CA2944610C - (5,6-dihydro)pyrimido[4,5-e]indolizines - Google Patents
(5,6-dihydro)pyrimido[4,5-e]indolizines Download PDFInfo
- Publication number
- CA2944610C CA2944610C CA2944610A CA2944610A CA2944610C CA 2944610 C CA2944610 C CA 2944610C CA 2944610 A CA2944610 A CA 2944610A CA 2944610 A CA2944610 A CA 2944610A CA 2944610 C CA2944610 C CA 2944610C
- Authority
- CA
- Canada
- Prior art keywords
- carboxamide
- indolizine
- anilino
- methoxy
- dihydropyrimido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000002478 indolizines Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 571
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 50
- 201000011510 cancer Diseases 0.000 claims abstract description 26
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 159
- URGAFFAIKGXTJC-UHFFFAOYSA-N indolizine-7-carboxamide Chemical compound C1=C(C(=O)N)C=CN2C=CC=C21 URGAFFAIKGXTJC-UHFFFAOYSA-N 0.000 claims description 127
- 125000003545 alkoxy group Chemical group 0.000 claims description 93
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 71
- 150000003839 salts Chemical class 0.000 claims description 65
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 50
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
- 102100036109 Dual specificity protein kinase TTK Human genes 0.000 claims description 38
- 101000659223 Homo sapiens Dual specificity protein kinase TTK Proteins 0.000 claims description 38
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 37
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- -1 piperidinylamino, azetidinylamino, tetrahydropyranylamino Chemical group 0.000 claims description 24
- 125000001153 fluoro group Chemical group F* 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 15
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 15
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 14
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 12
- 125000004043 oxo group Chemical group O=* 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- 125000002393 azetidinyl group Chemical group 0.000 claims description 9
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000003566 oxetanyl group Chemical group 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 206010027476 Metastases Diseases 0.000 claims description 6
- 239000013543 active substance Substances 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 208000002699 Digestive System Neoplasms Diseases 0.000 claims description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 210000000038 chest Anatomy 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 206010059282 Metastases to central nervous system Diseases 0.000 claims description 3
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 3
- 206010029098 Neoplasm skin Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 3
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims description 3
- 201000011523 endocrine gland cancer Diseases 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 208000037841 lung tumor Diseases 0.000 claims description 3
- 208000023958 prostate neoplasm Diseases 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 2
- BBQZWKVMDCAMHS-UHFFFAOYSA-N pyrimido[4,5-e]indolizine-7-carboxamide Chemical compound N1=CN=CC2=C1N1C=CC(=C1C=C2)C(=O)N BBQZWKVMDCAMHS-UHFFFAOYSA-N 0.000 claims 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 5
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 4
- DNWWRRFJUYGOIW-UHFFFAOYSA-N CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(C=CC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)OC Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(C=CC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCNCC1)OC DNWWRRFJUYGOIW-UHFFFAOYSA-N 0.000 claims 3
- UYPNZGVGCJECJV-UHFFFAOYSA-N CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC12)C=NC(=N3)NC3=C(C=C(C=C3)N3CCNCC3)OC Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC12)C=NC(=N3)NC3=C(C=C(C=C3)N3CCNCC3)OC UYPNZGVGCJECJV-UHFFFAOYSA-N 0.000 claims 3
- 206010039491 Sarcoma Diseases 0.000 claims 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 claims 2
- XPORPDHLTHKBQR-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-[2-methoxy-4-[4-(2-methoxyacetyl)piperazin-1-yl]anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide Chemical compound CC1=C(C(=CC=C1)C)NC(=O)C=1C=CN2C3=C(CCC=12)C=NC(=N3)NC1=C(C=C(C=C1)N1CCN(CC1)C(COC)=O)OC XPORPDHLTHKBQR-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 claims 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 205
