WO2022033542A1 - 5元杂芳环并吡啶酮类化合物及其应用 - Google Patents

5元杂芳环并吡啶酮类化合物及其应用 Download PDF

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WO2022033542A1
WO2022033542A1 PCT/CN2021/112202 CN2021112202W WO2022033542A1 WO 2022033542 A1 WO2022033542 A1 WO 2022033542A1 CN 2021112202 W CN2021112202 W CN 2021112202W WO 2022033542 A1 WO2022033542 A1 WO 2022033542A1
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compound
present
pharmaceutically acceptable
compounds
acceptable salt
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French (fr)
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沈春莉
刘勇
吴成德
陈曙辉
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南京明德新药研发有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of 5-membered heteroaromatic ring and pyridone compounds, in particular to compounds represented by formula (I) and pharmaceutically acceptable salts thereof.
  • BET bromodomain and extra-terminal domain
  • This protein family has 4 members: BRD2, BRD3, BRD4, BRDT, which act as acetylated lysines on histones the "reader”. Acetylation of histones is an important way to regulate gene transcription and chromosome structure.
  • BET proteins recognize and bind to acetylated lysines on histones, thereby promoting chromosome decompression and recruiting multiple transcription factors to form a large transcriptional regulatory protein The complex promotes the activation of RNA polymerase II and stimulates the initiation and elongation of transcription, and activates gene transcription, thereby realizing the epigenetic regulation of genes.
  • BET inhibitors can effectively downregulate the gene and protein levels of c-MYC and PD-L1 in tumor cells, thereby realizing the dual functions of tumor proliferation inhibition and immune killing of tumors. Its antitumor activity has been demonstrated.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T is selected from N and CH;
  • T 1 , T 2 and T 3 are each independently selected from N and CH;
  • R 2 are each independently selected from F, Cl, Br and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
  • n 0, 1 and 2;
  • L 1 is selected from a single bond, -C(R c )(R d )- and -N(R e )-;
  • R a and R b are each independently selected from F, Cl, Br and I;
  • Rc and Rd are each independently selected from H, F, Cl, Br, I and CH3 ;
  • R c and R d together with the carbon atoms to which they are attached form a C 3-5 cycloalkyl optionally substituted with 1, 2 or 3 R;
  • R e is selected from H and CH 3 ;
  • R is selected from F, Cl, Br and I.
  • R 1 is selected from said Optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
  • R 1 is selected from Other variables are as defined in the present invention.
  • R 2 are independently selected from F, Cl, Br and CH 3 , and said CH 3 is optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 2 are independently selected from F, and other variables are as defined in the present invention.
  • R c and R d together with the carbon atoms to which they are attached constitute a cyclopropyl group optionally substituted with 1, 2 or 3 R, other variables as defined herein.
  • R c and R d together with the carbon atoms to which they are attached form a cyclopropyl group, and other variables are as defined in the present invention.
  • the above L 1 is selected from single bond, -CH 2 -, -NH- and Other variables are as defined in the present invention.
  • T is selected from N and CH;
  • T 1 , T 2 and T 3 are each independently selected from N and CH;
  • R 2 are each independently selected from F, Cl, Br and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
  • n 0, 1 and 2;
  • L 1 is selected from a single bond, -C(R c )(R d )- and -N(R e )-;
  • R a and R b are each independently selected from F, Cl, Br and I;
  • Rc and Rd are each independently selected from H, F, Cl, Br, I and CH3 ;
  • Rc and Rd together with the atoms to which they are attached form a C3-5cycloalkyl optionally substituted with 1, 2 or 3 Rs;
  • R e is selected from H and CH 3 ;
  • R is selected from F, Cl, Br and I.
  • R 1 is selected from said Optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
  • R 1 is selected from Other variables are as defined in the present invention.
  • R 2 are independently selected from F, Cl, Br and CH 3 , and said CH 3 is optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 2 are independently selected from F, and other variables are as defined in the present invention.
  • R c and R d together with the atoms to which they are attached form a cyclopropyl group optionally substituted with 1, 2 or 3 R, other variables as defined herein.
  • R c and R d together with the atoms to which they are attached constitute a cyclopropyl group, and other variables are as defined in the present invention.
  • the above L 1 is selected from single bond, -CH 2 -, -NH- and Other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R 1 and R 2 are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the compounds of the present invention all have significant BET Bromodomain inhibitory activity; the compounds of the present invention have short half-lives, wider plasma distribution, and moderate bioavailability; the compounds of the present invention exhibit significant tumor-inhibiting effects, and animals tolerated during administration Sex is good.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the term “isomer” is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers isomer.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the substituent can bond to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene.
  • substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine rings. The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines Express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” refers to a “ring” of 5-7 atoms arranged around it.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-3 alkylamino groups include C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 and the like.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the solvent used in the present invention is commercially available.
