to obtain an intermediate A-7, the reaction condition f is carried out under the catalysis of organic base or inorganic base, the organic base comprises triethylamine and N, N-diisopropylethylamine, and the inorganic base comprises sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide and potassium hydroxide; the reaction solvent is a polar solvent comprising methanol, ethanol, propanol, acetone, N-dimethylformamide and dimethyl sulfoxide; the preferable reaction conditions are that sodium hydroxide is used as an acid-binding agent, ethanol is used as a solvent, and the reaction is carried out at the temperature of 80 ℃. The intermediate A-7 and substituted aliphatic amine are subjected to acylation reaction to obtain an intermediate A-8, wherein the reaction conditions g are 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), O- (benzotriazole-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HBTU), O- (5-chlorobenzotriazole-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HCTU), O- (benzotriazole-1-yl) -bis (dimethylamino) carbonium tetrafluoroborate (TBTU), O- (N-succinimidyl) -bis (dimethylamino) carbonium tetrafluoroborate (TSTU) and O- (N-endo-5-norbornene-2, 3-dicarboximide) -bis (dimethylamino) carbonium tetrafluoroborate (TNTU), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA), thiomethylphosphoryl azide (MPTA), bis (2-oxo-3-oxazolidinyl) phosphoryl chloride (BOP-Cl) or 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphate-2, 4, 6-trioxides (T3P) as condensing agents; the reaction solvent is a polar solvent comprising methanol, ethanol, propanol, acetone, N-dimethylformamide and dimethyl sulfoxide; the preferable reaction conditions are N, N-dimethylformamide as a solvent and HATU as a condensing agent. The intermediate A-8 is subjected to a Boc protecting group removing reaction to obtain a target product A-9, and the reaction condition h is that the heating is carried out for 4-12h under the catalysis of acid; the acid is trifluoroacetic acid and hydrochloric acid, preferably hydrochloric acid; the reaction solvent is methanol, ethanol, isopropanol, N-dimethylformamide, 1, 4-dioxane, ethyl acetate or dimethyl sulfoxide, and preferably the acid/solvent is hydrochloric acid/ethyl acetate; the reaction temperature is 25-80 ℃.
And a second route: the reaction conditions and operating methods in route two employ the corresponding reaction conditions and operating methods in route one.
And a third route: carrying out esterification reaction on an initial raw material B-1 to obtain an intermediate B-2, wherein a reaction condition is that ester is formed under the catalysis of strong acid, or acylation reaction is carried out on an acylation reagent to form ester, or ester is formed under the catalysis of Dicyclohexylcarbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP); the reaction solvent is methanol, ethanol or propanol, preferably methanol; the reaction temperature was 80 ℃. Performing cyclization reaction on the intermediate B-2 and the substituted alpha-halogenated saturated carbonyl compound to obtain an intermediate B-3, wherein the reaction condition B is performed under the condition that organic base or inorganic base is used as an acid-binding agent, the organic base comprises triethylamine and N, N-diisopropylethylamine, and the inorganic base comprises sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide and potassium hydroxide; the reaction solvent is a polar solvent comprising methanol, ethanol, propanol, acetone, N-dimethylformamide and dimethyl sulfoxide; the preferable reaction condition is that potassium carbonate is used as an acid-binding agent, ethanol is used as a solvent, and the reaction is carried out at the temperature of 80 ℃. The intermediate B-3 is subjected to iodination reaction to obtain an intermediate B-4, and the reaction condition c is that the iodination is carried out under the catalysis of iodine, N-iodosuccinimide (NIS) or iodine chloride; the reaction solvent is methanol or ethanolAlcohols, propanol, trifluoroethanol, acetonitrile, acetone, tetrahydrofuran, N-dimethylformamide or dimethyl sulfoxide; the preferable reaction condition is that N-iodosuccinimide is used as a catalyst, trifluoroethanol is used as a solvent, and the reaction is carried out at the temperature of 25-60 ℃. The intermediate B-4 and substituted aryl boric acid or aliphatic boric acid are subjected to Suzuki reaction to obtain an intermediate B-5, and the reaction condition d is that palladium complex is catalyzed, inorganic base is heated and reacts under the anaerobic condition; the palladium complex is Pd (PPh) 3 ) 4 、PdCl 2 、PdCl 2 (dppf)、Pd(OAc) 2 Or Pd (PPh) 3 ) 2 Cl 2 Preferably PdCl 2 (dppf); the inorganic base is potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate or potassium fluoride, preferably potassium carbonate; the reaction solvent is one or a mixed solvent of more than two of ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, dimethyl sulfoxide, water and glycol dimethyl ether, and the solvent is preferably a mixed solvent obtained by mixing 1, 4-dioxane and water in a volume ratio of 4: 1; the reaction temperature is 80-140 ℃. Performing ester hydrolysis reaction on the intermediate B-5 to obtain an intermediate B-6, wherein the reaction condition e is carried out under the catalysis of organic base or inorganic base, the organic base comprises triethylamine and N, N-diisopropylethylamine, and the inorganic base comprises sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide and potassium hydroxide; the reaction solvent is methanol, ethanol, propanol, acetone, N-dimethylformamide or dimethyl sulfoxide; the preferable reaction conditions are that sodium hydroxide is used as an acid-binding agent, ethanol is used as a solvent, and the reaction is carried out at the temperature of 80 ℃. And (3) carrying out acylation reaction on the intermediate B-6 and the substituted aliphatic amine to obtain an intermediate B-7, wherein the reaction condition f adopts the reaction condition of a reaction route g in the route I. And reacting the intermediate B-7 by removing a Boc protecting group to obtain a target product B-8, wherein the reaction condition g adopts the reaction condition of the reaction route h in the route I.
The invention also provides application of the aromatic six-membered ring benzimidazole derivative or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the derivative as a lysine specific demethylase 1 inhibitor.
The invention also provides the aromatic six-membered ring benzimidazole derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the derivative, which is used for preparing a medicament for treating tumor diseases.
The invention has the advantages that:
1) the 46 preferred aromatic six-membered ring benzimidazole derivatives provided by the invention are used as LSD1 inhibitors, and show better activity at an in vitro enzyme level.
2) The invention provides a novel framework compound for the research field of LSD1 inhibitors, which is different from the existing irreversible inhibitor with the parent nucleus structure of the trans-phenylcyclopropylamine.
3) The raw materials of the synthetic route adopted by the invention are cheap and easily available, the used reagent is a common reagent, the reaction condition is mild, the post-treatment is simple, and the compound can be efficiently prepared.
Detailed Description
The examples are intended to illustrate, but not to limit, the scope of the invention. The NMR of the compound was measured by Bruker ARX-400 and the mass spectrum by Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
TABLE 1 structural formula, chemical name, relative molecular mass of examples
Example 1
Synthesis of N- (2-aminoethyl) -2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide using the preparative route of route one
Step 1: preparation of methyl 4-chloro-3-nitrobenzoate (A-2)
4-chloro-3-nitrobenzoic acid (10g, 49.6mmol) was added to a 500mL single-neck reaction flask, 250mL of methanol was added, and the mixture was stirred at room temperature to dissolve completely. Then, 10mL of concentrated sulfuric acid is slowly added into the reaction solution dropwise, and after the addition is finished, the temperature is raised to 65 ℃ for continuous reaction for 4 hours. And cooling the reaction solution to room temperature, concentrating the reaction solution under reduced pressure, adding 400mL of water while stirring, separating out a white solid, performing suction filtration, rinsing the filter cake with water, and drying to obtain a crude white solid 10.2g, wherein the yield is 95.4%.
And 2, step: preparation of methyl 3-nitro-4- (p-tolylamino) benzoate (A-3)
A-2(5.4g, 25mmol) and 4-methylaniline (8g, 75mmol) were added to a 250mL reaction flask, 50mL of dimethyl sulfoxide was added, and the temperature was raised to 70 ℃ to react for 12 h. The reaction solution was cooled to room temperature, 100mL of water was added to precipitate an orange solid, which was filtered and the filter cake rinsed with water, dried to give a crude orange solid 6.2g with a yield of 86.7%.
And step 3: preparation of methyl 3-amino-4- (p-tolylamino) benzoate (A-4)
A-3(2g, 7mmol) and 10% palladium on carbon (0.2g) were charged to a 100mL reaction flask, and 40mL of methanol was added. And reacting at room temperature for 12 hours under the condition of hydrogen. Filtering, and concentrating the filtrate under reduced pressure to obtain crude light yellow solid 1.7g with yield of 94.9%.
