WO2020221376A1 - 一种预防和/或治疗癌症的化合物及其制备方法和应用 - Google Patents

一种预防和/或治疗癌症的化合物及其制备方法和应用 Download PDF

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WO2020221376A1
WO2020221376A1 PCT/CN2020/098472 CN2020098472W WO2020221376A1 WO 2020221376 A1 WO2020221376 A1 WO 2020221376A1 CN 2020098472 W CN2020098472 W CN 2020098472W WO 2020221376 A1 WO2020221376 A1 WO 2020221376A1
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alkyl
cancer
compound
heterocycloalkyl
cycloalkyl
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French (fr)
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何伟
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北京嘉林药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/10—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 aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention relates to the field of medicine, and relates to a compound for preventing and/or treating cancer and a preparation method thereof.
  • BRG1 and BRM are the core ATPase subunits of mammalian chromatin remodeling complex SWI/SNF. They have similar structures and complementary functions.
  • the ATP hydrolase domain of BRG1 can bind and hydrolyze ATP to provide energy, so that the chromatin remodeling complex binds to chromatin and mediates the dissociation of DNA from nucleosomes to regulate gene transcription.
  • the C-terminus of BRG1 is a histone code reader domain, which can specifically recognize acetylated lysine. This process is essential for the binding of the chromatin remodeling complex to the correct chromatin site.
  • BRG1 is involved in the regulation of some transcriptional mutations and tumor development, such as CD44, c-fos, etc.
  • BRG1 is an important tumor suppressor gene in lung cancer, bladder cancer, breast cancer, prostate cancer, gastric cancer and other cancers.
  • Takahiro Oike et al. also reported that BRM protein can be used as a candidate target for the treatment of BRG1-deficient lung cancer.
  • CN105523955A discloses a series of compounds for cancer treatment, especially for non-small cell lung cancer with BRG1 gene deletion.
  • the compounds disclosed therein still have the defects of insufficient activity and poor druggability, especially for 2-(1H- For pyrazol-3-yl)phenol type compounds, the substituents on the pyrazole ring can only be applied to alkyl substituents, which greatly limits the scope of application.
  • the purpose of the present invention is to provide a compound for preventing and/or treating cancer and its preparation method and application.
  • the compound for preventing and/or treating cancer provided by the present invention has high activity and good druggability.
  • the present invention provides a compound of formula (I), and a pharmaceutically acceptable salt, stereoisomer, ether, ester, prodrug or solvate thereof,
  • R 1 , R 2 and R 3 are independently selected from -H, -OH, -halogen, -CN, -OC 0-10 alkyl, -C 1-10 linear or branched alkyl, -N( C 0-10 alkyl) (C 0-10 alkyl), -C 3-10 cycloalkyl, -O heterocycloalkyl or -N heterocycloalkyl, the -CN, -OC 0-10 alkane Group, -C 1-10 straight or branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -C 3-10 cycloalkyl, -O heterocycloalkyl and
  • the H on the C atom in the -N heterocycloalkyl group is independently substituted by the following groups: -SO 2 , -SO 2 N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2
  • R 4 is selected from -halogen, -CN, -OC 0-10 alkyl, -C 1-10 linear/branched alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-10 cycloalkyl, -O heterocycloalkyl or -N heterocycloalkyl, -N heterocyclic aryl, -O heterocyclic aryl, -S heterocyclic aryl or phenyl, the -OC 0-10 alkyl, -C 1-10 linear/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-10 cycloalkyl, -O heterocyclic ring Alkyl or -N heterocycloalkyl, -N heterocyclic aryl, -O heterocyclic aryl, -S heterocyclic aryl, and H on the C atom in phenyl are independently substituted by the following groups: -
  • X is present or not, and when X is present, X is -CH 2 -or -CO-.
  • R 1 , R 2 and R 3 are independently selected from -H, -OH, -halogen, -CN, -C 1-3 linear alkyl, -N (C 0-10 alkyl) (C 0 -10 alkyl) or -C 3-10 cycloalkyl, the -C 1-3 linear alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl) and -C 3-
  • the H on the C atom in the 10 cycloalkyl group is independently substituted by the following groups: -SO 2 , -halogen, -CN, -OCH 2 F, -OCHF 2 , -OCF 3 , -C 1-3 straight chain alkane Group, -O heterocycloalkyl, -N heterocycloalkyl, -N heterocyclic aryl, -O heterocyclic aryl or -S heterocyclic aryl;
  • R 4 is selected from -C 1-4 linear alkyl group, m, n, p, q and t are independently selected from integers between 0-4;
  • R 5 , R 6 , R 9 and R 10 are independently selected from -H, -OH, -halogen, -CN, -CF 3 , -C 1-4 linear alkyl, -N (C 0-10 alkyl ) (C 0-10 alkyl), -C 3-6 cycloalkyl or -SO 2 (C 0-10 alkyl), the -C 1-4 linear alkyl group, -N (C 0-10 Alkyl) (C 0-10 alkyl), -C 3-6 cycloalkyl and -SO 2 (C 0-10 alkyl), the H on the C atom is independently substituted by the following groups: -OH,- Halogen, -CN, -SO 2 , -OCHF 2 , -OCF 3 or -CF 3 ;
  • R 7 and R 8 are independently selected from -H, -C 1-4 linear alkyl, C 3-6 cycloalkyl, -CON (C 0-10 alkyl) (C 0-10 alkyl) or- CO (C 0-10 alkyl), the -C 1-4 linear alkyl, C 3-6 cycloalkyl, -CON (C 0-10 alkyl) (C 0-10 alkyl),-
  • the H on the C atom in CO (C 0-10 alkyl) is independently substituted with the following groups: -OH, -halogen, -CN, -SO 2 , -OCHF 2 , -OCF 3 or -CF 3 .
  • R 1 and R 3 are selected from H, R 2 is selected from halogen, and the halogen is F;
  • n is selected from 0, 1, or 2
  • m, p, q, and t are independently selected from 0, 1, or 2.
  • the R 4 is selected from -CH 3 ,
  • the specific compound structure is as follows:
  • the present invention provides a pharmaceutical composition, comprising the compound of formula (I) described in the above technical scheme, and pharmaceutically acceptable salts, stereoisomers, ethers, esters, prodrugs or solvates, and pharmaceutically acceptable Acceptable excipients.
  • the present invention provides the compound of formula (I) described in the above technical solution, and a pharmaceutically acceptable salt, stereoisomer, ether, ester, prodrug or solvate thereof, or the pharmaceutical composition described in the above technical solution Application in the prevention and/or treatment of cancer.
  • the present invention provides the compound of formula (I) described in the above technical solution, and a pharmaceutically acceptable salt, stereoisomer, ether, ester, prodrug or solvate thereof, or the pharmaceutical composition described in the above technical solution Application in the preparation of drugs for preventing and/or treating cancer.
  • the cancer includes lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, pancreatic islet cell Carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia or lymphoid malignancy, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell Lung cancer, adenocarcinoma, lung cancer, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, stomach cancer, bowel cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, meta
  • the present invention provides compounds of formula (I), and pharmaceutically acceptable salts, stereoisomers, ethers, esters, prodrugs or solvates thereof.
  • the compound for preventing and/or treating cancer provided by the present invention has high activity and good druggability.