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 163
- 238000000034 method Methods 0.000 description 162
- 238000000746 purification Methods 0.000 description 158
- 238000002953 preparative HPLC Methods 0.000 description 156
- 238000006243 chemical reaction Methods 0.000 description 145
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
- 239000007858 starting material Substances 0.000 description 125
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 115
- 239000000243 solution Substances 0.000 description 95
- 239000000203 mixture Substances 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 239000011541 reaction mixture Substances 0.000 description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 51
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 44
- 229910052938 sodium sulfate Inorganic materials 0.000 description 44
- 235000011152 sodium sulphate Nutrition 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 239000012267 brine Substances 0.000 description 42
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 42
- 239000012044 organic layer Substances 0.000 description 40
- 125000004432 carbon atom Chemical group C* 0.000 description 37
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 36
- 238000010511 deprotection reaction Methods 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 32
- 238000010168 coupling process Methods 0.000 description 29
- 238000005859 coupling reaction Methods 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- 239000000725 suspension Substances 0.000 description 24
- 150000001412 amines Chemical class 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 20
- 230000000694 effects Effects 0.000 description 19
- FOYHNROGBXVLLX-UHFFFAOYSA-N 2,6-diethylaniline Chemical compound CCC1=CC=CC(CC)=C1N FOYHNROGBXVLLX-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 125000003277 amino group Chemical group 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 239000000758 substrate Substances 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 12
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 11
- WLKUSVNHZXUEFO-UHFFFAOYSA-N 4-fluoro-2-methoxy-1-nitrobenzene Chemical compound COC1=CC(F)=CC=C1[N+]([O-])=O WLKUSVNHZXUEFO-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- WFNLHDJJZSJARK-UHFFFAOYSA-N 2-chloro-6-methylaniline Chemical compound CC1=CC=CC(Cl)=C1N WFNLHDJJZSJARK-UHFFFAOYSA-N 0.000 description 10
- JJVKJJNCIILLRP-UHFFFAOYSA-N 2-ethyl-6-methylaniline Chemical compound CCC1=CC=CC(C)=C1N JJVKJJNCIILLRP-UHFFFAOYSA-N 0.000 description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 108010056274 polo-like kinase 1 Proteins 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 125000004494 ethyl ester group Chemical group 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000012047 saturated solution Substances 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dithiothreitol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 8
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 8
- 108091000080 Phosphotransferase Proteins 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
- 102000020233 phosphotransferase Human genes 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- ALOCUZOKRULSAA-UHFFFAOYSA-N 1-methylpiperidin-4-amine Chemical compound CN1CCC(N)CC1 ALOCUZOKRULSAA-UHFFFAOYSA-N 0.000 description 6
- LDUCMSVRKKDATH-UHFFFAOYSA-N 2-bromo-6-methylaniline Chemical compound CC1=CC=CC(Br)=C1N LDUCMSVRKKDATH-UHFFFAOYSA-N 0.000 description 6
- QOWALNIZDHZTSM-UHFFFAOYSA-N 5-bromo-2-chloropyrimidin-4-amine Chemical compound NC1=NC(Cl)=NC=C1Br QOWALNIZDHZTSM-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
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- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 102000001253 Protein Kinase Human genes 0.000 description 5
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- 238000003556 assay Methods 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
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- 229910052757 nitrogen Inorganic materials 0.000 description 5
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- 238000011533 pre-incubation Methods 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 108060006633 protein kinase Proteins 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 4
- JHFOWEGCZWLHNW-UHFFFAOYSA-N 4-fluoro-2-methyl-1-nitrobenzene Chemical compound CC1=CC(F)=CC=C1[N+]([O-])=O JHFOWEGCZWLHNW-UHFFFAOYSA-N 0.000 description 4
