WO2022179584A1 - 新型ezh2抑制剂及其用途 - Google Patents
新型ezh2抑制剂及其用途 Download PDFInfo
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- WO2022179584A1 WO2022179584A1 PCT/CN2022/077792 CN2022077792W WO2022179584A1 WO 2022179584 A1 WO2022179584 A1 WO 2022179584A1 CN 2022077792 W CN2022077792 W CN 2022077792W WO 2022179584 A1 WO2022179584 A1 WO 2022179584A1
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- Prior art keywords
- alkyl
- cancer
- compound
- halogen
- hydrogen
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title description 6
- 101150090105 Ezh2 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 claims abstract description 16
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 230000001404 mediated effect Effects 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- -1 C 1 -C 6 alkyl Chemical group 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000000217 alkyl group Chemical class 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229940002612 prodrug Drugs 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010027406 Mesothelioma Diseases 0.000 claims description 2
- 229910003827 NRaRb Inorganic materials 0.000 claims description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 claims description 2
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 11
- 238000006243 chemical reaction Methods 0.000 description 109
- 239000000243 solution Substances 0.000 description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 26
- 238000003756 stirring Methods 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 239000011780 sodium chloride Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 125000006413 ring segment Chemical group 0.000 description 12
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 12
- 125000002619 bicyclic group Chemical group 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 108010000597 Polycomb Repressive Complex 2 Proteins 0.000 description 8
- 102000002272 Polycomb Repressive Complex 2 Human genes 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 125000003367 polycyclic group Chemical group 0.000 description 8
- ALJRPIAYJALVFG-UHFFFAOYSA-N tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCOS1(=O)=O ALJRPIAYJALVFG-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- NZTBBJYAWNVCOE-XYPYZODXSA-N CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CC1)C#C Chemical compound CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CC1)C#C NZTBBJYAWNVCOE-XYPYZODXSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 6
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
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- 210000001853 liver microsome Anatomy 0.000 description 5
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- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 5
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- 238000000746 purification Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VTLCTOJLDMFEHV-UHFFFAOYSA-N 3-(chloromethyl)-4-methoxy-6-methyl-2-phenylmethoxypyridine Chemical compound C(C1=CC=CC=C1)OC1=NC(=CC(=C1CCl)OC)C VTLCTOJLDMFEHV-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 108010033040 Histones Proteins 0.000 description 4
- 102000006947 Histones Human genes 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
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- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 4
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- 230000014759 maintenance of location Effects 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- HRARFISHYLFDSY-UHFFFAOYSA-N 3-(chloromethyl)-4,6-dimethyl-2-phenylmethoxypyridine Chemical compound CC1=CC(C)=C(CCl)C(OCC=2C=CC=CC=2)=N1 HRARFISHYLFDSY-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- NSQSAUGJQHDYNO-UHFFFAOYSA-N n-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide Chemical compound C=1C(C=2C=CC(CN3CCOCC3)=CC=2)=CC(C(=O)NCC=2C(NC(C)=CC=2C)=O)=C(C)C=1N(CC)C1CCOCC1 NSQSAUGJQHDYNO-UHFFFAOYSA-N 0.000 description 3
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Classifications
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
Definitions
- the present application belongs to the field of chemical medicine, and specifically relates to a novel EZH2 inhibitor and use thereof.
- the abnormal activity of the core components of polycomb repressive complex 2 (PRC2) (EZH2, EED and SUZ12) is closely related to the occurrence, development and invasion of various diseases, especially malignant tumors.
- the core component of PRC2, EZH2 is significantly expressed in breast cancer, prostate cancer, colorectal cancer, soft tissue sarcoma, follicular lymphoma and other malignant tumor tissues, and its overexpression level is positively correlated with tumor progression and poor prognosis.
- Down-regulation of EZH2 expression by genetic methods can significantly inhibit tumor cell proliferation and invasion.
- recurrent somatic mutations of EZH2 have been identified in tumor cells such as disseminated large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).
- DLBCL disseminated large B-cell lymphoma
- FL follicular lymphoma
- Tazemetostat is the only EZH2 inhibitor currently approved by the FDA for the treatment of soft tissue sarcoma and follicular lymphoma (800mg/kg BID). At the same time, other redeveloped EZH2 inhibitors are still in clinical stage, CPI-1205 (clinical phase I/II), CPI-0209 (clinical phase I), DS-3201 (clinical phase II), SHR-2554 (clinical phase II) )Wait.
- the current research on Tazemetostat shows that it has problems such as insufficient stability, high dosage, and easy development of drug resistance. Therefore, the development of EZH2 inhibitors with novel compound structure, good activity and stability is still urgently needed.
- the present application discloses a class of compounds that can act as EZH2 inhibitors and their use in the preparation of medicaments for treating EZH2-mediated diseases.
- the application provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
- R 1 , R 2 , R 3 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, cyano or amino;
- L, U, V, T are each independently selected from C or N, and at least one is N;
- Y is selected from hydrogen, halogen or C 1 -C 6 alkyl
- X is selected from hydrogen, halogen, C 1 -C 6 alkyl, alkoxy or -SR 4 , and R 4 is C 1 -C 6 alkyl;
- Z is C3 - C7cycloalkyl or 4- to 7 -membered heterocyclyl, each of which is optionally replaced by 1 to 3 groups selected from halogen, C1 - C6 alkyl, halogenated C1 - C6 group substitution of alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy or -NRaRb;
- Ra is hydrogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl
- Rb is C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, or 4- to 7-membered heterocyclyl, wherein the heterocyclyl is optionally surrounded by 1 to 3 groups selected from halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy group substitution;
- Ra and Rb together with the nitrogen atom to which they are attached form optionally substituted with 1 to 3 groups selected from halogen, C1 - C6 alkyl, halogenated C1 - C6 alkyl or -ORc 4- to 7-membered heterocyclyl;
- Rc is C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl;
- n' are each independently 0, 1 or 2;
- n 0, 1, 2, 3, or 4;
- Formula (I) is Formula (Ia):
- R 1 , R 2 , R 3 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, cyano or amino;
- L, U, V, T are each independently selected from C or N, and at least one is N;
- Y is selected from hydrogen, halogen or C 1 -C 6 alkyl
- X is selected from hydrogen, halogen, C 1 -C 6 alkyl, alkoxy or -SR 4 , and R 4 is C 1 -C 6 alkyl;
- n' are each independently 0, 1 or 2;
- n 0, 1, 2, 3, or 4;
- Formula (I) is Formula (Ib):
- R 1 , R 2 , R 3 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl, cyano or amino;
- U and V are independently selected from C or N;
- X is selected from hydrogen, halogen, C 1 -C 6 alkyl, alkoxy or -SR 4 , and R 4 is C 1 -C 6 alkyl;
- n' are each independently 0, 1 or 2;
- n 0, 1, 2, 3, or 4;
- Formula (I) is Formula (Ic):
- X is selected from hydrogen, halogen, C 1 -C 6 alkyl, alkoxy or -SR 4 , and R 4 is C 1 -C 6 alkyl;
- n' are each independently 0, 1 or 2;
- n 0, 1, 2, 3, or 4;
- the compound of formula (I) is selected from:
- the application provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the foregoing compound, or a pharmaceutically acceptable salt, ester, prodrug, complex, solvate, hydrate or isomer thereof; and a pharmaceutically acceptable carrier or excipient.
- the present application provides use of the aforementioned compounds, or pharmaceutically acceptable salts, esters, prodrugs, complexes, solvates, hydrates or isomers thereof, for the manufacture of a medicament for the treatment of EZH2-mediated diseases.
- the disease is cancer.
- the cancer is lung cancer, gastric cancer, liver cancer, breast cancer, nasopharyngeal cancer, pancreatic cancer, ovarian cancer, cervical cancer, colorectal cancer, glioma, melanoma, prostate cancer, kidney cancer, Esophageal cancer, mesothelioma, head and neck cancer, bladder cancer, salivary gland cancer, leukemia or lymphoma.
- R 1 , R 2 , R 3 , U, V, m, n, n' As previously defined, it can be used to prepare the aforementioned compounds.
- isomer includes enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of a given structure.
- this application includes the R and S configurations, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers as well as enantiomers, diastereomers for each asymmetric center Isomers and geometric (or conformational) isomer mixtures.
- Suitable acid addition salts are formed from acids, which form non-toxic salts such as hydrochloride/chloride.
- Suitable base salts are formed from bases, which form non-toxic salts such as calcium and sodium salts. Hemi-salts of acids and bases, such as hemi-sulfate and hemi-calcium salts, can also be formed.
- terapéuticaally effective amount refers to an amount of a compound of the present application that (i) treats a particular disease, condition or disorder; (ii) alleviates, alleviates or eliminates one or more symptoms of a particular disease, condition or disorder or (iii) preventing or delaying the onset of one or more symptoms of the specified disease, condition or disorder described herein.
- pharmaceutically acceptable carrier or excipient refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
- alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group.
- Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl , 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl base, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2 ,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3 - Dimethylbutyl, etc.
- alkenyl refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond.
- an alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms.
- C 2-6 alkenyl includes straight or branched chain unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to vinyl, 1-propenyl , 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
- alkynyl refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond.
- the alkynyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 3 to 6 carbon atoms.
- C 2-6 alkynyl includes straight or branched chain unsaturated groups (having at least one carbon-carbon triple bond) of 2 to 6 carbon atoms.
- alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
- alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms (eg 3, 4, 5 or 6 carbon atoms), most preferably 5 to 6 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
- Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
- spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but each ring does not have complete Conjugated pi electron system.
- a spiro atom which may contain one or more double bonds, but each ring does not have complete Conjugated pi electron system.
- it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
- the spirocycloalkyl groups are divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl, More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
- fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but each ring does not have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
- bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but not each ring. Has a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
- heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon.
- It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
- Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazolyl Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl.
- Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
- spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O )m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but each ring does not have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the spiroheterocyclyl groups are divided into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl, More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
- fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), The remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
- bridged heterocyclyl refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but each ring does not have A fully conjugated pi-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
- m is an integer from 0 to 2
- it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
- the heterocyclic group includes the above-mentioned heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the same as the parent structure
- the rings linked together are heterocyclyl, non-limiting examples of which include:
- aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, such as benzene base and naphthyl.
- heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
- Heteroaryl is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl and the like.
- the heteroaryl group includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
- hydroxyalkyl refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.
- haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
- haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
- deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
- deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.
- cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.
- cycloalkyloxy refers to -O-cycloalkyl, wherein cycloalkyl is as defined above.
- heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
- arylalkyl refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.
- hydroxy refers to the -OH group.
- halogen refers to fluorine, chlorine, bromine or iodine.
- amino refers to -NH2 .
- cyano refers to -CN.
- nitro refers to -NO2 .
- Example 1 10-((1r,4r)-4-(dimethylamino)cyclohexyl)-8,10-dimethyl-6-((6-methyl-4-(methylthio)- 2-oxo-1,2-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepine[6,7,1-hi][1,3 Synthesis of ]Dioxazolo[4,5-e]indol-7(4H)-one
- reaction solution was poured into 30% aqueous sodium hydroxide solution on ice (500 mL), extracted twice with ethyl acetate, the organic phase was washed with saturated brine solution, and dried with MgSO 4 , and spin-dried to obtain Intermediate 1.3 (32.60 g, 100% yield), directly into the next reaction.
- Example 2 8-Chloro-10-((1r,4r)-4-(dimethylamino)cyclohexyl)-10-methyl-6-((6-methyl-4-(methylthio)- 2-oxo-1,2-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepine[6,7,1-hi][1,3 ]dioxa[4,5-e]indol-7(4H)-one
- Methyl 3,4-dihydroxy-2-chlorobenzoate (20 g, 0.10 mol, 1.0 eq.), dichloromethane (100 mL) and acetic acid (10 mL) were added to the reaction flask under an ice-water bath, and then the solution was added dropwise.
- Bromine (17.50g, 0.1mol, 1.1eq.) was naturally warmed to room temperature and reacted overnight for 12h.
- the reaction solution was spin-dried, water (100 mL) was added to make slurry, and suction filtered.
- the filter cake was slurried with dichloromethane (20 mL) and filtered again with suction.
- reaction solution was poured into 30% aqueous sodium hydroxide solution on ice (300 mL), extracted twice with ethyl acetate, the organic phase was washed with saturated saline solution, dried over MgSO4 , and spin-dried to obtain Intermediate 2.3 (21.30 g, 100% yield). rate), directly into the next reaction.
- Example 3 10-((1r,4r)-4-(dimethylamino)cyclohexyl)-8,10-dimethyl-6-((6-methyl-4-(methylthio)-2 -oxo-2,3-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepine[6,7,1-hi][1,3] Synthesis of Dioxa[4,5-e]indazol-7(4H)-one
- Methyl 3,4-dihydroxy-2,5-dimethylbenzoate (10.0 g, 51.48 mmol, 1.0 eq.) was dissolved in toluene (150 mL). Under stirring, add tert-butyl trans-N-(4-ethynylcyclohexyl)carbamate (11.50g, 51.47mmol, 1.0eq.), Ru3 (CO) 12 (0.64g, 1.54mmol, 0.03eq.) , heated to 105°C after nitrogen replacement for 3 times, reacted overnight for 10h, and added tert-butyl trans-N-(4-ethynylcyclohexyl)carbamate (11.50g, 51.48mmol, 1.2eq.), Ru 3 ( CO) 12 (0.639g, 1.54mmol, 0.03eq.), evacuated with nitrogen for 3 times, heated to 105°C, and reacted for 10h.
- reaction solution was poured into 30% aqueous sodium hydroxide solution on ice (250 mL), extracted twice with ethyl acetate, the organic phase was washed with saturated saline solution, dried over MgSO 4 , and spin-dried to obtain Intermediate 3.2 (10.42 g, 100% yield). rate), directly into the next reaction.
- Example 7 (4S,10R)-10-((1r,4R)-4-(dimethylamino)cyclohexyl)-4,8,10-trimethyl-6-((6-methyl-4 -(Methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepine[6,7,1 Synthesis of -hi][1,3]dioxa[4,5-e]indol-7(4H)-one
- Example 8 (10R)-10-((1r,4R)-4-(dimethylamino)cyclohexyl)-5,8,10-trimethyl-6-((6-methyl-4-( Methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepine[6,7,1-hi Synthesis of ][1,3]dioxa[4,5-e]indol-7(4H)-one
- Example 12 (R)-10-((1r,4R)-4-(dimethylamino)cyclohexyl)-8,10-dimethyl-6-((6-methyl-4-(methylthio) yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepin[6,7,1-hi][ Synthesis of 1,3]dioxa[4,5-e]indazol-7(4H)-one
- Example 13 (S)-10-((1r,4S)-4-(dimethylamino)cyclohexyl)-8,10-dimethyl-6-((6-methyl-4-(methylthio) yl)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepin[6,7,1-hi][ Synthesis of 1,3]dioxa[4,5-e]indazol-7(4H)-one
- Example 14 (4R,10R)-10-((1r,4R)-4-(dimethylamino)cyclohexyl)-4,8,10-trimethyl-6-((6-methyl-4 -(Methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepine[6,7,1 Synthesis of -hi][1,3]dioxa[4,5-e]indazol-7(4H)-one
- Example 15 (4S,10R)-10-((1r,4R)-4-(dimethylamino)cyclohexyl)-4,8,10-trimethyl-6-((6-methyl-4 -(Methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepine[6,7,1 Synthesis of -hi][1,3]dioxa[4,5-e]indazol-7(4H)-one
- Example 17 (4R,10R)-10-((1r,4R)-4-(dimethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxy- 1,2-Dihydropyridin-3-yl)methyl)-4,8,10-trimethyl-5,6-dihydro-[1,4]diazepine[6,7,1-hi Synthesis of ][1,3]dioxa[4,5-e]indol-7(4H)-one
- Example 18 (4S,10R)-10-((1r,4R)-4-(dimethylamino)cyclohexyl)-6-((4-methoxy-6-methyl-2-oxy- 1,2-Dihydropyridin-3-yl)methyl)-4,8,10-trimethyl-5,6-dihydro-[1,4]diazepine[6,7,1-hi Synthesis of ][1,3]dioxa[4,5-e]indol-7(4H)-one
- Example 20 ((5R,10R)-10-((1r,4R)-4-(dimethylamino)cyclohexyl)-5,8,10-trimethyl-6-((6-methyl- 4-(Methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepine[6,7, Synthesis of 1-hi][1,3]dioxa[4,5-e]indol-7(4H)-one
- Example 22 (4R,10S)-8-chloro-10-((1r,4S)-4-(dimethylamino)cyclohexyl)-4,10-dimethyl-6-((6-methyl) -4-(Methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5,6-dihydro-[1,4]diazepine[6,7 Synthesis of ,1-hi][1,3]dioxa[4,5-e]indol-7(4H)-one
- PRC2 complexes were purchased from Carna Biosciences (Japan), Histone H3(21-44)-GK(biotin), Streptavidin-XL665 and Mab Anti histone H3K27Me1-Eu(K) were purchased from Cisbio (France).
- SAM (30 mM), DTT (1 M), 10% BAS, Tris-HCl (50 mM), NaCl (50 mM), 10% Tween and dimethyl sulfoxide (DMSO) were purchased from Sigma. 384-well white plates were purchased from CORNING (USA).
- the assay buffer used in the experiment consisted of 50 mM Tris-HCl, 50 mM NaCl, 1 mM DTT, 0.01% Tween, 0.1% BSA.
- the final concentrations of PRC2, Histone H3(21-44)-GK(biotin), SAM and DMSO were 1 ng/ ⁇ L, 5 ⁇ M, 15 ⁇ M and 1%, respectively.
- 5 ⁇ L detection antibody Mab Anti histone H3K27Me1-Eu(K) and 5 ⁇ L Streptavidin-XL665 were added and incubated at room temperature for 2 h.
- the plate was read on a SPARK multifunctional enzyme labeling instrument of TECAN (Switzerland) with excitation wavelength of 320 nm and emission wavelength of 665 nm.
- Compound IC50 values were determined using a sigmoidal dose-response model (variable slope, four parameters) in Prism7 (LaJolla, CA).
- Karpas422 cells were purchased from Cell Bank of Chinese Academy of Sciences (Shanghai); RPMI1640 medium, penicillin-streptomycin dual antibody and 0.5% trypsin (10X) were purchased from ThermoFisher (Waltham, MA, USA). Certified fetal bovine serum (FBS) was purchased from Biological Industries (Israel). Corning 96-well cell culture plates were purchased from CORNING (USA). Counting Kit-8 detection kit was purchased from Biyuntian (China).
- DMSO solution of compound stock plate was added to 99 ⁇ L cell culture medium, the final maximum concentration of compound in the assay was 10 ⁇ M, and the final concentration of DMSO was (0.5%).
- 100 ⁇ L of compound solutions in culture medium were added to each well of SU-DHL-10 and Karpas422 cell plates. After adding compound solutions, place the 96-well plate in a 37°C, 5% CO2 incubator for 8 days.
- the Counting Kit-8 detection kit the cell viability was determined by quantifying the amount of formazan produced in the cell culture in direct proportion to the number of viable cells. After a 2-hour incubation, readings were performed using a SPARK multi-plate reader from TECAN under the program of chemiluminescence.
- a sigmoidal dose-response model (variable slope, four parameters) was used in Prism 7 (LaJolla, CA) to determine the concentration of compound at which cell viability was inhibited by 50% ( IC50 value).
- Human liver microsomes were from Corning, and ICR/CD-1 rat liver microsomes (male) were also from Corning, and were stored in a -80°C refrigerator, respectively.
- Sodium dihydrogen phosphate, potassium dihydrogen phosphate and NADPH were purchased from Sigma.
- the test substance was prepared with DMSO to prepare a high-concentration stock solution, which was diluted with DMSO to a working solution of 200 ⁇ M before use, and the final concentration of the test substance was 1 ⁇ M.
- To solution A was added solution B until the pH was 7.4.
- an appropriate amount of NADPH was weighed, and a phosphate solution was used to prepare a working solution with a concentration of 10 mM.
