CN114805261A - Benzofuran LSD1 inhibitor and preparation method thereof - Google Patents
Benzofuran LSD1 inhibitor and preparation method thereof Download PDFInfo
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- CN114805261A CN114805261A CN202110061056.8A CN202110061056A CN114805261A CN 114805261 A CN114805261 A CN 114805261A CN 202110061056 A CN202110061056 A CN 202110061056A CN 114805261 A CN114805261 A CN 114805261A
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- C07—ORGANIC CHEMISTRY
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
- C07D401/12—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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- 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
- C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- 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
- C07D405/12—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 linked by a chain containing hetero atoms as chain links
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- 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
- C07D409/12—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 linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to the technical field of chemical synthesis medicines, and relates to novel benzofuran derivatives, pharmaceutically acceptable salts of the derivatives, a preparation method of the derivatives and application of the derivatives as lysine specific demethylase-1 (LSD1) inhibitors. The structure of the pharmaceutically acceptable salt and the stereoisomer of the derivative is shown as a general formula (I). Wherein, X, R 1 、R 2 、R 3 、W 1 And W 2 As described in the claims and specification. The derivative, the pharmaceutically acceptable salt and isomer of the derivative or the composition containing the derivative have obvious effect of inhibiting the specific demethylase-1 of the amino acid, and can be used for preparing the LSD1 inhibitor.
Description
Technical Field
The invention belongs to the technical field of chemical synthetic drugs, and relates to novel benzofuran derivatives, pharmaceutically acceptable salts of the derivatives, a preparation method of the derivatives and application of the derivatives as lysine specific demethylase-1 (LSD1) inhibitors.
Background
Histone lysine demethylase has been of great importance in the development of drugs in the field of epigenetics, until 2004, the Shi Yang project group discovered for the first time histone lysine-specific demethylase 1, revealing that histone methylation is a reversible and controllable process (Cell 2004,119, 941-953.). It was found that LSD1 can specifically remove the monomethyl or the dimethyl group of histone lysine with the aid of the cofactor Flavin Adenine Dinucleotide (FAD), and can respectively play the roles of gene transcription activation and transcription inhibition by acting on methylated lysine. Further regulating and controlling downstream signal channels to play a regulating role. By removing the double methylation modification of H3K4, LSD1 can induce the silencing of tumor suppressor genes with transcriptional co-repressors, thereby promoting the growth of tumor cells. Researchers have subsequently reported that LSD1 acts as a target for tumor therapy, and that its inhibitors may exert better tumor therapeutic effects when used in combination with other drugs (e.g., kinase inhibitors). 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.
More than six hundred LSD1 inhibitors have been reported, with no commercially available LSD1 inhibitor being available for tumor therapy. The number of LSD1 inhibitors currently in clinical study is 11, and they can be classified into irreversible inhibitors and reversible inhibitors. 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. At present, representative LSD1 inhibitors ORY-1001, ORY-2001, GSK-2879552 and IMG-7289 in the clinical research stage are all irreversible inhibitors taking trans-phenyl cyclopropylamine as a structural parent nucleus. 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. The compound of the general formula I as an LSD1 inhibitor shows better activity at the enzyme level in vitro.
Disclosure of Invention
The invention aims to provide benzofuran derivatives shown in a general formula I, and pharmaceutically acceptable salts and stereoisomers of the derivatives, which are used for preparing LSD1 inhibitors,
wherein:
X＝CH 2 or NR, O, S; r is H or C1-C6 alkyl;
R 2 is-CH 2 -, carbonyl or thiocarbonyl;
R 3 is a substituted or unsubstituted 5-10 membered heterocyclic group or-N (R) 4 ) 2 Said heterocyclic ringThe substituent group contains 1-3 heteroatoms of N, O or S, and is C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C6 alkylamino;
each R 4 Independently selected from hydrogen, C1-C7 fatty primary amines, C1-C7 fatty secondary amines, C1-C7 fatty tertiary amines;
W 1 and W 2 Independently selected from N, C-H, C-F, C-NH 2 、C-CH 3 ；
R 1 Is optionally substituted or unsubstituted 5-10 membered aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, C1-C6 alkyl, 5-10 membered heterocyclyl, said substituents being C1-C6 alkyl, C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, nitro, amino, 5-10 membered aryl.
The invention preferably relates to benzofuran derivatives shown in a general formula (I), and pharmaceutically acceptable salts and stereoisomers thereof,
wherein:
X＝CH 2 or NR, O, S; r is H or C1-C6 alkyl;
R 2 is-CH 2 -, carbonyl or thiocarbonyl;
R 3 is a substituted or unsubstituted 5-6 membered heterocyclic group or-N (R) 4 ) 2 The heterocyclic group contains 1-2N heteroatoms, and the substituent is C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C6 alkylamino;
each R 4 Independently selected from propylamine, N-methylpropylamine, N-dimethylpropylamine.
The invention preferably relates to derivatives shown in the general formula (I), and pharmaceutically acceptable salts and stereoisomers thereof,
wherein the content of the first and second substances,
R 3 is a substituted or unsubstituted group as follows:
the invention preferably relates to derivatives shown in the general formula (I), and pharmaceutically acceptable salts and stereoisomers thereof,
wherein the content of the first and second substances,
W 1 and W 2 Independently selected from N, C-H, C-F, C-NH 2 、C-CH 3 ；
The invention preferably relates to derivatives shown in the general formula (I), and pharmaceutically acceptable salts and stereoisomers thereof,
wherein the content of the first and second substances,
R 1 is optionally substituted or unsubstituted 5-6 membered aryl, 5-6 membered heteroaryl, C3-C6 cycloalkyl, C1-C6 alkyl, 5-6 membered heterocyclyl, said substituents being C1-C6 alkyl, C1-C6 alkoxy, halogen, halo C1-C6 alkyl, nitro, amino, 5-6 membered aryl;
preferably, R 1 Is phenyl or naphthyl which is optionally substituted or unsubstituted, and the substituent is C1-C6 alkyl, C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, nitryl, amino, phenyl;
the compounds of general formula (I) and pharmaceutically acceptable salts thereof according to the present invention are preferably the following compounds, but these compounds are not meant to limit the present invention in any way:
4- (3- (piperazin-1-ylmethyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((4-aminopiperidin-1-yl) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
(R) -4- (3- ((3-aminopiperidin-1-yl) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((piperidin-4-ylamino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((pyrrolidin-3-ylamino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((4-aminocyclohexyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((piperidin-3-ylamino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-Aminopyrrolidin-1-yl) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
(S) -4- (3- ((3-aminopiperidin-1-yl) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((((1r, 4r) -4-aminocyclohexyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((2-aminoethyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((methyl (2- (methylamino) ethyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((methyl (3- (methylamino) propyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-aminopropyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((4-aminobutyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((5-aminopentyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((6-aminohexyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((4-methylpiperazin-1-yl) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((methyl (2- (methylamino) ethyl) amino) methyl) -6- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) benzonitrile
4- (3- ((methyl (3- (methylamino) propyl) amino) methyl) -6- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-Aminopyrrolidin-1-yl) methyl) -6- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-Aminopyrrolidin-1-yl) methyl) -6- (3, 5-difluorophenyl) benzofuran-5-yl) benzonitrile
(R) -4- (3- ((3-aminopiperidin-1-yl) methyl) -6- (3-nitrophenyl) benzofuran-5-yl) benzonitrile