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- AGJSNMGHAVDLRQ-IWFBPKFRSA-N methyl (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-IWFBPKFRSA-N 0.000 description 1
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- 235000021317 phosphate Nutrition 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
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- 229920001184 polypeptide Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
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- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- ISYORFGKSZLPNW-UHFFFAOYSA-N propan-2-ylazanium;chloride Chemical compound [Cl-].CC(C)[NH3+] ISYORFGKSZLPNW-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000001990 protein-drug conjugate Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- FVLAYJRLBLHIPV-UHFFFAOYSA-N pyrimidin-5-amine Chemical compound NC1=CN=CN=C1 FVLAYJRLBLHIPV-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
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- ZFLJHSQHILSNCM-UHFFFAOYSA-N reversine Chemical compound C1CCCCC1NC1=NC(NC=2C=CC(=CC=2)N2CCOCC2)=NC2=C1N=CN2 ZFLJHSQHILSNCM-UHFFFAOYSA-N 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
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- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
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- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
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- QNGHCFVWYKWWMU-BDAKNGLRSA-N tert-butyl (3s,4r)-4-amino-3-methoxypiperidine-1-carboxylate Chemical compound CO[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N QNGHCFVWYKWWMU-BDAKNGLRSA-N 0.000 description 1
- SHPZKFGBAFQIRP-UHFFFAOYSA-N tert-butyl 3-(3-methyl-4-nitrophenoxy)azetidine-1-carboxylate Chemical compound C1=C([N+]([O-])=O)C(C)=CC(OC2CN(C2)C(=O)OC(C)(C)C)=C1 SHPZKFGBAFQIRP-UHFFFAOYSA-N 0.000 description 1
- WPGLRFGDZJSQGI-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(N)C1 WPGLRFGDZJSQGI-UHFFFAOYSA-N 0.000 description 1
- RADGPXZWMLVDDP-UHFFFAOYSA-N tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate Chemical compound C1=C(N)C(OC)=CC(N2CCN(CC2)C(=O)OC(C)(C)C)=C1 RADGPXZWMLVDDP-UHFFFAOYSA-N 0.000 description 1
- FEYLUKDSKVSMSZ-UHFFFAOYSA-N tert-butyl n-(4-aminocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(N)CC1 FEYLUKDSKVSMSZ-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 150000003942 tert-butylamines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 150000008523 triazolopyridines Chemical class 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000024719 uterine cervix neoplasm Diseases 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP14163734 | 2014-04-07 | ||
| EP14163734.8 | 2014-04-07 | ||
| EP15153207 | 2015-01-30 | ||
| EP15153207.4 | 2015-01-30 | ||
| PCT/EP2015/056839 WO2015155042A1 (en) | 2014-04-07 | 2015-03-30 | (5,6-dihydro)pyrimido[4,5-e]indolizines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2944610A1 CA2944610A1 (en) | 2015-10-15 |
| CA2944610C true CA2944610C (en) | 2024-01-09 |
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| CA2944610A Active CA2944610C (en) | 2014-04-07 | 2015-03-30 | (5,6-dihydro)pyrimido[4,5-e]indolizines |
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|---|---|
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| EP (1) | EP3129374B1 (enExample) |
| JP (1) | JP6518690B2 (enExample) |
| KR (1) | KR102432420B1 (enExample) |
| CN (1) | CN106132963B (enExample) |
| AU (1) | AU2015243694B2 (enExample) |
| BR (1) | BR112016022342B1 (enExample) |
| CA (1) | CA2944610C (enExample) |
| DK (1) | DK3129374T3 (enExample) |
| ES (1) | ES2716165T3 (enExample) |
| HU (1) | HUE043108T2 (enExample) |
| MX (1) | MX368767B (enExample) |
| PL (1) | PL3129374T3 (enExample) |
| PT (1) | PT3129374T (enExample) |
| RU (1) | RU2692479C2 (enExample) |
| WO (1) | WO2015155042A1 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015155042A1 (en) * | 2014-04-07 | 2015-10-15 | Netherlands Translational Research Center B.V. | (5,6-dihydro)pyrimido[4,5-e]indolizines |
| US11208696B2 (en) | 2015-04-17 | 2021-12-28 | Netherlands Translational Research Center B.V. | Prognostic biomarkers for TTK inhibitor chemotherapy |
| ES2858753T3 (es) * | 2016-02-19 | 2021-09-30 | Phoenix Molecular Designs | Derivados de 6-oxo-N-(1-(bencil)-1H-pirazol-4-il)-6,7,8,9-tetrahidropirido[3',2':4,5]pirrolo[1,2-a]pirazin-2-carboxamida como inhibidores de cinasa S6 ribosómica (RSK) p90 para el tratamiento del cáncer |
| CN109311848B (zh) | 2016-06-07 | 2022-02-01 | 北京加科思新药研发有限公司 | 可用作shp2抑制剂的新型杂环衍生物 |
