ZA200305383B - Naphthostyril derivatives and their use as inhibitors of cyclin-dependent kinases. - Google Patents

Naphthostyril derivatives and their use as inhibitors of cyclin-dependent kinases. Download PDF

Info

Publication number: ZA200305383B
Authority: ZA; South Africa
Prior art keywords: fluoro; pyrrol; indol; benzo; compound
Prior art date: 2001-01-23

Application number

ZA200305383A

Other languages

English (en)

Inventor

Chen Yi

Frederick Martin Konzelmann

Kin-Chun Luk

Dermatakis Apostolos Liu J Jin

Original Assignee

Hoffmann La Roche

Priority date (The priority date 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 date listed.)

2001-01-23

Filing date

2003-07-11

Publication date

2004-10-11

2003-07-11 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

2004-10-11 Publication of ZA200305383B publication Critical patent/ZA200305383B/en

Links

GPYLCFQEKPUWLD-UHFFFAOYSA-N 1h-benzo[cd]indol-2-one Chemical class C1=CC(C(=O)N2)=C3C2=CC=CC3=C1 GPYLCFQEKPUWLD-UHFFFAOYSA-N 0.000 title claims description 4
108091007914 CDKs Proteins 0.000 title description 16
102000003903 Cyclin-dependent kinases Human genes 0.000 title description 11
108090000266 Cyclin-dependent kinases Proteins 0.000 title description 11
239000003112 inhibitor Substances 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims description 96
239000000203 mixture Substances 0.000 claims description 36
206010028980 Neoplasm Diseases 0.000 claims description 23
238000000034 method Methods 0.000 claims description 19
150000003839 salts Chemical class 0.000 claims description 16
229910052736 halogen Inorganic materials 0.000 claims description 15
201000011510 cancer Diseases 0.000 claims description 13
229910052739 hydrogen Inorganic materials 0.000 claims description 13
150000002148 esters Chemical class 0.000 claims description 11
150000002367 halogens Chemical class 0.000 claims description 11
238000002360 preparation method Methods 0.000 claims description 11
125000004429 atom Chemical group 0.000 claims description 10
229910052799 carbon Inorganic materials 0.000 claims description 10
125000005842 heteroatom Chemical group 0.000 claims description 9
125000003118 aryl group Chemical group 0.000 claims description 8
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 claims description 8
239000008194 pharmaceutical composition Substances 0.000 claims description 8
RJHDCDKLLSBCCT-YFHOEESVSA-N 5-fluoro-4-[(z)-1-iodo-3-oxo-3-(1h-pyrrol-2-yl)prop-1-enyl]-1,3-dihydroindol-2-one Chemical compound FC1=CC=C2NC(=O)CC2=C1\C(I)=C\C(=O)C1=CC=CN1 RJHDCDKLLSBCCT-YFHOEESVSA-N 0.000 claims description 7
210000000481 breast Anatomy 0.000 claims description 7
210000001072 colon Anatomy 0.000 claims description 7
239000003814 drug Substances 0.000 claims description 7
125000000623 heterocyclic group Chemical group 0.000 claims description 7
210000004072 lung Anatomy 0.000 claims description 7
125000005010 perfluoroalkyl group Chemical group 0.000 claims description 7
UCCQAENGEYATHZ-UHFFFAOYSA-N 5-(2-aminoethoxy)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(OCCN)=CC=3C1=CC=CN1 UCCQAENGEYATHZ-UHFFFAOYSA-N 0.000 claims description 6
CQCXWWWNUFQYJS-UHFFFAOYSA-N 5-[(2-aminoethyl)amino]-6-fluoro-3-(1h-pyrrol-2-yl)benzo[cd]indol-2(1h)-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(NCCN)=CC=3C1=CC=CN1 CQCXWWWNUFQYJS-UHFFFAOYSA-N 0.000 claims description 6
208000026310 Breast neoplasm Diseases 0.000 claims description 6
208000029742 colonic neoplasm Diseases 0.000 claims description 6
208000037841 lung tumor Diseases 0.000 claims description 6
230000008569 process Effects 0.000 claims description 6
208000023958 prostate neoplasm Diseases 0.000 claims description 6
230000002062 proliferating effect Effects 0.000 claims description 5
VPWYHLCQSGEDNI-UHFFFAOYSA-N tert-butyl 4-[3-[3,4-dimethyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrol-2-yl]-3-hydroxyprop-1-ynyl]-5-fluoro-2-[(2-methylpropan-2-yl)oxycarbonyloxy]indole-1-carboxylate Chemical compound CC1=CN(C(=O)OC(C)(C)C)C(C(O)C#CC=2C=3C=C(OC(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C=3C=CC=2F)=C1C VPWYHLCQSGEDNI-UHFFFAOYSA-N 0.000 claims description 5
JQCPWYXLCQFXOO-UHFFFAOYSA-N 5-(2-aminoethylsulfanyl)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one;hydrochloride Chemical compound Cl.C=12C=3C(=O)NC2=CC=C(F)C=1C(SCCN)=CC=3C1=CC=CN1 JQCPWYXLCQFXOO-UHFFFAOYSA-N 0.000 claims description 4
GDMFHZWESGTFGR-UHFFFAOYSA-N 5-(2-aminoethylsulfinyl)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(S(=O)CCN)=CC=3C1=CC=CN1 GDMFHZWESGTFGR-UHFFFAOYSA-N 0.000 claims description 4
FNZRNRPNWVXECL-UHFFFAOYSA-N 5-ethoxy-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(OCC)=CC=3C1=CC=CN1 FNZRNRPNWVXECL-UHFFFAOYSA-N 0.000 claims description 4
ABXYGMKNQJBBKL-UHFFFAOYSA-N 6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C1=CC(=C23)C(F)=CC=C2NC(=O)C3=C1C1=CC=CN1 ABXYGMKNQJBBKL-UHFFFAOYSA-N 0.000 claims description 4
DBKUFLLBGAVHCU-UHFFFAOYSA-N 6-fluoro-5-(4-hydroxypiperidin-1-yl)-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C1CC(O)CCN1C1=CC(C=2NC=CC=2)=C2C3=C1C(F)=CC=C3NC2=O DBKUFLLBGAVHCU-UHFFFAOYSA-N 0.000 claims description 4
LRJJNDKQSLDGKE-UHFFFAOYSA-N 6-fluoro-5-[3-(hydroxymethyl)piperidin-1-yl]-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C1C(CO)CCCN1C1=CC(C=2NC=CC=2)=C2C3=C1C(F)=CC=C3NC2=O LRJJNDKQSLDGKE-UHFFFAOYSA-N 0.000 claims description 4
206010006187 Breast cancer Diseases 0.000 claims description 4