  • One aspect of the present invention provides compounds of formula (I), and pharmaceutically acceptable salts, stereoisomers, ethers, esters, prodrugs or solvates thereof,
  • R 1 , R 2 and R 3 are independently selected from -H, -OH, -halogen, -CN, -OC 0-10 alkyl, -C 1-10 linear/branched alkyl, -N( C 0-10 alkyl) (C 0-10 alkyl), -C 3-10 cycloalkyl, -O heterocycloalkyl or -N heterocycloalkyl, where the H on the C atom can be replaced by the following groups Substitution: -SO 2 , -SO 2 N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) COO (C 0-10 alkyl), -OCON (C 0-10 alkyl
  • R 4 is selected from -halogen, -CN, -OC 0-10 alkyl, -C 1-10 linear/branched alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -N heteroaryl, -O heteroaryl, -S heteroaryl, phenyl, where C atom
  • the H above can be substituted by the following groups: -SO 2 , -SO 2 C (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) (C 0-10 Alkyl), -CO (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -halogen, -CN, -OCH 2 F, -OCHF 2 , -OCF 3 , -OC 0-10
  • X may be present or not. When X is present, X is -CH 2 -or -CO-.
  • R 1 , R 2 and R 3 are independently selected from -H, -OH, -halogen, -CN, -C 1-3 linear alkyl, -N (C 0-10 alkyl) ( C 0-10 alkyl), -C 3-10 cycloalkyl, wherein the H on the C atom can be substituted by the following groups: -SO 2 , -halogen, -CN, -OCH 2 F, -OCHF 2 ,- OCF 3 , -C 1-3 linear alkyl, -O heterocycloalkyl, -N heterocycloalkyl, -N heterocyclic aryl, -O heterocyclic aryl, or -S heterocyclic aryl.
  • R 1 and R 3 are H, and R 2 is selected from halogen. More preferably, the halogen is F.
  • R 4 is selected from C 1-4 linear alkyl groups, m, n, p, q and t are independently selected from integers between 0 and 4, preferably, selected from integers between 0 and 2, when m, n, p, q or t is 0, it represents all The defined group does not exist. More preferably, n is selected from 0, 1 or 2, and m, p, q and t are independently selected from 0, 1 or 2.
  • R 5 , R 6 , R 9 and R 10 are independently selected from -H, -OH, -halogen, -CN, -CF 3 , -C 1-4 linear alkyl, -N (C 0-10 alkyl ) (C 0-10 alkyl), -C 3-6 cycloalkyl, -SO 2 (C 0-10 alkyl), wherein the H on the C atom can be substituted by the following groups: -OH, -halogen, -CN, -SO 2 , -OCHF 2 , -OCF 3 or -CF 3 .
  • R 7 and R 8 are independently selected from -H, -C 1-4 linear alkyl, -C 3-6 cycloalkyl, -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl), where the H on the C atom can be substituted by the following groups: -OH, -halogen, -CN, -SO 2 , -OCHF 2 , -OCF 3 or -CF 3 .
  • the R 4 is selected from -CH 3 ,
  • the compound of formula (I) of the present invention can be carried out using the following reaction route:
  • the R 2 is selected from -H, -OH, -halogen, -CN, -OC 0-10 alkyl, -C 1-10 linear/branched alkyl, -N (C 0-10 alkyl ) (C 0-10 alkyl), -C 3-10 cycloalkyl, -O heterocycloalkyl or -N heterocycloalkyl, wherein the H on the C atom can be substituted by the following groups: -SO 2 , -SO 2 N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -CON (C 0-10 alkyl) Group) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) COO (C 0-10 alkyl) , -OCON (C 0-10 alkyl,
  • R 4 is selected from -halogen, -CN, -OC 0-10 alkyl, -C 1-10 linear/branched alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -N heteroaryl, -O heteroaryl, -S heteroaryl or phenyl, wherein C atom
  • the H above can be substituted by the following groups: -SO 2 , -SO 2 C (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) (C 0-10 Alkyl), -CO (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -halogen, -CN, -OCH 2 F, -OCHF 2 , -OCF 3 , -OC 0
  • n and p are independently selected from an integer between 0 and 4.
  • n and p are independently selected from 0, 1, or 2.
  • R 6 is selected from -H, -OH, -halogen, -CN, -CF 3 , -C 1-4 linear alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl),- C 3-6 cycloalkyl, -SO 2 (C 0-10 alkyl), where the H on the C atom can be substituted by the following groups: -OH, -halogen, -CN, -SO 2 , -OCHF 2 , -OCF 3 or -CF 3 .
  • R 3 is selected from -H, -OH, -halogen, -CN, -OC 0-10 alkyl, -C 1-10 linear/branched chain alkyl, -N (C 0-10 alkyl) ( C 0-10 alkyl), -C 3-10 cycloalkyl, -O heterocycloalkyl or -N heterocycloalkyl, wherein the H on the C atom can be substituted by the following groups: -SO 2 , -SO 2 N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2 (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) COO (C 0-10 alkyl),- OCON (C 0-10 alkyl) (C 0-10 alky
  • R 4 is selected from -halogen, -CN, -OC 0-10 alkyl, -C 1-10 linear/branched alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -N heterocyclic aromatic, -O heterocyclic aromatic, -S heterocyclic aromatic or phenyl, where the C atom is The H can be substituted by the following groups: -SO 2 , -SO 2 C (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) (C 0-10 alkyl) Group), -CO (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -halogen, -CN, -OCH 2 F, -OCHF 2 ,- OCF 3 , -OC 0
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts or base addition salts.
  • the acid addition salt includes, but is not limited to, a salt from an inorganic acid or an organic acid.
  • the inorganic acid salt includes a salt of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, or phosphonic acid.
  • Salts of organic acids include salts of aliphatic monocarboxylic acids, dicarboxylic acids, or phenyl substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic or aromatic sulfonic acids.
  • these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate , Hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberic acid, decanoate Diacid salt, fumarate, maleate, mandelic acid, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, Benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartaric acid, methanesulfonate or amino acid-containing salt; the amino acid-containing salt includes arginine Acid salt, gluconate or galacturonate.
  • Acid addition salts can be prepared by contacting the free base with a sufficient amount of the desired acid in a conventional manner to form a salt.
  • the free base form can be regenerated by contacting the salt with a base, and the free base can be isolated in a conventional manner.
  • the alkali addition salt is formed by the compound of formula (I) and a metal or an amine; the metal includes an alkali metal or alkaline earth metal hydroxide; and the amine is an organic amine.
  • Ions of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium.
  • suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N- Methyl glucosamine or procaine.
  • Base addition salts can be prepared by contacting the free acid with a sufficient amount of the desired base to form a salt in a conventional manner. The free acid form can be regenerated by contacting the salt with an acid, and the free acid can be separated in a conventional manner.
  • stereoisomers described in the present invention include enantiomers, diastereomers or geometric isomers.
  • Some of the compounds of the present invention have cycloalkyl groups, which can be substituted on more than one carbon atom. In this case, all their geometric forms, including cis and trans, and mixtures thereof, fall within the scope of the present invention. Within range.
  • solvate in the present invention refers to the physical combination of the compound of the present invention and one or more solvent molecules.
  • This physical bonding includes various degrees of ionic or covalent bonding, including hydrogen bonding.
  • solvates can be separated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • Solvate includes solution-phase or isolatable solvates. Representative solvates include ethanolates, methanolates and the like.
  • “Hydrate” is one or more solvent molecule is H 2 O solvate.
  • the prodrug in the present invention refers to the form of the compound of formula (1) that is suitable for administration to patients without excessive toxicity, irritation and allergic reactions and is effective for its application purpose, including acetal, ester and zwitterionic forms.
  • the prodrug is transformed in vivo (for example by hydrolysis in blood) to obtain the parent compound of formula (1).
  • the present invention further provides a pharmaceutical composition, which comprises a compound of the present invention (for example, a compound of formula I, and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs and solvates thereof), and a pharmaceutically acceptable carrier , Diluent or excipient.
  • a pharmaceutical composition which comprises a compound of the present invention (for example, a compound of formula I, and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs and solvates thereof), and a pharmaceutically acceptable carrier , Diluent or excipient.
  • the pharmaceutical composition contains a therapeutically effective amount of a compound of the invention.