  • Phosphorus tribromide (2.02 g, 7.37 mmol, 99% purity, 1 eq) was added dropwise to a solution of compound 1-7 (2.33 g, 7.37 mmol, 1 eq) in dichloromethane (30 mL) at 0°C, and added dropwise. The reaction was completed at 20°C for 3 hours. Water (20 mL) was slowly added dropwise to the constantly stirring reaction solution to quench the reaction, and then extracted with dichloromethane (20 mL*3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. , the filtrate was concentrated under reduced pressure.
  • reaction solution was diluted with ethyl acetate (10 mL), washed with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution was diluted with ethyl acetate (10 mL) and filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative chromatography (chromatographic column: Phenomenex Gemini-NX 80*30mm*3 ⁇ m; mobile phase: [water (10mM NH 4 HCO 3 ) -ACN]; acetonitrile %: 43%-73%, 9 min) to give compound 2.
  • Test 1 IC50 characterization of compounds at 10 concentrations.
  • BRD buffer composition 50 mM HEPES-HCl, pH 7.5, 100 mM NaCl, 0.1% BSA, 0.05% CHAPS and 1% DMSO.
  • mice Male CD-1 mice were used as the test animals, and the LC/MS/MS method was used to determine the drug concentrations in the plasma of mice at different times after intravenous and intragastric administration of the test compounds respectively. To study its pharmacokinetic behavior in mice and evaluate its pharmacokinetic characteristics.
  • Test drug test compound.
  • mice Four male CD-1 mice were divided into two groups. After an overnight fast, one group was administered intravenously, and the other group was administered intragastrically.
  • mice Male CD-1 mice were intravenously administered with test compounds, and 30 ⁇ L of blood was collected at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours, respectively, and placed in commercial test tubes containing EDTA-K 2 . After the test compound was administered to the gavage group, 30 ⁇ L of blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, respectively, and placed in a commercial test tube containing EDTA-K 2 . The tubes were centrifuged at 3000g for 15 minutes to separate the plasma and stored at -60°C. Animals were allowed to eat 2 hours after dosing.
  • LC/MS/MS method was used to determine the content of the tested compounds in the plasma of mice after intravenous and intragastric administration.
  • the linear range of the method was 2.00-6000 nmol/L; plasma samples were analyzed after acetonitrile precipitation.
  • MC38 mouse colon cancer cells
  • the culture medium was DMEM medium containing 10% fetal bovine serum, and the culture conditions were 37° C., 5% carbon dioxide. 1:5 was passed every other day, 3 to 4 times a week, and it was the 18th generation at the time of inoculation.
  • mice were resuspended in DPBS at a density of 2 x 106 cells/mL.
  • 0.1 mL of DPBS (containing 2 ⁇ 10 5 MC38 cells) was subcutaneously inoculated into the right back of each mouse.
  • the mice were randomly divided into groups and administered according to the tumor volume.
