JP4842137B2 - Mekのヘテロ環系阻害剤及びその使用方法 - Google Patents
Mekのヘテロ環系阻害剤及びその使用方法 Download PDFInfo
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- JP4842137B2 JP4842137B2 JP2006541579A JP2006541579A JP4842137B2 JP 4842137 B2 JP4842137 B2 JP 4842137B2 JP 2006541579 A JP2006541579 A JP 2006541579A JP 2006541579 A JP2006541579 A JP 2006541579A JP 4842137 B2 JP4842137 B2 JP 4842137B2
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- Japan
- Prior art keywords
- alkyl
- formula
- compound
- heteroaryl
- hydrogen
- 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.)
- Expired - Fee Related
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- 238000000034 method Methods 0.000 title claims abstract description 109
- 239000003112 inhibitor Substances 0.000 title description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 217
- 150000003839 salts Chemical class 0.000 claims abstract description 64
- 125000001072 heteroaryl group Chemical group 0.000 claims description 217
- 125000000217 alkyl group Chemical group 0.000 claims description 181
- 125000003118 aryl group Chemical group 0.000 claims description 181
- -1 resolved enantiomers Chemical class 0.000 claims description 166
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 118
- 229910052736 halogen Inorganic materials 0.000 claims description 115
- 150000002367 halogens Chemical class 0.000 claims description 115
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 102
- 229910052739 hydrogen Inorganic materials 0.000 claims description 91
- 239000001257 hydrogen Substances 0.000 claims description 89
- 238000002360 preparation method Methods 0.000 claims description 78
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 68
- 125000003342 alkenyl group Chemical group 0.000 claims description 57
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 55
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 46
- 125000000304 alkynyl group Chemical group 0.000 claims description 45
- 150000002431 hydrogen Chemical class 0.000 claims description 45
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 44
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
- 150000001412 amines Chemical class 0.000 claims description 25
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 23
- 239000012453 solvate Substances 0.000 claims description 22
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 21
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- DYMRYCZRMAHYKE-UHFFFAOYSA-N n-diazonitramide Chemical compound [O-][N+](=O)N=[N+]=[N-] DYMRYCZRMAHYKE-UHFFFAOYSA-N 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 11
- 150000001448 anilines Chemical class 0.000 claims description 11
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- ZHAJJMZPTVRKCV-UHFFFAOYSA-N 3-amino-6-(4-bromo-2-fluoroanilino)-7-fluoro-n-(2-hydroxyethoxy)-[1,2]oxazolo[4,5-b]pyridine-5-carboxamide Chemical compound OCCONC(=O)C=1N=C2C(N)=NOC2=C(F)C=1NC1=CC=C(Br)C=C1F ZHAJJMZPTVRKCV-UHFFFAOYSA-N 0.000 claims description 3
- YGQVCBNGVKCECU-UHFFFAOYSA-N 6-(4-bromo-2-fluoroanilino)-7-fluoropyrazolo[1,5-a]pyrimidine-5-carboxamide Chemical compound NC(=O)C1=NC2=CC=NN2C(F)=C1NC1=CC=C(Br)C=C1F YGQVCBNGVKCECU-UHFFFAOYSA-N 0.000 claims description 3
- LJWVYYHROWSNKN-UHFFFAOYSA-N 6-(4-bromo-2-fluoroanilino)-n-(cyclopropylmethoxy)-7-fluoro-2,3-dimethylpyrazolo[4,3-b]pyridine-5-carboxamide Chemical compound C1CC1CONC(=O)C1=NC2=C(C)N(C)N=C2C(F)=C1NC1=CC=C(Br)C=C1F LJWVYYHROWSNKN-UHFFFAOYSA-N 0.000 claims description 3
- FOQCURBOFFHLQF-UHFFFAOYSA-N 7-(4-bromo-2-fluoroanilino)-n-(2-hydroxyethoxy)imidazo[1,2-b]pyridazine-6-carboxamide Chemical compound OCCONC(=O)C1=NN2C=CN=C2C=C1NC1=CC=C(Br)C=C1F FOQCURBOFFHLQF-UHFFFAOYSA-N 0.000 claims description 3
- IAWNGBFZRJEFCJ-UHFFFAOYSA-N n-ethoxy-6-(2-fluoro-4-methylsulfanylanilino)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxamide Chemical compound CCONC(=O)C1=NC2=CC=NN2C(C)=C1NC1=CC=C(SC)C=C1F IAWNGBFZRJEFCJ-UHFFFAOYSA-N 0.000 claims description 3
- DUJVPVUCDJIHEW-UHFFFAOYSA-N 3-amino-6-(4-bromo-2-fluoroanilino)-7-fluoro-n-(2-hydroxyethoxy)-2-methylpyrazolo[4,3-b]pyridine-5-carboxamide Chemical compound OCCONC(=O)C1=NC2=C(N)N(C)N=C2C(F)=C1NC1=CC=C(Br)C=C1F DUJVPVUCDJIHEW-UHFFFAOYSA-N 0.000 claims description 2