4- (3- ((2- (methylamino) ethylamino) methyl) -6- (3-nitrophenyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-Aminopyrrolidin-1-yl) methyl) -6- (3-nitrophenyl) benzofuran-5-yl) benzonitrile
(R) -4- (3- ((3-aminopiperidin-1-yl) methyl) -6- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-Aminopyrrolidin-1-yl) methyl) -6- (4-fluorophenyl) benzofuran-5-yl) benzonitrile
4- (3- ((methyl (3- (methylamino) propyl) amino) methyl) -6- (3-nitrophenyl) benzofuran-5-yl) benzonitrile
4- (6- (naphthalen-2-yl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- (3, 5-dimethylphenyl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- (3-fluorophenyl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- ([1,1' -biphenyl ] -4-yl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- (4-ethylphenyl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- (2-fluoro-4-methylphenyl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6-phenyl-3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- (1-methyl-1H-indol-5-yl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (3- ((pyrrolidin-3-ylamino) methyl) -6- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) benzonitrile
4- (6- (pyrimidin-5-yl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
(S) -4- (3- ((pyrrolidin-3-ylamino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
(R) -4- (3- ((pyrrolidin-3-ylamino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
5- (4-cyanophenyl) -N- (piperidin-4-ylmethyl) -6- (p-tolyl) -1H-indole-3-carboxamide
5- (4-cyanophenyl) -1-methyl-N- (piperidin-4-yl) -6- (p-tolyl) -1H-indole-3-carboxamide
(S) -4- (3- (3-aminopiperidine-1-carbonyl) -6- (p-tolyl) -1H-indol-5-yl) benzonitrile
5- (4-cyanophenyl) -1-methyl-N- (piperidin-4-ylmethyl) -6- (p-tolyl) -1H-indole-2-carboxamide
5- (4-cyanophenyl) -1-methyl-N- (piperidin-4-yl) -6- (p-tolyl) -1H-indole-2-carboxamide
(S) -4- (3- (3-aminopiperidine-1-carbonyl) -6- (p-tolyl) benzothien-5-yl) benzonitrile
Furthermore, the compounds of formula I of the present invention may form pharmaceutically acceptable salts with acids according to methods common in the art to which the present invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with salts with acids being particularly preferred: 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, benzoic acid.
"halogen" in the present invention means fluorine, chlorine, bromine or iodine; "alkyl" refers to straight or branched chain alkyl; "aromatic heterocycle" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, which ring system refers to an organic group having aromatic character and obtained by removing a plurality of 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, and the like.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way.
The compounds of formula (I) according to the invention can be prepared according to the methods of scheme one, two, three or four.
As shown in route one, where all the variable factors applied are as defined in the claims.
Reacting A I with acetyl chloride or acetic anhydride to obtain intermediate AII, wherein a is carried out at room temperature under the condition that an organic base (such as triethylamine, N-diisopropylethylamine and the like) or an inorganic base (such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide and the like) is used as an acid-binding agent; the reaction solvent can be polar solvent such as methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc.; preferably, potassium carbonate is used as an acid-binding agent, acetonitrile is used as a solvent, and the reaction is carried out at 25 ℃. Intermediate AII is rearranged to obtain intermediate A III, and reaction condition b can be that various Lewis acids (such as aluminum trichloride, boron trifluoride, sulfur trioxide, ferric bromide and the like) are used as catalysts; the reaction solvent can be toluene, N-dimethylformamide, dimethyl sulfoxide and the like or no solvent; the catalytic conditions are preferably aluminum trichloride and solvent-free, and the reaction temperature is preferably 150 ℃. Performing nucleophilic substitution reaction on AIII and ethyl bromoacetate to obtain an intermediate A IV, wherein the reaction condition c is performed at room temperature or under a heating condition under the condition that an organic base (such as triethylamine, N-diisopropylethylamine and the like) or an inorganic base (such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide and the like) is used as an acid-binding agent; the reaction solvent can be polar solvent such as methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc.; preferably, potassium carbonate is used as an acid-binding agent, acetone is used as a solvent, and the reaction is carried out at 80 ℃. A IV and intermediate A V obtained by hydrolysis reaction under room temperature or heating condition in the presence of an organic base (such as triethylamine, N-diisopropylethylamine, etc.) or an inorganic base (such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, etc.); the reaction solvent can be methanol, ethanol, propanol, or propanolPolar solvents such as ketones, N-dimethylformamide, dimethyl sulfoxide and the like; preferably, sodium hydroxide is used as an acid-binding agent, a mixed solvent of methanol and water (the volume ratio is 1:1) is used as a solvent, and the reaction is carried out at 70 ℃. The intermediate A V is subjected to condensation reaction to obtain an intermediate A VI, and the reaction condition e is that sodium acetate is used as alkali, acetic anhydride and glacial acetic acid are used as solvents, and the reaction is carried out at 120 ℃. And (3) carrying out oxidation reaction on the intermediate A VI to obtain an intermediate A VII, wherein the reaction condition f is that selenium dioxide is used as an oxidant, dioxane is used as a solvent, and the reaction is carried out at 100 ℃. Carrying out Suzuki reaction on the intermediate A VII and substituted aryl boric acid to obtain an intermediate A VIII, wherein the reaction condition g is that the palladium complex is catalyzed, and the heating reaction is carried out under inorganic base and 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 PdCl 2 (dppf); the inorganic base can be potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium fluoride and the like, and sodium carbonate is preferred; the solvent can be ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, dimethyl sulfoxide, water and glycol dimethyl ether, etc., or can be a mixed solvent composed of two solvents, preferably a mixed solvent of glycol dimethyl ether and water (volume ratio is 10: 1); the reaction temperature may be 80 to 140 ℃ and preferably 110 ℃. The intermediate VIII and substituted aryl boric acid are subjected to suzuki reaction to obtain an intermediate IX, and the reaction condition h is that palladium complex catalysis, inorganic base and heating reaction are carried out under the anaerobic condition; 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 (OAc) 2 And X-phos; the inorganic base may be potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium fluoride, etc., preferably potassium phosphate; the solvent can be ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, dimethyl sulfoxide, water and glycol dimethyl ether, etc., or can be a mixed solvent composed of two solvents, preferably a mixed solvent of glycol dimethyl ether and water (volume ratio is 10: 1); the reaction temperature may be 80 to 140 ℃ and preferably 80 ℃. Halogenating the intermediate A IX to obtain an intermediate A X, wherein the reaction condition i is that thionyl chloride is subjected to halogenationTaking dichloro as a solvent, and reacting at 25 ℃. Intermediate A X and substituted fatty amine undergo nucleophilic substitution reaction to obtain intermediate XI, and reaction condition j is carried out at room temperature or under heating condition under the condition that an organic base (such as triethylamine, N-diisopropylethylamine and the like) or an inorganic base (such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide and the like) is used as an acid-binding agent; the reaction solvent can be polar solvent such as methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc.; preferably, potassium carbonate is used as an acid-binding agent, N, N-dimethylformamide is used as a solvent, and the reaction is carried out at the temperature of 80 ℃. The intermediate XI is subjected to Boc protecting group removal reaction to obtain a target product, and the reaction condition k is acid catalysis, and the heating is carried out for 4-12 hours; the acid can be trifluoroacetic acid, hydrochloric acid/ethanol, hydrochloric acid/dioxane, hydrochloric acid/ethyl acetate, etc., preferably hydrochloric acid/ethyl acetate; the solvent can be methanol, ethanol, isopropanol, N-dimethylformamide, dimethyl sulfoxide, etc., preferably ethyl acetate; the reaction temperature may be 25-80 ℃, preferably 25 ℃; the reaction time is preferably 4 hours.