Abstract
公开了一种式(I)所示的化合物、其立体异构体或其药学上可接受的盐，以及其用于制备治疗EZH2介导的疾病药物的用途。
Description
本申请属于化学医药领域，具体涉及一种新型EZH2抑制剂及其用途。
多梳抑制复合物2(PRC2)核心组分(EZH2，EED和SUZ12)的活性异常与多种疾病，尤其是恶性肿瘤的发生、发展及侵袭密切相关。PRC2的核心组分EZH2在乳腺癌、前列腺癌、大肠癌、软组织肉瘤、滤泡性淋巴瘤等多种恶性肿瘤组织中表达显著升高，其过表达水平与肿瘤恶化程度及不良预后呈正相关，通过遗传学方法下调EZH2的表达，可显著抑制肿瘤细胞的增殖和侵袭。同时在弥散性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)等肿瘤细胞中已鉴定出EZH2的再发性体细胞突变。
Tazemetostat是目前FDA批准的唯一的EZH2抑制剂，用于治疗软组织肉瘤和滤泡性淋巴瘤(800mg/kg BID)。同时其他再开发的EZH2抑制剂均仍处于临床阶段，CPI-1205(临床I/II期)、CPI-0209(临床I期)、DS-3201(临床II期)、SHR-2554(临床II期)等。目前针对Tazemetostat的研究显示，其存在稳定性不足、给药剂量高、容易产生耐药性等问题，因此开发具有新颖的化合物结构、良好的活性及稳定性的EZH2抑制剂仍亟需进行。
发明内容
本申请公开了一类可作为EZH2抑制剂的化合物以及其在制备用于治疗EZH2介导的疾病的药物中的用途。
一方面，本申请提供了式(I)所示的化合物、其立体异构体或其药学上可接受的盐：
其中，R
1、R
2、R
3各自独立地选自氢、卤素、C
1-C
6烷基、羟基、氰基或氨基；
L、U、V、T各自独立地选自C或N，且至少一个为N；
Y选自氢、卤素或C
1-C
6烷基；
X选自氢、卤素、C
1-C
6烷基、烷氧基或-S-R
4，R
4为C
1-C
6烷基；
Z是C
3-C
7环烷基或4到7元杂环基，其中的每一个任选地被1到3个选自卤素、C
1-C
6烷基、卤代C
1-C
6烷基、C
1-C
6烷氧基、卤代C
1-C
6烷氧基或-NRaRb的基团取代；
Ra是氢、C
1-C
6烷基或卤代C
1-C
6烷基；
Rb是C
1-C
6烷基、卤代C
1-C
6烷基或4到7元杂环基，其中所述杂环基任选地被1到3个选自卤素、C
1-C
6烷基、卤代C
1-C
6烷基、C
1-C
6烷氧基或卤代C
1-C
6烷氧基的基团取代；
或Ra和Rb与其所附接的氮原子一起形成任选地被1到3个选自卤素、C
1-C
6烷基、卤代C
1-C
6烷基或-ORc的基团取代的4到7元杂环基；
Rc是C
1-C
6烷基、卤代C
1-C
6烷基或C
3-C
7环烷基；
m、n’各自独立地为0、1或2；
n为0、1、2、3或4；以及
在某些实施方案中，式(I)是式(Ia)：
其中，R
1、R
2、R
3各自独立地选自氢、卤素、C
1-C
6烷基、羟基、氰基或氨基；
L、U、V、T各自独立地选自C或N，且至少一个为N；
Y选自氢、卤素或C
1-C
6烷基；
X选自氢、卤素、C
1-C
6烷基、烷氧基或-S-R
4，R
4为C
1-C
6烷基；
m、n’各自独立地为0、1或2；
n为0、1、2、3或4；以及
在某些实施方案中，式(I)是式(Ib)：
其中，R
1、R
2、R
3各自独立地选自氢、卤素、C
1-C
6烷基、羟基、氰基或氨基；
U、V各自独立地选自C或N；
X选自氢、卤素、C
1-C
6烷基、烷氧基或-S-R
4，R
4为C
1-C
6烷基；
m、n’各自独立地为0、1或2；
n为0、1、2、3或4；以及
在某些实施方案中，式(I)是式(Ic)：
其中，R
1、R
2、R
3各自独立地选自氢、卤素、C
1-C
6烷基、羟基、氰基或氨基；U、V各自独立地选自C或N；
X选自氢、卤素、C
1-C
6烷基、烷氧基或-S-R
4，R
4为C
1-C
6烷基；
m、n’各自独立地为0、1或2；
n为0、1、2、3或4；以及
在某些实施方案中，式(I)所示的化合物选自：
另一方面，本申请提供一种药物组合物，其包含治疗有效量的前述化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体；以及药学上可接受的载体或赋形剂。
另一方面，本申请提供前述化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备治疗EZH2介导的疾病药物的用途。
在某些实施方案中，所述疾病为癌症。
在某些实施方案中，所述癌症为肺癌、胃癌、肝癌、乳腺癌、鼻咽癌、胰腺癌、卵巢癌、宫颈癌、结肠直肠癌、胶质瘤、黑色素瘤、前列腺癌、肾癌、食道癌、间皮瘤、头颈癌、膀胱癌、唾腺癌、白血病或淋巴瘤。
另一方面，本申请提供式(II)所示的化合物或其立体异构体：
其中，R
1、R
2、R
3、U、V、m、n、n’、
如前述所定义，其可用于制备前述化合物。
术语：
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“异构体”包括给定结构的对映异构形式、非对映异构形式和几何(或构象)异构形式。例如，本申请包括每个不对称中心的R和S构型、Z和E双键异构体、Z和E构象异构体、单一立体化学异构体及对映异构体、非对映异构体和几何(或构象)异构体混合物。
术语“药学上可接受的盐”指，诸如其酸加成盐和/或碱盐。合适的酸加成盐由酸形成，其形成无毒盐，例如盐酸盐/氯化物。合适的碱盐由碱形成，其形成无毒盐，例如钙盐和钠盐。 还可形成酸和碱的半盐，例如半硫酸盐和半钙盐。
术语“治疗有效量”是指本申请化合物的以下量，其(i)治疗具体的疾病、病症或障碍；(ii)减轻、缓解或消除具体的疾病、病症或障碍的一种或多种症状；或(iii)预防或延迟本申请所述具体的疾病、病症或障碍的一种或多种症状的发作。
术语“药学上可接受的载体或赋形剂”是指不破坏用其配制的化合物的药理活性的无毒载体、辅料或媒介物。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。含有1至6个碳原子的低级烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。
术语“烯基”指具有至少一个碳-碳双键的脂族烃，包括具有至少一个碳-碳双键的直链和支链。在一些实施方案中，烯基基团具有2至20个碳原子、2至10个碳原子、2至6个碳原子、3至6个碳原子或2至4个碳原子。例如，术语“C
2-6烯基”包括2至6个碳原子的直链或支链不饱和基团(具有至少一个碳-碳双键)，包括但不限于乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。
术语“炔基”指具有至少一个碳-碳三键的脂族烃，包括具有至少一个碳-碳三键的直链和支链。在一些实施方案中，炔基基团具有2至20个碳原子、2至10个碳原子、2至6个碳原子、或3至6个碳原子。例如，“C
2-6炔基”包括2至6个碳原子的直链或支链不饱和基团(具有至少一个碳-碳三键)。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基如上所定义。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子(例如3、4、5或6个碳原子)，最优选包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基，更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至6个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基，更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但每个环均不具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。
所述杂环基包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基和哒嗪基等。
所述杂芳基包括如上所述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“氘代烷氧基”指烷氧基被一个或多个氘原子取代，其中烷氧基如上所定义。
术语“环烷基烷基”指烷基被一个或多个环烷基取代，其中环烷基和烷基如上所定义。
术语“环烷基氧基”指-O-环烷基，其中环烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基和烷基如上所定义。
术语“芳基烷基”指烷基被一个或多个芳基取代，其中芳基和烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH
2。
术语“氰基”指-CN。
术语“硝基”指-NO
2。
术语“羧基”指-C(O)OH。
实施例1：10-((1r，4r)-4-(二甲基氨基)环己基)-8,10-二甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二噁唑[4,5-e]吲哚-7(4H)-酮的合成
在冰水浴下向反应瓶中加入3,4-二羟基-2-甲基苯甲酸甲酯(20.00g，0.11mol，1.0eq.)，二氯甲烷(DCM，100mL)与乙酸(10mL)，而后滴加液溴(17.57g，0.11mol，1.0eq.)，自然升温至室温，过夜反应12h。旋干反应液，加入水(100mL)打浆，抽滤。滤饼用二氯甲烷(20mL)打浆后再次抽滤。将滤饼用油泵抽干，得中间体1.1(24.60g，85.9％产率)。MS:[M+H]
+＝261。
将中间体1.1(24.60g，0.094mol，1.0eq.)溶于甲苯(250mL)。搅拌下加入反式-N-(4-乙炔基环己基)氨基甲酸叔丁酯(25.00g，0.11mol，1.2eq.)，Ru
3(CO)
12(1.81g，0.003mol，0.03eq.)，氮气置换3次后加热至105℃，过夜反应10h后补加反式-N-(4-乙炔基环己基)氨基甲酸叔丁酯(25.00g，0.11mol，1.2eq.)，Ru
3(CO)
12(1.81g，0.003mol，0.03eq.)，氮气抽充3次后加热至105℃，再反应10h。反应液冷却至室温后，垫硅藻土过滤。滤液浓缩后通过柱层析分离纯化(PE:EA)＝10:1，得到中间体1.2(36.70g，80.4％产率)。MS:[M+H]
+＝485。
向反应瓶中加入中间体1.2(36.70g，0.076mol，1.0eq.)，加入乙酸酐(120mL)溶解，滴入1滴浓硫酸。冰盐浴条件下，滴加稀硝酸(110mL)。控制内温不超过45℃，滴加完毕后室温反应1h。将反应液倒入冰的30％氢氧化钠水溶液中(500mL)，乙酸乙酯萃取两次，饱和食盐水溶液洗涤有机相，并用MgSO
4干燥，旋干后得中间体1.3(32.60g，100％产率)， 直接投入下一步反应。
DCM溶解中间体1.3(32.60g，0.076mol，1.0eq.)，加入三乙胺(23.00g，0.23mol，3.0eq.)和DMAP(0.93g，0.0076mol，0.1eq.)。冰浴条件下，加入二碳酸二叔丁酯(24.80g，0.11mol，1.5eq.)。将该反应转移至室温，反应2h。浓缩反应液后通过柱层析分离纯化(PE:EA＝4:1)，得中间体1.4(22.89g，56.9％产率)。MS:[M+H]
+＝530。
向装有中间体1.4(2.20g，0.0043mol，1.0eq.)的反应瓶中加入二异丙胺(200mL)和四氢呋喃(20mL)。搅拌溶解后加入CuI(7.74mg，0.043mmol，0.01eq.)、TMSA(1.57g，0.0086mol，2eq.)和Pd(PPh
3)
2Cl
2(0.090g，0.13mmol，0.03eq.)。氮气置换三次后升温至70℃，反应6h。硅藻土过滤反应液。旋干反应液后，通过柱层析分离纯化(PE:EA＝4:1)，得中间体1.5(1.89g，80.3％产率)，为深棕色油状物。MS:[M+H]
+＝547。
向装有中间体1.5(1.89g，0.035mol，1.0eq.)的反应瓶中加入TBAF的四氢呋喃溶液(1M，10mL)，室温搅拌1h。旋干反应液后，加入水，乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤后无水硫酸镁干燥。通过柱层析分离纯化(PE:EA＝4:1)，得中间体1.6(1.49g，90.9％产率)。MS:[M+H]
+＝475。
向装有中间体1.6(1.49g，0.003mol，1.0eq.)的反应瓶中加入DCM(15mL)和DMF(15mL)。搅拌溶解后加入二水合氯化亚锡(3.56g，0.150mol，5.0eq.)。室温搅拌2h。向反应液中加入饱和碳酸氢钠水溶液(2L)。乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤，MgSO
4干燥。旋干后通过柱层析分离纯化(PE:EA＝4:1)，得中间体1.7(0.89g，63.9％产率)。MS:[M+H]
+＝445。
向装有中间体1.7(0.89g，0.002mol，1.0eq.)的反应瓶中，加入吡啶(10mL)、Cp(PPh
3)
2RuCl(0.15g，0.003mol，0.1eq.)。氮气置换三次后升温至90℃反应2h。硅藻土过滤反应液。通过柱层析分离纯化(PE:EA＝4:1)，得中间体1.8(0.81g，90.6％产率)。MS:[M+H]
+＝445。
1H NMR(400MHz,DMSO-d
6)δ10.91(s,1H),7.30-7.24(m,1H),6.75(d,J＝7.9Hz,1H),6.37-6.34(m,1H),3.87(s,3H),3.25-3.10(m,1H),2.48(s,3H),1.93-1.74(m,5H),1.59(s,3H),1.36(s,9H),1.30-1.06(m,4H).
