EA030196B1 - Ингибиторы энхансера zeste гомолога 2 - Google Patents
Ингибиторы энхансера zeste гомолога 2 Download PDFInfo
- Publication number
- EA030196B1 EA030196B1 EA201592068A EA201592068A EA030196B1 EA 030196 B1 EA030196 B1 EA 030196B1 EA 201592068 A EA201592068 A EA 201592068A EA 201592068 A EA201592068 A EA 201592068A EA 030196 B1 EA030196 B1 EA 030196B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- methyl
- alkyl
- oxo
- dihydropyridin
- dimethyl
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 34
- 102000058017 Enhancer of Zeste Homolog 2 Human genes 0.000 title abstract 3
- 101710196274 Histone-lysine N-methyltransferase EZH2 Proteins 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 223
- -1 (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl Chemical group 0.000 claims description 418
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 139
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 111
- 229910052736 halogen Inorganic materials 0.000 claims description 76
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 74
- 229910052739 hydrogen Inorganic materials 0.000 claims description 74
- 239000001257 hydrogen Substances 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- 150000003839 salts Chemical class 0.000 claims description 63
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 60
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 54
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 53
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 52
- 150000002367 halogens Chemical class 0.000 claims description 50
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 46
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 45
- DAUYIKBTMNZABP-UHFFFAOYSA-N thiophene-3-carboxamide Chemical compound NC(=O)C=1C=CSC=1 DAUYIKBTMNZABP-UHFFFAOYSA-N 0.000 claims description 33
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 32
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 239000001301 oxygen Substances 0.000 claims description 18
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 18
- 125000003386 piperidinyl group Chemical group 0.000 claims description 17
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 16
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 239000011593 sulfur Substances 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000002541 furyl group Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 125000004193 piperazinyl group Chemical group 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 claims description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- ISUJAGQKWSTODG-UHFFFAOYSA-N tert-butyl 4-[1-[4-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methylcarbamoyl]-3-methylthiophen-2-yl]propyl]piperidine-1-carboxylate Chemical compound S1C=C(C(=O)NCC=2C(NC(C)=CC=2C)=O)C(C)=C1C(CC)C1CCN(C(=O)OC(C)(C)C)CC1 ISUJAGQKWSTODG-UHFFFAOYSA-N 0.000 claims description 2
- FRTKPKWRJMIGMN-UHFFFAOYSA-N 2-cyano-n-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-4-methylthiophene-3-carboxamide Chemical compound S1C(C#N)=C(C(=O)NCC=2C(NC(C)=CC=2C)=O)C(C)=C1N(CC)C1CCOCC1 FRTKPKWRJMIGMN-UHFFFAOYSA-N 0.000 claims 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
- AHMAQXSPEKRSCD-UHFFFAOYSA-N tert-butyl 3-[3-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methylcarbamoyl]-5-[ethyl(oxan-4-yl)amino]-4-methylthiophen-2-yl]pyrrolidine-1-carboxylate Chemical compound S1C(C2CN(CC2)C(=O)OC(C)(C)C)=C(C(=O)NCC=2C(NC(C)=CC=2C)=O)C(C)=C1N(CC)C1CCOCC1 AHMAQXSPEKRSCD-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 65
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- 230000008569 process Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 358
- 239000000243 solution Substances 0.000 description 236
- 239000000203 mixture Substances 0.000 description 215
- 239000011541 reaction mixture Substances 0.000 description 191
- 238000005481 NMR spectroscopy Methods 0.000 description 141
- 239000007787 solid Substances 0.000 description 140
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 125
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 117