And 4, step 4: (E) preparation of methyl (A-5) -3- ((4-cyanobenzylidene) amino) -4- (p-tolylamino) benzoate
A-4(1.5g, 5.9mmol) and 4-cyanobenzaldehyde (1g, 7.6mmol) were added to a 100mL reaction flask, 0.5mL of acetic acid and 30mL of ethanol were added dropwise, and the temperature was raised to 80 ℃ for 12 hours. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to give 1.6g of a crude yellow solid which was used in the next reaction without further treatment, with a yield of 73.5%.
And 5: preparation of methyl 2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxylate (A-6)
A-5(1.6g, 4.3mmol) was added to a 100mL reaction flask, 30mL trifluoroethanol was added, N-iodosuccinimide (1.8g, 8mmol) was added slowly with stirring, and the temperature was raised to 50 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure, and a saturated sodium thiosulfate solution was added, followed by extraction with ethyl acetate (40 mL. times.3) and washing with a saturated sodium chloride solution (40 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purifying by silica gel column chromatography to obtain white solid 0.95g with yield 60.2%.
Step 6: preparation of 2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxylic acid (A-7)
A-6(5g, 13.6mmol) and sodium hydroxide (1.6g, 40.8mmol) were added to a 250mL reaction flask, 100mL ethanol was added, and reaction was carried out at 80 ℃ for 3 h. The reaction solution was cooled to room temperature, concentrated, diluted with water and filtered to remove insoluble matter, the pH was adjusted to 2 with 1N hydrochloric acid to precipitate a white solid, which was dried to give a crude white solid (4.3 g, 89.6% yield).
And 7: preparation of tert-butyl (2- (2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamido) ethyl) carbamate (A-8)
A-7(0.35g, 1mmol), N-t-butoxycarbonyl-1, 2-ethylenediamine (0.4g, 2.5mmol) and HATU (0.38g, 1.0mmol) were charged into a 50mL reaction flask, 10mL anhydrous N, N-dimethylformamide and 0.19mL N, N-diisopropylethylamine were added, and reacted at 40 ℃ for 12 hours. The reaction solution was poured into 50mL of water, extracted with dichloromethane (30 mL. times.3), washed with a saturated sodium chloride solution (30 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purifying by silica gel column chromatography to obtain white solid 0.4g with yield 80.7%.
And 8: preparation of N- (2-aminoethyl) -2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide (A-9)
A-8(0.25g, 0.5mmol) was charged into a 50mL reaction flask, 20mL of a 2N hydrochloric acid/ethyl acetate solution was added, and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, 5mL of water was added, and the pH was adjusted to 10 with 5N sodium hydroxide solution. Extraction was performed with dichloromethane (10 mL. times.3), washing was performed with saturated sodium chloride solution (10 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.18g of a white solid with a yield of 93.1%.
Examples 2-26 the preparation of example 1 was followed to prepare the corresponding compounds shown in Table 1.
Example 27
Synthesis of N- (2-aminoethyl) -2- (4-fluorophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide utilizing the preparative route of route II
Step 1: preparation of 3-nitro-4- (p-toluidine) benzoic acid (A-10)
3-Nitro-4- (p-toluidine) benzoic acid (A-10) was synthesized from Compound A-3 according to the procedure in step 6 of example 1.
Step 2: preparation of tert-butyl (2- (N-methyl-3-nitro-4- (p-tolylamino) benzamido) ethyl) carbamate (A-11)
Tert-butyl (2- (N-methyl-3-nitro-4- (p-tolylamino) benzamido) ethyl) carbamate (A-11) was synthesized from compound A-10 according to the procedure in step 7 of example 1.
And step 3: preparation of tert-butyl (2- (3-amino-N-methyl-4- (p-tolylamino) benzamido) ethyl) carbamate (A-12)
Tert-butyl (2- (3-amino-N-methyl-4- (p-tolylamino) benzamido) ethyl) carbamate (A-12) was synthesized from compound A-11 according to the procedure of step 3 in example 1.
And 4, step 4: (E) preparation of tert-butyl (2- (3- ((4-fluorobenzylidene) amino) -N-methyl-4- (p-tolylamino) benzoylamino) ethyl) carbamate (A-13)
Tert-butyl (E) - (2- (3- ((4-fluorobenzylidene) amino) -N-methyl-4- (p-tolylamino) benzoylamino) ethyl) carbamate (A-13) is synthesized from compound A-12 following the procedure of step 4 in example 1.