  • the compounds of the present invention can be formulated as pharmaceutical compositions in the following forms: syrups, elixirs, suspensions, powders, granules, tablets, capsules, lozenges, aqueous solutions, creams, ointments, lotions, gels Or emulsion, etc.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders packaged in vials or ampoules.
  • the unit dosage form can be a capsule, a tablet, or it can be the appropriate number of any of these dosage forms in a packaged form.
  • the amount of the active ingredient in the unit dose formulation can be changed or adjusted from 0.001 mg to 1000 mg, depending on the specific application and potency of the active ingredient. If desired, the composition may also contain other suitable therapeutic agents.
  • the pharmaceutically acceptable carrier depends in part on the specific composition to be administered and the specific method of administration of the composition. Therefore, there are various suitable formulations for the pharmaceutical composition of the present invention.
  • the compounds of the present invention are formulated as aerosols (ie, they can be "nebulized") to be administered via inhalation.
  • the aerosol can be placed in an acceptable pressurized propellant, which preferably includes dichlorodifluorohexane, propane or nitrogen.
  • Formulations suitable for parenteral administration such as, for example, administration by intravenous, intramuscular, intradermal and subcutaneous routes include aqueous and non-aqueous isotonic sterile injections, which may contain antioxidants, buffers, bacteriostatic agents, And solutes that make the preparation isotonic with the blood of the recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents, solubilizers, thickeners, stabilizers and preservatives.
  • the composition can be administered by, for example, intravenous infusion, oral, topical, intraperitoneal, intravesical and intrathecal administration.
  • the formulations of the compounds may be presented in unit-dose or multi-dose sealed containers such as ampoules and vials. Solutions and suspensions for injection can be prepared from sterile powders, granules and tablets of the type previously described.
  • the dose administered to the subject should be sufficient to produce a beneficial therapeutic response in the subject over time.
  • the dosage is determined by the efficacy of the specific compound used and the condition of the subject, as well as the body weight or body surface area of the subject to be treated. The size of the dose will depend on the existence, nature and extent of any adverse side effects that accompany the administration of the specific compound in the specific subject.
  • the physician can evaluate factors such as the circulating plasma level of the compound, compound toxicity, and/or disease progression.
  • the present invention also provides the use of compounds of formula (I), and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs and solvates thereof in the prevention and/or treatment of cancer.
  • the present invention also provides the use of compounds of formula (I), and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs and solvates thereof in cancer immunotherapy.
  • the present invention also provides the use of the compound of formula (I), and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs and solvates thereof in the preparation of drugs for preventing and/or treating cancer.
  • the cancer of the present invention includes lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, pancreatic islet cell carcinoma , Mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia or lymphoid malignancies, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer , Adenocarcinoma, lung cancer, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, stomach cancer, bowel cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, metastatic breast Cancer
  • C 0-10 alkyl refers to H
  • C 0-10 alkyl includes H, C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 Alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl.
  • C 1-10 alkylene in the present invention includes C 1 alkylene, C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene Group, C 7 alkylene, C 8 alkylene, C 9 alkylene, C 10 alkylene.
  • C 3-10 cycloalkyl in the present invention includes C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl Group, C 9 cycloalkyl, C 10 cycloalkyl.
  • C 1-6 alkyl in the present invention includes HC 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • C 1-6 linear alkyl group in the present invention includes methyl, ethyl, C 3 linear alkyl, C 4 linear alkyl, C 5 linear alkyl, C 6 linear alkyl .
  • C 3-6 cycloalkyl in the present invention includes C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl and C 6 cycloalkyl.
  • halogen in the present invention includes fluorine, chlorine, bromine and iodine.
  • heterocycloalkyl in the present invention refers to a non-aromatic saturated monocyclic or polycyclic ring system containing 3-10 ring atoms, preferably 5-10 ring atoms, wherein one or more of the ring atoms is not carbon Atoms, but for example nitrogen, oxygen or sulfur atoms.
  • Preferred heterocycloalkyl groups contain 5-6 ring atoms.
  • the prefix aza, oxa or thia before heterocycloalkyl means that at least one nitrogen, oxygen or sulfur atom is used as a ring atom.
  • Representative monocyclic heterocycloalkyl groups include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolane, 1,4- Dioxanyl, tetrahydrofuranyl, tetrahydrothienyl or tetrahydrothiopyranyl.
  • heterocyclic aromatic group in the present invention refers to an aromatic monocyclic or polycyclic ring system containing 5-14 ring atoms, preferably 5-10 ring atoms, wherein one or more ring atoms are not carbon atoms, and It is, for example, a nitrogen, oxygen or sulfur atom.
  • Preferred heterocyclic aromatic groups contain 5-6 ring atoms.
  • heterocyclic aromatic groups include pyrazinyl, furyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl , Pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, 2,3-diaza naphthyl, imidazo[1,2 -a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, Thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridyl, imidazo
  • Me in the present invention stands for the abbreviation of methyl.
  • Ph in the present invention stands for the abbreviation of phenyl.
  • Boc in the present invention stands for tert-butoxycarbonyl.
  • unit dosage form refers to physically discrete units suitable as a single dose for human subjects and other mammals, each unit containing a combination of a required pharmaceutical carrier and a calculated process during treatment. A predetermined amount of active substance that produces the desired preventive or therapeutic effect.
  • excipient in the present invention means that the ingredient has no biological activity or other undesirable impurities.
  • the ingredient can be incorporated into the disclosed pharmaceutical preparations and given to patients, but does not cause significant adverse biological effects or in a harmful manner. Interaction with other ingredients contained in the formulation.
  • treatment includes inhibiting, delaying, alleviating, attenuating, limiting, alleviating or relieving a disease, disorder, condition or state, its occurrence and/or progress, and/or its symptoms.
  • prevention includes reducing the risk of suffering from, infecting or experiencing a disease, disorder, condition or condition, its occurrence and/or progress, and/or its symptoms.
  • the term "about” in the present invention usually means +/-5% of the stated value, more usually +/-4% of the stated value, more usually +/-3% of the stated value, more usually Refers to +/- 2% of the stated value, more usually +/- 1% of the stated value, more usually +/- 0.5% of the stated value.
  • the compound R 4 -NH 2 (1.2eq), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 1.2eq), N,N-diisopropylethylamine (DIPEA, 3eq) was added to the THF solution of compound 24 (1eq), heated to 50°C, reacted for 6h, after the reaction, spin dry the solvent, add appropriate amount of distilled water , Extracted with dichloromethane. The crude product was purified by silica gel column chromatography to obtain compound 25.
  • BBr 3 (5eq) was added to the dichloromethane solution of compound 29 (1eq), reacted at room temperature for 2h, quenched by adding t sodium bicarbonate solution, and extracted with dichloromethane. The crude product was purified by silica gel column chromatography to obtain compounds BRM2-53-64, 67-68, 70.
  • Compound 14 was reduced by Pd/C in hydrogen to obtain a solid dissolved in dichloromethane.
  • Triphosgene and triethylamine 2.0eq were added to the above solution, reacted under reflux, and spin-dried, the resultant was subjected to silica gel column chromatography
  • Compound 15 was obtained by purification.
  • An aqueous solution of lithium hydroxide (LiOH) was added to the ethanol solution of the obtained compound, reacted at room temperature, the organic solvent was spin-dried, the pH was adjusted to 2.0, extracted with ethyl acetate, and the solvent was spin-dried to obtain compound 16.
  • Example 4 Cell activity test of the compounds prepared in Examples 1-3
  • CCK-8 method was used to test the cell proliferation toxicity of the molecule.
  • CCK-8 reagent contains WST-8: Chemical name: 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonate Acid benzene)-2H-tetrazole monosodium salt, which is reduced by dehydrogenase in cell mitochondria under the action of electron carrier 1-methoxy-5-methylphenazine dimethyl sulfate (1-MethoxyPMS) Highly water-soluble yellow formazan product (Formazan). The amount of formazan produced is directly proportional to the number of living cells.