向装有中间体1.8(0.81g，0.0018mol，1.0eq.)的反应瓶中加入DMF(50mL)，搅拌，降低温至0℃，缓慢加入NaH(0.087g，0.0022mol，1.2eq.)，反应0.5h后加入1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物(0.81g，0.0036mol，2.0eq.)。自然升温至室温，反应6h。向反应液中加入水，乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤有机相，MgSO
4干燥。旋干得中间体1.9(0.62g，58.1％产率)。MS:[M+H]
+＝588.
向装有中间体1.9(0.62g，0.001mol，1.0eq.)的反应瓶中加入甲醇(12mL)，再加入盐酸1,4-二氧六环溶液(4M，3mL)，升温至70℃，反应0.5h。旋干反应液后得中间体1.10，直接投入下一步反应。
向装有中间体1.10的反应瓶中加入甲醇(10mL)，搅拌溶解后加入碳酸铯(0.98g，0.003mol，3.0eq.)，升温至70℃，反应2h。旋干反应液后得中间体1.11，直接投入下一步反应。
向装有中间体1.11的反应瓶中加入DCM(10mL)，搅拌溶解后加入三乙胺(0.30g，0.003mol，3.0eq.)，冰水浴下加入二碳酸二叔丁酯(0.33g，0.0015mol，1.5eq.)。转移至室温反应1h。旋干反应液后，通过柱层析分离纯化(DCM:MeOH＝20:1)，得中间体1.12(0.29g，61.5％产率)。MS:[M+H]
+＝456。
向装有中间体1.12(0.29g，0.60mmol，1.0eq.)的反应瓶中加入DMF(5mL)，搅拌，冰水浴条件下加入t-BuOK(0.14g，12.0mol，2.0eq.)，搅拌20min后加入2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶(0.2g，0.72mmol，1.2eq.)。反应3h后，向反应液中加入水(50mL)，而后乙酸乙酯(50mL×3)萃取。饱和氯化钠水溶液洗涤，MgSO
4干燥。旋干后，通过柱层析分离纯化(PE:EA＝4:1)，得中间体1.13(0.39g，90.4％产率)。MS:[M+H]
+＝713。
将中间体1.13(0.39g，5.4mmol，1.0eq.)溶于5mL甲醇中，再加入盐酸1,4-二氧六环(1mL，7M)，升温至70℃，反应0.5h。旋干反应液，得中间体1.14(0.28g，100％产率)。
将中间体1.14(0.28g，5.4mmol，1.0eq.)溶于5mL甲醇中，加入甲醛水溶液(0.5mL，37％，10eq.)，搅拌15min后加入STAB(0.57g，2.7mmol，5eq.)，再搅拌15min。而后旋干反应液，通过柱层析分离纯化(DCM:MeOH＝8:1)，得实施例1标题化合物(0.28g，94.3％产率)。MS:[M+H]
+＝551。
1H NMR(400MHz,DMSO-d
6)11.70(s,1H),7.21(s,1H),6.30(s,1H),6.14(s,1H),4.73(s,2H),4.07(s,2H),3.51(s,2H),2.65(s,3H),2.41(d,J＝7.7Hz,6H),2.32-2.36(m,1H),2.30(s,3H),2.21(s,3H),1.89(s,5H),1.59(s,3H),1.19-1.28(m,4H)。
实施例2：8-氯-10-((1r，4r)-4-(二甲氨基)环己基)-10-甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮
在冰水浴下向反应瓶中加入3,4-二羟基-2-氯苯甲酸甲酯(20g，0.10mol，1.0eq.)，二氯甲烷(100mL)与乙酸(10mL)，而后滴加液溴(17.50g，0.1mol，1.1eq.)，自然升温至室温，过夜反应12h。旋干反应液，加入水(100mL)打浆，抽滤。滤饼用二氯甲烷(20mL)打浆后再次抽滤。将滤饼用油泵抽干，得中间体2.1(24.00g，85.7％产率)。MS:[M+H]
+＝280。
1H NMR(400MHz,DMSO),7.35(d,J＝3.3Hz,1H),3.70(s,3H)。
将中间体2.1(24.00g，0.085mol，1.0eq.)溶于甲苯(200mL)。搅拌下加入反式-N-(4-乙炔基环己基)氨基甲酸叔丁酯(20.00g，0.88mol，0.88.00eq.)，Ru
3(CO)
12(1.60g，0.00255mol，0.03eq.)，氮气置换3次后加热至105℃，过夜反应10h后补加反式-N-(4-乙炔基环己基)氨基甲酸叔丁酯(20.00g，0.88mol，0.88eq.)，氮气抽充3次后加热至105℃，再反应10h。反应液冷却至室温后，垫硅藻土过滤。浓缩后通过柱层析分离纯化(PE:EA)＝10:1，得到中间体2.2(24.00g，56.6％产率)。MS:[M+H]
+＝504。
向反应瓶中加入中间体2.2(24.00g，0.047mol，1.0eq.)，加入乙酸酐(120mL)溶解，滴入1滴浓硫酸。冰盐浴条件下滴加稀硝酸(60mL)。控制内温不超过45℃，滴加完毕后室温反应1h。将反应液倒入冰的30％氢氧化钠水溶液中(300mL)，乙酸乙酯萃取两次，饱和食盐水溶液洗涤有机相，MgSO
4干燥，旋干后得中间体2.3(21.30g，100％产率)，直接投入下一步反应。
DCM溶解中间体2.3(21.30g，0.047mol，1.0eq.)，加入三乙胺(15.00g，0.15mol，3.0eq.)，DMAP(0.57g，0.0047mol，0.1eq.)。冰浴条件下加入二碳酸二叔丁酯(17.50g，0.64mol，1.5eq.)。转移至室温反应2h。浓缩反应液后通过柱层析分离纯化(PE:EA＝4:1)，得中间体2.4(20.80g，75.0％产率)。MS:[M+H]
+＝549。
1H NMR(400MHz,DMSO),7.51(s,1H),6.75(d,J＝3.3Hz,1H),3.80(s,3H),3.21-3.05(m,1H),1.95-1.65(m,5H),1.70(s,3H),1.45(s,9H),1.30-1.15(m,4H)。
向装有中间体2.4(2.00g，3.80mmol，1.0eq.)的反应瓶中加入二异丙胺(20mL)和四氢呋喃(5mL)。搅拌溶解后加入CuI(7.10mg，0.038mmol，0.01eq.)、TMSA(1.38g，7.6mol，2eq.)、Pd(PPh
3)
2Cl
2(83.60mg，0.11mmol，0.03eq.)。氮气置换三次后升温至70℃，反应6h。硅藻土过滤反应液。旋干反应液后通过柱层析分离纯化(PE:EA＝4:1)，得中间体2.5(1.89g，80.3％产率)，为深棕色油状物。MS:[M+H]
+＝567。
向装有中间体2.5(1.89g，3.30mmol，1.0eq.)的反应瓶中加入TBAF的四氢呋喃溶液(1M，10mL)，室温搅拌1h。旋干反应液后，加入水，乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤后无水硫酸镁干燥。通过柱层析分离纯化(PE:EA＝4:1)，得中间体2.6(1.49g，90.3％产率)，为深棕色油状物。MS:[M+H]
+＝495。
向装有中间体2.6(1.49g，0.0030mmol，1.0eq.)的反应瓶中加入DCM(15mL)和DMF(15mL)。搅拌溶解后加入二水合氯化亚锡(3.38g，0.0150mmol，5.0eq.)，室温搅拌2h。向反应液中加入饱和碳酸氢钠水溶液(2L)。乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤，MgSO
4干燥。旋干后通过柱层析分离纯化(PE:EA＝4:1)，得中间体2.7(1.10g，78.6％产率)。MS:[M+H]
+＝465。
向装有中间体2.7(1.10g，0.0023mol，1.0eq.)的反应瓶中，加入吡啶(50mL)、Cp(PPh
3)
2RuCl(0.15g，0.00023mol，0.1eq.)。氮气置换三次后升温至90℃反应2h。硅藻土过滤反应液。通过柱层析分离纯化(PE:EA＝4:1)，得中间体1.8(1.00g，90.9％产率)。MS:[M+H]
+＝465。
向装有中间体2.8(1.00g，0.0022mol，1.0eq.)的反应瓶中加入DMF(20mL)。搅拌，降低温至0℃。缓慢加入NaH(0.10g，0.0026mol，1.2eq.)。0.5h后加入1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物(1.46g，0.0044mol，2.0eq.)。自然升温至室温，反应6h。向反应液中加入水，乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤有机相，MgSO
4干燥。旋干得中间体2.9(0.95g，73.0％产率)。MS:[M+H]
+＝608。
向装有中间体2.9(0.95g，0.0015mol，1.0eq.)的反应瓶中加入甲醇(12mL)，再加入盐酸1,4-二氧六环溶液(4M，3mL)，升温至70℃，反应0.5h。旋干反应液后得中间体2.10，直接投入下一步反应。
向装有中间体2.10的反应瓶中加入甲醇(10mL)，搅拌溶解后加入碳酸铯(1.38g，0.0045mol，3.0eq.)，升温至70℃，反应2h。旋干反应液后得中间体2.11，直接投入下一步反应。
向装有中间体2.11的反应瓶中加入DCM(60mL)，搅拌溶解后加入三乙胺(0.58g，0.0045 mol，3.0eq.)，冰水浴下加入二碳酸二叔丁酯(0.49g，0.0225mol，1.5eq.)。转移至室温反应1h。旋干反应液后通过柱层析分离纯化(DCM:MeOH＝20:1)，得中间体2.12(0.51g，71.4％产率)。MS:[M+H]
+＝476。
向装有中间体2.12(0.51g，0.001mol，1.0eq.)的反应瓶中加入DMF(30mL)，搅拌，冰水浴条件下加入t-BuOK(0.22g，0.002mol，2.0eq.)，搅拌20min后加入2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶(0.32g，0.0012mol，1.2eq.)。反应3h后，向反应液中加入水(200mL)，而后乙酸乙酯(80mL×3)萃取。饱和氯化钠水溶液洗涤，MgSO
4干燥。旋干后通过柱层析分离纯化(PE:EA＝4:1)，得中间体2.13(0.65g，91.5％产率)，为黄色固体。MS:[M+H]
+＝733.