And 5: preparation of tert-butyl (2- (2- (4-fluorophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamido) ethyl) carbamate (A-14)
Tert-butyl (2- (2- (4-fluorophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamido) ethyl) carbamate (A-14) was synthesized from compound A-13 according to the procedure in step 5 of example 1.
Step 6: preparation of N- (2-aminoethyl) -2- (4-fluorophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide (A-15)
According to the procedure of step 8 in example 1, N- (2-aminoethyl) -2- (4-fluorophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide (A-15) was synthesized from compound A-14.
Examples 28-31 the corresponding compounds shown in Table 1 were prepared using the procedure for the preparation of example 27.
Example 32
Synthesis of 4- (6- (piperazine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile via the preparative route of route three
Step 1: preparation of methyl 6-aminonicotinate (B-2)
Methyl 6-aminonicotinate (B-2) was synthesized from 6-aminonicotinic acid according to the procedure of step 1 in example 1.
Step 2: preparation of methyl 2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxylate (B-3)
B-2(10g, 65.8mmol), 2-bromo-4' -methylacetophenone (13.9g, 65.8mmol) and potassium carbonate (9.1g, 65.8mmol) were added to a 500mL reaction flask, 200mL of ethanol was added, and the reaction was carried out at 80 ℃ for 5 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to give 9.8g of a yellow solid with a yield of 56%.
And step 3: preparation of methyl 3-iodo-2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxylate (B-4)
B-3(8g, 30.1mmol) was added to a 250mL reaction flask, 100mL acetonitrile was added, and N-iodosuccinimide (7.4g, 32.9mmol) was added slowly with stirring and reacted at room temperature for 1 h. And (3) concentrating the reaction solution under reduced pressure, pouring the reaction solution into 100mL of water, precipitating yellow solid, performing suction filtration, rinsing a filter cake with water, and drying to obtain a crude yellow solid 11.3g, wherein the yield is 95.8%.
And 4, step 4: preparation of methyl 3- (4-cyanophenyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxylate (B-5)
Mixing B-4(5g, 12.8mmol), Pd (dppf) Cl 2 (0.5g, 0.7mmol), potassium carbonate (5.3g, 38.4mmol) and 4-cyanophenylboronic acid (2.3g, 15.6mmol) were charged to a 100mL reaction flask, and dioxane (30 mL) and water (7.5 mL) were added. The reaction is carried out for 12h at 90 ℃ under the protection of argon. The reaction mixture was cooled, concentrated, and 40mL of water was added, followed by extraction with ethyl acetate (40 mL. times.3) and washing with saturated brine (40 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The yellow solid is obtained by silica gel column chromatography and purification, and the yield is 72.3 percent.
And 5: preparation of 3- (4-cyanophenyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxylic acid (B-6)
According to the procedure of step 6 in example 1, 3- (4-cyanophenyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxylic acid (B-6) is synthesized from compound B-5.
Step 6: preparation of tert-butyl 4- (3- (4-cyanophenyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carbonyl) piperazine-1-carboxylate (B-7)
Tert-butyl 4- (3- (4-cyanophenyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carbonyl) piperazine-1-carboxylate (B-7) was synthesized according to the procedure of step 7 in example 1.
And 7: preparation of 4- (6- (piperazine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile (B-8)
According to the operation in step 8 of example 1,4- (6- (piperazine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile (B-8) is synthesized from the compound B-7.
Examples 33-46 the procedures used in example 32 were followed to prepare the corresponding compounds shown in Table 1.
In vitro pharmacological testing of a portion of the products of the invention
The kit 700120 of Cayman corporation was used to test the LSD1 inhibitory activity of all compounds of examples 1-46, and the specific procedures were as follows:
(1) assay setup 100% active wells, background wells, positive control wells and compound wells. Each group is provided with three multiple holes.
(2) 100% active pore: mu.L of LSD1 Buffer solution, 10. mu.L of solution (solution of the same components as those used to dissolve the compound and the positive drug), 20. mu.L of LSD1 enzyme, and 20. mu.L of LSD1 detection peptide were added in this order.
(3) Test wells and positive control wells: 120 mu L of LSD1 Buffer solution, 10 mu L of solution of the compound to be detected, 20 mu L of LSD1 enzyme and 20 mu L of LSD1 detection peptide are sequentially added.