  • an enzyme-linked immunoassay to measure the light absorption value at 450nm wavelength, it can indirectly reflect the number of living cells.
  • This method has been widely used in the activity detection of some biologically active factors, large-scale anti-tumor drug screening, cell proliferation tests, cytotoxicity tests, and drug sensitivity tests.
  • the CCK-8 method has high detection sensitivity, good repeatability, and low toxicity to cells. Therefore, the CCK-8 method is used to test the toxicity of molecules to cell proliferation.
  • the CCK-8 method is used to detect cell proliferation and toxicity of molecules with relatively good TSA test results.
  • IC 50 on the basis of Hela cells or U2OS cells (BRG1 + / BRM +) cytotoxic molecules tested at a concentration of IC 50 to determine the effects of off-target molecule.
  • Example 5 IC 50 value test of the compounds prepared in Examples 1-3
  • Collect the logarithmic phase cells adjust the cell suspension concentration, add 100uL to each well of a 96-well plate, and pave the plate to adjust the density of the cells to be tested to 1000-10000 wells (the edge holes are filled with sterile PBS, and different selections are made according to the different cells.

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Abstract

本发明提供了式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，所述的化合物能够用于预防和/或治疗癌症，

Description

一种预防和/或治疗癌症的化合物及其制备方法和应用
本申请要求于2019年04月29日提交中国专利局、申请号为CN201910357130.3、发明名称为“一种预防和/或治疗癌症的化合物及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医药领域，涉及一种预防和/或治疗癌症的化合物及其制备方法。
背景技术
BRG1和BRM是哺乳动物染色质重构复合物SWI/SNF的核心ATP酶亚单位，两者结构相似、功能互补。BRG1的ATP水解酶结构域可以结合并水解ATP提供能量，使染色质重构复合物结合到染色质上介导DNA从核小体上解离从而调节基因的转录。BRG1的C-末端是一个组蛋白密码的reader结构域，它可以特异性的识别乙酰化修饰的赖氨酸，该过程对于染色质重构复合物结合到正确的染色质位点至关重要。
已有研究认为，BRG1参与调控一些和肿瘤发生发展转录突变，如CD44、c-fos等，而且在肺癌、膀胱癌、乳腺癌、前列腺癌、胃癌等癌症中，BRG1是发病重要的抑癌基因。另外，Takahiro Oike等人也报道BRM蛋白可以作为BRG1缺乏型肺癌治疗的候选靶点。通过免疫组化分析方法显示，约10％的非小细胞肺癌(NSCLCs)患者中存在BRG1-缺乏和BRM过表达的现象，因此证明针对BRM靶点的疗法具有可行性，并且BRG1的缺失也发生在其他癌症中，包括胰腺，皮肤和脑癌，例如BRG1最近被确定为在成神经管细胞瘤中经常突变的基因，由此针对BRM蛋白的靶向治疗可适用于治疗各种癌症。
CN105523955A公开了一系列用于癌症治疗的化合物，特别是对于BRG1基因缺失的非小细胞肺癌具有治疗作用，然而其中披露的化合物仍然存在活性不足以及成药性差的缺陷，特别是对于2-(1H-吡唑-3-基)苯酚 类型的化合物而言，吡唑环上的取代基仅能够适用于烷基取代基团，极大的限制了应用范围。
发明内容
本发明的目的在于提供一种预防和/或治疗癌症的化合物及其制备方法和应用。本发明提供的预防和/或治疗癌症的化合物活性高且成药性好。
为了解决上述技术问题，本发明采用的技术方案是：
本发明提供了一种式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物，
Figure PCTCN2020098472-appb-000001
其中，R 1、R 2和R 3独立的选自-H、-OH、-卤素、-CN、-OC 0-10烷基、-C 1-10直链或支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-10环烷基、-O杂环烷基或-N杂环烷基，所述-CN、-OC 0-10烷基、-C 1-10直链或支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-10环烷基、-O杂环烷基和-N杂环烷基中的C原子上的H独立地被以下基团取代：-SO 2、-SO 2N(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)SO 2(C 0-10烷基)、-CON(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)CO(C 0-10烷基)、-N(C 0-10烷基)COO(C 0-10烷基)、-OCON(C 0-10烷基)(C 0-10烷基)、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-OC 0-10烷基、C 3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基；
R 4选自-卤素、-CN、-OC 0-10烷基、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、C 3-10环烷基、-O杂环烷基或-N杂环烷基、-N杂环芳香基、-O杂环芳香基、-S杂环芳香基或苯基，所述-OC 0-10烷基、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、C 3-10环烷基、-O杂环烷基或-N杂环烷基、-N杂环芳香基、-O杂环芳香基、-S杂环芳香基和苯基中的C原子上的H独立地被以下基团取代：-SO 2、-SO 2C(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)(C 0-10烷基)、-CO(C 0-10烷基)、-N(C 0-10烷基)CO(C 0-10烷基)、 -卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-OC 0-10烷基、-C 3-10环烷基、-O杂环烷基、-N杂环烷基、-苯基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基；
X存在或不存在，当X存在时，X为-CH 2-或-CO-。
优选的，
当X不存在时，所述化合物的结构通式为：
Figure PCTCN2020098472-appb-000002
当X为-CH 2-时，所述化合物的结构通式为：
Figure PCTCN2020098472-appb-000003
当X为-CO-时，所述化合物的结构通式为：
Figure PCTCN2020098472-appb-000004
优选的，R 1、R 2和R 3独立的选自-H、-OH、-卤素、-CN、-C 1-3直链烷基、-N(C 0-10烷基)(C 0-10烷基)或-C 3-10环烷基，所述-C 1-3直链烷基、-N(C 0-10烷基)(C 0-10烷基)和-C 3-10环烷基中的C原子上的H独立地被以下基团取代：-SO 2、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-C 1-3直链烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基；
R 4选自-C 1-4直链烷基、
Figure PCTCN2020098472-appb-000005
Figure PCTCN2020098472-appb-000006
m、n、p、q和t独立的选自0-4之间的整数；