OZUGCYRIXYMTBK-UHFFFAOYSA-N acetic acid;5-(3-aminopropylamino)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound CC(O)=O.C=12C=3C(=O)NC2=CC=C(F)C=1C(NCCCN)=CC=3C1=CC=CN1 OZUGCYRIXYMTBK-UHFFFAOYSA-N 0.000 claims description 4
UZWCMFALYCSKHW-UHFFFAOYSA-N acetic acid;6-fluoro-5-piperazin-1-yl-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound CC(O)=O.C12=C3C(F)=CC=C2NC(=O)C1=C(C=1NC=CC=1)C=C3N1CCNCC1 UZWCMFALYCSKHW-UHFFFAOYSA-N 0.000 claims description 4
125000001072 heteroaryl group Chemical group 0.000 claims description 4
208000020816 lung neoplasm Diseases 0.000 claims description 4
SOOBKBMOGATQSY-UHFFFAOYSA-N tert-butyl 4-[3-[3,4-dimethyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrol-2-yl]-3-oxoprop-1-ynyl]-5-fluoro-2-[(2-methylpropan-2-yl)oxycarbonyloxy]indole-1-carboxylate Chemical compound CC1=CN(C(=O)OC(C)(C)C)C(C(=O)C#CC=2C=3C=C(OC(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C=3C=CC=2F)=C1C SOOBKBMOGATQSY-UHFFFAOYSA-N 0.000 claims description 4
JUZKPTPSMNPJAH-UHFFFAOYSA-N 5-(2-aminoethoxy)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.C=12C=3C(=O)NC2=CC=C(F)C=1C(OCCN)=CC=3C1=CC=CN1 JUZKPTPSMNPJAH-UHFFFAOYSA-N 0.000 claims description 3
YGKRRPRJPAHTBZ-UHFFFAOYSA-N 5-(2-aminoethylamino)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C=12C=3C(=O)NC2=CC=C(F)C=1C(NCCN)=CC=3C1=CC=CN1 YGKRRPRJPAHTBZ-UHFFFAOYSA-N 0.000 claims description 3
ICBYBTDOHYGFJD-UHFFFAOYSA-N 5-(2-aminoethylamino)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.C=12C=3C(=O)NC2=CC=C(F)C=1C(NCCN)=CC=3C1=CC=CN1 ICBYBTDOHYGFJD-UHFFFAOYSA-N 0.000 claims description 3
GJWREBSBNVGINK-UHFFFAOYSA-N 5-(2-aminoethylsulfanyl)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(SCCN)=CC=3C1=CC=CN1 GJWREBSBNVGINK-UHFFFAOYSA-N 0.000 claims description 3
DYYJWJGHQDHFLC-UHFFFAOYSA-N 5-(2-aminoethylsulfinyl)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one;hydrochloride Chemical compound Cl.C=12C=3C(=O)NC2=CC=C(F)C=1C(S(=O)CCN)=CC=3C1=CC=CN1 DYYJWJGHQDHFLC-UHFFFAOYSA-N 0.000 claims description 3
NAXHLQWKWRGFOK-UHFFFAOYSA-N 5-[(2-amino-2-methylpropyl)amino]-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(NCC(C)(N)C)=CC=3C1=CC=CN1 NAXHLQWKWRGFOK-UHFFFAOYSA-N 0.000 claims description 3
KYEOZKUGBAEJRO-UHFFFAOYSA-N 5-[2-(diethylamino)ethylamino]-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(NCCN(CC)CC)=CC=3C1=CC=CN1 KYEOZKUGBAEJRO-UHFFFAOYSA-N 0.000 claims description 3
CCXFNKVTQXJTFP-UHFFFAOYSA-N 5-butan-2-yl-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(C(C)CC)=CC=3C1=CC=CN1 CCXFNKVTQXJTFP-UHFFFAOYSA-N 0.000 claims description 3
ULMSOKRPLKOUKP-UHFFFAOYSA-N 6-fluoro-5-(2-hydroxyethylsulfinyl)-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(S(=O)CCO)=CC=3C1=CC=CN1 ULMSOKRPLKOUKP-UHFFFAOYSA-N 0.000 claims description 3
CZJUVDUMFZEZIA-UHFFFAOYSA-N 6-fluoro-5-(2-hydroxyethylsulfonyl)-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(S(=O)(=O)CCO)=CC=3C1=CC=CN1 CZJUVDUMFZEZIA-UHFFFAOYSA-N 0.000 claims description 3
DYRKHLOFLBMAGH-UHFFFAOYSA-N 6-fluoro-5-(3-hydroxypropoxy)-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(OCCCO)=CC=3C1=CC=CN1 DYRKHLOFLBMAGH-UHFFFAOYSA-N 0.000 claims description 3
PHJMZSOICSKGSN-UHFFFAOYSA-N 6-fluoro-5-methyl-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(C)=CC=3C1=CC=CN1 PHJMZSOICSKGSN-UHFFFAOYSA-N 0.000 claims description 3
SAUBMILAURAZDW-UHFFFAOYSA-N 6-fluoro-5-morpholin-4-yl-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C12=C3C(F)=CC=C2NC(=O)C1=C(C=1NC=CC=1)C=C3N1CCOCC1 SAUBMILAURAZDW-UHFFFAOYSA-N 0.000 claims description 3
DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
RMTMSYZHBIXLDA-UHFFFAOYSA-N n-[2-[[6-fluoro-2-oxo-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-5-yl]amino]ethyl]acetamide Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(NCCNC(=O)C)=CC=3C1=CC=CN1 RMTMSYZHBIXLDA-UHFFFAOYSA-N 0.000 claims description 3
238000007911 parenteral administration Methods 0.000 claims description 3
239000000546 pharmaceutical excipient Substances 0.000 claims description 3
PGTXXTNUKWABKI-UHFFFAOYSA-N 5-(2-aminoethylsulfanyl)-3-(3,4-dimethyl-1h-pyrrol-2-yl)-6-fluoro-1h-benzo[cd]indol-2-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CC1=CNC(C=2C=3C(=O)NC4=CC=C(F)C(C=34)=C(SCCN)C=2)=C1C PGTXXTNUKWABKI-UHFFFAOYSA-N 0.000 claims description 2
PIGVRBXVSCGJKI-UHFFFAOYSA-N 5-(2-aminoethylsulfonyl)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(S(=O)(=O)CCN)=CC=3C1=CC=CN1 PIGVRBXVSCGJKI-UHFFFAOYSA-N 0.000 claims description 2
UZVLKAPGUJAQCL-JTQLQIEISA-N 6-fluoro-5-[(3s)-pyrrolidin-3-yl]sulfanyl-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C12=C3C(F)=CC=C2NC(=O)C1=C(C=1NC=CC=1)C=C3S[C@H]1CCNC1 UZVLKAPGUJAQCL-JTQLQIEISA-N 0.000 claims description 2
239000004480 active ingredient Substances 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims description 2
239000000126 substance Substances 0.000 claims description 2
MTGXEGMUAMMCSQ-ZDUSSCGKSA-N tert-butyl (3s)-3-[[6-fluoro-2-oxo-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-5-yl]sulfanyl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1SC1=CC(C=2NC=CC=2)=C2C3=C1C(F)=CC=C3NC2=O MTGXEGMUAMMCSQ-ZDUSSCGKSA-N 0.000 claims description 2
125000005843 halogen group Chemical group 0.000 claims 3
KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical compound Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 claims 1
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