- AKXNRVYWUNBSPW-UHFFFAOYSA-N 5-(5-amino-1,3,4-oxadiazol-2-yl)-n-(4-bromo-2-fluorophenyl)-7-fluoro-3-methyl-[1,2]oxazolo[4,5-b]pyridin-6-amine Chemical compound N=1N=C(N)OC=1C=1N=C2C(C)=NOC2=C(F)C=1NC1=CC=C(Br)C=C1F AKXNRVYWUNBSPW-UHFFFAOYSA-N 0.000 claims description 2
- UFCCAYRGFQHOMV-UHFFFAOYSA-N 5-[6-(4-bromo-2-fluoroanilino)-7-fluoro-2,3-dimethylpyrazolo[4,3-b]pyridin-5-yl]-1,3,4-oxadiazol-2-amine Chemical compound N=1N=C(N)OC=1C1=NC2=C(C)N(C)N=C2C(F)=C1NC1=CC=C(Br)C=C1F UFCCAYRGFQHOMV-UHFFFAOYSA-N 0.000 claims description 2
- CRQMWNMYTJZPPB-UHFFFAOYSA-N 5-[7-(4-bromo-2-fluoroanilino)imidazo[1,2-b]pyridazin-6-yl]-1,3,4-oxadiazol-2-amine Chemical class O1C(N)=NN=C1C(C(=C1)NC=2C(=CC(Br)=CC=2)F)=NN2C1=NC=C2 CRQMWNMYTJZPPB-UHFFFAOYSA-N 0.000 claims description 2
- ITUFCFGGXOKBPH-UHFFFAOYSA-N 6-(4-bromo-2-fluoroanilino)-7-fluoro-n-(2-hydroxyethoxy)-3-methylimidazo[4,5-b]pyridine-5-carboxamide Chemical compound OCCONC(=O)C=1N=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1F ITUFCFGGXOKBPH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 2
- OBBCQHYXZOIRNT-UHFFFAOYSA-N azido(nitro)cyanamide Chemical group [O-][N+](=O)N(C#N)N=[N+]=[N-] OBBCQHYXZOIRNT-UHFFFAOYSA-N 0.000 claims 7
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 7
- KUUBTBAYMLAGKB-UHFFFAOYSA-N 5-[6-(4-bromo-2-fluoroanilino)-7-fluoropyrazolo[1,5-a]pyrimidin-5-yl]-1,3,4-oxadiazol-2-amine Chemical compound O1C(N)=NN=C1C1=NC2=CC=NN2C(F)=C1NC1=CC=C(Br)C=C1F KUUBTBAYMLAGKB-UHFFFAOYSA-N 0.000 claims 1
- LJNCDWUIYIHZBE-UHFFFAOYSA-N 6-(4-bromo-2-fluoroanilino)-n-(cyclopropylmethoxy)-7-fluoro-3-methyl-[1,2]oxazolo[4,5-b]pyridine-5-carboxamide Chemical compound C1CC1CONC(=O)C=1N=C2C(C)=NOC2=C(F)C=1NC1=CC=C(Br)C=C1F LJNCDWUIYIHZBE-UHFFFAOYSA-N 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 abstract description 51
- 239000000651 prodrug Substances 0.000 abstract description 51
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 47
- 241000124008 Mammalia Species 0.000 abstract description 35
- 238000011282 treatment Methods 0.000 abstract description 33
- 201000010099 disease Diseases 0.000 abstract description 30
- 206010028980 Neoplasm Diseases 0.000 abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 21
- 230000003463 hyperproliferative effect Effects 0.000 abstract description 18
- 201000011510 cancer Diseases 0.000 abstract description 16
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 abstract description 7
- 230000004968 inflammatory condition Effects 0.000 abstract description 4
- 206010061218 Inflammation Diseases 0.000 abstract description 2
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 161
- 125000003710 aryl alkyl group Chemical group 0.000 description 99
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 81
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 75
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
- 238000006243 chemical reaction Methods 0.000 description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 230000015572 biosynthetic process Effects 0.000 description 48
- 238000003786 synthesis reaction Methods 0.000 description 48
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 239000000203 mixture Substances 0.000 description 45
- 239000003960 organic solvent Substances 0.000 description 43
- 239000000047 product Substances 0.000 description 42
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 37
- 239000011541 reaction mixture Substances 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
- BPXYEYJNCXITEY-UHFFFAOYSA-N diazonio(trifluoromethoxy)azanide Chemical compound FC(F)(F)ON=[N+]=[N-] BPXYEYJNCXITEY-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 32
- 239000002585 base Substances 0.000 description 30
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- 229920006395 saturated elastomer Polymers 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 150000001408 amides Chemical class 0.000 description 21
- 239000000460 chlorine Chemical group 0.000 description 21