Route two shows where all the variable factors applied are as defined in the claims.
The intermediate B2 is obtained by bromination reaction of the starting material B1, the bromination reagent can be NBS, bromine and the like, a proper amount of catalyst can be added, and the preferred halogenation reagent is NBS; the reaction solvent can be tetrahydrofuran, diethyl ether, dichloromethane, chloroform, toluene, methanol, etc., preferably tetrahydrofuran; the reaction temperature is 0-60 ℃. Intermediate B2 is esterified to obtain intermediate B3, and the acylation conditions can be thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride and phosphorus tribromide; the reaction solvent can be tetrahydrofuran, diethyl ether, dichloromethane, chloroform, toluene, methanol, etc., preferably methanol; the reaction temperature is 0-60 ℃. The intermediate B3 and substituted aryl boric acid are subjected to suzuki reaction to obtain an intermediate B4, and the reaction condition c is that palladium complex is catalyzed, inorganic base is heated and reacts under the anaerobic condition; 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 PdCl 2 (dppf); the inorganic base may bePotassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium fluoride and the like, preferably sodium carbonate; the solvent can be ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, dimethyl sulfoxide, water and glycol dimethyl ether, etc., or can be a mixed solvent composed of two solvents, preferably a mixed solvent of glycol dimethyl ether and water (volume ratio is 10: 1); the reaction temperature may be 80 to 140 ℃ and preferably 110 ℃. The intermediate B4 and substituted aryl boric acid are subjected to suzuki reaction to obtain an intermediate B5, and the reaction condition d is that palladium complex is catalyzed, inorganic base is heated and reacts under the anaerobic condition; 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 (OAc) 2 And X-phos; the inorganic base may be potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium fluoride, etc., preferably potassium phosphate; the solvent can be ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, dimethyl sulfoxide, water and ethylene glycol dimethyl ether, etc., or can be a mixed solvent composed of two solvents, preferably a mixed solvent of ethylene glycol dimethyl ether and water (volume ratio is 10: 1); the reaction temperature may be 80 to 140 ℃ and preferably 80 ℃. B5 and intermediate B6 obtained by hydrolysis, wherein the reaction is carried out at room temperature or under heating condition under the condition that e is organic base (such as triethylamine, N-diisopropylethylamine and the like) or inorganic base (such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide and the like); the reaction solvent can be polar solvent such as methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc.; preferably, sodium hydroxide is used as an acid-binding agent, a mixed solvent of methanol and water (the volume ratio is 1:1) is used as a solvent, and the reaction is carried out at 70 ℃. And (3) carrying out acylation reaction on the intermediate B6 and the substituted aliphatic amine to obtain an intermediate B7, wherein the reaction condition f: is O- (7-azabenzotriazole-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HATU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HBTU), O- (5-chlorobenzotriazole-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HCTU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium tetrafluoroborate (TBTU), O- (N-succinyl)Imino) -bis (dimethylamino) carbenium tetrafluoroborate (TSTU), O- (N-endo-5-norbornene-2, 3-dicarboximide) -bis (dimethylamino) carbenium tetrafluoroborate (TNTU), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA, thiodimethylphosphoryl azide (MPTA), bis (2-oxo-3-oxazolidinyl) phosphoryl chloride (BOP-Cl),2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphoric acid-2, 4, 6-trioxide (T3P) and the like as condensing agents at room temperature or under heating; the reaction solvent can be polar solvent such as methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc.; preferably N, N-dimethylformamide as a solvent and HATU as a condensing agent, and reacting at 40 ℃. The intermediate B7 is reacted by removing Boc protecting group to obtain target product, and the reaction condition g is heating for 4-12 hours under the catalysis of acid; the acid can be trifluoroacetic acid, hydrochloric acid/ethanol, hydrochloric acid/dioxane, hydrochloric acid/ethyl acetate, etc., preferably hydrochloric acid/ethyl acetate; the solvent can be methanol, ethanol, isopropanol, N-dimethylformamide, dimethyl sulfoxide, etc., preferably ethyl acetate; the reaction temperature may be 25-80 ℃, preferably 25 ℃; the reaction time is preferably 4 hours.
Route three shows where all the variable factors applied are as defined in the claims.
The intermediate C2 is obtained from the initial raw material C1 through diazotization reduction reaction, sodium nitrite is used as a reaction reagent, a reaction solvent is concentrated hydrochloric acid, stannous chloride is used as a reducing agent, and the reaction temperature is-10 ℃. The intermediate C2 is condensed with ethyl pyruvate to obtain an intermediate C3, C3 is cyclized under the condition of polyoxy phosphorus to obtain an intermediate C4, the intermediate C4 is subjected to suzuki reaction with substituted aryl boric acid to obtain an intermediate C5, and the reaction condition d is that the palladium complex is catalyzed, inorganic base is heated and reacts under the anaerobic condition; 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 PdCl 2 (dppf); the inorganic base can be potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium fluoride and the like, and sodium carbonate is preferred; the solvent can be ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, and dimethylSulfoxide, water and glycol dimethyl ether, or a mixed solvent of two solvents, preferably a mixed solvent of glycol dimethyl ether and water (in a volume ratio of 10: 1); the reaction temperature may be 80 to 140 ℃ and preferably 110 ℃. The intermediate C5 and substituted aryl boric acid are subjected to suzuki reaction to obtain an intermediate C6, and the reaction condition e is that palladium complex is catalyzed, inorganic base is heated and reacts under the anaerobic condition; 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 (OAc) 2 And X-phos; the inorganic base may be potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium fluoride, etc., preferably potassium phosphate; the solvent can be ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, dimethyl sulfoxide, water and glycol dimethyl ether, etc., or can be a mixed solvent composed of two solvents, preferably a mixed solvent of glycol dimethyl ether and water (volume ratio is 10: 1); the reaction temperature may be 80 to 140 ℃ and preferably 80 ℃. C6 and intermediate C7 obtained by hydrolysis reaction under room temperature or heating condition, wherein the reaction condition f is organic base (such as triethylamine, N-diisopropylethylamine, etc.) or inorganic base (such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide, etc.); the reaction solvent can be polar solvent such as methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc.; preferably, sodium hydroxide is used as an acid-binding agent, a mixed solvent of methanol and water (the volume ratio is 1:1) is used as a solvent, and the reaction is carried out at 70 ℃. Acylation reaction is carried out on the intermediate C7 and substituted aliphatic amine to obtain an intermediate C8, and the reaction condition g: is O- (7-azabenzotriazole-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HATU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HBTU), O- (5-chlorobenzotriazole-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HCTU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium tetrafluoroborate (TBTU), O- (N-succinimidyl) -bis (dimethylamino) carbonium tetrafluoroborate (TSTU), O- (N-endo-5-norbornene-2, 3-dicarbodiimide) -bis (dimethylamino) carbonium tetrafluoroborate (TNTU), Diphenylphosphoryl chloride (DPP-Cl),Diethyl cyanophosphate (DECP), diphenyl phosphorazidate (DPPA, thiodimethylphosphoryl azide (MPTA), bis (2-oxo-3-oxazolidinyl) phosphoryl chloride (BOP-Cl),2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphate-2, 4, 6-trioxatriophosphoric acid-2, 4, 6-trioxatrio-compound (T3P) and the like are taken as condensing agents, the reaction solvent can be a polar solvent such as methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide and the like, preferably N, N-dimethylformamide is taken as a solvent and HATU is taken as a condensing agent, the reaction is carried out at 40 ℃, the intermediate C8 is subjected to a reaction for removing Boc protecting groups to obtain a target product, and the reaction condition h is that the heating is carried out for 4 to 12 hours under the catalysis of acid, and the acid can be trifluoroacetic acid, Hydrochloric acid/ethanol, hydrochloric acid/dioxane, hydrochloric acid/ethyl acetate, and the like, preferably hydrochloric acid/ethyl acetate; the solvent can be methanol, ethanol, isopropanol, N-dimethylformamide, dimethyl sulfoxide, etc., preferably ethyl acetate; the reaction temperature may be 25-80 ℃, preferably 25 ℃; the reaction time is preferably 4 hours.