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 110
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 61
- 235000002639 sodium chloride Nutrition 0.000 description 54
- 239000000741 silica gel Substances 0.000 description 51
- 229910002027 silica gel Inorganic materials 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 49
- 125000001072 heteroaryl group Chemical group 0.000 description 49
- 239000000126 substance Substances 0.000 description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 44
- 125000003118 aryl group Chemical group 0.000 description 42
- 239000012044 organic layer Substances 0.000 description 42
- 239000000725 suspension Substances 0.000 description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 41
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 40
- 238000004587 chromatography analysis Methods 0.000 description 37
- 239000012071 phase Substances 0.000 description 37
- 230000000694 effects Effects 0.000 description 35
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- 235000019198 oils Nutrition 0.000 description 33
- 239000012267 brine Substances 0.000 description 32
- 239000003795 chemical substances by application Substances 0.000 description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 30
- 229910052700 potassium Inorganic materials 0.000 description 29
- 239000000047 product Substances 0.000 description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 26
- 238000000746 purification Methods 0.000 description 25
- 239000000377 silicon dioxide Substances 0.000 description 24
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 23
- 239000002246 antineoplastic agent Substances 0.000 description 22
- 150000002989 phenols Chemical class 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 19
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- 108020004414 DNA Proteins 0.000 description 18
- 238000002347 injection Methods 0.000 description 18
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- 239000011734 sodium Substances 0.000 description 18
- ZMDPNGUJHPRAMG-UHFFFAOYSA-N 3-(aminomethyl)-4,6-dimethyl-1h-pyridin-2-one;hydrochloride Chemical compound Cl.CC1=CC(C)=C(CN)C(=O)N1 ZMDPNGUJHPRAMG-UHFFFAOYSA-N 0.000 description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 17
- 239000000843 powder Substances 0.000 description 17
- 239000012047 saturated solution Substances 0.000 description 17
- 239000007788 liquid Substances 0.000 description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
- 238000004007 reversed phase HPLC Methods 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- 206010065553 Bone marrow failure Diseases 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- 239000002552 dosage form Substances 0.000 description 15
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- 239000000543 intermediate Substances 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- FCKSGPKSSPUXOP-UHFFFAOYSA-N methyl 4-methylthiophene-3-carboxylate Chemical compound COC(=O)C1=CSC=C1C FCKSGPKSSPUXOP-UHFFFAOYSA-N 0.000 description 15
- 125000002971 oxazolyl group Chemical group 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
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- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 12
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 102100037580 Sesquipedalian-1 Human genes 0.000 description 12
- 101710169844 Sesquipedalian-1 Proteins 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
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- 150000001412 amines Chemical class 0.000 description 11
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- 239000002904 solvent Substances 0.000 description 11
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 11
- 208000026310 Breast neoplasm Diseases 0.000 description 10
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 10
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- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 10
- MBNIQASQLNRJAV-UHFFFAOYSA-N methyl 5-iodo-4-methylthiophene-3-carboxylate Chemical compound COC(=O)C1=CSC(I)=C1C MBNIQASQLNRJAV-UHFFFAOYSA-N 0.000 description 10