  • Tumor diameters were measured with vernier calipers twice a week.
  • TGI percent or relative tumor proliferation rate T/C (%).
  • Relative tumor proliferation rate T/C (%) T RTV /C RTV ⁇ 100 (T RTV : the average RTV of the treatment group; C RTV : the average RTV of the negative control group).
  • TGI (%) reflecting tumor growth inhibition rate.
  • TGI(%) [(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group))/(average tumor volume at the end of treatment in the solvent control group-starting treatment in the solvent control group time average tumor volume)] ⁇ 100.
  • T weight /C weight represents the tumor weight of the administration group and the vehicle control group, respectively.

Abstract

一类5元杂芳环并吡啶酮类化合物，具体公开了式(I)所示化合物及其药学上可接受的盐。

Description

5元杂芳环并吡啶酮类化合物及其应用
本申请主张如下优先权
CN202010817455.8，申请日：2020年8月14日；
CN202110532688.8，申请日：2021年5月14日。
发明领域
本发明涉及一类5元杂芳环并吡啶酮类化合物，具体涉及式(I)所示化合物及其药学上可接受的盐。
背景技术
BET(bromodomain and extra-terminal domain)是溴结构域和额外C-末端结构域，该蛋白家族有4个成员：BRD2，BRD3，BRD4，BRDT，它们可充当组蛋白上乙酰化修饰的赖氨酸的“reader”。组蛋白的乙酰化是调控基因转录及染色体结构的重要方式，BET蛋白识别并结合组蛋白上乙酰化修饰的赖氨酸，从而促进染色体解压缩并招募多种转录因子形成一个大的转录调控蛋白复合体，促进RNA聚合酶Ⅱ活化并激发转录的起始和延伸，并激活基因转录，从而实现基因的表观遗传调控。BET抑制剂可有效下调肿瘤细胞的c-MYC和PD-L1基因及蛋白水平，从而实现肿瘤增殖抑制和免疫杀伤肿瘤双重功能，在抗肿瘤方面具有巨大的潜力，在血液系统恶性肿瘤的临床试验已经证实了其抗肿瘤活性。
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2021112202-appb-000001
其中，
T选自N和CH；
T 1、T 2和T 3分别独立地选自N和CH；
R 1选自-S(＝O) 2-C 1-3烷基、-S(＝O)(＝NH)-C 1-3烷基和-S(＝O) 2-C 1-3烷氨基，所述-S(＝O) 2-C 1-3烷基、-S(＝O)(＝N)-C 1-3烷基和-S(＝O) 2-C 1-3烷氨基任选被1、2或3个R a取代；
R 2分别独立地选自F、Cl、Br和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
m选自0、1和2；
L 1选自单键、-C(R c)(R d)-和-N(R e)-；
R a和R b分别独立地选自F、Cl、Br和I；
R c和R d分别独立地选自H、F、Cl、Br、I和CH 3；
或者，R c和R d与它们相连的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R取代；
R e选自H和CH 3；
R选自F、Cl、Br和I。
本发明的一些方案中，上述，R 1选自
Figure PCTCN2021112202-appb-000002
所述
Figure PCTCN2021112202-appb-000003
任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自
Figure PCTCN2021112202-appb-000004
其他变量如本发明所定义。
本发明的一些方案中，上述R 2分别独立地选自F、Cl、Br和CH 3，所述CH 3任选被1、2或3个R b取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 2分别独立地选自F，其他变量如本发明所定义。
本发明的一些方案中，上述R c和R d与它们相连的碳原子共同构成环丙基，所述环丙基任选被1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R c和R d与它们相连的碳原子共同构成环丙基，其他变量如本发明所定义。
本发明的一些方案中，上述L 1选自单键、-CH 2-、-NH-和
Figure PCTCN2021112202-appb-000005
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元R 1-L 1-选自
Figure PCTCN2021112202-appb-000006
Figure PCTCN2021112202-appb-000007
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2021112202-appb-000008
选自
Figure PCTCN2021112202-appb-000009
Figure PCTCN2021112202-appb-000010
其他变量如本发明所定义。
在本发明的一些方案中，上述式(I)所示化合物或其药学上可接受的盐，
其中，
T选自N和CH；
T 1、T 2和T 3分别独立地选自N和CH；
R 1选自-S(＝O) 2-C 1-3烷基和-S(＝O)(＝NH)-C 1-3烷基，所述-S(＝O) 2-C 1-3烷基和-S(＝O)(＝N)-C 1-3烷基任选被1、2或3个R a取代；
R 2分别独立地选自F、Cl、Br和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
m选自0、1和2；
L 1选自单键、-C(R c)(R d)-和-N(R e)-；
R a和R b分别独立地选自F、Cl、Br和I；
R c和R d分别独立地选自H、F、Cl、Br、I和CH 3；
或者，R c和R d与它们相连的原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R取代；
R e选自H和CH 3；
R选自F、Cl、Br和I。
本发明的一些方案中，上述R 1选自