Route four shows where all the variable factors applied are as defined in the claims.
The intermediate D2 is obtained by bromination reaction of the starting material D1, AIBN is used as a catalyst, the reaction solvent is carbon tetrachloride, and the reaction temperature is 80 ℃. The intermediate D2 is subjected to oxidation reaction to obtain an intermediate D3, D3 is subjected to cyclization under the condition of methyl thioglycolate to obtain an intermediate D4.D4, and is subjected to hydrolysis reaction to obtain an intermediate D5, wherein the reaction is carried out at room temperature or under a heating condition under the condition that an organic base (such as triethylamine, N-diisopropylethylamine and the like) or an inorganic base (such as sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, sodium hydroxide, potassium hydroxide and the like) is adopted as the reaction condition D; the reaction solvent can be polar solvent such as methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc.; preferably, sodium hydroxide is used as an acid-binding agent, a mixed solvent of methanol and water (the volume ratio is 1:1) is used as a solvent, and the reaction is carried out at 70 ℃. And (3) carrying out acylation reaction on the intermediate D5 and the substituted aliphatic amine to obtain an intermediate D6, wherein the reaction condition is as follows: is O- (7-azabenzotriazole-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HATU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HBTU), O- (5-chlorobenzotriazole-1-yl) -bis (dimethylamino) carboniumHexafluorophosphate (HCTU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbenium tetrafluoroborate (TBTU), O- (N-succinimidyl) -bis (dimethylamino) carbenium tetrafluoroborate (TSTU), O- (N-endo-5-norbornene-2, 3-dicarboximide) -bis (dimethylamino) carbenium tetrafluoroborate (TNTU), diphenylphosphoryl chloride (DPP-Cl), diethyl cyanophosphate (DECP), diphenylphosphoryl azide (DPPA, thiodimethylphosphoryl azide (MPTA), bis (2-oxo-3-oxazolidinyl) phosphoryl chloride (BOP-Cl),2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxotriphosphoric acid-2, 4, 6-trioxides (T3P) as a condensing agent, at room temperature or under heating; the reaction solvent can be polar solvent such as methanol, ethanol, propanol, acetone, N-dimethylformamide, dimethyl sulfoxide, etc.; preferably N, N-dimethylformamide as a solvent and HATU as a condensing agent, and reacting at 40 ℃. The intermediate D6 and substituted aryl boric acid are subjected to suzuki reaction to obtain an intermediate D7, and the reaction condition f is that palladium complex is catalyzed, inorganic base is heated and reacts under the anaerobic condition; 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 PdCl 2 (dppf); the inorganic base can be potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium fluoride and the like, and sodium carbonate is preferred; the solvent can be ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dimethylformamide, dimethyl sulfoxide, water and glycol dimethyl ether, etc., or can be a mixed solvent composed of two solvents, preferably a mixed solvent of glycol dimethyl ether and water (volume ratio is 10: 1); the reaction temperature may be 80 to 140 ℃ and preferably 110 ℃. The intermediate D7 and substituted aryl boric acid are subjected to suzuki reaction to obtain an intermediate D8, and the reaction condition g is that palladium complex is catalyzed, inorganic base is heated and reacts under an anaerobic condition; 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 (OAc) 2 And X-phos; the inorganic base may be potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium fluoride, etc., preferably potassium phosphate; the solvent can be ethanol, 1, 4-dioxane, tetrahydrofuran, toluene, N-dioxaneMethyl formamide, dimethyl sulfoxide, water and glycol dimethyl ether, etc., or a mixed solvent composed of two solvents, wherein the solvent is preferably a mixed solvent of glycol dimethyl ether and water (the volume ratio is 10: 1); the reaction temperature may be 80 to 140 ℃ and preferably 80 ℃. The intermediate D8 is reacted by removing Boc protecting group to obtain target product, and the reaction condition h is acid catalysis, and is heated for 4-12 hours; the acid can be trifluoroacetic acid, hydrochloric acid/ethanol, hydrochloric acid/dioxane, hydrochloric acid/ethyl acetate, etc., preferably hydrochloric acid/ethyl acetate; the solvent can be methanol, ethanol, isopropanol, N-dimethylformamide, dimethyl sulfoxide, etc., preferably ethyl acetate; the reaction temperature may be 25-80 ℃, preferably 25 ℃; the reaction time is preferably 4 hours.
The specific implementation mode is as follows:
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 4- (3- (piperazin-1-ylmethyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
Step A-preparation of 4-bromo-3-chlorophenylacetate
4-bromo-3-chlorophenol (8.0g, 38.6mmol) and potassium carbonate (5.3g, 38.6mmol) were added to a 250mL reaction flask, 100mL acetonitrile was added, and the mixture was stirred at room temperature for 30 min. Acetyl chloride (3.0g, 38.6mmol) was added dropwise to the reaction mixture, and after the addition was complete, the temperature was raised to 60 ℃ to continue the reaction for 6 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 50mL of ethyl acetate was added to dissolve the crude product. The ethyl acetate phase was washed with water (10 mL. times.3), with saturated brine (10 mL. times.3), dried over anhydrous sodium sulfate, and concentrated to give a crude white solid (8.7g, yield 90.0%).
Step A-2 preparation of 1- (5-bromo-4-chloro-2-hydroxyphenyl) ethan-1-one
A II (8.7g, 34.7mmol) and anhydrous aluminum trichloride (1.7g, 10.0mmol) were added to a 100mL reaction flask and reacted at 150 ℃ for 30 min. The reaction mixture was stirred vigorously for 5min with 40mL of water and 40mL of ethyl acetate. The ethyl acetate phase was separated, dried over anhydrous sodium sulfate and concentrated to give a crude product as a white solid 7.8g with a yield of 90.0%.