238000001783 near-resonance Rayleigh scattering spectroscopy Methods 0.000 claims 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 266
235000019439 ethyl acetate Nutrition 0.000 description 89
239000000243 solution Substances 0.000 description 70
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 64
239000011541 reaction mixture Substances 0.000 description 64
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
239000007787 solid Substances 0.000 description 52
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 36
229920006395 saturated elastomer Polymers 0.000 description 34
239000012267 brine Substances 0.000 description 32
239000000284 extract Substances 0.000 description 32
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 28
239000000741 silica gel Substances 0.000 description 26
229910002027 silica gel Inorganic materials 0.000 description 26
238000006243 chemical reaction Methods 0.000 description 22
238000003756 stirring Methods 0.000 description 22
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
239000000725 suspension Substances 0.000 description 20
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
239000012043 crude product Substances 0.000 description 19
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
235000019270 ammonium chloride Nutrition 0.000 description 18
239000000460 chlorine Substances 0.000 description 17
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
238000003818 flash chromatography Methods 0.000 description 15
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
239000012044 organic layer Substances 0.000 description 12
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
238000001556 precipitation Methods 0.000 description 11
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
239000010410 layer Substances 0.000 description 10
239000011734 sodium Substances 0.000 description 10
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
238000004128 high performance liquid chromatography Methods 0.000 description 9
JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 9
238000010992 reflux Methods 0.000 description 9
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
-1 small molecule compounds Chemical class 0.000 description 8
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
229910052786 argon Inorganic materials 0.000 description 7
239000000969 carrier Substances 0.000 description 7
238000000746 purification Methods 0.000 description 7
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
239000000706 filtrate Substances 0.000 description 6
239000000543 intermediate Substances 0.000 description 6
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
MUPAISSPSPASDX-UHFFFAOYSA-N tert-butyl 5-fluoro-2-[(2-methylpropan-2-yl)oxycarbonyloxy]-4-[3-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrol-2-yl]-3-oxoprop-1-ynyl]indole-1-carboxylate Chemical compound FC1=CC=C2N(C(=O)OC(C)(C)C)C(OC(=O)OC(C)(C)C)=CC2=C1C#CC(=O)C1=CC=CN1C(=O)OC(C)(C)C MUPAISSPSPASDX-UHFFFAOYSA-N 0.000 description 6
102000016736 Cyclin Human genes 0.000 description 5
108050006400 Cyclin Proteins 0.000 description 5
108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 5
102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 5
230000022131 cell cycle Effects 0.000 description 5
PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 5
230000000694 effects Effects 0.000 description 5
MIFAIQVSQMDIEY-UHFFFAOYSA-N 6-fluoro-5-(2-hydroxyethylsulfanyl)-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(SCCO)=CC=3C1=CC=CN1 MIFAIQVSQMDIEY-UHFFFAOYSA-N 0.000 description 4
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
235000011114 ammonium hydroxide Nutrition 0.000 description 4
210000004027 cell Anatomy 0.000 description 4
239000007903 gelatin capsule Substances 0.000 description 4
229910052760 oxygen Inorganic materials 0.000 description 4
238000012746 preparative thin layer chromatography Methods 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
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 4
WPYIAPGMDSGGPU-UHFFFAOYSA-N tert-butyl 2-(1-hydroxyprop-2-ynyl)pyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CC=C1C(O)C#C WPYIAPGMDSGGPU-UHFFFAOYSA-N 0.000 description 4
UQRJTHYLBKPHPH-UHFFFAOYSA-N tert-butyl 5-fluoro-4-iodo-2-[(2-methylpropan-2-yl)oxycarbonyloxy]indole-1-carboxylate Chemical compound FC1=CC=C2N(C(=O)OC(C)(C)C)C(OC(=O)OC(C)(C)C)=CC2=C1I UQRJTHYLBKPHPH-UHFFFAOYSA-N 0.000 description 4
229960000549 4-dimethylaminophenol Drugs 0.000 description 3
SFVVVZBVMTUBCL-UHFFFAOYSA-N 5-(2-aminoethylamino)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one;hydrochloride Chemical compound Cl.C=12C=3C(=O)NC2=CC=C(F)C=1C(NCCN)=CC=3C1=CC=CN1 SFVVVZBVMTUBCL-UHFFFAOYSA-N 0.000 description 3
KDAQAWMOIAQWGQ-UHFFFAOYSA-N 5-fluoro-4-[3-oxo-3-(1h-pyrrol-2-yl)propyl]-1,3-dihydroindol-2-one Chemical compound FC1=CC=C2NC(=O)CC2=C1CCC(=O)C1=CC=CN1 KDAQAWMOIAQWGQ-UHFFFAOYSA-N 0.000 description 3
UPPMBTMATLNYOX-UHFFFAOYSA-N 6-fluoro-5-(2-hydroxyethoxy)-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(OCCO)=CC=3C1=CC=CN1 UPPMBTMATLNYOX-UHFFFAOYSA-N 0.000 description 3
SWDWTTRSGVDCKP-UHFFFAOYSA-N 6-fluoro-5-(2-hydroxyethylamino)-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(NCCO)=CC=3C1=CC=CN1 SWDWTTRSGVDCKP-UHFFFAOYSA-N 0.000 description 3
YZVUSTSAIKJMLH-UHFFFAOYSA-N 6-fluoro-5-methoxy-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(OC)=CC=3C1=CC=CN1 YZVUSTSAIKJMLH-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
239000000908 ammonium hydroxide Substances 0.000 description 3