(4) Background wells: 140. mu.L of LSD1 Buffer solution, 10. mu.L of solution (solution of the same components as those used to dissolve the compound and the positive drug), and 20. mu.L of LSD1 enzyme were added in this order.
(5) And in the solution adding process, the 96-well plate is placed on an ice bag for cooling, so that the enzymatic reaction is prevented from being carried out. After addition, incubation at room temperature for 30min in the dark.
(6) After incubation for 30min, 20. mu.L of horseradish peroxidase solution and 10. mu.L of fluorogenic substrate solution were added to each well in sequence. Incubated at room temperature for 10min in the dark.
(7) Excitation is carried out at 530nM wavelength by a microplate reader, and the intensity of emitted fluorescence is detected at 590 nM.
Percent inhibition ═ 100% active wells-sample wells)/100% active wells 100
TABLE 2 nuclear magnetic hydrogen spectrum, enzyme inhibitory activity data of the compounds prepared in examples 1-46
The aromatic six-membered ring benzimidazole derivatives shown in the general formula (I) and pharmaceutically acceptable salts thereof can be independently applied, but are usually mixed with a medicinal carrier for administration, the medicinal carrier is selected according to the required administration route and standard pharmaceutical practice, and the preparation methods of various medicinal dosage forms of the compounds, such as tablets, capsules, injections, aerosols, suppositories, films, dripping pills, external liniments and ointments, are used respectively below, so that the novel application of the compounds in the pharmaceutical field is explained.
Example 47
Tablet formulation
10g of the aromatic six-membered ring benzimidazole derivative prepared in example 1 was added with 20g of an auxiliary material according to a general pharmaceutical tableting method, mixed uniformly, and compressed into 100 tablets each weighing 300 mg.
Example 48
Capsule preparation
10g of the aromatic six-membered ring benzimidazole derivative prepared in example 2 was contained, 20g of an auxiliary material was uniformly mixed according to the requirement of a pharmaceutical capsule, and the mixture was filled into empty capsules, each capsule weighing 300 mg.
Example 49
Injection preparation
10g of the aromatic six-membered ring benzimidazole derivative obtained in example 3 was adsorbed by activated carbon according to a conventional pharmaceutical method, filtered through a 0.65 μm microporous membrane, and filled in a nitrogen tank to prepare a water-injection preparation, each containing 2mL, in total, 100 bottles.
Example 50
Aerosol formulation
Containing 10g of the aromatic six-membered ring benzimidazole derivative prepared in example 1, dissolved in an appropriate amount of propylene glycol, and then added with distilled water and other additives to prepare 500mL of a clear solution.
Example 51
Suppository
Containing 10g of the aromatic six-membered ring benzimidazole derivative obtained in example 1, grinding, adding appropriate amount of glycerin, grinding, adding melted glycerin gelatin, grinding, pouring into mold coated with lubricant, and making into suppository 50
Example 52
Film agent
Polyvinyl alcohol, medicinal glycerin and water were stirred to swell and then heated to dissolve, and filtered with a 80-mesh screen, 10g of the aromatic six-membered ring benzimidazole derivative obtained in example 18 was added to the filtrate and stirred to dissolve, and 100 films were formed on a film coating machine.
Example 53
Drop pills
Contains 10g of the aromatic six-membered ring benzimidazole derivative prepared in example 5, and 50g of a base such as gelatin, etc., which are heated, melted and mixed uniformly, and then dropped into low-temperature liquid paraffin to prepare 1000 pills.
Example 54
External liniment
The aromatic six-membered ring benzimidazole derivative composition was prepared by mixing 10g of the aromatic six-membered ring benzimidazole derivative prepared in example 5 with 2.5g of an emulsifier and other adjuvants, grinding the mixture, and adding 200mL of distilled water.