Figure PCTCN2021112202-appb-000011
所述
Figure PCTCN2021112202-appb-000012
Figure PCTCN2021112202-appb-000013
任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自
Figure PCTCN2021112202-appb-000014
其他变量如本发明所定义。
本发明的一些方案中，上述R 2分别独立地选自F、Cl、Br和CH 3，所述CH 3任选被1、2或3个R b取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 2分别独立地选自F，其他变量如本发明所定义。
本发明的一些方案中，上述R c和R d与它们相连的原子共同构成环丙基，所述环丙基任选被1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R c和R d与它们相连的原子共同构成环丙基，其他变量如本发明所定义。
本发明的一些方案中，上述L 1选自单键、-CH 2-、-NH-和
Figure PCTCN2021112202-appb-000015
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元R 1-L 1-选自
Figure PCTCN2021112202-appb-000016
Figure PCTCN2021112202-appb-000017
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2021112202-appb-000018
选自
Figure PCTCN2021112202-appb-000019
Figure PCTCN2021112202-appb-000020
其他变量如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自：
Figure PCTCN2021112202-appb-000021
其中，
R 1和R 2如本发明所定义。
本发明还提供了下式所示化合物或其药学上可接受的盐，
Figure PCTCN2021112202-appb-000022
Figure PCTCN2021112202-appb-000023
技术效果
本发明化合物均具有显著的BET Bromodomain抑制活性；本发明化合物的半衰期较短，血浆外分布较广，生物利用度适中；本发明化合物展现出显著的抑瘤效果，且给药期间，动物耐受性良好。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、 硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除非另有说明，术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2021112202-appb-000024
和楔形虚线键
Figure PCTCN2021112202-appb-000025
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021112202-appb-000026
和直形虚线键
Figure PCTCN2021112202-appb-000027
表示立体中心的相对构型，用波浪线
Figure PCTCN2021112202-appb-000028
表示楔形实线键
Figure PCTCN2021112202-appb-000029
或楔形虚线键
Figure PCTCN2021112202-appb-000030
或用波浪线
Figure PCTCN2021112202-appb-000031
表示直形实线键
Figure PCTCN2021112202-appb-000032
或直形虚线键
Figure PCTCN2021112202-appb-000033
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体 过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2021112202-appb-000034
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时， 这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2021112202-appb-000035
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2021112202-appb-000036
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2021112202-appb-000037
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2021112202-appb-000038
直形虚线键
Figure PCTCN2021112202-appb-000039
或波浪线
Figure PCTCN2021112202-appb-000040
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2021112202-appb-000041
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2021112202-appb-000042
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2021112202-appb-000043
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2021112202-appb-000044
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2021112202-appb-000045
仍包括
Figure PCTCN2021112202-appb-000046
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，“C 3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C 3-5环烷基包括C 3-4和C 4-5环烷基等；其可以是一价、二价或者多价。C 3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2021112202-appb-000047