230000001028 anti-proliverative effect Effects 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
229910052801 chlorine Inorganic materials 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
239000011521 glass Substances 0.000 description 3
230000002401 inhibitory effect Effects 0.000 description 3
239000000463 material Substances 0.000 description 3
229940098779 methanesulfonic acid Drugs 0.000 description 3
239000003921 oil Substances 0.000 description 3
235000019198 oils Nutrition 0.000 description 3
229920005862 polyol Polymers 0.000 description 3
150000003077 polyols Chemical class 0.000 description 3
239000002244 precipitate Substances 0.000 description 3
238000004007 reversed phase HPLC Methods 0.000 description 3
229910052938 sodium sulfate Inorganic materials 0.000 description 3
235000011152 sodium sulphate Nutrition 0.000 description 3
VXRBDESFZINNQF-UHFFFAOYSA-N tert-butyl 2-(1-hydroxyprop-2-ynyl)-3,4-dimethylpyrrole-1-carboxylate Chemical compound CC1=CN(C(=O)OC(C)(C)C)C(C(O)C#C)=C1C VXRBDESFZINNQF-UHFFFAOYSA-N 0.000 description 3
SKPRHKSSURLBIU-UHFFFAOYSA-N tert-butyl n-[2-[[6-fluoro-2-oxo-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-5-yl]oxy]ethyl]carbamate Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(OCCNC(=O)OC(C)(C)C)=CC=3C1=CC=CN1 SKPRHKSSURLBIU-UHFFFAOYSA-N 0.000 description 3
UDQFLAQNEDCDRC-UHFFFAOYSA-N tert-butyl n-[2-[[6-fluoro-2-oxo-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-5-yl]sulfanyl]ethyl]carbamate Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(SCCNC(=O)OC(C)(C)C)=CC=3C1=CC=CN1 UDQFLAQNEDCDRC-UHFFFAOYSA-N 0.000 description 3
210000004881 tumor cell Anatomy 0.000 description 3
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
KZCLDLUMZLRZEC-UHFFFAOYSA-N 5-[2-(dimethylamino)ethylamino]-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C=12C=3C(=O)NC2=CC=C(F)C=1C(NCCN(C)C)=CC=3C1=CC=CN1 KZCLDLUMZLRZEC-UHFFFAOYSA-N 0.000 description 2
CXQSEWLYRHCWRQ-UHFFFAOYSA-N 5-ethyl-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(CC)=CC=3C1=CC=CN1 CXQSEWLYRHCWRQ-UHFFFAOYSA-N 0.000 description 2
SXMJIZRSNGTEOK-UHFFFAOYSA-N 5-fluoro-4-iodo-1,3-dihydroindol-2-one Chemical compound FC1=CC=C2NC(=O)CC2=C1I SXMJIZRSNGTEOK-UHFFFAOYSA-N 0.000 description 2
WCQSNLFSQWRGKS-UHFFFAOYSA-N 6-fluoro-3-(1h-pyrrol-2-yl)-4,5-dihydro-1h-benzo[cd]indol-2-one Chemical compound C1CC(=C23)C(F)=CC=C2NC(=O)C3=C1C1=CC=CN1 WCQSNLFSQWRGKS-UHFFFAOYSA-N 0.000 description 2
RSONOBKYSUKHLI-UHFFFAOYSA-N 6-fluoro-5-(3-hydroxypiperidin-1-yl)-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C1C(O)CCCN1C1=CC(C=2NC=CC=2)=C2C3=C1C(F)=CC=C3NC2=O RSONOBKYSUKHLI-UHFFFAOYSA-N 0.000 description 2
IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
102000004190 Enzymes Human genes 0.000 description 2
108090000790 Enzymes Proteins 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
125000000217 alkyl group Chemical group 0.000 description 2
239000003963 antioxidant agent Substances 0.000 description 2
239000002585 base Substances 0.000 description 2
230000005587 bubbling Effects 0.000 description 2
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
239000003054 catalyst Substances 0.000 description 2
230000004663 cell proliferation Effects 0.000 description 2
239000013000 chemical inhibitor Substances 0.000 description 2
239000003153 chemical reaction reagent Substances 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
238000001816 cooling Methods 0.000 description 2
239000010779 crude oil Substances 0.000 description 2
125000000753 cycloalkyl group Chemical group 0.000 description 2
238000010511 deprotection reaction Methods 0.000 description 2
201000010099 disease Diseases 0.000 description 2
239000008298 dragée Substances 0.000 description 2
239000003925 fat Substances 0.000 description 2
238000009472 formulation Methods 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
239000001257 hydrogen Substances 0.000 description 2
238000002347 injection Methods 0.000 description 2
239000007924 injection Substances 0.000 description 2
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
150000007522 mineralic acids Chemical class 0.000 description 2
231100000252 nontoxic Toxicity 0.000 description 2
230000003000 nontoxic effect Effects 0.000 description 2
150000007524 organic acids Chemical class 0.000 description 2
239000000825 pharmaceutical preparation Substances 0.000 description 2
125000006239 protecting group Chemical group 0.000 description 2
108090000623 proteins and genes Proteins 0.000 description 2
230000022983 regulation of cell cycle Effects 0.000 description 2
230000001105 regulatory effect Effects 0.000 description 2
YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
238000000926 separation method Methods 0.000 description 2
239000002002 slurry Substances 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
235000009518 sodium iodide Nutrition 0.000 description 2
239000002904 solvent Substances 0.000 description 2
239000007858 starting material Substances 0.000 description 2
238000006467 substitution reaction Methods 0.000 description 2
239000000829 suppository Substances 0.000 description 2
230000004083 survival effect Effects 0.000 description 2
208000024891 symptom Diseases 0.000 description 2
238000003786 synthesis reaction Methods 0.000 description 2
230000002194 synthesizing effect Effects 0.000 description 2
NSHLHMBABZKJHP-UHFFFAOYSA-N tert-butyl 2-formylpyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CC=C1C=O NSHLHMBABZKJHP-UHFFFAOYSA-N 0.000 description 2