Example 55
Ointment formulation
Contains 10g of the aromatic six-membered ring benzimidazole derivative obtained in example 35, and is finely ground and then uniformly ground with 500g of an oily base such as vaseline.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (9)
1. An aromatic six-membered ring benzimidazole derivative or a pharmaceutically acceptable salt thereof is characterized in that the aromatic six-membered ring benzimidazole derivative has a general structural formula as shown in the specification;
wherein:
w and X are each independently C or N, and when one is C, the other can only be N;
R 1 and R 2 Each independently selected from aryl, heteroaryl, cycloalkyl, alkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl; wherein said aryl, heteroaryl, cycloalkyl, alkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaryl, alkyl may contain one or more substituents;
R 3 is-CH 2 -, carbonyl or thiocarbonyl;
R 4 is substituted N-heterocyclyl, substituted-N (H) -heterocyclylalkyl, substituted-N (Me) -heterocyclylalkyl or-N (R) 5 ) 2 ；
R 5 Selected from hydrogen, C1-C7 fatty primary amines, C1-C7 fatty secondary amines, C1-C7 fatty tertiary amines, preferably propylamine, N-methylpropylamine or N, N-dimethylpropylamine.
2. The aromatic six-membered ring benzimidazole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R in the general formula (I) 4 is-N (R) 5 ) 2 When R is 5 Is any one of the following structures:
3. the aromatic six-membered ring benzimidazole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the aromatic six-membered ring benzimidazole derivative is any one of the following 46 compounds:
n- (2-aminoethyl) -2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
4- (5- (3-methylpiperidine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
4- (5- (morpholine-4-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
4- (5- (3-aminopiperidine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
N- (3-aminopropyl) -2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N- (piperidin-4-ylmethyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N- (piperidin-3-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
4- (5- (4-methylpiperazine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
2- (4-cyanophenyl) -N- (piperidin-4-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N- (pyrrolidin-3-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
4- (5- (4-methylpiperidine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
4- (5- (2-methylpiperidine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
2- (4-cyanophenyl) -N, N-dimethyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N- (2- (methylamino) ethyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
(R) -2- (4-cyanophenyl) -N- (pyrrolidin-3-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
(R) -2- (4-cyanophenyl) -N- (piperidin-3-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
(R) -4- (5- (2-methylpiperazine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
(S) -4- (5- (2-methylpiperazine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
4- (5- (2-methylpiperazine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
N- (6-aminohexyl) -2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- (4-cyanophenyl) -N-methyl-N- (2- (methylamino) ethyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (4-aminobutyl) -2- (4-cyanophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (2-aminoethyl) -2- (4-cyanophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
(S) -4- (5- (3-aminopyrrolidine-1-carbonyl) -1- (p-tolyl) -1H-benzo [ d ] imidazol-2-yl) benzonitrile
(R) -2- (4-cyanophenyl) -N- (pyrrolidin-3-yl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (2-aminoethyl) -2- (4-fluorophenyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (2-aminoethyl) -N-methyl-2- (4-nitrophenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
2- ([1,1' -biphenyl ] -4-yl) -N- (2-aminoethyl) -N-methyl-1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (2-aminoethyl) -N-methyl-1- (p-tolyl) -2- (4- (trifluoromethyl) phenyl) -1H-benzo [ d ] imidazole-5-carboxamide
N- (2-aminoethyl) -N-methyl-2- (4- (methylsulfonyl) phenyl) -1- (p-tolyl) -1H-benzo [ d ] imidazole-5-carboxamide
4- (6- (piperazine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
3- (4-cyanophenyl) -N- (piperidin-4-yl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
4- (6- (4-aminopiperidine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
N- (4-aminobutyl) -3- (4-cyanophenyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
N- (2-aminoethyl) -3- (4-cyanophenyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
4- (6- (3-aminopiperidine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
3- (4-cyanophenyl) -N- (piperidin-4-ylmethyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
3- (4-cyanophenyl) -N- (piperidin-3-yl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
(R) -4- (6- (3-aminopyrrolidine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
3- (4-cyanophenyl) -N- (2- (methylamino) ethyl) -2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide
(R) -4- (6- (2-methylpiperazine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
(S) -4- (6- (2-methylpiperazine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
4- (6- (4-methylpiperidine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
4- (6- (2-methylpiperidine-1-carbonyl) -2- (p-tolyl) imidazo [1,2-a ] pyridin-3-yl) benzonitrile
3- (4-cyanophenyl) -N-methyl-2- (p-tolyl) imidazo [1,2-a ] pyridine-6-carboxamide.
4. A pharmaceutical composition, which is prepared by mixing the aromatic six-membered ring imidazoles derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 as an active ingredient with a pharmaceutically acceptable carrier or excipient, and preparing into a clinically acceptable dosage form.