R 5、R 6、R 9和R 10独立的选自-H、-OH、-卤素、-CN、-CF 3、-C 1-4直链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-6环烷基或-SO 2(C 0-10烷基)，所述-C 1-4直链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-6环烷基和-SO 2(C 0-10烷基)中C原子上的H独立地被以下基团取代：-OH、-卤素、-CN、-SO 2、-OCHF 2、-OCF 3或-CF 3；
R 7和R 8独立的选自-H、-C 1-4直链烷基、C 3-6环烷基、-CON(C 0-10烷基)(C 0-10烷基)或-CO(C 0-10烷基)，所述-C 1-4直链烷基、C 3-6环烷基、-CON(C 0-10烷基)(C 0-10烷基)、-CO(C 0-10烷基)中C原子上的H独立地被以下基团取代：-OH、-卤素、-CN、-SO 2、-OCHF 2、-OCF 3或-CF 3。
优选的，R 1和R 3选自H，R 2选自卤素，所述卤素为F；
n选自0、1或2，m、p、q和t独立的选自0、1或2。
优选的，所述R 4选自-CH 3、
Figure PCTCN2020098472-appb-000007
Figure PCTCN2020098472-appb-000008
Figure PCTCN2020098472-appb-000009
优选的，具体化合物结构如下：
Figure PCTCN2020098472-appb-000010
Figure PCTCN2020098472-appb-000011
本发明提供了一种药物组合物，包括上述技术方案所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物以及药学上可接受的辅料。
本发明提供了上述技术方案所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物或上述技术方案所述的药物组合物在预防和/或治疗癌症中的应用。
本发明提供了上述技术方案所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物或上述技术方案所述的 药物组合物在制备预防和/或治疗癌症的药物中的应用。
优选的，所述的癌症包括淋巴瘤、母细胞瘤、髓母细胞瘤、视网膜母细胞瘤、肉瘤、脂肪肉瘤、滑膜细胞肉瘤、神经内分泌肿瘤、类癌肿瘤、胃泌素瘤、胰岛细胞癌、间皮瘤、神经鞘瘤、听神经瘤、脑膜瘤、腺癌、黑素瘤、白血病或淋巴样恶性肿瘤、鳞状细胞癌、上皮鳞状细胞癌、肺癌、小细胞肺癌、非小细胞肺癌、腺癌肺癌、肺鳞癌、腹膜癌、肝细胞癌、胃癌、肠癌、胰腺癌、成胶质细胞瘤、子宫颈癌、卵巢癌、肝癌、膀胱癌、肝癌、乳腺癌、转移性乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌、梅克尔细胞癌、食管癌、胆道肿瘤、头颈部癌或血液恶性肿瘤。
本发明提供了式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物。本发明提供的预防和/或治疗癌症的化合物活性高且成药性好。
具体实施方式
下面结合实施例对本发明进一步说明。
本发明的一个方面提供式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物，
Figure PCTCN2020098472-appb-000012
其中，R 1、R 2和R 3独立的选自-H、-OH、-卤素、-CN、-OC 0-10烷基、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-10环烷基、-O杂环烷基或-N杂环烷基，其中C原子上的H可被以下基团取代：-SO 2、-SO 2N(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)SO 2(C 0-10烷基)、-CON(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)CO(C 0-10烷基)、-N(C 0-10烷基)COO(C 0-10烷基)、-OCON(C 0-10烷基)(C 0-10烷基)、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-OC 0-10烷基、C 3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂 环芳香基；
R 4选自-卤素、-CN、-OC 0-10烷基、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基、-S杂环芳香基、苯基，其中C原子上的H可被以下基团取代：-SO 2、-SO 2C(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)(C 0-10烷基)、-CO(C 0-10烷基)、-N(C 0-10烷基)CO(C 0-10烷基)、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-OC 0-10烷基、-C 3-10环烷基、-O杂环烷基、-N杂环烷基、-苯基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基；
X可以存在或不存在，当X存在时，X为-CH 2-或-CO-。
当X不存在时，所述化合物的结构通式为：
Figure PCTCN2020098472-appb-000013
当X为-CH 2-时，所述化合物的结构通式为：
Figure PCTCN2020098472-appb-000014
当X为-CO-时，所述化合物的结构通式为：
Figure PCTCN2020098472-appb-000015
优选的，其中，R 1、R 2和R 3独立的选自-H、-OH、-卤素、-CN、-C 1-3直链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-10环烷基，其中C原子上的H可被以下基团取代：-SO 2、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-C 1-3直链烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基。
在本发明的优选实施例中，R 1、R 3为H，R 2选自卤素，更优选的，所述卤素为F。
R 4选自C 1-4直链烷基、
Figure PCTCN2020098472-appb-000016
Figure PCTCN2020098472-appb-000017
m、n、p、q和t独立的选自0-4之间的整数，优选的，选自0-2之间的整数，当m、n、p、q或t为0时，代表所限定的基团不存在。更优选的，n选自0、1或2，m、p、q和t独立的选自0、1或2。
R 5、R 6、R 9和R 10独立的选自-H、-OH、-卤素、-CN、-CF 3、-C 1-4直链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-6环烷基、-SO 2(C 0-10烷基)，其中C原子上的H可被以下基团取代：-OH、-卤素、-CN、-SO 2、-OCHF 2、-OCF 3或-CF 3。
R 7和R 8独立的选自-H、-C 1-4直链烷基、-C 3-6环烷基、-CON(C 0-10烷基)(C 0-10烷基)、-CO(C 0-10烷基)，其中C原子上的H可被以下基团取代：-OH、-卤素、-CN、-SO 2、-OCHF 2、-OCF 3或-CF 3。
在本发明的优选实施方式中，所述R 4选自-CH 3、
Figure PCTCN2020098472-appb-000018
Figure PCTCN2020098472-appb-000019
Figure PCTCN2020098472-appb-000020
在本发明更具体实施方式中，提供如下的具体化合物：
Figure PCTCN2020098472-appb-000021
Figure PCTCN2020098472-appb-000022
Figure PCTCN2020098472-appb-000023
本发明所述的式(I)的化合物可以采用如下的反应路线进行：
路线1：2,3-二氢-4(1H)-喹唑啉酮类(BRM246-52,65-66,69,71-72)的合成
Figure PCTCN2020098472-appb-000024
其中，所述R 2选自-H、-OH、-卤素、-CN、-OC 0-10烷基、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-10环烷基、-O杂环烷基或-N杂环烷基，其中C原子上的H可被以下基团取代：-SO 2、-SO 2N(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)SO 2(C 0-10烷基)、-CON(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)CO(C 0-10烷基)、-N(C 0-10烷基)COO(C 0-10烷基)、-OCON(C 0-10烷基)(C 0-10烷基)、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-OC 0-10烷基、-C 3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基。