BAVRCDIDEGIDOK-UHFFFAOYSA-N tert-butyl 5-fluoro-4-[3-hydroxy-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrol-2-yl]prop-1-ynyl]-2-[(2-methylpropan-2-yl)oxycarbonyloxy]indole-1-carboxylate Chemical compound FC1=CC=C2N(C(=O)OC(C)(C)C)C(OC(=O)OC(C)(C)C)=CC2=C1C#CC(O)C1=CC=CN1C(=O)OC(C)(C)C BAVRCDIDEGIDOK-UHFFFAOYSA-N 0.000 description 2
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
230000001225 therapeutic effect Effects 0.000 description 2
238000004809 thin layer chromatography Methods 0.000 description 2
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 2
235000015112 vegetable and seed oil Nutrition 0.000 description 2
239000008158 vegetable oil Substances 0.000 description 2
239000011701 zinc Substances 0.000 description 2
DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 1
BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
OPCJOXGBLDJWRM-UHFFFAOYSA-N 1,2-diamino-2-methylpropane Chemical compound CC(C)(N)CN OPCJOXGBLDJWRM-UHFFFAOYSA-N 0.000 description 1
YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
229940035437 1,3-propanediol Drugs 0.000 description 1
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
LVXHXYIXLGSCMQ-UHFFFAOYSA-N 1H-benzo[cd]indol-2-one hydrochloride Chemical compound Cl.N1C(C2=C3C(C=CC=C13)=CC=C2)=O LVXHXYIXLGSCMQ-UHFFFAOYSA-N 0.000 description 1
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
DIIDIHMSJICLIZ-UHFFFAOYSA-N 2-sulfanylethylcarbamic acid Chemical compound OC(=O)NCCS DIIDIHMSJICLIZ-UHFFFAOYSA-N 0.000 description 1
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
GUQGKTHAOXNYHX-UHFFFAOYSA-N 5-(3-aminopropylamino)-6-fluoro-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C=12C=3C(=O)NC2=CC=C(F)C=1C(NCCCN)=CC=3C1=CC=CN1 GUQGKTHAOXNYHX-UHFFFAOYSA-N 0.000 description 1
FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
REZHAIXSMRZBRK-UHFFFAOYSA-N 6-fluoro-5-(2-oxoimidazolidin-1-yl)-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C12=C3C(F)=CC=C2NC(=O)C1=C(C=1NC=CC=1)C=C3N1CCNC1=O REZHAIXSMRZBRK-UHFFFAOYSA-N 0.000 description 1
DNXLFICBXNMUNW-NSHDSACASA-N 6-fluoro-5-[[(2s)-pyrrolidin-2-yl]methylsulfanyl]-3-(1h-pyrrol-2-yl)-1h-benzo[cd]indol-2-one Chemical compound C12=C3C(F)=CC=C2NC(=O)C1=C(C=1NC=CC=1)C=C3SC[C@@H]1CCCN1 DNXLFICBXNMUNW-NSHDSACASA-N 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
101100439046 Caenorhabditis elegans cdk-2 gene Proteins 0.000 description 1
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
229920002261 Corn starch Polymers 0.000 description 1
VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
102000002554 Cyclin A Human genes 0.000 description 1
108010068192 Cyclin A Proteins 0.000 description 1
102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 1
101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
230000006820 DNA synthesis Effects 0.000 description 1
PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
241000282412 Homo Species 0.000 description 1
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
DPYOGJFEPCLTPC-RYUDHWBXSA-N O-[(1S,3S)-3-[tert-butyl(dimethyl)silyl]oxycyclopentyl] ethanethioate Chemical compound C(C)(C)(C)[Si](O[C@@H]1C[C@H](CC1)OC(C)=S)(C)C DPYOGJFEPCLTPC-RYUDHWBXSA-N 0.000 description 1
PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
235000019502 Orange oil Nutrition 0.000 description 1
229930040373 Paraformaldehyde Natural products 0.000 description 1
108091000080 Phosphotransferase Proteins 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
102000001253 Protein Kinase Human genes 0.000 description 1
108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
230000018199 S phase Effects 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
229930006000 Sucrose Natural products 0.000 description 1
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
230000002159 abnormal effect Effects 0.000 description 1
239000002253 acid Substances 0.000 description 1
239000013543 active substance Substances 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
125000001931 aliphatic group Chemical group 0.000 description 1
150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
230000004075 alteration Effects 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
239000005557 antagonist Substances 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
230000033228 biological regulation Effects 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
239000000872 buffer Substances 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
125000004432 carbon atom Chemical group C* 0.000 description 1
229910002091 carbon monoxide Inorganic materials 0.000 description 1
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
230000032823 cell division Effects 0.000 description 1
238000007385 chemical modification Methods 0.000 description 1
235000015165 citric acid Nutrition 0.000 description 1
239000011248 coating agent Substances 0.000 description 1
239000003086 colorant Substances 0.000 description 1
229910052802 copper Inorganic materials 0.000 description 1
239000010949 copper Substances 0.000 description 1
239000008120 corn starch Substances 0.000 description 1
125000004122 cyclic group Chemical group 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
235000013681 dietary sucrose Nutrition 0.000 description 1
HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
230000004069 differentiation Effects 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000003995 emulsifying agent Substances 0.000 description 1