将中间体2.13(0.65g，0.89mmol，1.0eq.)溶于5mL甲醇中，再加入盐酸1,4-二氧六环(0.5mL，7M)，升温至70℃，反应0.5h。旋干反应液，得中间体2.14(0.56g，100％产率)。
将中间体2.14(0.56g，0.89mmol，1.0eq.)溶于50mL甲醇中，加入甲醛水溶液(1.0mL，37％，10eq.)，搅拌15min后加入STAB(0.95g，4.45mmol，5eq.),再搅拌15min。而后旋干反应液，通过柱层析分离纯化(DCM:MeOH＝8:1)，得实施例2标题化合物(0.28g，48.3％产率)。MS:[M+H]
+＝571。
1H NMR(400MHz,DMSO)δ11.73(s,1H),7.35(d,J＝3.3Hz,1H),6.38(d,J＝3.3Hz,1H),6.15(s,1H),4.73(d,J＝17.8Hz,2H),4.23(d,J＝6.5Hz,2H),3.55(s,2H),2.63(s,3H),2.43(s,3H),2.49(s,3H),2.30-2.36(m,1H),2.22(s,3H),1.95-2.05(m,4H),1.65(d,J＝6.4Hz,3H),1.48-1.55(m,1H),1.25-1.40(m,4H)。
实施例3:10-((1r，4r)-4-(二甲氨基)环己基)-8,10-二甲基-6-((6-甲基-4-(甲硫基)-2-氧代-2,3-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲达唑-7(4H)-酮的合成
将3,4-二羟基-2,5-二甲基苯甲酸甲酯(10.0g，51.48mmol，1.0eq.)溶于甲苯(150mL)。搅拌下加入反式-N-(4-乙炔基环己基)氨基甲酸叔丁酯(11.50g，51.47mmol，1.0eq.)，Ru
3(CO)
12(0.64g，1.54mmol，0.03eq.)，氮气置换3次后加热至105℃，过夜反应10h后补加反式-N-(4-乙炔基环己基)氨基甲酸叔丁酯(11.50g，51.48mmol，1.2eq.)，Ru
3(CO)
12(0.639g，1.54mmol，0.03eq.)，氮气抽充3次后加热至105℃，再反应10h。反应液冷却至室温后，垫硅藻土过滤。浓缩后通过柱层析分离纯化(PE:EA)＝10:1，得到中间体3.1(12.86g，59.53％产率)。MS:[M+H]
+＝420。
向反应瓶中加入中间体3.1(12.00g，0.028mol，1.0eq.)，加入乙酸酐(60mL)溶解，滴入1滴浓硫酸。冰盐浴条件下滴加稀硝酸(55mL)。控制内温不超过45℃，滴加完毕后室温反应1h。将反应液倒入冰的30％氢氧化钠水溶液中(250mL)，乙酸乙酯萃取两次，饱和食盐水溶液洗涤有机相，MgSO
4干燥，旋干后得中间体3.2(10.42g，100％产率)，直接投入下一步反应。
DCM溶解中间体3.2(10.42g，0.028mol，1.0eq.)，加入三乙胺(8.67g，0.085mol，3.0eq.)，DMAP(0.37g，0.0028mol，0.1eq.)。冰浴条件下加入二碳酸二叔丁酯(9.36g，0.043mol，1.5eq.)。转移至室温反应2h。浓缩反应液后通过柱层析分离纯化(PE:EA＝4:1)，得中间体3.3(6.75g，50.8％产率)。MS:[M+H]
+＝465。
向装有中间体3.3(6.75g，0.0145mol,1.0eq.)的反应瓶中加入DCM 80mL)和DMF(80mL)。搅拌溶解后加入二水合氯化亚锡(16.4g，0.073mol，5.0eq.)。室温搅拌2h。向反应液中加入饱和碳酸氢钠水溶液(1L)。乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤， MgSO
4干燥。旋干后通过柱层析分离纯化(PE:EA＝4:1)，得中间体3.4(5.10g，80.9％产率)。MS:[M+H]
+＝435。
向装有中间体3.4(5.10g，0.012mol，1.0eq.)的反应瓶中，加入氯仿(50mL)乙酸酐(8.17g,0.029mol，2.5eq.)乙酸钾(0.58g,0.006mol,0.5eq.)。升温70℃后，滴加亚硝酸异戊酯(3.46g，0.029mol，2.5eq.)。反应1小时，向反应液中加入水(50mL)。乙酸乙酯100mL*2萃取两次，饱和氯化钠水溶液洗涤，MgSO
4干燥。旋干后通过柱层析分离纯化(PE:EA＝4:1)，得中间体3.5(4.20g，80.7％产率)。MS:[M+H]
+＝446。
向装有中间体3.5(1.00g，0.0022mol，1.0eq.)的反应瓶中加入DMF(10mL)。搅拌，降低温至0℃。缓慢加入NaH(0.108g，0.0027mol，1.2eq.)。0.5h后加入1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物(1.02g，0.0045mol，2.0eq.)。自然升温至室温，反应6h。向反应液中加入水，乙酸乙酯萃取两次，饱和氯化钠水溶液洗涤有机相，MgSO
4干燥。旋干得中间体3.6(0.850g，64.4％产率)。MS:[M+H]
+＝589。
向装有中间体3.6(0.850g，0.0015mol，1.0eq.)的反应瓶中加入甲醇(10mL)，再加入盐酸1,4-二氧六环溶液(4M，3mL)，升温至70℃，反应0.5h。旋干反应液后得中间体3.7，直接投入下一步反应。
向装有中间体3.7的反应瓶中加入甲醇(10mL)，搅拌溶解后加入碳酸铯(1.41g，0.0045mol，3.0eq.)，升温至70℃，反应2h。旋干反应液后得中间体3.8，直接投入下一步反应。
向装有中间体3.8的反应瓶中加入DCM(10mL)，搅拌溶解后加入三乙胺(0.438g，0.0045mol，3.0eq.)，冰水浴下加入二碳酸二叔丁酯(0.472g，0.0022mol，1.5eq.)。转移至室温反应1h。旋干反应液后通过柱层析分离纯化(DCM:MeOH＝20:1)，得中间体3.9(0.35g，53.1％产率)。MS:[M+H]
+＝457。
向装有中间体3.9(0.35g，0.765mmol，1.0eq.)的反应瓶中加入DMF(10mL)，搅拌，冰水浴条件下加入t-BuOK(0.174g，1.53mmol，2.0eq.)，搅拌20min后加入2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶(0.256g，0.92mmol，1.2eq.)。反应3h后，向反应液中加入水(50mL)，而后乙酸乙酯(50mL×3)萃取。饱和氯化钠水溶液洗涤，MgSO
4干燥。旋干后通过柱层析分离纯化(PE:EA＝4:1)，得中间体3.10(0.24g，43.8％产率)，为黄色固体。MS:[M+H]
+＝714。
将中间体3.10(0.24g，0.336mmol，1.0eq.)溶于10mL甲醇中，再加入盐酸1,4-二氧六环(3mL，7M)，升温至70℃，反应0.5h。旋干反应液，得中间体2.11(0.51g，100％产率)。
将中间体3.10(0.51g，0.336mmol，1.0eq.)溶于10mL甲醇中，加入甲醛水溶液(1.10mL，37％，10eq.)，搅拌15min后加入STAB(0.35g，1.68mmol，5eq.),再搅拌15min。而后旋干反应液，通过柱层析分离纯化(DCM:MeOH＝8:1)，得实施例3标题化合物(0.11g，59.5％产率)。MS:[M+H]
+＝552。
1H NMR(400MHz,DMSO-d
6)11.71(s,1H),8.04(s,1H),6.15(s,1H),4.73(s,2H),4.07(s,2H),3.51(s,2H),2.65(s,3H),2.41(d,J＝7.7Hz,6H), 2.32-2.36(m,1H),2.30(s,3H),2.21(s,3H),1.89(s,5H),1.59(s,3H),1.19-1.28(m,4H)。
中间体1.4.1甲基(R)-7-溴-2-((1r，4S)-4-((叔丁氧羰基)氨基)环己基)-2,4-二甲基-6-硝基苯并[d][1,3]二恶英-5-羧酸酯和中间体1.4.2甲基(S)-7-溴-2-((1R,4R)-4-((叔丁氧羰基)氨基)环己基)-2,4-二甲基-6-硝基苯并[d][1,3]二噁英-5-羧酸酯
通过中间体1.4的手性分离制备化合物1.4.1和化合物1.4.2，具体信息如下：
分离设备:Waters UPC2 analytical SFC
色谱柱:ChiralCel OJ，150×4.6mm I.D.，3μm
流动相:A for CO
2and B for Methanol(0.1％NH
3H
2O)
梯度:B 10％
流速:2.0mL/min
波长:220nm
化合物1.4.1保留时间4.22分钟，[α]＝-30.3°(MeOH，c＝1.0g/100mL)
化合物1.4.2保留时间3.70分钟，[α]＝25.4°(MeOH，c＝1.0g/100mL)
HPLC设备：Shimadzu LC-20AD
MS:[M+H]
+＝529。
1H NMR(400MHz,DMSO)δ6.76(d,J＝7.8Hz,1H),3.79(s,3H),3.18(s,1H),2.18(s,3H),1.90-1.75(m,5H),1.70(s,3H),1.37(s,9H),1.27-1.09(m,4H)。
实施例4:(R)-10-((1r，4R)-4-(二甲氨基)环己基)-8,10-二甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物4采用实施例1中相似步骤合成，将中间体1.4拆分后，替换为1.4.1(2.20g，0.0043mol，1.0eq.)制得。MS:[M+H]
+＝551。
1H NMR(400MHz,DMSO-d
6)δ11.71(s,1H),7.21(d,J＝3.1Hz,1H),6.30(d,J＝3.0Hz,1H),6.14(s,1H),4.72(s,2H),4.06(s,2H),3.51(s,2H),2.68(s,1H),2.54(s,6H),2.42(s,3H),2.40(s,3H),2.21(s,3H),2.08-1.76(m,5H),1.59(s,3H),1.36-1.20(m,4H)。
实施例5:(S)-10-((1r，4S)-4-(二甲氨基)环己基)-8,10-二甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物5采用实施例1中相似步骤合成，将中间体1.4拆分后，替换为1.4.2(2.20g，0.0043mol，1.0eq.)制得。MS:[M+H]
+＝551。
1H NMR(400MHz,DMSO-d
6)11.70(s,1H),7.21(s,1H),6.30(s,1H),6.14(s,1H),4.73(s,2H),4.07(s,2H),3.51(s,2H),2.65(s,3H),2.41(d,J＝7.7Hz,6H),2.32-2.36(m,1H),2.30(s,3H),2.21(s,3H),1.89(s,5H),1.59(s,3H),1.29-1.19(m,4H)。