Step A-3 Synthesis of ethyl 2- (2-acetyl-4-bromo-5-chlorophenoxy) acetate
A III (7.8g, 31.2mmol), potassium carbonate (4.3g, 31.2mmol) and ethyl bromoacetate (5.2g, 31.2mmol) were added to a 250mL reaction flask and reacted at 60 ℃ for 4 h. The reaction mixture was cooled, concentrated by rotary drying, extracted with 40mL of water and ethyl acetate (40 mL. times.3), and washed with saturated brine (40 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated to give a crude product as a yellow solid 9.4g with a yield of 90.0%.
Step A-4 preparation of 2- (2-acetyl-4-bromo-5-chlorophenoxy) acetic acid
A IV (9.4g, 28.1mmol) and sodium hydroxide (1.1g, 28.1mmol) were added to a 250mL reaction flask, 40mL methanol and 40mL water were added, and the reaction was carried out at 70 ℃ for 2 h. The reaction mixture was cooled, concentrated, and the PH was adjusted to 2 with 1N hydrochloric acid to precipitate a white solid, which was dried to obtain 7.8g of a crude white solid with a yield of 90.0%.
Step A-5 Synthesis of 5-bromo-6-chloro-3-methylbenzofuran
A V (7.8g, 25.3mmol), sodium acetate (2.1g, 25.3mmol), glacial acetic acid 50mL and acetic anhydride 50mL were reacted at 120 ℃ with stirring for 10 h. The reaction solution was poured into 50mL of ice water, extracted with ethyl acetate (40 mL. times.3), and the ethyl acetate was combined and washed with saturated brine (10 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 3.5g of a white solid with a yield of 56.8%.
Step A-6 preparation of (5-bromo-6-chlorobenzofuran-3-yl) methanol
A VI (3.5g, 14.4mmol), selenium dioxide (1.6g, 14.4mmol) and 50mL dioxane were added to a 100mL reaction flask and reacted at 100 ℃ for 40 h. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed 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 2.5g is obtained by silica gel column chromatography purification, and the yield is 66.3%.
Step A-7 Synthesis of 4- (6-chloro-3- (hydroxymethyl) benzofuran-5-yl) benzonitrile
A VII (2.5g, 9.5mmol), Pd (dppf) Cl 2 (0.4g, 0.5mmol), potassium fluoride (0.8g, 14.4mmol), 4-cyanophenylboronic acid (1.4g, 9.5mmol) and dioxane 50mL were added to a 100mL reaction flask and reacted at 90 ℃ for 10h under argon. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (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 yellow solid 1.6g with yield 60.3%.
Step A-8: synthesis of 4- (3- (hydroxymethyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
A VIII (1.6g, 5.7mmol), Pd (OAc) 2 (0.07g, 0.3mmol), X-phos (2.7g, 5.7mmol), 4-methylphenylboronic acid (1.4g, 5.7mmol), ethylene glycol dimethyl ether (50 mL) and water (5 mL) were added to a 100mL reaction flask and reacted at 70 ℃ for 10h under argon. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (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 yellow solid 1.0g with yield of 50.3%.
Step A-9: preparation of 4- (3- (chloromethyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
A IX (1.0g, 2.9mmol), thionyl chloride (0.3g, 2.9mmol) and 20mL of dichloromethane were added to a 100mL reaction flask and reacted at room temperature for 3 h. The reaction mixture was cooled and concentrated under reduced pressure to give an oily substance, which was dissolved in 40ml of ethyl acetate and washed with water and saturated brine in this order. After drying over anhydrous sodium sulfate, the mixture was concentrated and purified by silica gel column chromatography to obtain 0.9g of a yellow oily liquid with a yield of 90.0%.
Step A-10: preparation of tert-butyl 4- ((5- (4-cyanophenyl) -6- (p-tolyl) benzofuran-3-yl) methyl) piperazine-1-carboxylate
A X (0.1g, 0.3mmol), 1-Boc-piperazine (0.05g, 0.3mmol), potassium carbonate (0.04g, 0.3mmol) and DMF 5mL were added to a 10mL reaction flask and reacted at room temperature for 10 h. To the reaction solution, 20mL of water was added, and the mixture was extracted with 40mL of ethyl acetate, and washed with water and saturated brine in this order. Dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give 80.0mg of a yellow oily liquid with a yield of 52.5%.
Step A-11: preparation of 4- (3- (piperazin-1-ylmethyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
AX (80.0mg, 0.15mmol) was added to 5ml 6N HCl/MeOH and the reaction stirred at room temperature for 2 h. The solvent was concentrated under reduced pressure, 5ml of water was added, and the pH was adjusted to 10 with saturated sodium hydroxide solution. Ethyl acetate (10 mL. times.3) was extracted, and the ethyl acetates were combined and washed with saturated brine (10 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 55.7mg of an orange solid with a yield of 86.8%.
Syntheses of examples 02-40 were carried out according to the synthetic method of example 01.
Example 43: synthesis of (S) -4- (3- (3-aminopiperidine-1-carbonyl) -6- (p-tolyl) -1H-indol-5-yl) benzonitrile
Step B-1: preparation of 5-bromo-6-chloro-1H-indole-3-carboxylic acid
B1(5.0g, 25.6mmol), NBS (4.6g, 25.6mmol) and 50mL of carbon tetrachloride were added to a 100mL reaction flask and reacted at 70 ℃ for 10h under argon. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (40 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by silica gel column chromatography to give 3.0g of a yellow solid in 75.3% yield.
Step B-2: preparation of 5-bromo-6-chloro-1H-indole-3-carboxylic acid ethyl ester
B2(5.0g, 18.2mmol), thionyl chloride (4.3g, 36.4mmol) and 50mL of ethanol were added to a 100mL reaction flask and reacted at 70 ℃ for 10 h. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (40 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by silica gel column chromatography to give 3.0g of a yellow solid in 75.3% yield.
Step B-3: preparation of 6-chloro-5- (4-cyanophenyl) -1H-indole-3-carboxylic acid ethyl ester
Mixing B3(2.9g, 9.5mmol), Pd (dppf) Cl 2 (0.4g, 0.5mmol), potassium fluoride (0.8g, 14.4mmol), 4-cyanophenylboronic acid (1.4g, 9.5mmol) and dioxane 50mL were added to a 100mL reaction flask and reacted at 90 ℃ for 10h under argon. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (40 mL. times.3). The ethyl acetate phaseDried over anhydrous sodium sulfate and concentrated under reduced pressure. Purifying by silica gel column chromatography to obtain yellow solid 1.6g with yield 60.3%.
Step B-4: preparation of ethyl 5- (4-cyanophenyl) -6- (p-tolyl) -1H-indole-3-carboxylate
Mixing B4(1.85g, 5.7mmol), Pd (OAc) 2 (0.07g, 0.3mmol), X-phos (2.7g, 5.7mmol), 4-methylphenylboronic acid (1.4g, 5.7mmol), ethylene glycol dimethyl ether (50 mL) and water (5 mL) were added to a 100mL reaction flask and reacted at 70 ℃ for 10h under argon. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (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 yellow solid 1.0g with yield of 50.3%.