- PCJPGNCABBDNJU-UHFFFAOYSA-N 3-(aminomethyl)-4,6-dimethyl-1h-pyridin-2-one Chemical compound CC1=CC(C)=C(CN)C(=O)N1 PCJPGNCABBDNJU-UHFFFAOYSA-N 0.000 description 9
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- 201000009030 Carcinoma Diseases 0.000 description 8
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
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- CQZPEBDZIWYWEL-UHFFFAOYSA-N methyl 5-amino-4-methylthiophene-3-carboxylate Chemical compound COC(=O)C1=CSC(N)=C1C CQZPEBDZIWYWEL-UHFFFAOYSA-N 0.000 description 8
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- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 235000012773 waffles Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 1
- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 description 1
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Epidemiology (AREA)
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| US201361907024P | 2013-11-21 | 2013-11-21 | |
| US201461936460P | 2014-02-06 | 2014-02-06 | |
| PCT/IB2014/061012 WO2014177982A1 (en) | 2013-04-30 | 2014-04-25 | Enhancer of zeste homolog 2 inhibitors |
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| EA201592068A1 EA201592068A1 (ru) | 2016-05-31 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2862289C (en) * | 2012-02-10 | 2019-11-26 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| US9688665B2 (en) | 2012-10-15 | 2017-06-27 | Epizyme, Inc. | Methods of treating cancer |
| NZ630205A (en) * | 2013-04-30 | 2017-03-31 | Glaxosmithkline Intellectual Property (No 2) Ltd | Enhancer of zeste homolog 2 inhibitors |
| ES2640386T3 (es) | 2013-07-10 | 2017-11-02 | Glaxosmithkline Intellectual Property (No. 2) Limited | Potenciador de inhibidores del homólogo Zeste 2 |
| SI3406609T1 (sl) | 2014-02-06 | 2024-10-30 | Nxera Pharma Uk Limited | Biciklične aza spojine kot agonisti muskarinskega receptorja |
| CN107148419A (zh) * | 2014-10-28 | 2017-09-08 | 葛兰素史密斯克莱知识产权（第2 号）有限公司 | Zeste增强子同源物2抑制剂 |
| AR102767A1 (es) | 2014-12-05 | 2017-03-22 | Lilly Co Eli | Inhibidores de ezh2 |
| UY36758A (es) * | 2015-06-30 | 2016-12-30 | Glaxosmithkline Ip No 2 Ltd | Inhibidores del potenciador del homólogo zeste 2 |
| SG10201909199PA (en) | 2015-08-24 | 2019-11-28 | Epizyme Inc | Method for treating cancer |
| TW201718598A (zh) | 2015-08-27 | 2017-06-01 | 美國禮來大藥廠 | Ｅｚｈ２抑制劑 |
| JP2018532761A (ja) * | 2015-11-06 | 2018-11-08 | エピザイム，インコーポレイティド | Ｅｚｈ２阻害剤を用いた癌の処置のための小児投与 |
| JP6828229B2 (ja) | 2015-11-19 | 2021-02-10 | ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． | ベンゾフラン誘導体、その製造方法および医薬におけるその使用 |
| EP3452483B1 (en) | 2016-05-05 | 2020-04-01 | GlaxoSmithKline Intellectual Property (No. 2) Limited | Enhancer of zeste homolog 2 inhibitors |
| US20170337814A1 (en) * | 2016-05-20 | 2017-11-23 | Donald Edward Morgan | Safety alerting drivers device and system |
| US10968215B2 (en) | 2016-09-07 | 2021-04-06 | Shanghai Haihe Pharmaceutical Co., Ltd. | Pyrido five-element aromatic ring compound, preparation method therefor and use thereof |
| WO2018125983A1 (en) | 2016-12-30 | 2018-07-05 | Mitobridge, Inc. | Oxopyridine derivatives useful as aminocarboxymuconate semialdehyde decarboxylase (acmsd) inhibitors |
| US10266542B2 (en) | 2017-03-15 | 2019-04-23 | Mirati Therapeutics, Inc. | EZH2 inhibitors |
| HUE059536T2 (hu) | 2018-01-31 | 2022-11-28 | Mirati Therapeutics Inc | PRC2-inhibitorok |
| CN112399857A (zh) | 2018-07-09 | 2021-02-23 | 盲人庇护基金会 | Prc2亚单位的抑制治疗眼失调 |
| US12421228B2 (en) | 2019-04-22 | 2025-09-23 | Mirati Therapeutics, Inc. | Naphthyridine derivatives as PRC2 inhibitors |
| MX2021012756A (es) * | 2019-05-31 | 2022-04-18 | Haisco Pharmaceuticals Pte Ltd | Derivado de un anillo inhibidor de btk, metodo de preparacion de este y aplicacion farmaceutica para este. |
| CN114269748A (zh) | 2019-06-05 | 2022-04-01 | 米拉蒂医疗股份有限公司 | 作为用于治疗癌症的PRC2抑制剂的咪唑并[1,2-c]嘧啶衍生物 |
| KR20220066892A (ko) | 2019-08-22 | 2022-05-24 | 주노 쎄러퓨티크스 인코퍼레이티드 | Ｔ 세포 요법 및 제스트 동족체 2의 인핸서 (ｅｚｈ2) 억제제의 병용 요법 및 관련 방법 |
| CN110964200A (zh) * | 2019-12-19 | 2020-04-07 | 新纳奇材料科技江苏有限公司 | 一种基于聚硅氧烷馏出物的羟基封端聚硅氧烷的制备方法 |