R 4选自-卤素、-CN、-OC 0-10烷基、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基、-S杂环芳香基或苯基，其中C原子上的H可被以下基团取代：-SO 2、-SO 2C(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)(C 0-10烷基)、-CO(C 0-10烷基)、-N(C 0-10烷基)CO(C 0-10烷基)、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-OC 0-10烷基、-C 3-10环烷基、-O杂环烷基、-N杂环烷基、-苯基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基。
路线2：2,3-二氢-4(1H)-喹唑啉酮类(BRM253-64,67-68,70)的合成
Figure PCTCN2020098472-appb-000025
其中，n和p独立的选自0-4之间的整数，优选的，n和p独立的选自0、1或2。
R 6选自-H、-OH、-卤素、-CN、-CF 3、-C 1-4直链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-6环烷基、-SO 2(C 0-10烷基)，其中C原子上的H可被以下基团取代：-OH、-卤素、-CN、-SO 2、-OCHF 2、-OCF 3或-CF 3。
路线3：亚苯甲酰基脲系列化合物(GL110-122)的合成
Figure PCTCN2020098472-appb-000026
其中，R 3选自-H、-OH、-卤素、-CN、-OC 0-10烷基、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-10环烷基、-O杂环烷基或-N杂环烷基，其中C原子上的H可被以下基团取代：-SO 2、-SO 2N(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)SO 2(C 0-10烷基)、-CON(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)CO(C 0-10烷基)、-N(C 0-10烷基)COO(C 0-10烷基)、-OCON(C 0-10烷基)(C 0-10烷基)、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-OC 0-10烷基、-C 3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基。
R 4选自-卤素、-CN、-OC 0-10烷基、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、C 3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基、-S杂环芳香基或苯基，其中C原子上的H可被以下基团取代：-SO 2、-SO 2C(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)(C 0-10烷基)、-CO(C 0-10烷基)、-N(C 0-10烷基)CO(C 0-10烷基)、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-OC 0-10烷基、-C 3-10环烷基、-O杂环烷基、-N杂环烷基、-苯基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基。
本发明所述化合物的药学上可接受的盐中包括酸加成盐或碱加成盐。
所述的酸加成盐包括但是不限于来自无机酸或有机酸的盐，所述无机 酸的盐包括盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸或膦酸的盐，所述有机酸的盐包括脂肪族单羧酸、二羧酸或苯基取代的链烷酸、羟基链烷酸、链烷二酸、芳香酸、脂肪族或芳香族磺酸的盐。因此，这些盐包括但是不限于硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、盐酸盐、氢溴酸盐、碘酸盐、乙酸盐、丙酸盐、辛酸盐、异丁酸盐、乙二酸盐、丙二酸盐、琥珀酸盐、辛二酸、癸二酸盐、富马酸盐、马来酸盐、苦杏仁酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、酞酸盐、苯磺酸盐、甲苯磺酸盐、苯基乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸、甲磺酸盐或含氨基酸的盐；所述含氨基酸的盐包括精氨酸盐、葡糖酸盐或半乳糖醛酸盐。酸加成盐可以通过以常规方式使游离碱与足够量的所需酸接触形成盐的方式制备。可通过使盐与碱接触重新生成游离碱形式，并且以常规方式分离该游离碱。
所述的碱加成盐由所述式(I)的化合物与金属或者胺形成；所述金属包括碱金属或碱土金属的氢氧化物；所述胺为有机胺。用作阳离子的金属的离子包括但是不限于钠、钾、镁、和钙。适当的胺的例子包括但是不限于N,N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺(乙烷-1,2-二胺)、N-甲基葡糖胺或普鲁卡因。碱加成盐可通过以常规方式使游离酸与足够量的所需碱接触形成盐的方式制备。可通过使盐与酸接触重新生成游离酸形式，并且以常规方式分离游离酸。
本发明所述的立体异构体包括对映体、非对映体或几何异构体的形式存在。本发明的一些化合物具有环烷基，其可在超过一个碳原子上被取代，在这种情况下，其所有的几何形式，包括顺式和反式，及其混合物，都处在本发明的范围内。
本发明所述的溶剂化物是指本发明的化合物与一种或多种溶剂分子的物理结合。该物理结合包括各种程度的离子或共价键合，包括氢键合。在某些情况下，溶剂化物可被分离出来，例如当一个或多个溶剂分子掺入到结晶固体的晶格中。“溶剂化物”包括溶液相的或可分离的溶剂化物。代表性的溶剂化物包括乙醇化物、甲醇化物等。“水合物”是其中一个或多个 溶剂分子为H 2O的溶剂化物。
本发明所述的前药指适于对患者给药的无过分毒性、刺激性和变态反应等的并且对其应用目的有效的式(1)化合物形式，包括缩醛、酯和两性离子形式。前药在体内转化(例如通过在血液中水解)得到式(1)的母体化合物。
本发明另外提供了药物组合物，其包含本发明的化合物(例如式I化合物，及其药学上可接受的盐、立体异构体、酯、前药和溶剂化物)，以及可药用的载体、稀释剂或赋形剂。优选地，药物组合物包含治疗有效量的本发明的化合物。
本发明的化合物可以配制为以下形式的药物组合物：糖浆剂、酏剂、悬浮剂、粉剂、颗粒剂、片剂、胶囊、锭剂、水溶液、霜剂、膏剂、洗液剂、凝胶剂或乳剂等。
药物制剂优选为单位剂型。在这种形式中，该制剂被再分成包含适当的量的活性组分的单位剂量。单位剂型可以是包装好的制剂，该包装含有离散的量的制剂，诸如包装在小瓶或者安瓿中的片剂、胶囊和粉剂。另外，单位剂型可以是胶囊，片剂或者其可以是在包装形式中的适当数目的任何这些剂型。
单位剂量制剂中活性组分的量可从0.001毫克到1000毫克之间改变或调整，根据活性组分的具体应用和效力而定。如果需要，组合物还可包含其它适合的治疗剂。
可药用载体部分地根据给用的具体组合物而定，并根据组合物的具体给药方法而定。因此，本发明的药物组合物存在各种适当的制剂。
本发明的化合物，单独或与其它适当的组分结合，被制成气雾剂(即，它们可被“雾化”)以经由吸入被给药。气雾剂可被置于可接受的被加压的发射剂中，所述发射剂优选包括二氯二氟己烷、丙烷或氮气。
适于非肠胃给药诸如例如通过静脉内、肌内、皮内和皮下途径给药的制剂包括含水和非水的等渗无菌注射液，其可包含抗氧化剂，缓冲剂，抑菌剂，和使制剂与接受者的血液等渗的溶质，以及含水和非水的无菌悬浮剂，其可包含助悬剂，增溶剂，增稠剂，稳定剂和防腐剂。在本发明的实 践中，组合物可通过例如静脉内输注，经口，局部，腹膜内，膀胱内和鞘内给药。化合物的制剂可存在于单位剂量或者多剂量密封容器诸如安瓿和小瓶中。注射用溶液液和悬浮液可从先前所述类型的无菌粉剂、颗粒和片剂制备。
在本发明的环境下，对对象剂量给用应当足够，随着时间在对象体内产生有益的治疗学应答。剂量通过所用的具体化合物的效力和对象的病况、以及待治疗对象的体重或者体表面积而定。剂量的大小将根据在具体对象中伴随具体化合物给药产生的任何不利副作用的存在、性质和程度而定。在正被治疗的病症的治疗或者预防中确定待给药的化合物的有效量中，医师可以评价诸如化合物的循环血浆水平、化合物毒性和/或疾病进程等因素而定。
本发明还提供了式(I)的化合物，及其药学上可接受的盐、立体异构体、酯、前药和溶剂化物在预防和/或治疗癌症中的应用。
本发明还提供了式(I)的化合物，及其药学上可接受的盐、立体异构体、酯、前药和溶剂化物在癌症免疫疗法中的应用。
本发明还提供了式(I)的化合物，及其药学上可接受的盐、立体异构体、酯、前药和溶剂化物在制备预防和/或治疗癌症的药物中的应用。