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 20
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 125000004429 atom Chemical group 0.000 description 19
- 238000005859 coupling reaction Methods 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 18
- 208000035475 disorder Diseases 0.000 description 17
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 16
- 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 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 230000008878 coupling Effects 0.000 description 15
- 238000010168 coupling process Methods 0.000 description 15
- 230000001404 mediated effect Effects 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 230000010261 cell growth Effects 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 229910052717 sulfur Inorganic materials 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- 238000007363 ring formation reaction Methods 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 230000002159 abnormal effect Effects 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 229910052763 palladium Inorganic materials 0.000 description 11
- 230000037361 pathway Effects 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 10
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 10
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 125000000539 amino acid group Chemical group 0.000 description 10
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000003682 fluorination reaction Methods 0.000 description 10
- 238000010561 standard procedure Methods 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 9
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 102000043136 MAP kinase family Human genes 0.000 description 9
- 108091054455 MAP kinase family Proteins 0.000 description 9
- 229910019142 PO4 Inorganic materials 0.000 description 9
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
- 239000012046 mixed solvent Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000010452 phosphate Substances 0.000 description 9
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 9
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 9
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 238000005660 chlorination reaction Methods 0.000 description 8
- 238000006880 cross-coupling reaction Methods 0.000 description 8
- 230000032050 esterification Effects 0.000 description 8
- 238000005886 esterification reaction Methods 0.000 description 8
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000001959 radiotherapy Methods 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 7
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 7
- 229940124647 MEK inhibitor Drugs 0.000 description 7
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000007859 condensation product Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000003102 growth factor Substances 0.000 description 7
- 239000002207 metabolite Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 7
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 6
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 description 6
- 201000004681 Psoriasis Diseases 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- PXAJQJMDEXJWFB-UHFFFAOYSA-N acetone oxime Chemical compound CC(C)=NO PXAJQJMDEXJWFB-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001540 azides Chemical class 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
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| US3855675A (en) * | 1971-05-25 | 1974-12-24 | Squibb & Sons Inc | 1-(2-furanylmethyl)-1h-pyrazolo(3,4-b)pyridine-5-methanones |
| JPS50135097A (https=) * | 1974-03-20 | 1975-10-25 | ||
| WO1998047899A1 (en) * | 1997-04-24 | 1998-10-29 | Ortho-Mcneil Corporation, Inc. | Substituted pyrrolopyridines useful in the treatment of inflammatory diseases |
| WO2003077914A1 (en) * | 2002-03-13 | 2003-09-25 | Array Biopharma, Inc | N3 alkylated benzimidazole derivatives as mek inhibitors |
| WO2003077855A2 (en) * | 2002-03-13 | 2003-09-25 | Array Biopharma, Inc | N3 alkylated benzimidazole derivatives as mek inhibitors |
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