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：aq代表水；eq代表当量、等量；DCM代表二氯甲烷；PE代表石油醚；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；Cbz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；TEA代表三乙胺；iPrOH代表2-丙醇；mp代表熔点；AcOH代表乙酸；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；Pd(OAc) 2代表乙酸钯；DBU代表1,8-二氮杂二环十一碳-7-烯。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2021112202-appb-000048
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2021112202-appb-000049
合成路线：
Figure PCTCN2021112202-appb-000050
步骤1：化合物1-2的合成
将化合物1-1(5g,45.01mmol,1eq)加入到乙二醇单甲醚(100mL)和水合肼(10.30g,174.89mmol,10mL,纯度85％,3.89eq)的混合液中，氮气保护下110℃搅拌20小时。反应液冷却至室温有固体析出，过滤，滤饼干燥，得到化合物1-2。 1H NMR(400MHz,CDCl 3)δ10.28(br s,1H),7.52(s,1H),6.95(d,J＝7.2Hz,1H),5.63(d,J＝6.8Hz,1H),5.38(d,J＝2.0Hz,1H),4.09(s,2H)。
步骤2：化合物1-3的合成
将化合物1-2(3.5g,27.97mmol,1eq)及丙醛(2.79g,48.09mmol,3.5mL,1.72eq)加入到乙醇(100mL)中并在80℃下搅拌4小时。反应液冷却至0℃，有固体析出，过滤，滤饼减压去除残留溶剂，得到化合物1-3。 1H NMR(400MHz,DMSO-d 6)δ10.55(br s,1H),10.11(br s,1H),7.28(t,J＝4.8Hz,1H),7.10(d,J＝7.2Hz,1H),5.84(d,J＝3.6Hz,1H),5.55(s,1H),2.20-2.27(m,2H),1.04(t,J＝7.2Hz,3H)。
步骤3：化合物1-4的合成
将化合物1-3(1.0g,6.05mmol,1eq)溶于二苯醚(30mL)中，在220℃下搅拌6小时。反应液冷却至室温，有固体析出，过滤。滤饼加甲醇(20mL)溶解并过滤，去除少量黑色不溶物。滤液旋干，得到的粗品用甲醇(5mL)室温打浆10分钟，过滤得到化合物1-4。LCMS(ESI)m/z：148.8[M+1] +； 1H NMR(400MHz,DMSO-d 6)δ11.00(br s,1H),10.51(br s,1H),6.87(d,J＝2.4Hz,1H),6.76(s,1H),6.27(d,J＝6.8Hz,1H),2.31(s,3H)。
步骤4：化合物1-6的合成
将化合物1-5(10g,39.92mmol,1eq)溶于DMSO(300mL)中，再加入2,4-二氟苯酚(4.00g,30.75mmol,0.77eq)及碳酸钾(10.00g,72.36mmol,1.81eq)，添加完毕后在100℃反应5小时。向反应液中加入水(500 mL)，然后用乙酸乙酯(200mL*3)萃取，合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，溶液减压浓缩，得到化合物1-6。LCMS(ESI)m/z：343.7[M+1] +。
步骤5：化合物1-7的合成
将化合物1-6(8.6g,24.99mmol,1eq)溶于乙醇(70mL)中，降温至0℃后加入硼氢化钠(1.89g,50.09mmol,2eq)，添加完毕升温至80℃反应3小时。反应液加水(100mL)淬灭，然后用乙酸乙酯(100mL*3)萃取，合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经硅胶柱纯化(石油醚/乙酸乙酯＝3/1)得到化合物1-7。LCMS(ESI)m/z：317.6[M+1] +。
步骤6：化合物1-8的合成
0℃下往化合物1-7(2.33g,7.37mmol,1eq)溶于二氯甲烷(30mL)的溶液中滴加三溴化磷(2.02g,7.37mmol,纯度99％,1eq)，滴加完毕在20℃下反应3小时。往不停搅拌的反应液中慢慢滴加水(20mL)淬灭反应，然后用二氯甲烷(20ml*3)萃取，合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经硅胶柱纯化(石油醚/乙酸乙酯＝10/1)得到化合物1-8。LCMS(ESI)m/z：379.9[M+1] +； 1H NMR(400MHz,CDCl 3)δ7.93(S,1H),7.92(S,1H),7.12-7.18(m,1H),6.84-6.87(m,2H),4.32(s,2H)。
步骤7：化合物1-9的合成
往化合物1-8(2.34g,6.17mmol,1eq)溶于乙硫醇(2.62g,42.18mmol,3.12mL,6.83eq)的溶液中加入碳酸铯(3.04g,9.34mmol,1.51eq)，添加完毕于20℃下反应16小时。反应接上尾气吸收装置，室温下减压将溶剂全部抽至4M氢氧化钠水溶液吸收瓶中。得到的粗品1-9不进行处理，直接用于下一步反应。
步骤8：化合物1-10的合成
往化合物1-9(2.22g,6.16mmol,1eq)溶于甲醇(30mL)的溶液中，加入单过硫酸氢钾(11.4g,18.54mmol,3.01eq)的水(30mL)溶液，添加完毕后20℃反应1小时。再次加单过硫酸氢钾(7.6g,12.36mmol,2.01eq)在20℃继续反应2小时。往不停搅拌的反应液中慢慢加入水(50mL)，有固体析出，过滤，滤饼经硅胶柱纯化(石油醚/乙酸乙酯＝10/1)得到化合物1-10。LCMS(ESI)m/z：393.8[M+1] +； 1H NMR(400MHz,CDCl 3)δ8.08(d,J＝2.0Hz,1H),7.98(d,J＝2.0Hz,1H),7.21-7.23(m,1H),6.93-6.98(m,2H),4.10(s,2H),2.95(q,J＝7.6Hz,2H),1.42(t,J＝7.6Hz,3H)。
步骤9：化合物1的合成
往化合物1-10(50mg,337.47μmol,1eq)和化合物1-4(137mg,349.30μmol,1.04eq)溶于1，4-二氧六环(3mL)的溶液中加入磷酸钾(145mg,683.11μmol,2.02eq)，碘化亚铜(7mg,36.76μmol,1.09e-1eq)及反式-1,2-环己二胺(5mg,43.79μmol,5.37μL,0.13eq)，反应在110℃下搅拌40小时。反应液加乙酸乙酯(10mL)稀释，用水(5mL)及饱和食盐水(5mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经层析板(二氯甲烷/甲醇＝10/1)纯化，得到化合物1。LCMS(ESI)m/z：459.8[M+1] +；1H NMR(400MHz, CDCl 3)δ9.74(br s,1H),8.10(s,1H),7.93(s,1H),7.15-7.21(m,1H),6.92-7.07(m,4H),6.39(d,J＝8.0Hz,1H),4.23(s,2H),3.06(q,J＝8.0Hz,2H),2.57(s,3H),1.48(t,J＝8.0Hz,3H)。