5. A method for preparing the aromatic six-membered ring benzimidazole derivative or the pharmaceutically acceptable salt thereof according to claim 3, wherein the method for preparing the aromatic six-membered ring benzimidazole derivative comprises the following steps:
route one: carrying out esterification reaction on an initial raw material A-1 to obtain an intermediate A-2, wherein a reaction condition is that ester is formed under the catalysis of strong acid, or ester is formed through acylation of an acylation reagent, or ester is formed under the catalysis of dicyclohexylcarbodiimide and 4-dimethylaminopyridine, and the reaction temperature is 65-85 ℃; the intermediate A-2 and substituted aromatic amine or aliphatic amine are subjected to nucleophilic substitution reaction to obtain an intermediate A-3, and the reaction condition b is carried out under the condition that organic base or inorganic base is used as an acid-binding agent; the intermediate A-3 is subjected to reduction reaction to obtain an intermediate A-4, wherein the reaction condition c is hydrogenation reduction under a palladium catalyst, or reduction is carried out by adopting a combination of reducing metal and inorganic acid, and the combination of reducing metal and inorganic acid comprises iron powder/ammonium chloride, iron powder/hydrochloric acid and zinc powder/acetic acid; the intermediate A-4 and substituted aromatic aldehyde or aliphatic aldehyde are subjected to nucleophilic addition dehydration reaction to obtain an intermediate A-5, the reaction condition d is that the reaction is carried out under the catalysis of acetic acid, p-toluenesulfonic acid or Lewis acid, and the reaction temperature is 80-100 ℃; the intermediate A-5 is subjected to cyclization reaction under the catalysis of iodine to obtain an intermediate A-6, and the reaction condition e is carried out under the catalysis of iodine, N-iodosuccinimide or iodine chloride; the intermediate A-6 is subjected to ester hydrolysis reaction to obtain an intermediate A-7, and the reaction condition f is carried out under the catalysis of organic base or inorganic base; carrying out acylation reaction on the intermediate A-7 and substituted aliphatic amine to obtain an intermediate A-8, wherein the reaction condition g is carried out under the condition of a condensing agent; the intermediate A-8 is subjected to a Boc protecting group removing reaction to obtain a target product A-9, and the reaction condition h is that the heating is carried out for 4-12h under the catalysis of acid; the acid is trifluoroacetic acid or hydrochloric acid, and the reaction temperature is 25-80 ℃;
and a second route: the reaction conditions and the operation method in the second route adopt the corresponding reaction conditions and operation method in the first route;
and a third route: carrying out esterification reaction on an initial raw material B-1 to obtain an intermediate B-2, wherein a reaction condition is that ester is formed under the catalysis of strong acid, or an acylation reagent is acylated to form ester, or dicyclohexylcarbodiimide and 4-dimethylaminopyridine are catalyzed to form ester; the intermediate B-2 and the substituted alpha-halogenated saturated carbonyl compound are subjected to cyclization reaction to obtain an intermediate B-3, and the reaction condition B is carried out under the condition that organic base or inorganic base is used as an acid-binding agent; the intermediate B-3 is subjected to iodination reaction to obtain an intermediate B-4, and the reaction condition c is that iodination is carried out under the catalysis of iodine, N-iodosuccinimide or iodine chloride; the intermediate B-4 and substituted aryl boric acid or aliphatic boric acid are subjected to Suzuki reaction to obtain an intermediate B-5, the reaction condition d is that palladium complex is catalyzed, inorganic base is heated and reacts under the anaerobic condition, and the reaction temperature is 80-140 ℃; the intermediate B-5 is subjected to ester hydrolysis reaction to obtain an intermediate B-6, and the reaction condition e is carried out under the catalysis of organic base or inorganic base; carrying out acylation reaction on the intermediate B-6 and the substituted aliphatic amine to obtain an intermediate B-7, wherein the reaction condition f adopts the reaction condition of a reaction route g in the route I; and reacting the intermediate B-7 by removing a Boc protecting group to obtain a target product B-8, wherein the reaction condition g adopts the reaction condition of the reaction route h in the route I.