Step B-5: preparation of 5- (4-cyanophenyl) -6- (p-tolyl) -1H-indole-3-carboxylic acid
B5(10.8g, 28.1mmol) and sodium hydroxide (1.1g, 28.1mmol) were added to a 250mL reaction flask, 40mL methanol and 40mL water were added, and the reaction was carried out at 70 ℃ for 2 h. The reaction mixture was cooled, concentrated, and the PH was adjusted to 2 with 1N hydrochloric acid to precipitate a white solid, which was dried to obtain 7.8g of a crude white solid with a yield of 90.0%.
Step B-6: preparation of tert-butyl (1- (5- (4-cyanophenyl) -6- (p-tolyl) indole-3-carbonyl) piperidin-3-yl) carbamate
Intermediate B6(0.35g, 1mmol), S-3-amino Boc-piperidine (0.20g, 1.0mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.38g, 1.0mmol) were added to a 10mL reaction flask, 2mL anhydrous DMF and 0.26g N, N-diisopropylethylamine were added and reacted at room temperature for 12 h. The reaction solution was poured into 20mL of water, extracted with 10 mL. times.3 of methylene chloride, the methylene chloride phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was separated and purified by silica gel column chromatography to give 0.33g of a white solid with a yield of 56.1%.
Step B-7: preparation of (S) -4- (3- (3-aminopiperidine-1-carbonyl) -6- (p-tolyl) -1H-indol-5-yl) benzonitrile
B7(80.0mg, 0.15mmol) was added to 5ml 6N HCl/MeOH and the reaction stirred at room temperature for 2 h. The solvent was concentrated under reduced pressure, 5ml of water was added, and the pH was adjusted to 10 with saturated sodium hydroxide solution. Ethyl acetate (10 mL. times.3) was extracted, and the ethyl acetate was combined and washed with saturated brine (10 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 55.7mg of an orange solid with a yield of 86.8%.
Syntheses of examples 41-42 were carried out according to the synthesis method of example 43.
Example 45: synthesis of 5- (4-cyanophenyl) -1-methyl-N- (piperidin-4-yl) -6- (p-tolyl) -1H-indole-2-carboxamide
Step C1: preparation of (4-bromo-3-chlorobenzene) hydrazine hydrochloride
C1(5.0g, 24.2mmol) and sodium nitrite (1.7g, 24.2mmol) were charged into a 100mL reaction flask, and 20mL concentrated HCl was added and reacted at-10 ℃ for 2 h. Adding stannous chloride (5.5g, 24.2mmol) and reacting at-10 deg.c for 2 hr. Filtration, drying and concentration under reduced pressure gave 7.1g of pale yellow solid with a yield of 86.8%.
Step C2: (E) preparation of ethyl (E) -2- (2- (4-bromo-3-chlorophenyl) hydrazinolactone) propionate
C2(5.0g, 19.4mmol) and ethyl pyruvate (2.3g, 19.4mmol) were charged into a 100mL reaction flask, and 20mL of ethanol was added and reacted at room temperature for 2 hours. Pouring into ice water, precipitating solid, filtering, drying to obtain light yellow solid 7.1g, yield 86.8%.
Step C3: preparation of 5-bromo-6-chloro-1-methyl-1H-indole-2-carboxylic acid ethyl ester
C2(6.2g, 19.4mmol) was added to a 100mL reaction flask, 20mL of polyphosphoric acid was added, and the reaction was carried out at 120 ℃ for 2 h. Poured into ice water, precipitated solid was filtered and dried to obtain a pale yellow solid (3.5 g), and then methyl iodide (2.8g, 19.4mmol), potassium carbonate (2.7g, 19.4mmol) and 8ml DMF were added and reacted at 40 ℃ for 2 hours. Pouring into ice water, separating out solid, filtering and drying to obtain 5.6g of light yellow solid with the yield of 66.8%.
Step C4: preparation of 6-chloro-5- (4-cyanophenyl) -1-methyl-1H-indole-2-carboxylic acid ethyl ester
Mixing C4(2.9g, 9.5mmol), Pd (dppf) Cl 2 (0.4g, 0.5mmol), potassium fluoride (0.8g, 14.4mmol), 4-cyanophenylboronic acid (1.4g, 9.5mmol) and dioxane 50mL were added to a 100mL reaction flask and reacted at 90 ℃ for 10h under argon. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (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 yellow solid 1.9g with yield 60.3%.
Step C5: preparation of ethyl 5- (4-cyanophenyl) -1-methyl-6- (p-tolyl) -1H-indole-2-carboxylate
Mixing C5(1.9g, 5.7 mm)ol)、Pd(OAc) 2 (0.07g, 0.3mmol), X-phos (2.7g, 5.7mmol), 4-methylphenylboronic acid (1.4g, 5.7mmol), ethylene glycol dimethyl ether (50 mL) and water (5 mL) were added to a 100mL reaction flask and reacted at 70 ℃ for 10h under argon. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (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 yellow solid 1.2g with yield of 50.3%.
Step C6: preparation of 5- (4-cyanophenyl) -1-methyl-6- (p-tolyl) -1H-indole-2-carboxylic acid
C6(10.7g, 28.1mmol) and sodium hydroxide (1.1g, 28.1mmol) were added to a 250mL reaction flask, 40mL methanol and 40mL water were added, and the reaction was carried out at 70 ℃ for 2 h. The reaction mixture was cooled, concentrated, and the PH was adjusted to 2 with 1N hydrochloric acid to precipitate a white solid, which was dried to obtain 7.8g of a crude white solid with a yield of 90.0%.
Step C7: preparation of tert-butyl 4- (5- (4-cyanophenyl) -1-methyl-6- (p-tolyl) -1H-indole-2-carboxamido) piperidine-1-carboxylate
Intermediate C7(0.35g, 1mmol), 1-Boc-3-aminopyrrolidine (0.20g, 1.0mmol), 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.38g, 1.0mmol) were added to a 10mL reaction flask, 2mL anhydrous DMF and 0.26g N, N-diisopropylethylamine were added and reacted at room temperature for 12 h. The reaction solution was poured into 20mL of water, extracted with 10 mL. times.3 of methylene chloride, the methylene chloride phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was separated and purified by silica gel column chromatography to give 0.33g of a white solid with a yield of 56.1%.
Step C8: preparation of 5- (4-cyanophenyl) -1-methyl-N- (piperidin-4-yl) -6- (p-tolyl) -1H-indole-2-carboxamide
C8(80.0mg, 0.15mmol) was added to 5ml 6N HCl/MeOH and the reaction stirred at room temperature for 2 h. The solvent was concentrated under reduced pressure, 5ml of water was added, and the pH was adjusted to 10 with saturated sodium hydroxide solution. Ethyl acetate (10 mL. times.3) was extracted, and the ethyl acetate was combined and washed with saturated brine (10 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 55.7mg of an orange solid with a yield of 86.8%.
The synthesis of example 44 was obtained following the synthesis method of example 45.