实施例2
Figure PCTCN2021112202-appb-000051
合成路线：
Figure PCTCN2021112202-appb-000052
步骤1：化合物2-2的合成
将化合物2-1(2g,10.47mmol,1eq)和乙基磺酰氯(1.4g,10.89mmol,1.03mL,1.04eq)加入到吡啶(10mL)中，26℃下搅拌5小时。往反应液中加入乙酸乙酯(50mL)及水(50mL)并用1M盐酸溶液调节水相pH＝6，分离有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩。得到化合物2-2。
步骤2：化合物2-3的合成
往化合物2-2(1g,3.53mmol,1eq)和2,4-二氟苯酚(460mg,3.54mmol,1.00eq)溶于N,N-二甲基甲酰胺(10mL)的溶液中加入碳酸铯(2.4g,7.37mmol,2.09eq)，反应在150℃微波下反应4小时。反应液加水(30mL)处理，然后用乙酸乙酯(20mL*3)萃取，合并有机相用水(20mL)及饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，粗品经硅胶柱(石油醚/乙酸乙酯＝3/1)纯化，得到化合物2-3。LCMS(ESI)m/z：392.9、394.9[M+1] +。
步骤3：化合物2的合成
将化合物1-4(65mg,438.71μmol,1eq)和化合物2-3(180mg,457.78μmol,1.04eq)溶于二氧六环(3mL)中，再加入磷酸钾(200.00mg,918.66μmol,2.09eq)，(1R,2R)-1，2-环己二胺(12mg,105.08μmol,0.24eq)，碘化亚铜(15mg,78.8μmol,0.18eq)，升温至110℃反应32小时。反应液加乙酸乙酯(10mL)稀释后过滤，滤液减压浓缩，粗品用制备色谱仪纯化(色谱柱:Phenomenex Gemini-NX 80*30mm*3μm；流动相:[水(10mM NH 4HCO 3)-ACN]；乙腈％:43％-73％,9min)，得到化合物2。LCMS(ESI)m/z：461.0[M+1] +； 1H NMR (400MHz,CDCl 3)δ9.07(br s,1H),8.21(d,J＝2.5Hz,1H),7.78(dd,J＝4.0,8.0Hz,1H),7.2(s,1H),7.14-7.19(m,1H),7.0(d,J＝8.0Hz,1H),6.98–6.91(m,2H),6.83(s,1H),3.35(q,J＝7.4Hz,2H),2.49(s,3H),1.51(t,J＝8.0Hz,3H)。
实施例3
Figure PCTCN2021112202-appb-000053
合成路线：
Figure PCTCN2021112202-appb-000054
步骤1：化合物3-1的合成
往化合物1-8(2.4g,6.33mmol,1eq)溶于乙醇(10mL)和水(5mL)的溶液中加入亚硫酸钠(860mg,6.82mmol,1.08eq)，反应在80℃下搅拌15小时。反应液减压去除溶剂，残留物加水(20mL)稀释并用二氯甲烷(20mL*2)洗涤，水相冷冻干燥，得到化合物3-1，直接用于下一步反应。
步骤2：化合物3-2的合成
0℃往化合物3-1(2.5g,6.58mmol,1eq)的二氯甲烷(5mL)溶液中加入N,N-二甲基甲酰胺(95.00mg,1.30mmol,0.1mL,1.98e-1eq)及草酰氯(1.45g,11.42mmol,1mL,1.74eq)，反应在24℃下搅拌13小时。反应液直接旋干，得到化合物3-2，直接用于下一步反应。LCMS(ESI)m/z：397.4[M+1] +。
步骤3：化合物3-3的合成
0℃往化合物3-2(200mg,501.75μmol,1eq)和N,N-二甲胺(150mg,1.84mmol,168.54μL,3.67eq,HCl)的二氯甲烷(5mL)溶液中加入4-N,N-二甲胺基吡啶(17mg,139.15μmol,2.77e-1eq)和DBU(808.00mg,5.31mmol,800.00μL,10.58eq)，反应在24℃下搅拌3小时。反应液加二氯甲烷(10mL)稀释，并用1M HCl调节pH＝6，分离有机相，用无水硫酸钠干燥，过滤，滤液浓缩。粗品用制备板(二氯甲烷/甲醇＝10/1) 纯化，得到化合物3-3。LCMS(ESI)m/z：407.0,409.0[M+1] +；1H NMR(400MHz,CDCl 3)δ8.09(d,J＝2.0Hz,1H),7.98(d,J＝2.0,1H),7.26-7.22(m,1H),7.01-6.93(m,2H),4.12(s,2H),2.84(s,6H)。
步骤4：化合物3的合成
往化合物3-3(160mg,392.90μmol,1eq)和化合物1-4(80mg,539.95μmol,1.37eq)溶于二氧六环(10mL)的溶液中加入磷酸钾(210mg,989.31μmol,2.52eq)，碘化亚铜(16mg,84.01μmol,2.14e-1eq)及(1R,2R)-1，2-环己二胺(16mg,140.12μmol,17.19μL,3.57e-1eq)，反应在110℃下搅拌35小时。反应液直接过滤，滤饼加甲醇(10mL)洗涤，滤液减压浓缩。粗品用制备板(二氯甲烷/甲醇＝10/1)纯化，得到粗品进一步用制备色谱仪纯化(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(10mM NH 4HCO 3)-ACN]；乙腈％:33％-63％,9min)，得到化合物3。LCMS(ESI)m/z：475.2[M+1] +； 1H NMR(400MHz,CDCl 3)δ11.07(br s,1H),8.01(d,J＝2.0Hz,1H),7.85(d,J＝2.0,1H),7.15-7.05(m,2H),6.92(s,1H),6.89-6.82(m,2H),6.41(d,J＝8.0Hz,1H),4.10(s,2H),2.82(s,6H),2.48(s,3H)。
实施例4
Figure PCTCN2021112202-appb-000055
合成路线：
Figure PCTCN2021112202-appb-000056
步骤1：化合物4-1的合成
24℃下往化合物3-2(2.2g,5.52mmol,1eq)中加入甲胺(10g,96.60mmol,30％纯度,17.50eq)(～30％的乙醇溶液)，反应搅拌3小时。反应液直接浓缩，残留物加乙酸乙酯(20mL)溶解并用水(10mL)及饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液加压浓缩，粗品用硅胶柱纯化(二氯甲烷/甲醇＝10/1)，得到化合物4-1。LCMS(ESI)m/z：392.9,394.9[M+1] +。