实施例6:(4R,10R)-10-((1r，4R)-4-(二甲氨基)环己基)-4,8,10-三甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物6采用实施例4中相似步骤合成,将1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物替换为(S)-5-甲基-1,2,3-氧杂噻唑烷-3-羧酸叔丁酯-2,2-二氧化物即可制得。MS:[M+H]
+＝565。
1H NMR(400MHz,DMSO-d
6)δ11.65(s,1H),7.36-7.26(m,1H),6.29(s,1H),6.13(s,1H),5.12(s,2H),4.53(s,2H),4.23(s,1H),3.46(s,3H),2.68(s,1H),2.51(s,3H),2.44(s,3H),2.39(s,3H),2.21(s,3H),1.95(m,5H),1.60(s,3H),1.43(s,3H),1.32(m,4H)。
实施例7:(4S,10R)-10-((1r,4R)-4-(二甲氨基)环己基)-4,8,10-三甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物7采用实施例6中相似步骤合成，将(R)-4-甲基-1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物替换为(R)-5-甲基-1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物即可制得。MS:[M+H]
+＝565。
1H NMR(400MHz,DMSO-d
6)δ11.67(s,1H),7.31(s,1H),6.30(s,1H),6.13(s,1H),5.11(s,1H),4.51(d,J＝15.8Hz,2H),3.50-3.43(m,2H),2.68(s,1H),2.63(s,6H),2.44(s,3H),2.39(s,3H),2.21(s,3H),2.09-1.87(m,5H),1.61(s,3H),1.44(s,3H),1.39-1.20(m,4H)。
实施例8:(10R)-10-((1r，4R)-4-(二甲氨基)环己基)-5,8,10-三甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物8采用实施例6中相似步骤合成,将(R)-4-甲基-1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物替换为4-甲基-1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物即可制得。MS:[M+H]
+＝565。
1H NMR(400MHz,DMSO)δ11.69(s,1H),7.18(d,J＝2.9Hz,1H),6.30(d,J＝3.0Hz,1H),6.13(s,1H),4.93(d,J＝13.8Hz,1H),4.54(d,J＝13.7Hz,1H),4.31(dd,J＝13.5,4.5Hz,1H),4.15(d,J＝13.5Hz,1H),3.90-3.80(m,1H),2.52(s,3H),2.47(s,3H),2.42(s,6H),2.38-2.25(m, 1H),2.20(s,3H),2.06-1.83(m,5H),1.60(s,3H),1.42-1.20(m,4H),0.59(d,J＝7.0Hz,3H)。
实施例9:(R)-10-((1r，4R)-4-(二甲氨基)环己基)-6-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-8,10-二甲基-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物9采用实施例4中相似步骤合成,将2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶替换为2-(苄氧基)-3-(氯甲基)-4-甲氧基-6-甲基吡啶制得。MS:[M+H]
+＝535。
1H NMR(400MHz,DMSO-d
6)11.58(s,1H),7.21(s,1H),6.29(s,1H),6.14(s,1H),5.15(s,2H),4.33(s,2H),3.80(s,3H),3.51(s,2H),2.40(d,J＝8.0Hz,6H),2.32-2.36(m,1H),2.30(s,3H),2.21(s,3H),1.95-1.79(m,5H),1.59(s,3H),1.29-1.19(m,4H)。
实施例10:(S)-10-((1r，4S)-4-(二甲氨基)环己基)-6-((4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-8,10-二甲基-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物10采用实施例5中相似步骤合成，将2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶替换为2-(苄氧基)-3-(氯甲基)-4-甲氧基-6-甲基吡啶制得。MS:[M+H]
+＝535。
1H NMR(400MHz,DMSO-d
6)11.58(s,1H),7.21(s,1H),6.29(s,1H),6.14(s,1H),4.56(s,2H),4.33(s,2H),3.79(s,3H),3.51(s,2H),2.40(s,6H),2.32-2.36(m,1H),2.30(s,3H),2.21(s,3H),1.95-1.79(m,5H),1.59(s,3H),1.29-1.19(m,4H)。
实施例11:(R)-6-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-10-((1r，4R)-4-(二甲氨基)环己基)-8,10-二甲基-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物11采用实施例4中相似步骤合成，将2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶替换为2-(苄氧基)-3-(氯甲基)-4,6-二甲基吡啶制得。MS:[M+H]
+＝519。
1H NMR(400MHz, DMSO-d
6)11.66(s,1H),7.23(s,1H),6.31(s,1H),5.94(s,1H),4.74(s,2H),4.13(s,2H),3.63(s,2H),2.80(s,1H),2.38(s,3H),2.19(s,3H),2.15(s,3H),1.95-1.80(m,5H),1.60(s,3H),1.41-1.24(m,4H),1.11(s,6H)。
中间体3.5.1甲基(R)-2-((1r，4R)-4-((叔丁氧羰基)氨基)环己基)-2,4-二甲基-6H-[1,3]二氧杂环[4,5-e]吲唑-5-羧酸酯和中间体3.5.2甲基(S)-2-((1r，4S)-4-((叔丁氧羰基)氨基)环己基)-2,4-二甲基-6H-[1,3]二氧杂环[4,5-e]吲唑-5-羧酸酯的合成
通过中间体3.5的手性分离制备化合物3.5.1和化合物3.5.2，具体信息如下：
分离设备:Waters UPC2 analytical SFC
色谱柱:ChiralCel OJ，150×4.6mm I.D.，3μm
流动相:A for CO
2and B for Methanol(0.1％NH
3H
2O)
梯度:B 40％
流速:2.0mL/min
波长:220nm
化合物3.5.1保留时间2.72分钟，[α]＝38.0°(MeOH，c＝1.0g/100mL)
化合物3.5.2保留时间4.39分钟，[α]＝-29.1°(MeOH，c＝1.0g/100mL)
MS:[M+H]
+＝446。
1H NMR(400MHz,DMSO)δ12.91(s,1H),8.11(d,J＝1.3Hz,1H),6.75(d,J＝7.9Hz,1H),3.90(s,3H),3.23-3.11(m,1H),2.54(s,3H),1.94-1.77(m,5H),1.64(s,3H),1.36(s,9H),1.24-1.05(m,4H)。
实施例12：(R)-10-((1r，4R)-4-(二甲氨基)环己基)-8,10-二甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲达唑-7(4H)-酮的合成
化合物12采用实施例3中相似步骤合成，将中间体3.5拆分后，替换为3.5.1(2.20g，0.0043mol，1.0eq.)制得。MS:[M+H]
+＝552。
1H NMR(400MHz,DMSO)δ11.69(s,1H),8.03(s,1H),6.15(s,1H),4.75(s,2H),4.26(s,2H),3.60(s,2H),2.49(s,3H),2.42(s,3H),2.23(s,3H),2.17(s,6H),2.15-2.08(m,1H),1.89(m,5H),1.64(s,3H),1.21(m,4H)。
实施例13：(S)-10-((1r，4S)-4-(二甲氨基)环己基)-8,10-二甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲达唑-7(4H)-酮的合成
化合物13采用实施例12中相似步骤合成，将中间体3.5.1替换为3.5.2(2.20g，0.0043mol，1.0eq.)制得。MS:[M+H]
+＝552。
1H NMR(400MHz,DMSO)δ11.71(s,1H),8.04(s,1H),6.15(s,1H),4.75(s,2H),4.26(s,2H),3.59(s,2H),2.52(s,3H),2.49(s,6H),2.42(s,3H),2.34(s,1H),2.23(s,3H),1.98m,5H),1.65(s,3H),1.33-1.14(m,4H)。
实施例14：(4R,10R)-10-((1r，4R)-4-(二甲氨基)环己基)-4,8,10-三甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲达唑-7(4H)-酮的合成
实施例14采用实施例12中相似步骤合成，将1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物替换为(S)-5-甲基-1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物制得。MS:[M+H]
+＝566。