6. The preparation method of the aromatic six-membered ring imidazole derivatives according to claim 5, wherein in the first route, the organic base comprises triethylamine, N-diisopropylethylamine, and the inorganic base comprises sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide; the reaction solvent is any one of or a mixed solvent of more than two of methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dichloromethane, toluene, water, trifluoroethanol, acetone, 1, 4-dioxane, ethyl acetate, N-dimethylformamide and dimethyl sulfoxide; the condensing agent is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, O- (benzotriazole-1-yl) -bis (dimethylamino) carbenium hexafluorophosphate, O- (5-chlorobenzotriazole-1-yl) -bis (dimethylamino) carbenium hexafluorophosphate, O- (benzotriazole-1-yl) -bis (dimethylamino) carbenium tetrafluoroborate, O- (N-succinimide) -bis (dimethylamino) carbenium tetrafluoroborate, O- (N-endo-5-norbornene-2, 3-dicarbonimide) -bis (dimethylamino) carbenium tetrafluoroborate, diphenylphosphoryl chloride, N, N, N ', N' -tetramethylurea hexafluorophosphate, O- (benzotriazole-1-yl) -bis (dimethylamino) carbenium hexafluorophosphate, O- (5-chlorobenzotriazole-1-yl) -bis (dimethylamino) carbenium tetrafluoroborate, Diethyl cyanophosphate, diphenyl phosphorazidate, thiomethylphosphoryl azide, di (2-oxo-3-oxazolidinyl) phosphoryl chloride or 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphoric acid-2, 4, 6-trioxide.
7. The method for preparing the aromatic six-membered ring imidazole derivatives according to claim 5, wherein in the third route, the organic base comprises triethylamine, N-diisopropylethylamine, and the inorganic base comprises sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium fluoride; the reaction solvent is any one or a mixed solvent of more than two of methanol, ethanol, propanol, acetone, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, dimethyl sulfoxide, trifluoroethanol, acetonitrile, water and glycol dimethyl ether; the palladium complex is Pd (PPh) 3 ) 4 、PdCl 2 、PdCl 2 (dppf)、Pd(OAc) 2 Or Pd (PPh) 3 ) 2 Cl 2 。
8. Use of the aromatic six-membered ring imidazoles derivatives of any one of claims 1 to 3 or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 4 as lysine-specific demethylase 1 inhibitor.
9. Use of the aromatic six-membered ring imidazoles derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 4 for the preparation of a medicament for the treatment of a neoplastic disease.
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| CN202210630523.9A CN114853680A (en) | 2022-06-06 | 2022-06-06 | Aromatic six-membered ring imidazole derivative and preparation method and application thereof |
| CN202310062072.8A CN116120239A (en) | 2022-06-06 | 2023-01-16 | Aromatic six-membered cycloimidazole derivative, and preparation method and application thereof |
| PCT/CN2023/097215 WO2023236820A1 (en) | 2022-06-06 | 2023-05-30 | Aromatic six-membered ring-fused imidazole derivative, and preparation method therefor and use thereof |
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| CN202310062072.8A Pending CN116120239A (en) | 2022-06-06 | 2023-01-16 | Aromatic six-membered cycloimidazole derivative, and preparation method and application thereof |
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| WO2023236820A1 (en) * | 2022-06-06 | 2023-12-14 | 沈阳药科大学 | Aromatic six-membered ring-fused imidazole derivative, and preparation method therefor and use thereof |
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| WO2007086080A2 (en) * | 2006-01-30 | 2007-08-02 | Glenmark Pharmaceuticals Limited | NOVEL IMIDAZO[1,2-a]PYRIDINE CANNABINOID RECEPTOR LIGANDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| WO2009119776A1 (en) * | 2008-03-27 | 2009-10-01 | 武田薬品工業株式会社 | Fused heterocyclic derivative and use thereof |
| US8470819B2 (en) * | 2008-11-03 | 2013-06-25 | Merck Sharp & Dohme Corp. | Benzimidazole and aza-benzimidazole carboxamides |
| US8859555B2 (en) * | 2009-09-25 | 2014-10-14 | Oryzon Genomics S.A. | Lysine Specific Demethylase-1 inhibitors and their use |
| CN114364664A (en) * | 2019-07-09 | 2022-04-15 | 伊卡根有限责任公司 | BCAT modulation |
| TW202216693A (en) * | 2020-06-26 | 2022-05-01 | 美商坦帕斯醫療公司 | Trex1 inhibitors and uses thereof |
| CN114853680A (en) * | 2022-06-06 | 2022-08-05 | 沈阳药科大学 | Aromatic six-membered ring imidazole derivative and preparation method and application thereof |
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