步骤2：化合物4的合成
往碘化亚铜(38.33mg,201.28μmol,3.44e-1eq)，化合物4-1(230mg,584.94μmol,1eq)和化合物1-4(95.83mg,646.82μmol,1.11eq)的二氧六环(10mL)混合液中加入磷酸钾(316.25mg,1.49mmol,2.55eq)和(1R,2R)-1，2-环己二胺(19.17mg,167.85μmol,20.59μL,2.87e-1eq)，反应在氮气保护110℃下搅拌35小 时。反应液直接过滤，滤液减压浓缩，得到的残留物用硅胶柱纯化(二氯甲烷/甲醇＝10/1)，得到的粗品进一步用制备色谱仪纯化(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm；流动相:[水(0.05％NH 3H 2O)-ACN]；乙腈％:26％-56％,8min)，得到化合物4。LCMS(ESI)m/z：461.2[M+1] +； 1H NMR(400MHz,CDCl 3)δ8.12(s,1H),7.95(s,1H),7.26-7.24(m,1H),7.12(d,J＝8.0Hz,1H),6.94-6.89(m,2H),6.77(s,1H),6.47(d,J＝8.0Hz,1H),4.52-4.55(m,1H),4.25(s,2H),2.82(s,3H),2.50(s,3H)。
生物测试
实验例一、本发明化合物的BRD4生化活性检测
1.实验准备
测试1：对化合物进行10个浓度的IC 50表征。
评价化合物在10个浓度下对两个BRD(BRD4-1，BRD4-2)的IC 50，单孔，起始浓度10μM，3倍梯度稀释。
2.测试条件
BRD缓冲液成分：50mM HEPES-HCl，pH7.5，100mM NaCl，0.1％BSA，0.05％CHAPS和1％DMSO。
配体：组蛋白H4肽(1-21)K5/8/12/16Ac-Biotin
检测：AlphaScreen结合实验(Ex/Em＝680/520-620nm)
实验过程：
2.1将4X BRD加入反应板的孔中，除了无BRD对照孔，以缓冲液取代。
2.2使用Acoustic Technology(Echo550，纳升级)将化合物的100％DMSO溶液加入BRD混合物中。离心，在室温下温和的震荡，预孵育30分钟。
2.3加入4X配体，离心并震荡。
2.4温和震荡，室温孵育30分钟。
2.5避光加入4X donor beads(供体微珠)。离心并震荡。
2.6避光加入4X acceptor beads(受体微珠)。离心并震荡。避光温和震荡60分钟。
2.7使用Enspire进行Alpha检测(Ex/Em＝680/520-620nm)
3.实验结果
表1 BRD4检测IC 50测试结果
化合物 BRD4(BD1，BD2)，IC 50(nM)
1 6.21，1.44
结论：本发明化合物均具有显著的BET Bromodomain抑制活性。
实验例二、本发明化合物的药代动力学研究
1.摘要
1.1以雄性CD-1小鼠为受试动物，应用LC/MS/MS法测定小鼠静脉和灌胃分别给与测试化合物后不同时刻血浆中的药物浓度。研究其在小鼠体内的药代动力学行为，评价其药动学特征。
2.实验方案
2.1试验药品：测试化合物。
2.2药物配制
称取适量样品，加入溶媒，搅拌超声至澄清状态用于静脉给药。
称取适量样品，加入溶媒，搅拌超声至澄清状态用于灌胃给药。
2.3给药
雄性CD-1小鼠4只，分成2组，禁食一夜后，其中一组进行静脉给药，另外一组进行灌胃给药。
3.操作
雄性CD-1小鼠静脉给予测试化合物后，分别在0.0833，0.25，0.5，1，2，4，8及24小时采血30μL，置于含有EDTA-K 2的商业化试管中。灌胃给药组给予测试化合物后，分别在0.25，0.5，1，2，4，6，8及24小时采血30μL，置于含有EDTA-K 2的商业化试管中。试管在3000g离心15分钟分离血浆，并于-60℃保存。给药2小时后动物可进食。
用LC/MS/MS法测定小鼠静脉和灌胃给药后，血浆中待测化合物的含量。方法的线性范围为2.00～6000nmol/L；血浆样品经乙腈沉淀蛋白处理后进行分析。
4.药代动力学参数结果
表2药代动力学参数数据汇总
Figure PCTCN2021112202-appb-000057
“--”：无；
实验结论：本发明化合物的半衰期较短，血浆外分布较广，生物利用度适中。
实验例三、本发明化合物在MC38小鼠结肠癌细胞动物移植瘤模型中的体内药效研究
1.实验设计
表3体内药效实验动物分组及给药方案
组别 动物数 化合物治疗 剂量(mg/kg) 给药体积参数(μL/g) 给药途径 给药频次
1 7 溶媒组 -- 10 p.o. BID
2 7 化合物1 20 10 p.o. BID
注：p.o：口服；BID：一天两次。
2.实验材料
2.1实验动物
种属：小鼠。
品系：C57小鼠。
周龄及体重：7-8周龄。
性别：雌性。
供应商：上海西普尔-必凯实验动物有限公司。
3.实验方法与步骤
3.1细胞培养
名称：MC38(小鼠结肠癌细胞)。
来源：细胞购于赛百慷(上海)生物技术股份有限公司，由上海药明康德新药开发有限公司保种维持传代。
传代条件：培养液为含有10％胎牛血清的DMEM培养基，培养条件为37℃，5％二氧化碳。1：5隔天传，每周传代3～4次，接种时为第18代。
3.2肿瘤细胞接种
将细胞重悬于DPBS，密度为2×10 6个细胞/mL。0.1mL DPBS(含2×10 5个MC38细胞)皮下接种于每只小鼠的右后背，待肿瘤平均体积达到(72.97±4.6)mm 3时，根据肿瘤体积进行随机分组给药。
3.3肿瘤测量和实验指标
每周2次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5×a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝T RTV/C RTV×100(T RTV：治疗组平均RTV；C RTV：阴性对照组平均RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(相对肿瘤体积，RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即D0)测量所得肿瘤体积，V t为某一次测量时的肿瘤体积，T RTV与C RTV取同一天数据。
TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100。
在实验结束后将检测肿瘤重量，并计算T 重量/C 重量百分比，T 重量/C 重量分别表示给药组和溶媒对照组的瘤重。
3.4统计分析
统计分析基于试验结束时相对肿瘤体积和肿瘤重量运用SPSS软件进行分析。两组间比较用t-test进行分析，三组或多组间比较用one-way ANOVA进行分析，如果方差不齐(F值有显著性差异)，应用Games-Howell法进行检验。P<0.05认为有显著性差异。
4.实验结论
结果见表4.