| CN106551938B (zh) * | 2016-11-26 | 2017-11-24 | 广东安诺药业股份有限公司 | 一种治疗非酒精性脂肪肝的药物及其应用 |
| SMT202400385T1 (it) | 2017-03-23 | 2024-11-15 | Jacobio Pharmaceuticals Co Ltd | Nuovi derivati eterociclici utili come inibitori di shp2 |
| US20210393623A1 (en) | 2018-09-26 | 2021-12-23 | Jacobio Pharmaceuticals Co., Ltd. | Novel Heterocyclic Derivatives Useful as SHP2 Inhibitors |
| EP3924352A4 (en) | 2019-02-11 | 2022-11-16 | Phoenix Molecular Designs | CRYSTALLINE FORMS OF AN RSK INHIBITOR |
| KR20240107189A (ko) * | 2021-12-15 | 2024-07-08 | 신라젠(주) | 신생물성 질환 치료에 사용하기 위한 약제학적 병용물 |
| AU2022408915A1 (en) * | 2021-12-15 | 2024-06-27 | Sillajen, Inc. | Methods of treating neoplastic diseases |
| US20250049926A1 (en) * | 2021-12-15 | 2025-02-13 | Sillajen, Inc. | Pharmaceutical compositions comprising modified betacyclodextrins |
| AU2023228543A1 (en) * | 2022-03-04 | 2024-08-22 | Sillajen, Inc. | Pharmaceutical combinations for use in the treatment of neoplastic diseases. |
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| AU2002337142B2 (en) * | 2001-09-19 | 2007-10-11 | Aventis Pharma S.A. | Indolizines as kinase protein inhibitors |
| US7482354B2 (en) | 2003-05-22 | 2009-01-27 | Nerviano Medical Sciences S.R.L. | Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors |
| EP2118102B1 (en) | 2006-11-28 | 2013-06-12 | Nerviano Medical Sciences S.r.l. | Tricyclic indoles and (4,5-dihydro) indoles |
| HRP20160243T1 (hr) * | 2008-06-26 | 2016-04-08 | Les Laboratoires Servier | Pirazolo-kinazolini kao modulatori aktivnosti protein kinaze |
| WO2010111406A2 (en) | 2009-03-24 | 2010-09-30 | Myriad Pharmaceuticals, Inc. | Compounds and therapeutic uses thereof |
| CN102428086B (zh) | 2009-04-29 | 2014-08-20 | 内尔维阿诺医学科学有限公司 | Cdk抑制剂的盐类 |
| CN103626777B (zh) | 2009-07-29 | 2015-10-21 | 内尔维阿诺医学科学有限公司 | Plk抑制剂的盐类 |
| TW201107329A (en) | 2009-07-30 | 2011-03-01 | Oncotherapy Science Inc | Fused imidazole derivative having ttk inhibitory action |
| EP2343297A1 (en) | 2009-11-30 | 2011-07-13 | Bayer Schering Pharma AG | Triazolopyridines |
| US20130303532A1 (en) * | 2010-12-17 | 2013-11-14 | Bayer Intellectual Property Gmbh | Imidazopyrazines for use as mps-1 and tkk inhibitors in the treatment hyperproliferative disorders |
| BR112013018515B1 (pt) * | 2011-01-26 | 2021-06-29 | Nerviano Medical Sciences S.R.I | Derivados de pirrol tricíclico, processo para sua preparação e seu uso como inibidores da quinase |
| JP6523267B2 (ja) | 2013-06-24 | 2019-05-29 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | Ｆｓｈｒの調節剤としてのイミダゾール化合物及びその使用 |
| WO2015155042A1 (en) * | 2014-04-07 | 2015-10-15 | Netherlands Translational Research Center B.V. | (5,6-dihydro)pyrimido[4,5-e]indolizines |
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- 2015-03-30 RU RU2016141405A patent/RU2692479C2/ru active
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- 2015-03-30 PL PL15712912T patent/PL3129374T3/pl unknown
- 2015-03-30 PT PT15712912T patent/PT3129374T/pt unknown
- 2015-03-30 JP JP2016560952A patent/JP6518690B2/ja active Active
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- 2015-03-30 ES ES15712912T patent/ES2716165T3/es active Active
- 2015-03-30 HU HUE15712912A patent/HUE043108T2/hu unknown
- 2015-03-30 EP EP15712912.3A patent/EP3129374B1/en active Active
- 2015-03-30 KR KR1020167031029A patent/KR102432420B1/ko active Active
Also Published As
| Publication number | Publication date |
|---|---|
| KR20170013866A (ko) | 2017-02-07 |
| RU2016141405A3 (enExample) | 2018-10-02 |
| BR112016022342A8 (pt) | 2021-07-20 |
| PT3129374T (pt) | 2019-03-25 |
| BR112016022342A2 (pt) | 2017-08-15 |
| EP3129374A1 (en) | 2017-02-15 |
| MX2016012997A (es) | 2016-12-07 |
| RU2692479C2 (ru) | 2019-06-25 |
| JP2017510595A (ja) | 2017-04-13 |
| DK3129374T3 (en) | 2019-04-08 |
| US20170096432A1 (en) | 2017-04-06 |
| WO2015155042A1 (en) | 2015-10-15 |
| ES2716165T3 (es) | 2019-06-10 |
| JP6518690B2 (ja) | 2019-05-22 |
| USRE50082E1 (en) | 2024-08-20 |
| CA2944610A1 (en) | 2015-10-15 |
| HUE043108T2 (hu) | 2019-07-29 |
| AU2015243694B2 (en) | 2019-01-17 |
| CN106132963B (zh) | 2019-08-06 |
| AU2015243694A1 (en) | 2016-11-03 |
| USRE48974E1 (en) | 2022-03-15 |
| CN106132963A (zh) | 2016-11-16 |
| RU2016141405A (ru) | 2018-05-07 |
| EP3129374B1 (en) | 2018-12-19 |
| KR102432420B1 (ko) | 2022-08-17 |
| MX368767B (es) | 2019-10-15 |
| PL3129374T3 (pl) | 2019-07-31 |
| BR112016022342B1 (pt) | 2022-10-04 |
| US9856258B2 (en) | 2018-01-02 |
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