1H NMR(400MHz,DMSO)δ11.70(s,1H),8.03(s,1H),6.13(s,1H),5.01(s,1H),4.60(d,J＝13.9Hz,2H),3.68-3.45(m,2H),2.46(s,3H),2.43(s,3H),2.23(s,3H),2.17(s,6H),2.14-2.08(m,1H),2.02-1.75(m,5H),1.63(s,3H),1.42(s,3H),1.25-1.14(m,4H)。
实施例15：(4S,10R)-10-((1r，4R)-4-(二甲氨基)环己基)-4,8,10-三甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲唑-7(4H)-酮的合成
实施例15采用实施例12中相似步骤合成，将1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物替换为(R)-5-甲基-1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物制得。MS:[M+H]
+＝566。
1H NMR(400MHz,DMSO)δ11.70(s,1H),8.03(s,1H),6.14(s,1H),5.02(s,1H),4.59(m,2H),3.55(s,2H),2.46(s,3H),2.43(s,3H),2.33(s,1H),2.27(s,6H),2.22(s,3H),1.91(d,J＝22.4Hz,5H),1.64(s,3H),1.41(d,J＝14.4Hz,3H),1.23(s,4H)。
实施例16：(R)-1-氯-10-((1r，4R)-4-(二甲氨基)环己基)-8,10-二甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
将中间4.4(0.81g，1.8mmol，1.0eq.)溶于二氯甲烷中，加入N-氯代丁二酰亚胺(0.36g，2.7mmol，1.5eq.)，常温搅拌过夜。而后旋干反应液，通过柱层析分离纯化得中间体16.1(0.81g，92.0％产率)。MS:[M+H]
+＝479。
化合物16用化合物4相类似的合成方法，以中间体16.1替换中间体4.4制得。MS:[M+H]
+＝586。
1H NMR(400MHz,DMSO-d
6)δ11.72(s,1H),7.39(s,1H),6.14(s,1H),4.71(s,3H),4.03(s,2H),3.50(s,2H),2.68(s,1H),2.54(s,2H),2.50(s,3H),2.43(s,3H),2.39(s,3H),2.21(s,3H),2.05-1.87(m,5H),1.63(s,3H),1.34-1.19(m,4H)。
实施例17:(4R,10R)-10-((1r，4R)-4-(二甲氨基)环己基)-6-((4-甲氧基-6-甲基-2-氧基-1,2-二氢吡啶-3-基)甲基)-4,8,10-三甲基-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物17采用实施例6中相似步骤合成,将2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶替换为2-(苄氧基)-3-(氯甲基)-4-甲氧基-6-甲基吡啶制得。MS:[M+H]
+＝549.24。
1H NMR(400MHz,DMSO-d
6)δ:11.53(s,1H),7.30(s,1H),6.29(d,1H),6.14(s,1H),5.15(s,2H),4.33(s,2H),3.80(s,3H),3.51-3.79(m,2H),2.35(m,7H),2.21(s,3H),1.58(m,3H),1.90(m,4H),1.85(s,3H),1.39-1.23(m,7H)。
实施例18:(4S,10R)-10-((1r，4R)-4-(二甲氨基)环己基)-6-((4-甲氧基-6-甲基-2-氧基-1,2-二氢吡啶-3-基)甲基)-4,8,10-三甲基-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物18采用实施例7中相似步骤合成,将2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶替换为2-(苄氧基)-3-(氯甲基)-4-甲氧基-6-甲基吡啶制得。MS:[M+H]
+＝549.27。
1H NMR(400MHz,DMSO-d
6)δ:11.53(s,1H),7.30(s,1H),6.29(d,1H),6.13(s,1H),5.09(brs,2H),4.23(m,2H),3.80(s,3H),2.60(m,2H),2.37(m,6H),2.21(s,3H),1.91-1.86(m,8H),1.58(s,3H),1.38-1.25(m,7H)。
实施例19:(4R,10R)-6-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-10-((1r，4R)-4-(二甲氨基)环己基)-4,8,10-三甲基-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物19采用实施例6中相似步骤合成,将2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶替换为2-(苄氧基)-3-(氯甲基)-4,6-二甲基吡啶制得。MS:[M+H]
+＝533.36。
1H NMR(400MHz,DMSO-d
6)δ:11.60(s,1H),7.31(s,1H),6.30(s,1H),5.92(s,1H),5.06(s,1H),4.47(s,2H),3.69(s,1H),3.59(s,1H),2.51(s,2H),2.35(s,3H),2.39(s,2H),2.22(s,6H),2.15(s,3H),1.92-1.87(m,5H),1.58(s,3H),1.44-1.43(m,3H),1.20-1.18(m,4H)。
实施例20:((5R,10R)-10-((1r，4R)-4-(二甲氨基)环己基)-5,8,10-三甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物20采用实施例4中相似步骤合成,将1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物替换 为(R)-4-甲基-1,2,3-噁硫唑烷-3-羧酸叔丁酯-2,2-二氧化物即可制得。MS:[M+H]
+＝565.46。
1H NMR(400MHz,DMSO-d
6)δ:11.69(s,1H),7.18(d,J＝2.9Hz,1H),6.30(d,J＝3.0Hz,1H),6.13(s,1H),4.93(d,J＝13.8Hz,1H),4.54(d,J＝13.7Hz,1H),4.31(dd,J＝13.5,4.5Hz,1H),4.15(d,J＝13.5Hz,1H),3.90-3.80(m,1H),2.52(s,3H),2.47(s,3H),2.42(s,6H),2.38-2.25(m,1H),2.20(s,3H),2.06-1.83(m,5H),1.60(s,3H),1.42-1.20(m,4H),0.59(d,J＝7.0Hz,3H)。
实施例21:(S)-8-氯-10-((1r，4S)-4-(二甲氨基)环己基)-10-甲基-6-((6-甲基-4-(甲硫基)-2-氧基-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物21采用实施例2中相似步骤合成,将中间体1.4拆分后，替换为1.4.1即可制得。MS:[M+H]
+＝571.14。
1H NMR(400MHz,DMSO-d
6)δ:11.72(s,1H),7.33(s,1H),6.38(d,1H),6.15(s,1H),4.70(s,2H),4.08(s,2H),3.55(s,2H),2.51(s,3H),2.43(s,3H),2.22(m,8H),1.92(m,4H),1.64(m,3H),1.23(m,4H)。
实施例22:(4R,10S)-8-氯-10-((1r，4S)-4-(二甲氨基)环己基)-4,10-二甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物22采用实施例21中相似步骤合成,将1,2,3-噁硫唑烷-3-羧酸叔丁酯2,2-二氧化物替换为(S)-5-甲基-1,2,3-噁硫唑烷-3-羧酸叔丁酯-2,2-二氧化物即可制得。MS:[M+H]
+＝585.16。
1H NMR(400MHz,DMSO-d
6)δ:11.68(s,1H),7.43(d,1H),6.28(d,1H),6.13(s,1H),5.05(s,2H),4.52(s,2H),3.50(s,2H),2.51-2.50(m,3H),2.49(s,3H),2.20(m,7H),1.91(m,4H),1.62(m,3H),1.32(m,7H)。
实施例23:(R)-8-氯-10-((1r，4R)-4-(二甲氨基)环己基)-10-甲基-6-((6-甲基-4-(甲硫基)-2-氧基-1,2-二氢吡啶-3-基)甲基)-5,6-二氢-[1,4]二氮杂卓[6,7,1-hi][1,3]二氧杂[4,5-e]吲哚-7(4H)-酮的合成
化合物23采用实施例2中相似步骤合成,将中间体1.4拆分后，替换为1.4.2即可制得。MS:[M+H]
+＝572.23。
1H NMR(400MHz,DMSO-d
6)δ:11.73(s,1H),7.35(d,J＝3.3Hz,1H),6.38(d,J＝3.3Hz,1H),6.15(s,1H),4.73(d,J＝17.8Hz,2H),4.56(s,2H),3.55(s,2H),2.63(s,3H),2.43(s,3H),2.34(s,1H),2.22(s,7H),2.01(m,4H),1.62(m,3H),1.38(m,7.5Hz,4H)。
实施例24:(4R,10S)-8-氯-6-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基)-10-((1r，4S)-4-(二甲氨基)环己基)-4,10-二甲基-5,6-二氢-[1,4]二氮杂[6,7,1-hi][1,3]二噁英[4,5-e]吲哚-7(4H)-酮的合成
化合物24采用实施例22中相似步骤合成,将2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶替换为2-(苄氧基)-3-(氯甲基)-4,6-二甲基吡啶即可制得。MS:[M+H]
+＝572.42。
1H NMR(400MHz,DMSO-d
6)δ:11.65(s,1H),7.54(s,1H),6.38(d,1H),5.93(s,1H),5.08(s,1H),4.52(m,2H),3.74(s,1H),3.35(s,2H),2.51-2.50(m,3H),2.21(s,2H),2.06(m,6H),1.85(m,5H),1.63(m,3H),1.47(m,3H),1.14(m,5H)。
实验例1
PRC2/EZH 2HTRF酶抑制实验