230000001804 emulsifying effect Effects 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
239000000796 flavoring agent Substances 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
235000013355 food flavoring agent Nutrition 0.000 description 1
235000003599 food sweetener Nutrition 0.000 description 1
239000012458 free base Substances 0.000 description 1
238000004108 freeze drying Methods 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
235000011087 fumaric acid Nutrition 0.000 description 1
239000007789 gas Substances 0.000 description 1
239000008103 glucose Substances 0.000 description 1
229960001031 glucose Drugs 0.000 description 1
235000011187 glycerol Nutrition 0.000 description 1
150000002391 heterocyclic compounds Chemical class 0.000 description 1
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
150000002430 hydrocarbons Chemical group 0.000 description 1
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
229940071870 hydroiodic acid Drugs 0.000 description 1
125000002883 imidazolyl group Chemical group 0.000 description 1
230000006872 improvement Effects 0.000 description 1
238000001802 infusion Methods 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
150000007529 inorganic bases Chemical class 0.000 description 1
229960004903 invert sugar Drugs 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
239000011630 iodine Substances 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
239000008101 lactose Substances 0.000 description 1
239000011981 lindlar catalyst Substances 0.000 description 1
239000007788 liquid Substances 0.000 description 1
WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 1
GWGVDNZFTPIGDY-UHFFFAOYSA-M magnesium;ethyne;chloride Chemical compound [Mg+2].[Cl-].[C-]#C GWGVDNZFTPIGDY-UHFFFAOYSA-M 0.000 description 1
239000001630 malic acid Substances 0.000 description 1
235000011090 malic acid Nutrition 0.000 description 1
LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
RSMUVYRMZCOLBH-UHFFFAOYSA-N metsulfuron methyl Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC(=O)NC1=NC(C)=NC(OC)=N1 RSMUVYRMZCOLBH-UHFFFAOYSA-N 0.000 description 1
239000002480 mineral oil Substances 0.000 description 1
235000010446 mineral oil Nutrition 0.000 description 1
230000011278 mitosis Effects 0.000 description 1
238000002156 mixing Methods 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
229910052757 nitrogen Inorganic materials 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
230000000771 oncological effect Effects 0.000 description 1
239000010502 orange oil Substances 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
230000003204 osmotic effect Effects 0.000 description 1
125000001715 oxadiazolyl group Chemical group 0.000 description 1
235000006408 oxalic acid Nutrition 0.000 description 1
150000005623 oxindoles Chemical class 0.000 description 1
FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
229920002866 paraformaldehyde Polymers 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
150000003904 phospholipids Chemical class 0.000 description 1
102000020233 phosphotransferase Human genes 0.000 description 1
BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
VUNPWIPIOOMCPT-UHFFFAOYSA-N piperidin-3-ylmethanol Chemical compound OCC1CCCNC1 VUNPWIPIOOMCPT-UHFFFAOYSA-N 0.000 description 1
HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
229920000166 polytrimethylene carbonate Polymers 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000002265 prevention Effects 0.000 description 1
108090000765 processed proteins & peptides Proteins 0.000 description 1
239000000651 prodrug Substances 0.000 description 1
229940002612 prodrug Drugs 0.000 description 1
230000035755 proliferation Effects 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
108060006633 protein kinase Proteins 0.000 description 1
125000003373 pyrazinyl group Chemical group 0.000 description 1
ZSKGQVFRTSEPJT-UHFFFAOYSA-N pyrrole-2-carboxaldehyde Chemical compound O=CC1=CC=CN1 ZSKGQVFRTSEPJT-UHFFFAOYSA-N 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
125000001453 quaternary ammonium group Chemical group 0.000 description 1
125000005493 quinolyl group Chemical group 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
229930195734 saturated hydrocarbon Natural products 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
125000000547 substituted alkyl group Chemical group 0.000 description 1
229960004793 sucrose Drugs 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
239000004094 surface-active agent Substances 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
230000008685 targeting Effects 0.000 description 1
238000003419 tautomerization reaction Methods 0.000 description 1
AIVOYFQVTNBARM-UHFFFAOYSA-N tert-butyl 2-formyl-3,4-dimethylpyrrole-1-carboxylate Chemical compound CC1=CN(C(=O)OC(C)(C)C)C(C=O)=C1C AIVOYFQVTNBARM-UHFFFAOYSA-N 0.000 description 1
GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
125000003831 tetrazolyl group Chemical group 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
230000007704 transition Effects 0.000 description 1
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 1
229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
230000004222 uncontrolled growth Effects 0.000 description 1
239000012178 vegetable wax Substances 0.000 description 1
239000001993 wax Substances 0.000 description 1
238000005303 weighing Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1