表4
组别 剂量(mpk) TGI(％) P值
化合物1 20 77.7 0.001
结论：经过15天的给药观察，与溶媒对照组相比，本发明化合物展现出显著的抑瘤效果；且给药期间，动物耐受性良好。

Claims (12)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021112202-appb-100001
    其中，
    T选自N和CH；
    T 1、T 2和T 3分别独立地选自N和CH；
    R 1选自-S(＝O) 2-C 1-3烷基、-S(＝O)(＝NH)-C 1-3烷基和-S(＝O) 2-C 1-3烷氨基，所述-S(＝O) 2-C 1-3烷基、-S(＝O)(＝N)-C 1-3烷基和-S(＝O) 2-C 1-3烷氨基任选被1、2或3个R a取代；
    R 2分别独立地选自F、Cl、Br和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
    m选自0、1和2；
    L 1选自单键、-C(R c)(R d)-和-N(R e)-；
    R a和R b分别独立地选自F、Cl、Br和I；
    R c和R d分别独立地选自H、F、Cl、Br、I和CH 3；
    或者，R c和R d与它们相连的碳原子共同构成C 3-5环烷基，所述C 3-5环烷基任选被1、2或3个R取代；
    R e选自H和CH 3；
    R选自F、Cl、Br和I。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1选自
    Figure PCTCN2021112202-appb-100002
    Figure PCTCN2021112202-appb-100003
    所述
    Figure PCTCN2021112202-appb-100004
    任选被1、2或3个R a取代。
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，R 1选自
    Figure PCTCN2021112202-appb-100005
    Figure PCTCN2021112202-appb-100006
  4. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 2分别独立地选自F、Cl、Br和CH 3，所述CH 3任选被1、2或3个R b取代。
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，R 2分别独立地选自F。
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R c和R d与它们相连的碳原子共同构成环丙基，所述环丙基任选被1、2或3个R取代。
  7. 根据权利要求6所述化合物或其药学上可接受的盐，其中，R c和R d与它们相连的碳原子共同构成环丙基。
  8. 根据权利要求1或7所述化合物或其药学上可接受的盐，其中，L 1选自单键、-CH 2-、-NH-和
    Figure PCTCN2021112202-appb-100007
  9. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元R 1-L 1-选自
    Figure PCTCN2021112202-appb-100008
    Figure PCTCN2021112202-appb-100009
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2021112202-appb-100010
    选自
    Figure PCTCN2021112202-appb-100011
    Figure PCTCN2021112202-appb-100012
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其化合物选自：
    Figure PCTCN2021112202-appb-100013
    其中，
    R 1和R 2如权利要求1所定义。
  12. 下式所示化合物或其药学上可接受的盐，
    Figure PCTCN2021112202-appb-100014
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105164127A (zh) * 2013-03-11 2015-12-16 艾伯维公司 溴结构域抑制剂
WO2018086604A1 (zh) * 2016-11-10 2018-05-17 山东罗欣药业集团股份有限公司 一种含氮杂环类化合物、其制备方法、药物组合物及应用
WO2018086585A1 (zh) * 2016-11-10 2018-05-17 山东罗欣药业集团股份有限公司 一种含氮杂环类化合物、其制备方法、药物组合物及应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105164127A (zh) * 2013-03-11 2015-12-16 艾伯维公司 溴结构域抑制剂
WO2018086604A1 (zh) * 2016-11-10 2018-05-17 山东罗欣药业集团股份有限公司 一种含氮杂环类化合物、其制备方法、药物组合物及应用
WO2018086585A1 (zh) * 2016-11-10 2018-05-17 山东罗欣药业集团股份有限公司 一种含氮杂环类化合物、其制备方法、药物组合物及应用

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