Example 46: synthesis of (S) -4- (3- (3-aminopiperidine-1-carbonyl) -6- (p-tolyl) benzothien-5-yl) benzonitrile
Step D1: preparation of 1-bromo-2-chloro-4- (dibromomethyl) -5-fluorobenzene
D1(5.0g, 25.6mmol), NBS (9.2g, 51.2mmol),0.5g AIBN and 50mL carbon tetrachloride were added to a 100mL reaction flask and reacted at 70 ℃ for 10h under argon. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (40 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The yellow oily liquid 6.0g is obtained by silica gel column chromatography purification, and the yield is 90.3%.
Step D2: preparation of 4-bromo-5-chloro-2-fluorobenzaldehyde
D2(9.8g, 25.6mmol) and DMSO 20mL were added to a 100mL reaction flask and reacted at 100 ℃ for 2 h. The reaction mixture was cooled, 100mL of water was added, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (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 yellow solid 6.0g with yield 60.3%.
Step D3: preparation of methyl 6-bromo-5-chlorobenzothiophene-2-carboxylate
D3(3.7g, 15.5mmol), methyl thioglycolate (1.6g, 15.5mmol), potassium carbonate (2.1g, 15.5mmol) and 20mL of DMF were added to a 100mL reaction flask and reacted at 40 ℃ for 12 h. The reaction mixture was cooled, 100mL of water was added, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (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 yellow solid 6.0g with yield 60.3%.
Step D4: preparation of 6-bromo-5-chlorobenzothiophene-2-carboxylic acid
D4(8.6g, 28.1mmol) and sodium hydroxide (1.1g, 28.1mmol) were added to a 250mL reaction flask, 40mL methanol and 40mL water were added, and the reaction was carried out at 70 ℃ for 2 h. The reaction mixture was cooled, concentrated, and the PH was adjusted to 2 with 1N hydrochloric acid to precipitate a white solid, which was dried to obtain 7.8g of a crude white solid with a yield of 90.0%.
Step D5: preparation of tert-butyl (R) - (1- (6-bromo-5-chlorobenzo [ b ] thiophene-2-carbonyl) piperidin-3-yl) carbamate
Intermediate D5(0.4g, 1.4mmol), (S) -3-amino Boc-piperidine (0.42g, 2.1mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.78g, 2.1mmol) was added to a 10mL reaction flask, 2mL anhydrous DMF and 0.26g N, N-diisopropylethylamine were added and reacted at room temperature for 12 h. The reaction solution was poured into 20mL of water, extracted with 10mL × 3 of dichloromethane, the dichloromethane phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was separated and purified by silica gel column chromatography to give 0.45g of a yellow solid with a yield of 85.0%.
Step D6: preparation of tert-butyl (R) - (1- (5-chloro-6- (p-tolyl) benzothiophene-2-carbonyl) piperidin-3-yl) carbamate
Mixing D6(0.9g, 1.9mmol), Pd (dppf) Cl 2 (0.1g, 0.1mmol), potassium fluoride (0.2g, 2.8mmol), 4-methylphenylboronic acid (0.2g, 1.9mmol) and 50mL dioxane were added to a 100mL reaction flask and reacted at 90 ℃ for 10h under argon. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (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 yellow solid 0.4g with yield 60.3%.
Step D7: preparation of tert-butyl (R) - (1- (5- (4-cyanophenyl) -6- (p-tolyl) benzothiophene-2-carbonyl) piperidin-3-yl) carbamate
Mixing D7(0.4g, 0.82mmol), Pd (OAc) 2 (0.02g, 0.08mmol), X-phos (0.08g, 0.17mmol), 4-cyanophenylboronic acid (0.36g, 2.5mmol), ethylene glycol dimethyl ether (50 mL) and water (5 mL) were added to a 100mL reaction flask and reacted at 70 ℃ for 10h under argon. The reaction mixture was cooled, concentrated, extracted with ethyl acetate (40 mL. times.3), and washed with saturated brine (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 yellow solid 0.15g with yield of 40.3%.
Step D8: preparation of (R) -4- (2- (3-aminopiperidine-1-carbonyl) -6- (p-tolyl) benzo [ b ] thiophen-5-yl) benzonitrile
D8(80.0mg, 0.15mmol) was added to 5ml 6N HCl/MeOH and the reaction stirred at room temperature for 2 h. The solvent was concentrated under reduced pressure, 5ml of water was added, and the pH was adjusted to 10 with saturated sodium hydroxide solution. Ethyl acetate (10 mL. times.3) was extracted, and the ethyl acetate was combined and washed with saturated brine (10 mL. times.3). The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an orange solid (55.7 mg, 86.8% yield).
In vitro pharmacological testing of a portion of the products of the invention
The kit 700120 of Cayman company for purchasing the invention detects the LSD1 inhibitory activity of the partial compound, and the specific operation steps are 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 of the microplate reader, and the intensity of emitted fluorescence at 590nM is detected.
Percent inhibition ═ 100% active wells-sample wells)/100% active wells 100
TABLE 2 nuclear magnetic hydrogen spectrum, enzyme inhibition activity data of examples
Note: in vitro enzyme level Activity test IC 50 Are specified in the following ranges:
A：<0.1μΜ
b: 0.1 μ Μ to <1 μ Μ
C: >1 μ Μ to <50 μ Μ
D：>50μΜ
The compounds of general formula I and pharmaceutically acceptable salts or prodrugs thereof of the present invention can be administered alone, but are usually administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice, and their novel use is illustrated below in the context of methods for the preparation of various pharmaceutical dosage forms of the compounds, e.g., tablets, capsules, injections, aerosols, suppositories, films, drops, liniments and ointments, respectively.
Example 49: tablet formulation
10g of the compound of claim 1 (taking the compound of example 1 as an example) is mixed with 20g of auxiliary materials according to a general pharmaceutical tabletting method, and then the mixture is pressed into 100 tablets, wherein each tablet is 300 mg.
Example 50: capsule preparation
10g of the compound containing the compound in claim 1 (taking the compound in the example 2 as an example) is mixed with 20g of auxiliary materials according to the requirement of a pharmaceutical capsule, and then the mixture is filled into empty capsules, wherein each capsule weighs 300 mg.
Example 51: injection preparation
Using 10g of the compound of claim 1 (exemplified by the compound of example 3), adsorbing with activated carbon, filtering through a 0.65 μm microporous membrane, and filling into nitrogen gas bottles to obtain water-injection preparations, each containing 2mL, and filling 100 bottles in total.
Example 52: aerosol formulation
Dissolving 10g of the compound of claim 1 (example 5) in propylene glycol, adding distilled water and other additives, and making into 500mL of clear solution.
Example 53: suppository
50 suppositories are prepared by grinding 10g of the compound of claim 1 (example 9) with the appropriate amount of glycerin, mixing well, adding molten glycerin gelatin, grinding well, pouring into lubricant-coated molds
Example 54: film agent
Using 10g of the compound containing the compound of claim 1 (in the case of the compound of example 23), polyvinyl alcohol, medicinal glycerin, water and the like were swollen with stirring and then dissolved by heating, and the compound of example 18 was added to the filtrate and dissolved with stirring, and 100 sheets were formed into a film by a film-coating machine.
Example 55: drop pills
10g of the compound containing the compound of claim 1 (taking the compound in example 30 as an example) and 50g of a matrix such as gelatin are heated, melted and mixed uniformly, and then dropped into low-temperature liquid paraffin to prepare 1000 pills.