Classifications

- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- 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
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
- 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
- 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
- C07D403/14—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 three or more hetero rings

Landscapes

Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Urology & Nephrology (AREA)
Endocrinology (AREA)
Reproductive Health (AREA)
Pulmonology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

ZA200305383A 2001-01-23 2003-07-11 Naphthostyril derivatives and their use as inhibitors of cyclin-dependent kinases. ZA200305383B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US26365801P	2001-01-23	2001-01-23

Publications (1)

Publication Number	Publication Date
ZA200305383B true ZA200305383B (en)	2004-10-11

Family

ID=23002712

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
ZA200305383A ZA200305383B (en)	2001-01-23	2003-07-11	Naphthostyril derivatives and their use as inhibitors of cyclin-dependent kinases.

Country Status (17)

Country	Link
US (2)	US6504034B2 (zh)
EP (1)	EP1358180B1 (zh)
JP (1)	JP4091434B2 (zh)
KR (1)	KR100563429B1 (zh)
CN (1)	CN1231479C (zh)
AR (1)	AR035738A1 (zh)
AT (1)	ATE283852T1 (zh)
AU (1)	AU2002240905B2 (zh)
BR (1)	BR0206621A (zh)
CA (1)	CA2434381C (zh)
DE (1)	DE60202131T2 (zh)
ES (1)	ES2232736T3 (zh)
MX (1)	MXPA03006423A (zh)
PE (1)	PE20020916A1 (zh)
UY (1)	UY27132A1 (zh)
WO (1)	WO2002059109A2 (zh)
ZA (1)	ZA200305383B (zh)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JP2011525915A (ja) *	2008-06-26	2011-09-29	アムジエン・インコーポレーテツド	キナーゼ阻害薬としてのアルキニルアルコール類
CN109665987B (zh) *	2018-12-28	2022-02-18	河南大学	萘内酰亚胺-多胺缀合物及其制备方法和用途
CA3130469A1 (en) *	2019-04-12	2020-10-15	C4 Therapeutics, Inc.	Tricyclic degraders of ikaros and aiolos
AU2021361043A1 (en) *	2020-10-14	2023-06-08	C4 Therapeutics, Inc.	Tricyclic ligands for degradation of ikzf2 or ikzf4
WO2023154417A1 (en) *	2022-02-09	2023-08-17	C4 Therapeutics, Inc.	Morphic forms of cft7455 and methods of manufacture thereof

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5081131A (en) *	1986-01-13	1992-01-14	American Cyanamid Company	Omega-((hetero)alkyl)benz(cd)-indol-2-amines
KR930011300B1 (ko)	1989-07-25	1993-11-29	다이호오 야꾸힌 고오교오 가부시끼가이샤	옥시인돌유도체
WO1992007830A2 (en)	1990-10-29	1992-05-14	Pfizer Inc.	Oxindole peptide antagonists
FR2694004B1 (fr)	1992-07-21	1994-08-26	Adir	Nouvelles 3-(Hydroxybenzylidényl)-indoline-2-ones et 3-(hydroxybenzylidényl)-indoline-2-thiones, leurs procédés de préparation, et les compositions pharmaceutiques qui les contiennent.
GB9313638D0 (en)	1993-07-01	1993-08-18	Erba Carlo Spa	Arylidene and heteroarylidene oxindole derivatives and process for their preparation
GB9423997D0 (en)	1994-11-28	1995-01-11	Erba Carlo Spa	Substituted 3-arylidene-7-azaoxindole compounds and process for their preparation
GB9501567D0 (en)	1995-01-26	1995-03-15	Pharmacia Spa	Hydrosoluble 3-arylidene-2-oxindole derivatives as tyrosine kinase inhibitors
GB9507298D0 (en)	1995-04-07	1995-05-31	Pharmacia Spa	Substituted indolylmethylene-oxindale analogues as tyrosine kinase inhibitors
US5880141A (en)	1995-06-07	1999-03-09	Sugen, Inc.	Benzylidene-Z-indoline compounds for the treatment of disease
DE29513441U1 (de)	1995-08-22	1995-10-19	Engelhardt, Rolf, 45883 Gelsenkirchen	Aschenbecher zum Mitführen
AU4155697A (en)	1996-08-23	1998-03-06	Sugen, Inc.	Indolinone combinatorial libraries and related products and methods for the treatment of disease
US5750556A (en) *	1996-10-30	1998-05-12	American Home Products Corporation	2-(aminomethyl)-3,4,7,9-tetrahydro-2H-pyrano- 2,3-E!indol-8-ones and derivatives
WO1998050356A1 (en)	1997-05-07	1998-11-12	Sugen, Inc.	2-indolinone derivatives as modulators of protein kinase activity
JP2002532492A (ja)	1998-12-17	2002-10-02	エフ．ホフマン−ラロシュアーゲー	サイクリン−依存性キナーゼ、特にｃｄｋ２のインヒビターとしての４−アルケニル（及びアルキニル）オキシドール