本发明所述的癌症包括淋巴瘤，母细胞瘤，髓母细胞瘤，视网膜母细胞瘤，肉瘤，脂肪肉瘤，滑膜细胞肉瘤，神经内分泌肿瘤，类癌肿瘤，胃泌素瘤，胰岛细胞癌，间皮瘤，神经鞘瘤，听神经瘤，脑膜瘤，腺癌，黑素瘤，白血病或淋巴样恶性肿瘤，鳞状细胞癌，上皮鳞状细胞癌，肺癌，小细胞肺癌，非小细胞肺癌，腺癌肺癌，肺鳞癌，腹膜癌，肝细胞癌，胃癌，肠癌，胰腺癌，成胶质细胞瘤，子宫颈癌，卵巢癌，肝癌，膀胱癌，肝癌，乳腺癌，转移性乳腺癌，结肠癌，直肠癌，结肠直肠癌，子宫癌，唾液腺癌，肾癌，前列腺癌，外阴癌，甲状腺癌，肝癌，肛门癌，阴茎癌，梅克尔细胞癌，食管癌，胆道肿瘤，头颈部癌和血液恶性肿瘤。
本发明中所述的术语C 0-10烷基，C 0烷基是指H，因此，C 0-10烷基包括H、C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基、C 6烷基、C 7烷基、C 8烷基、C 9烷基、C 10烷基。
本发明中所述的术语C 1-10亚烷基，包括C 1亚烷基、C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基、C 6亚烷基、C 7亚烷基、C 8亚烷基、C 9亚烷基、C 10亚烷基。
本发明中所述的术语C 3-10环烷基，包括C 3环烷基、C 4环烷基、C 5环烷基、C 6环烷基、C 7环烷基、C 8环烷基、C 9环烷基、C 10环烷基。
本发明中所述的术语C 1-6烷基，包括HC 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基、C 6烷基。
本发明中所述的术语C 1-6直链烷基，包括甲基、乙基、C 3直链烷基、C 4直链烷基、C 5直链烷基、C 6直链烷基。
本发明中所述的术语C 3-6环烷基，包括C 3环烷基、C 4环烷基、C 5环烷基、C 6环烷基。
本发明所述的术语卤素，包括氟、氯、溴、碘。
本发明所述的术语杂环烷基是指含3-10个环原子，优选5-10个环原子的非芳香的饱和单环或多环环系，其中的一个或多个环原子不是碳原子，而是例如氮、氧或硫原子。优选的杂环烷基含有5-6个环原子。杂环烷基前的前缀氮杂、氧杂或硫杂分别是指至少有一个氮、氧或硫原子作为环原子。代表性的单环杂环烷基包括哌啶基、吡咯烷基、哌嗪基、吗啉基、硫代吗啉基、噻唑烷基、1,3-二氧戊环基、1,4-二氧杂环己烷基、四氢呋喃基、四氢噻吩基或四氢噻喃基。
本发明所述的术语杂环芳香基是指含5-14个环原子，优选5-10个环原子的芳香单环或多环环系，其中的一个或多个环原子不是碳原子，而是例如氮、氧或硫原子。优选的杂环芳香基含有5-6个环原子。代表性的杂环芳香基包括吡嗪基、呋喃基、噻吩基、吡啶基、嘧啶基、异噁唑基、异噻唑基、噁唑基、噻唑基、吡唑基、呋咱基、吡咯基、吡唑基、三唑基、1,2,4-硫杂二唑基、吡嗪基、哒嗪基、喹喔啉基、2,3-二氮杂萘基、咪唑并[1,2-a]吡啶、咪唑并[2,1-b]噻唑基、苯并呋咱基、吲哚基、氮杂吲哚基、苯并咪唑基、苯并噻吩基、喹啉基、咪唑基、噻吩并吡啶基、喹唑啉基、噻吩并嘧啶基、吡咯并吡啶基、咪唑并吡啶基、异喹啉基、苯并氮杂吲哚基、1,2,4-三嗪基、苯并噻唑基等。
本发明所述的术语Me代表甲基的缩写。
本发明所述的术语Ph代表苯基的缩写。
本发明所述的术语Boc代表叔丁氧羰基的缩写。
本发明所述的术语“单位剂型”指适合作为人受试者和其它哺乳动物的单一剂量的物理上离散的单位，每个单位包含与需要的药物载体结合的经计算可在治疗期间的过程中产生期望的预防或治疗效果的预定量的活性物质。
本发明所述的术语“辅料”含义是该成分没有生物活性或其他不良活性的杂质，例如该成分可以纳入公开的药物制剂并给与患者，但不引起显著的不良生物效果或以有害的方式和该制剂中包含的其他成分产生相互作用。
本发明所述的术语“治疗”包括抑制、延迟、缓和、减弱、限制、减轻或消退疾病、障碍、病症或状态，其发生和/或进程，和/或其症状。
本发明所述的术语“预防”包括减小以下风险：患有、感染或经历疾病、障碍、病症或状态，其发生和/或进程，和/或其症状。
本发明所述的术语“包含”表示“开放”或“包含性”用语，使得它们包括列举的要素，而且还允许包括额外的、未提及的要素。
本发明所述的术语“约”通常意指所述值的+/-5％，更通常指所述值的+/-4％，更通常指所述值的+/-3％，更通常指所述值的+/-2％，更通常指所述值的+/-1％，更通常指所述值的+/-0.5％。
实施例1化合物BRM246-52,65-66,69,71-72的制备
路线1：2,3-二氢-4(1H)-喹唑啉酮类(BRM246-52,65-66,69,71-72)的合成
Figure PCTCN2020098472-appb-000027
在N 2保护下，将化合物R 4-NH 2(1.2eq)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU，1.2eq)，N,N-二异丙基乙胺(DIPEA，3eq)加入化合物24(1eq)的THF溶液中，加热至50℃，反应6h，反应结束后旋干溶剂，加入适量蒸馏水，用二氯甲烷萃取。粗品用硅胶柱层析纯化得到化合物25。将Fe(5eq)、HCl(8eq)加入化合物25(1eq)的乙醇溶液，加热回流，反应1h，加入饱和的碳酸钠溶液，中和至弱碱性，用二氯甲烷萃取。粗品用硅胶柱层析纯化得到化合物26。在N 2保护下，将三溴化硼(BBr 3，5eq)加入化合物26(1eq)的二氯甲烷溶液中,室温反应2h，加入碳酸钠溶液淬灭，用二氯甲烷萃取。粗品用硅胶柱层析纯化得到化合物BRM2-51。在化合物26加入甲酸，加热回流1h，反应结束后旋干溶剂得到化合物27。在N 2保护下，将硼氢化钠(NaBH 4，30eq)加入化合物27的乙醇溶液中，反应3h，加水淬灭，用乙酸乙酯萃取。粗品用硅胶柱层析纯化得到化合物28。
在N 2保护下，将BBr 3(5eq)加入化合物28(1eq)的二氯甲烷溶液中,室温反应2h，加入碳酸氢钠溶液淬灭，用二氯甲烷萃取。粗品用硅胶柱层析纯化得到化合物BRM2-46-50、52、65-66、69、71-72。
实施例2化合物BRM253-64,67-68,70的制备
路线2：2,3-二氢-4(1H)-喹唑啉酮类(BRM253-64,67-68,70)的合成
Figure PCTCN2020098472-appb-000028
在N 2保护下，将硼酸化合物(1.1eq)，四(三苯基膦)钯(Pd[P(C 6H 5) 3] 4，0.01eq)，K 2CO 3(3eq)加入乙二醇二甲醚(DME)：H 2O(3:1)溶液中，加热至80℃，反应12h，加入适量蒸馏水，用二氯甲烷萃取。粗品用硅胶柱层析纯化得到化合物29。将BBr 3(5eq)加入化合物29(1eq)的二氯甲烷溶液中，室温反应2h，加入t碳酸氢钠溶液淬灭，用二氯甲烷萃取。粗品用硅胶柱层析纯化得到化合物BRM2-53-64、67-68、70。
实施例3化合物GL110-122的制备
亚苯甲酰基脲系列化合物(GL110-122)的合成
Figure PCTCN2020098472-appb-000029
将化合物13(1.0eq)加入到甘氨酸甲酯盐酸盐(1.0eq)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI，1.1eq)，3-羟基-1,2,3-苯并三嗪-4(3H)-酮(HOOBt，1.1eq)以及N，N-二异丙基乙胺(DIPEA，4.0eq)二氯甲烷溶液中，室温反应，后旋干溶剂，所得物用硅胶柱层析纯化得到化合 物14。化合物14在氢气的中Pd/C还原，得到固体溶解于二氯甲烷中，向上述溶液中加入三光气以及三乙胺(2.0eq)，回流反应，旋干后，所得物用硅胶柱层析纯化得到化合物15。氢氧化锂(LiOH)的水溶液加入到所得化合物的乙醇溶液中，室温反应，旋干有机溶剂，调节PH值到2.0，乙酸乙酯萃取，旋干溶剂得到化合物16。有机胺,EDCI(1.1eq)，HOOBt(1.1eq)以及DIPEA(2.0eq)加入到化合物16的二氯甲烷溶液中，室温反应，后旋干溶剂，所得物用硅胶柱层析纯化得到化合物GL110--122。
实施例4实施例1-3制备的化合物的细胞活性测试
采用CCK-8法测试分子对细胞的增殖毒性。CCK-8试剂中含有WST–8：化学名：2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺酸苯)-2H-四唑单钠盐，它在电子载体1-甲氧基-5-甲基吩嗪硫酸二甲酯(1-MethoxyPMS)的作用下被细胞线粒体中的脱氢酶还原为具有高度水溶性的黄色甲臜产物(Formazan)。生成的甲臜物的数量与活细胞的数量成正比。用酶联免疫检测仪在450nm波长处测定其光吸收值，可间接反映活细胞数量。该方法已被广泛用于一些生物活性因子的活性检测、大规模的抗肿瘤药物筛选、细胞增殖试验、细胞毒性试验以及药敏试验等。相较于MTT法，CCK-8法检测灵敏度很高，重复性好，对细胞毒性小，故选用CCK-8法测试分子对细胞增殖毒性。
通过CCK-8法对TSA测试结果相对较好的分子进行细胞增殖毒性检测。首先单浓度测试分子对于H1299和A549细胞(BRM+/BRG1-)的细胞毒性(2个复孔)，在单浓度测试结果的基础上，选择毒性强的分子测试IC 50。在IC 50的基础上，对Hela细胞或U2OS细胞(BRG1+/BRM+)测试在IC 50浓度下的分子的细胞毒性以确定分子的脱靶效应。
实施例5实施例1-3制备的化合物的IC 50值测试
收集对数期细胞，调整细胞悬液浓度，在96孔板中每孔加入100uL，铺板使待测细胞调密度至1000-10000孔(边缘孔用无菌PBS填充，根据细胞的不同选择不同的细胞浓度)；5％CO 2，37℃孵育，至细胞单层铺满孔底(24h)，将培养基用药物替换，每孔100ul，设3个复孔；5％CO 2，37℃孵育24小时，倒置显微镜下观察细胞状态；将含有药物的培养基弃 掉，PBS洗涤板孔三次，每孔加入100ul 10％CCK-8溶液，继续培养1-4h；在酶联免疫检测仪450nm处测量各孔的吸光值。同时设置调零孔(培养基、CCK-8)，对照孔(细胞、相同浓度的药物溶解介质、培养液、CCK-8)。