PRC2复合物购买于Carna Biosciences(日本)，Histone H3(21-44)-GK(biotin)，Streptavidin-XL665 and Mab Anti histone H3K27Me1-Eu(K)购买于Cisbio(法国)。
SAM(30mM)，DTT(1M)，10％BAS，Tris-HCl(50mM)，NaCl(50mM)，10％Tween和二甲基亚砜(DMSO)购买于Sigma。384孔白板购买于CORNING(美国)。
实验所用的assay buffer由50mM Tris-HCl，50mM NaCl，1mM DTT，0.01％Tween，0.1％BSA组成。使用assay buffer配制5％DMSO的化合物、PRC2酶和Histone H3(21-44)-GK混合溶液，配制完成后，将2μL 5％DMSO的化合物和4μL的PRC2混合液分别加入Opti Plate-384White孔板中盖膜800转1min，室温孵育0.5h，加入4μL Histone H3(21-44)-GK(biotin)/SAM盖膜800转1min，室温孵育2h。PRC2、Histone H3(21-44)-GK(biotin)、SAM和DMSO终浓度分别为1ng/μL、5μM、15μM和1％。然后加入5μL检测抗体Mab Anti histone H3K27Me1-Eu(K)和5μL Streptavidin-XL665，室温孵育2h。在TECAN(Switzerland)的SPARK多功能酶标仪器上读取平板，激发光波长为320nm，发射光波长为665nm。在Prism7(LaJolla，CA)中使用S形剂量反应模型(可变斜率，四个参数)确定化合物IC
50值。
细胞增殖抑制实验
Karpas422细胞购自中国科学院细胞库(上海)；RPMI1640培养基、青霉素-链霉素双抗和0.5％的胰酶(10X)购自ThermoFisher(Waltham，MA，USA)。经认证的胎牛血清(FBS)购自Biological Industries(Israel)。康宁96孔细胞培养板购自CORNING(USA)。Counting Kit-8检测试剂盒购自碧云天(中国)。
为了评估合成化合物对人大细胞淋巴瘤SU-DHL-10，人类B细胞非霍奇金淋巴瘤细胞Karpas422的增殖抑制水平，将处于指数增长的SU-DHL-10、Karpas422细胞分别接种于含20％牛血清和1％青霉素-链霉素双抗的RPMI1640培养基，密度1000个细胞/mL，96孔板，每孔100μL，并放置在37℃，5％CO
2的培养箱中过夜。将化合物在DMSO中稀释，初始浓度为2mM，3倍稀释，12个浓度。将化合物储备板的1μL DMSO溶液添加到99μL细胞培养基，测定中化合物的最终最高浓度为10μM，并且DMSO的最终浓度为(0.5％)。将培养基中的100μL化合物溶液加到SU-DHL-10和Karpas422细胞板的每个孔中。在加入化合物溶液后，将96孔板放置于37℃，5％CO
2培养箱中孵育8天。采用Counting Kit-8检测试剂盒，通过定量细胞培养中生成的甲瓒物的数量与活细胞的数量成正比，测定细胞活力。2小时孵育后使用TECAN公司的SPARK多功能酶标仪在化学发光的程序下进行读数。在Prism 7(LaJolla，CA)中使用S形剂量反应模型(可变斜率，四个参数)确定化合物使细胞成活率抑制50％的浓度(IC
50值)。
本文所述的代表性化合物的EZH2酶抑制实验及细胞增殖抑制实验结果在表1中示出。
表1
从表1测试结果分析，此类化合物大多数具有优异的EZH2抑制活性，同时其中部分化合物的EZH2抑制活性同现有阳性参照具有更优的结果，尤其是化合物4、化合物6、化合物7、化合物12及化合物16。同时此类化合物也表现出了明显的增殖移植活性，和已经上市的药物Tazemetostat相比具有明显的优势。
实验例2 体外肝微粒体稳定性测试
人肝微粒体来自Corning，ICR/CD-1大鼠肝微粒体(雄)也来自Corning，分别储存于-80℃冰箱。磷酸二氢钠、磷酸二氢钾、NADPH均购自Sigma.
将受试物用DMSO配制高浓度储备液，使用前用DMSO稀释到200μM的工作液，受试物的终浓度为1μM。先称取7.098g磷酸氢二钠，加入500mL纯水超声溶解，作为溶液A。称取3.400g磷酸二氢钾，加入250mL纯水超声溶解，作为溶液B。向溶液A里面加入溶液B，直至pH为7.4。实验前现称取适量NADPH，用磷酸盐溶液配制浓度为10mM的工作液。转移25μL NADPH或磷酸缓冲盐到上述孵育体系，加入2μL 200μM受化合试物。对于加NADPH的样品进行双平行制备；对于NADPH阴性的样品进行单平行制备。分别于0.5、5、15、30和60分钟，取30μL混悬液。加入180μL含内标的乙腈终止反应，涡旋10分钟。之后于3220g离心20分钟进行蛋白沉淀。将板子置于4℃冰箱放30分钟后，于3220g重新离心20分钟。转移100μL上清液到进样板，加入100μL纯水混匀，用于UPLC-MS/MS分析。所有的数据计算均通过Microsoft Excel软件进行。通过提取离子图谱检测峰面积。通过对母药消除百分比的自然对数与时间进行线性拟合，检测母药的体外半衰期(t
1/2)，计算清除率。
本文所述的代表性化合物的肝微粒体稳定性实验结果在表2中示出。
表2
从表2测试结果分析，此类化合物大多数具有优异的体外肝微粒稳定性，同时其中部分化合物的体外肝微粒体稳定性同现有阳性参照具有更优的结果，尤其是化合物3、化合物4、化合物6、化合物7、化合物9、化合物11、化合物12和化合物19。
Claims (11)
- 一种如下式(I)所示的化合物、其立体异构体或其药学上可接受的盐：
其中，R 1、R 2、R 3各自独立地选自氢、卤素、C 1-C 6烷基、羟基、氰基或氨基；L、U、V、T各自独立地选自C或N，且至少一个为N；Y选自氢、卤素或C 1-C 6烷基；X选自氢、卤素、C 1-C 6烷基、烷氧基或-S-R 4，R 4为C 1-C 6烷基；Z是C 3-C 7环烷基或4到7元杂环基，其中的每一个任选地被1到3个选自卤素、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基或-NRaRb的基团取代；Ra是氢、C 1-C 6烷基或卤代C 1-C 6烷基；Rb是C 1-C 6烷基、卤代C 1-C 6烷基或4到7元杂环基，其中所述杂环基任选地被1到3个选自卤素、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基的基团取代；或Ra和Rb与其所附接的氮原子一起形成任选地被1到3个选自卤素、C 1-C 6烷基、卤代C 1-C 6烷基或-ORc的基团取代的4到7元杂环基；Rc是C 1-C 6烷基、卤代C 1-C 6烷基或C 3-C 7环烷基；m、n’各自独立地为0、1或2；n为0、1、2、3或4；以及代表单键或双键。
- 根据权利要求1所述的化合物，其中式(I)是式(Ia)：
其中，R 1、R 2、R 3各自独立地选自氢、卤素、C 1-C 6烷基、羟基、氰基或氨基；L、U、V、T各自独立地选自C或N，且至少一个为N；Y选自氢、卤素或C 1-C 6烷基；X选自氢、卤素、C 1-C 6烷基、烷氧基或-S-R 4，R 4为C 1-C 6烷基；m、n’各自独立地为0、1或2；n为0、1、2、3或4；以及代表单键或双键。
- 根据权利要求1所述的化合物，其中式(I)是式(Ib)：
其中，R 1、R 2、R 3各自独立地选自氢、卤素、C 1-C 6烷基、羟基、氰基或氨基；U、V各自独立地选自C或N；X选自氢、卤素、C 1-C 6烷基、烷氧基或-S-R 4，R 4为C 1-C 6烷基；m、n’各自独立地为0、1或2；n为0、1、2、3或4；以及代表单键或双键。
- 根据权利要求1所述的化合物，其中式(I)是式(Ic)：
其中，R 1、R 2、R 3各自独立地选自氢、卤素、C 1-C 6烷基、羟基、氰基或氨基；U、V各自独立地选自C或N；X选自氢、卤素、C 1-C 6烷基、烷氧基或-S-R 4，R 4为C 1-C 6烷基；m、n’各自独立地为0、1或2；n为0、1、2、3或4；以及代表单键或双键。
- 根据权利要求1所述式(I)所示的化合物，其选自：
- 一种药物组合物，其包含治疗有效量的权利要求1所述的化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体；以及药学上可接受的载体或赋形剂。
- 权利要求1所述的化合物，或其药学上可接受的盐、酯、前药、络合物、溶剂化物、水合物或异构体用于制备治疗EZH2介导的疾病药物的用途。
- 根据权利要求7所述的用途，其中所述疾病为癌症。
- 根据权利要求8所述的用途，其中所述癌症为肺癌、胃癌、肝癌、乳腺癌、鼻咽癌、胰腺癌、卵巢癌、宫颈癌、结肠直肠癌、胶质瘤、黑色素瘤、前列腺癌、肾癌、食道癌、间皮瘤、头颈癌、膀胱癌、唾腺癌、白血病或淋巴瘤。
- 一种如下式(II)所示的化合物或其立体异构体：
其中，R 1、R 2、R 3、U、V、m、n、n’、如权利要求1所定义。
- 权利要求10所述的化合物用于制备权利要求1所述化合物的用途。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104870435A (zh) * | 2012-12-21 | 2015-08-26 | 辉瑞大药厂 | 芳基和杂芳基稠合的内酰胺类 |
| US20180265517A1 (en) * | 2017-03-15 | 2018-09-20 | Mirati Therapeutics, Inc. | EZH2 Inhibitors |
| WO2020171606A1 (ko) * | 2019-02-19 | 2020-08-27 | 한미약품 주식회사 | 신규한 헤테로트리시클릭 유도체 화합물 및 이의 용도 |
| WO2020224607A1 (zh) * | 2019-05-07 | 2020-11-12 | 南京药石科技股份有限公司 | Ezh2抑制剂及其用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104870435A (zh) * | 2012-12-21 | 2015-08-26 | 辉瑞大药厂 | 芳基和杂芳基稠合的内酰胺类 |
| US20180265517A1 (en) * | 2017-03-15 | 2018-09-20 | Mirati Therapeutics, Inc. | EZH2 Inhibitors |
| WO2020171606A1 (ko) * | 2019-02-19 | 2020-08-27 | 한미약품 주식회사 | 신규한 헤테로트리시클릭 유도체 화합물 및 이의 용도 |
| WO2020224607A1 (zh) * | 2019-05-07 | 2020-11-12 | 南京药石科技股份有限公司 | Ezh2抑制剂及其用途 |
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