2002
- 2002-01-10 US US10/043,732 patent/US6504034B2/en not_active Expired - Fee Related
- 2002-01-16 KR KR1020037009680A patent/KR100563429B1/ko not_active IP Right Cessation
- 2002-01-16 JP JP2002559411A patent/JP4091434B2/ja not_active Expired - Fee Related
- 2002-01-16 ES ES02706711T patent/ES2232736T3/es not_active Expired - Lifetime
- 2002-01-16 MX MXPA03006423A patent/MXPA03006423A/es active IP Right Grant
- 2002-01-16 AU AU2002240905A patent/AU2002240905B2/en not_active Ceased
- 2002-01-16 AT AT02706711T patent/ATE283852T1/de not_active IP Right Cessation
- 2002-01-16 EP EP02706711A patent/EP1358180B1/en not_active Expired - Lifetime
- 2002-01-16 CA CA002434381A patent/CA2434381C/en not_active Expired - Fee Related
- 2002-01-16 CN CNB028040406A patent/CN1231479C/zh not_active Expired - Fee Related
- 2002-01-16 DE DE60202131T patent/DE60202131T2/de not_active Expired - Lifetime
- 2002-01-16 WO PCT/EP2002/000366 patent/WO2002059109A2/en active IP Right Grant
- 2002-01-16 BR BR0206621-1A patent/BR0206621A/pt not_active IP Right Cessation
- 2002-01-21 AR ARP020100201A patent/AR035738A1/es not_active Application Discontinuation
- 2002-01-22 UY UY27132A patent/UY27132A1/es not_active Application Discontinuation
- 2002-01-22 PE PE2002000045A patent/PE20020916A1/es not_active Application Discontinuation
- 2002-08-20 US US10/224,022 patent/US6531598B1/en not_active Expired - Fee Related
2003
- 2003-07-11 ZA ZA200305383A patent/ZA200305383B/en unknown

Also Published As

Publication number	Publication date
UY27132A1 (es)	2002-07-31
DE60202131D1 (de)	2005-01-05
US6504034B2 (en)	2003-01-07
KR100563429B1 (ko)	2006-03-22
CA2434381C (en)	2009-11-24
WO2002059109A3 (en)	2002-09-19
PE20020916A1 (es)	2002-10-21
DE60202131T2 (de)	2005-12-01
ATE283852T1 (de)	2004-12-15
CA2434381A1 (en)	2002-08-01
JP4091434B2 (ja)	2008-05-28
CN1487931A (zh)	2004-04-07
US20020147343A1 (en)	2002-10-10
CN1231479C (zh)	2005-12-14
EP1358180B1 (en)	2004-12-01
US6531598B1 (en)	2003-03-11
JP2004517150A (ja)	2004-06-10
BR0206621A (pt)	2004-02-25
EP1358180A2 (en)	2003-11-05
WO2002059109A2 (en)	2002-08-01
MXPA03006423A (es)	2003-10-15
AU2002240905B2 (en)	2007-03-01
AR035738A1 (es)	2004-07-07
KR20030069223A (ko)	2003-08-25
ES2232736T3 (es)	2005-06-01

Publication	Publication Date	Title
KR102650026B1 (ko)	2024-03-22	Irak 억제제로서의 헤테로아릴 화합물 및 이의 용도
AU2016323612B2 (en)	2021-04-08	Heteroaryl compounds as IRAK inhibitors and uses thereof
CN107428765B (zh)	2020-12-29	用作irak抑制剂的哒嗪酮类大环化合物及其用途
CN107849055B (zh)	2020-08-07	用作irak1/4抑制剂的大环化合物及其用途
AU2015223049A1 (en)	2016-07-28	Heterocyclic compounds as Nav channel inhibitors and uses thereof
AU2015289044A1 (en)	2016-12-08	Novel naphthryidines and isoquinolines and their use as CDK8/19 inhibitors
AU2019249721A1 (en)	2020-09-17	Heteroaryl compounds as type II IRAK inhibitors and uses hereof
US20070293484A1 (en)	2007-12-20	Thiophene Heteroaryl Amines
JP2007538068A (ja)	2007-12-27	新規な縮合複素環およびそれらの使用
CN108430978B (zh)	2022-11-22	3-羟基-喹唑啉-2,4-二酮衍生物及其作为核酸酶调节剂的用途
CA3088766A1 (en)	2019-08-08	Quinoline compounds as irak inhibitors and uses thereof
ZA200305383B (en)	2004-10-11	Naphthostyril derivatives and their use as inhibitors of cyclin-dependent kinases.
WO2017045751A1 (en)	2017-03-23	Compounds as asic inhibitors and uses thereof
AU2002240905A1 (en)	2003-02-06	Naphthostyril derivatives and their use as inhibitors of cyclin-dependent kinases
RU2610275C2 (ru)	2017-02-08	Производное глутаримидов, его применение, фармацевтическая композиция на его основе, способ его получения
RU2610274C2 (ru)	2017-02-08	Производное глутаримидов, его применение, фармацевтическая композиция на его основе, способ его получения