| CN114787143A (zh) * | 2019-12-23 | 2022-07-22 | 四川海思科制药有限公司 | Zeste增强子同源物2抑制剂及其用途 |
| CN111233768B (zh) * | 2020-03-18 | 2021-08-03 | 徐州圣元化工有限公司 | 一种3-(二氟甲基)-1-甲基-1h-吡唑-4-羧酸乙酯的制备方法 |
| TW202404581A (zh) | 2022-05-25 | 2024-02-01 | 美商醫肯納腫瘤學公司 | Ｍｅｋ抑制劑及其用途 |
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| WO2013049770A2 (en) * | 2011-09-30 | 2013-04-04 | Glaxosmithkline Llc | Methods of treating cancer |
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| EP1708697A4 (en) * | 2004-01-30 | 2007-11-28 | Smithkline Beecham Corp | CHEMICAL COMPOUNDS |
| CN1989131A (zh) * | 2004-03-30 | 2007-06-27 | 希龙公司 | 取代的噻吩衍生物用作抗癌药 |
| US7696352B2 (en) * | 2004-06-18 | 2010-04-13 | Millennium Pharmaceuticals, Inc. | Factor Xa inhibitors |
| WO2007070818A1 (en) | 2005-12-14 | 2007-06-21 | Bristol-Myers Squibb Company | Six-membered heterocycles useful as serine protease inhibitors |
| KR20120059525A (ko) * | 2009-08-07 | 2012-06-08 | 메르크 파텐트 게엠베하 | 신규의 아자헤테로시클릭 화합물 |
| EP2566327B1 (en) | 2010-05-07 | 2017-03-29 | Glaxosmithkline LLC | Indoles |
| ES2528269T3 (es) | 2010-05-07 | 2015-02-06 | Glaxosmithkline Llc | Azaindazoles |
| EP2566328B1 (en) * | 2010-05-07 | 2015-03-04 | GlaxoSmithKline LLC | Indazoles |
| JP5908493B2 (ja) | 2010-12-01 | 2016-04-26 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニーＧｌａｘｏＳｍｉｔｈＫｌｉｎｅ ＬＬＣ | インドール |
| EP2681216B1 (en) | 2011-02-28 | 2017-09-27 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
| JO3438B1 (ar) | 2011-04-13 | 2019-10-20 | Epizyme Inc | مركبات بنزين مستبدلة بأريل أو أريل غير متجانس |
| TWI598336B (zh) | 2011-04-13 | 2017-09-11 | 雅酶股份有限公司 | 經取代之苯化合物 |
| CA2862289C (en) | 2012-02-10 | 2019-11-26 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| BR112014025508B1 (pt) | 2012-04-13 | 2020-11-17 | Eisai R&D Management Co., Ltd. | forma de sal de um inibidor de histona metiltransferase ezh2 humana |
| US9562041B2 (en) | 2012-05-16 | 2017-02-07 | Glaxosmithkline Llc | Enhancer of zeste homolog 2 inhibitors |
| NZ630205A (en) * | 2013-04-30 | 2017-03-31 | Glaxosmithkline Intellectual Property (No 2) Ltd | Enhancer of zeste homolog 2 inhibitors |
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- 2014-04-25 BR BR112015027527A patent/BR112015027527A2/pt not_active IP Right Cessation
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- 2014-04-25 HK HK16102708.1A patent/HK1214815A1/zh unknown
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2015
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2016
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| WO2013049770A2 (en) * | 2011-09-30 | 2013-04-04 | Glaxosmithkline Llc | Methods of treating cancer |
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| CHEMICAL ABSTRACTS, Columbus, Ohio, US; XP002726952 * |
| CHEMICAL ABSTRACTS, Columbus, Ohio, US; XP002726953 * |
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| DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002726955, retrieved from STN * |
Also Published As
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| ES2717680T3 (es) | 2019-06-24 |
| EP2991980A1 (en) | 2016-03-09 |
| KR20160003115A (ko) | 2016-01-08 |
| ZA201507398B (en) | 2017-01-25 |
| PH12015502414A1 (en) | 2016-02-22 |
| CN105308038A (zh) | 2016-02-03 |
| JP6373973B2 (ja) | 2018-08-15 |
| CN105308038B (zh) | 2018-05-29 |
| US9505745B2 (en) | 2016-11-29 |
| JP2016517878A (ja) | 2016-06-20 |
| BR112015027527A2 (pt) | 2017-07-25 |
| CL2015003200A1 (es) | 2016-04-22 |
| DOP2015000270A (es) | 2016-02-15 |
| WO2014177982A1 (en) | 2014-11-06 |
| SG11201508203TA (en) | 2015-11-27 |
| US20160102083A1 (en) | 2016-04-14 |
| US9790212B2 (en) | 2017-10-17 |
| AU2014261075B2 (en) | 2017-01-19 |
| EA201592068A1 (ru) | 2016-05-31 |
| MX2015015144A (es) | 2016-02-18 |
| EP2991980B1 (en) | 2019-01-02 |
| HK1214815A1 (zh) | 2016-08-05 |
| PE20151981A1 (es) | 2016-01-14 |
| NZ630205A (en) | 2017-03-31 |
| CA2910873A1 (en) | 2014-11-06 |
| US20170029412A1 (en) | 2017-02-02 |
| AU2014261075A1 (en) | 2015-11-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): AM AZ BY KZ KG TJ TM |
|
| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): RU |