对实施例1-3所制备的化合物进行 1H核磁及质谱表征，及其生物学数据如下表所示。
表1化合物的表征及生物学数据
Figure PCTCN2020098472-appb-000030
Figure PCTCN2020098472-appb-000031
Figure PCTCN2020098472-appb-000032
Figure PCTCN2020098472-appb-000033
Figure PCTCN2020098472-appb-000034
Figure PCTCN2020098472-appb-000035
Figure PCTCN2020098472-appb-000036
Figure PCTCN2020098472-appb-000037
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。对这些实施例的多种修改对本领域的专业技术人员来说是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (10)

  1. 一种式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物，
    Figure PCTCN2020098472-appb-100001
    其中，R 1、R 2和R 3独立的选自-H、-OH、-卤素、-CN、-OC 0-10烷基、-C 1-10直链或支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-10环烷基、-O杂环烷基或-N杂环烷基，所述-CN、-OC 0-10烷基、-C 1-10直链或支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-10环烷基、-O杂环烷基和-N杂环烷基中的C原子上的H独立地被以下基团取代：-SO 2、-SO 2N(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)SO 2(C 0-10烷基)、-CON(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)CO(C 0-10烷基)、-N(C 0-10烷基)COO(C 0-10烷基)、-OCON(C 0-10烷基)(C 0-10烷基)、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、-OC 0-10烷基、C 3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基；
    R 4选自-卤素、-CN、-OC 0-10烷基、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、C 3-10环烷基、-O杂环烷基或-N杂环烷基、-N杂环芳香基、-O杂环芳香基、-S杂环芳香基或苯基，所述-OC 0-10烷基、-C 1-10直链/支链烷基、-N(C 0-10烷基)(C 0-10烷基)、C 3-10环烷基、-O杂环烷基或-N杂环烷基、-N杂环芳香基、-O杂环芳香基、-S杂环芳香基和苯基中的C原子上的H独立地被以下基团取代：-SO 2、-SO 2C(C 0-10烷基)(C 0-10烷基)、-N(C 0-10烷基)(C 0-10烷基)、-CO(C 0-10烷基)、-N(C 0-10烷基)CO(C 0-10烷基)、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-OC 0-10烷基、-C 3-10环烷基、-O杂环烷基、-N杂环烷基、-苯基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基；
    X存在或不存在，当X存在时，X为-CH 2-或-CO-。
  2. 根据权利要求1所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物，其特征在于，
    当X不存在时，所述化合物的结构通式为：
    Figure PCTCN2020098472-appb-100002
    当X为-CH 2-时，所述化合物的结构通式为：
    Figure PCTCN2020098472-appb-100003
    当X为-CO-时，所述化合物的结构通式为：
    Figure PCTCN2020098472-appb-100004
  3. 根据权利要求2所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物，其特征在于，R 1、R 2和R 3独立的选自-H、-OH、-卤素、-CN、-C 1-3直链烷基、-N(C 0-10烷基)(C 0-10烷基)或-C 3-10环烷基，所述-C 1-3直链烷基、-N(C 0-10烷基)(C 0-10烷基)和-C 3-10环烷基中的C原子上的H独立地被以下基团取代：-SO 2、-卤素、-CN、-OCH 2F、-OCHF 2、-OCF 3、-C 1-3直链烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基；
    R 4选自-C 1-4直链烷基、
    Figure PCTCN2020098472-appb-100005
    Figure PCTCN2020098472-appb-100006
    m、n、p、q和t独立的选自0-4之间的整数；
    R 5、R 6、R 9和R 10独立的选自-H、-OH、-卤素、-CN、-CF 3、-C 1-4直 链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-6环烷基或-SO 2(C 0-10烷基)，所述-C 1-4直链烷基、-N(C 0-10烷基)(C 0-10烷基)、-C 3-6环烷基和-SO 2(C 0-10烷基)中C原子上的H独立地被以下基团取代：-OH、-卤素、-CN、-SO 2、-OCHF 2、-OCF 3或-CF 3；
    R 7和R 8独立的选自-H、-C 1-4直链烷基、C 3-6环烷基、-CON(C 0-10烷基)(C 0-10烷基)或-CO(C 0-10烷基)，所述-C 1-4直链烷基、C 3-6环烷基、-CON(C 0-10烷基)(C 0-10烷基)、-CO(C 0-10烷基)中C原子上的H独立地被以下基团取代：-OH、-卤素、-CN、-SO 2、-OCHF 2、-OCF 3或-CF 3。
  4. 根据权利要求3所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物，其特征在于，R 1和R 3选自H，R 2选自卤素，所述卤素为F；
    n选自0、1或2，m、p、q和t独立的选自0、1或2。
  5. 根据权利要求4所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物，其特征在于，所述R 4选自-CH 3、
    Figure PCTCN2020098472-appb-100007
    Figure PCTCN2020098472-appb-100008
  6. 根据权利要求5所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物，其特征在于，具体化合物结构如下：
    Figure PCTCN2020098472-appb-100009
    Figure PCTCN2020098472-appb-100010
  7. 一种药物组合物，包括权利要求1～6任一项所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物以及药学上可接受的辅料。
  8. 权利要求1～6任一项所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物或权利要求7所述的药物组 合物在预防和/或治疗癌症中的应用。
  9. 权利要求1～6任一项所述的式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药或溶剂化物或权利要求7所述的药物组合物在制备预防和/或治疗癌症的药物中的应用。
  10. 根据权利要求8或9所述的应用，其特征在于，所述的癌症包括淋巴瘤、母细胞瘤、髓母细胞瘤、视网膜母细胞瘤、肉瘤、脂肪肉瘤、滑膜细胞肉瘤、神经内分泌肿瘤、类癌肿瘤、胃泌素瘤、胰岛细胞癌、间皮瘤、神经鞘瘤、听神经瘤、脑膜瘤、腺癌、黑素瘤、白血病或淋巴样恶性肿瘤、鳞状细胞癌、上皮鳞状细胞癌、肺癌、小细胞肺癌、非小细胞肺癌、腺癌肺癌、肺鳞癌、腹膜癌、肝细胞癌、胃癌、肠癌、胰腺癌、成胶质细胞瘤、子宫颈癌、卵巢癌、肝癌、膀胱癌、肝癌、乳腺癌、转移性乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌、梅克尔细胞癌、食管癌、胆道肿瘤、头颈部癌或血液恶性肿瘤。
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