Example 56: external liniment
The compound of claim 1 (example 35) is mixed with 2.5g of emulsifier and other adjuvants according to conventional pharmaceutical method to obtain 10g, and then mixed with 200mL distilled water.
Example 57: ointment formulation
Prepared by grinding 10g of the compound containing the compound of claim 1 (taking the compound in example 40 as an example), and then uniformly grinding the ground product with 500g of an oily matrix 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 (10)
1. A derivative represented by the general formula (i), and pharmaceutically acceptable salts and stereoisomers thereof:
wherein:
X＝CH 2 or NR, O, S; r is H or C1-C6 alkyl;
R 2 is-CH 2 -, carbonyl or thiocarbonyl;
R 3 is a substituted or unsubstituted 5-10 membered heterocyclic group or-N (R) 4 ) 2 The heterocyclic group contains 1-3 heteroatoms of N, O or S, and the substituent is C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C6 alkylamino;
each R 4 Independently selected from hydrogen, C1-C7 fatty primary amines, C1-C7 fatty secondary amines, C1-C7 fatty tertiary amines;
W 1 and W 2 Independently selected from N, C-H, C-F, C-NH 2 、C-CH 3 ；
R 1 Is optionally substituted or unsubstituted 5-10 membered aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, C1-C6 alkyl, 5-10 membered heterocyclyl, said substituents being C1-C6 alkyl, C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, nitro, amino, 5-10 membered aryl.
2. The derivative of the general formula (I) as claimed in claim 1, and pharmaceutically acceptable salts, stereoisomers thereof,
wherein the content of the first and second substances,
R 3 is a substituted or unsubstituted 5-6 membered heterocyclic group or-N (R) 4 ) 2 SaidThe heterocyclic radical contains 1-2N heteroatoms, and the substituent is C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C6 alkylamino;
each R 4 Independently selected from propylamine, N-methylpropylamine, N-dimethylpropylamine.
3. The derivatives of the general formula (I) as claimed in claim 1 or 2, and pharmaceutically acceptable salts, stereoisomers thereof,
wherein the content of the first and second substances,
R 3 is a substituted or unsubstituted group as follows:
4. a derivative of the general formula (I), as claimed in any one of claims 1 to 3, and pharmaceutically acceptable salts, stereoisomers thereof,
wherein the content of the first and second substances,
X＝NH、O、S、N-CH 3 。
5. the derivative of the general formula (I), and the pharmaceutically acceptable salts, stereoisomers thereof according to any of claims 1 to 4,
wherein the content of the first and second substances,
R 1 is phenyl or naphthyl which is optionally substituted or unsubstituted, and the substituent is C1-C6 alkyl, C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, nitryl, amino or phenyl.
6. The derivatives, and pharmaceutically acceptable salts, stereoisomers thereof,
4- (3- (piperazin-1-ylmethyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((4-aminopiperidin-1-yl) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
(R) -4- (3- ((3-aminopiperidin-1-yl) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((piperidin-4-ylamino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((pyrrolidin-3-ylamino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((4-aminocyclohexyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((piperidin-3-ylamino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-Aminopyrrolidin-1-yl) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
(S) -4- (3- ((3-aminopiperidin-1-yl) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((((1r, 4r) -4-aminocyclohexyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((2-aminoethyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((methyl (2- (methylamino) ethyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((methyl (3- (methylamino) propyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-aminopropyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((4-aminobutyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((5-aminopentyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((6-aminohexyl) amino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((4-methylpiperazin-1-yl) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
4- (3- ((methyl (2- (methylamino) ethyl) amino) methyl) -6- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) benzonitrile
4- (3- ((methyl (3- (methylamino) propyl) amino) methyl) -6- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-Aminopyrrolidin-1-yl) methyl) -6- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-Aminopyrrolidin-1-yl) methyl) -6- (3, 5-difluorophenyl) benzofuran-5-yl) benzonitrile
(R) -4- (3- ((3-aminopiperidin-1-yl) methyl) -6- (3-nitrophenyl) benzofuran-5-yl) benzonitrile
4- (3- ((2- (methylamino) ethylamino) methyl) -6- (3-nitrophenyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-Aminopyrrolidin-1-yl) methyl) -6- (3-nitrophenyl) benzofuran-5-yl) benzonitrile
(R) -4- (3- ((3-aminopiperidin-1-yl) methyl) -6- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) benzonitrile
4- (3- ((3-Aminopyrrolidin-1-yl) methyl) -6- (4-fluorophenyl) benzofuran-5-yl) benzonitrile
4- (3- ((methyl (3- (methylamino) propyl) amino) methyl) -6- (3-nitrophenyl) benzofuran-5-yl) benzonitrile
4- (6- (naphthalen-2-yl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- (3, 5-dimethylphenyl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- (3-fluorophenyl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- ([1,1' -biphenyl ] -4-yl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- (4-ethylphenyl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- (2-fluoro-4-methylphenyl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6-phenyl-3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (6- (1-methyl-1H-indol-5-yl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
4- (3- ((pyrrolidin-3-ylamino) methyl) -6- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) benzonitrile
4- (6- (pyrimidin-5-yl) -3- ((pyrrolidin-3-ylamino) methyl) benzofuran-5-yl) benzonitrile
(S) -4- (3- ((pyrrolidin-3-ylamino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
(R) -4- (3- ((pyrrolidin-3-ylamino) methyl) -6- (p-tolyl) benzofuran-5-yl) benzonitrile
5- (4-cyanophenyl) -N- (piperidin-4-ylmethyl) -6- (p-tolyl) -1H-indole-3-carboxamide
5- (4-cyanophenyl) -1-methyl-N- (piperidin-4-yl) -6- (p-tolyl) -1H-indole-3-carboxamide
(S) -4- (3- (3-aminopiperidine-1-carbonyl) -6- (p-tolyl) -1H-indol-5-yl) benzonitrile
5- (4-cyanophenyl) -1-methyl-N- (piperidin-4-ylmethyl) -6- (p-tolyl) -1H-indole-2-carboxamide
5- (4-cyanophenyl) -1-methyl-N- (piperidin-4-yl) -6- (p-tolyl) -1H-indole-2-carboxamide
(S) -4- (3- (3-aminopiperidine-1-carbonyl) -6- (p-tolyl) benzothien-5-yl) benzonitrile.
7. A process for the preparation of derivatives of general formula (i) as claimed in claim 1, and pharmaceutically acceptable salts and stereoisomers thereof, by the following route:
8. a pharmaceutical composition comprising a derivative according to any one of claims 1 to 6, and pharmaceutically acceptable salts, stereoisomers thereof and a pharmaceutically acceptable carrier or excipient.
9. A pharmaceutical composition comprising a derivative according to any one of claims 1 to 6 and pharmaceutically acceptable salts, stereoisomers and other lysine-specific demethylase 1 inhibitors thereof.
10. Use of the derivative according to any one of claims 1 to 6 and pharmaceutically acceptable salts, stereoisomers thereof or the pharmaceutical composition according to claim 8 or 9 for the preparation of lysine-specific demethylase 1 inhibitors.
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| WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
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