IL184717A - Imidazo (1,2-a)pyridine compounds as vegf-r2 inhibitors - Google Patents

Info

Publication number

IL184717A

IL184717A IL184717A IL18471707A IL184717A IL 184717 A IL184717 A IL 184717A IL 184717 A IL184717 A IL 184717A IL 18471707 A IL18471707 A IL 18471707A IL 184717 A IL184717 A IL 184717A

Authority

IL

Israel

Prior art keywords

pyridin

mmol

phenyl

imidazo

butyl

Prior art date

2005-02-24

Links

• Espacenet
• Global Dossier
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• 239000003112 inhibitor Substances 0.000 title description 10
• 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 title description 3
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 208
• -1 N-oxo-pyridinyl Chemical group 0.000 claims description 202
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 201
• 150000001875 compounds Chemical class 0.000 claims description 167
• 229910052757 nitrogen Inorganic materials 0.000 claims description 103
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
• 125000004076 pyridyl group Chemical group 0.000 claims description 35
• 125000001424 substituent group Chemical group 0.000 claims description 35
• 125000002757 morpholinyl group Chemical group 0.000 claims description 30
• 125000000217 alkyl group Chemical group 0.000 claims description 27
• 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 claims description 26
• 125000000335 thiazolyl group Chemical group 0.000 claims description 26
• 206010028980 Neoplasm Diseases 0.000 claims description 24
• 150000003839 salts Chemical class 0.000 claims description 22
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
• 125000003545 alkoxy group Chemical group 0.000 claims description 17
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 17
• 125000003386 piperidinyl group Chemical group 0.000 claims description 17
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 17
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 14
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 14
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 14
• 230000033115 angiogenesis Effects 0.000 claims description 13
• 229910052739 hydrogen Inorganic materials 0.000 claims description 13
• 239000001257 hydrogen Substances 0.000 claims description 13
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 12
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 10
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 10
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 10
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 10
• 125000001544 thienyl group Chemical group 0.000 claims description 10
• 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 claims description 8
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 125000004193 piperazinyl group Chemical group 0.000 claims description 7
• 125000002883 imidazolyl group Chemical group 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
• 125000002971 oxazolyl group Chemical group 0.000 claims description 6
• 125000001425 triazolyl group Chemical group 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 125000001475 halogen functional group Chemical group 0.000 claims 4
• 239000012453 solvate Substances 0.000 claims 2
• 239000003085 diluting agent Substances 0.000 claims 1
• 239000003937 drug carrier Substances 0.000 claims 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 704
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 602
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 302
• 239000012141 concentrate Substances 0.000 description 188
• 238000003756 stirring Methods 0.000 description 181
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 152
• 239000007787 solid Substances 0.000 description 146
• 238000006243 chemical reaction Methods 0.000 description 145
• 239000000203 mixture Substances 0.000 description 119
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 117
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 110
• 235000019439 ethyl acetate Nutrition 0.000 description 109
• 239000000243 solution Substances 0.000 description 109
• 238000002360 preparation method Methods 0.000 description 107
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 105
• 238000000034 method Methods 0.000 description 100
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 99
• 239000004202 carbamide Substances 0.000 description 84
• 239000000047 product Substances 0.000 description 75
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 74
• 229940093499 ethyl acetate Drugs 0.000 description 73
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 70
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 63
• 239000011541 reaction mixture Substances 0.000 description 59
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 57
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 55
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 53
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 46
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
• 239000000284 extract Substances 0.000 description 44
• 239000012044 organic layer Substances 0.000 description 41
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 40
• 239000000377 silicon dioxide Substances 0.000 description 40
• 238000010992 reflux Methods 0.000 description 36
• 239000002002 slurry Substances 0.000 description 35
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 34
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 34
• 239000003921 oil Substances 0.000 description 33
• 235000019198 oils Nutrition 0.000 description 33
• 238000012799 strong cation exchange Methods 0.000 description 33
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 30
• 239000000741 silica gel Substances 0.000 description 29
• 229910002027 silica gel Inorganic materials 0.000 description 29
• 229960001866 silicon dioxide Drugs 0.000 description 29
• 125000005843 halogen group Chemical group 0.000 description 27
• 239000000706 filtrate Substances 0.000 description 26
• 235000019341 magnesium sulphate Nutrition 0.000 description 26
• 239000010410 layer Substances 0.000 description 25
• 229920006395 saturated elastomer Polymers 0.000 description 25
• 239000000725 suspension Substances 0.000 description 25
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• 230000002829 reductive effect Effects 0.000 description 24
• 239000002904 solvent Substances 0.000 description 22
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
• NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [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 21
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 21
• CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 20
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 20
• 238000010898 silica gel chromatography Methods 0.000 description 20
• 239000000543 intermediate Substances 0.000 description 19
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 17
• 238000010791 quenching Methods 0.000 description 17
• 229940086542 triethylamine Drugs 0.000 description 17
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 16
• 235000011056 potassium acetate Nutrition 0.000 description 16
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• 229910000027 potassium carbonate Inorganic materials 0.000 description 16
• 238000000746 purification Methods 0.000 description 16
• DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 16
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 15
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
• 238000004440 column chromatography Methods 0.000 description 15
• 239000007789 gas Substances 0.000 description 15
• 238000011282 treatment Methods 0.000 description 15
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 14
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 14
• 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 description 13
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
• 201000011510 cancer Diseases 0.000 description 13
• 239000012458 free base Substances 0.000 description 13
• 239000012299 nitrogen atmosphere Substances 0.000 description 13
• VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 13
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
• IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 12
• 239000012043 crude product Substances 0.000 description 12
• 239000000463 material Substances 0.000 description 12
• 229910000029 sodium carbonate Inorganic materials 0.000 description 12
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 11
• 150000001412 amines Chemical class 0.000 description 11
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
• 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 10
• 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 10
• 235000013877 carbamide Nutrition 0.000 description 10
• 238000004587 chromatography analysis Methods 0.000 description 10
• 239000006260 foam Substances 0.000 description 10
• 238000004128 high performance liquid chromatography Methods 0.000 description 10
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 9
• 241000124008 Mammalia Species 0.000 description 9
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 9
• 150000001408 amides Chemical class 0.000 description 9
• 125000003118 aryl group Chemical group 0.000 description 9
• 230000000694 effects Effects 0.000 description 9
• 238000003818 flash chromatography Methods 0.000 description 9
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
• WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 9
• VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 description 8
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
• 238000010438 heat treatment Methods 0.000 description 8
• UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical group C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 8
• 239000012074 organic phase Substances 0.000 description 8
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
• 229910000404 tripotassium phosphate Inorganic materials 0.000 description 8
• 238000005406 washing Methods 0.000 description 8
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 7
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 7
• LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 7
• 108091000080 Phosphotransferase Proteins 0.000 description 7
• 229910021529 ammonia Inorganic materials 0.000 description 7
• 239000004305 biphenyl Substances 0.000 description 7
• 239000003153 chemical reaction reagent Substances 0.000 description 7
• 238000001816 cooling Methods 0.000 description 7
• 238000001035 drying Methods 0.000 description 7
• 239000003480 eluent Substances 0.000 description 7
• 150000002148 esters Chemical class 0.000 description 7
• 125000001207 fluorophenyl group Chemical group 0.000 description 7
• 230000002401 inhibitory effect Effects 0.000 description 7
• 229910052763 palladium Inorganic materials 0.000 description 7
• 239000012071 phase Substances 0.000 description 7
• 102000020233 phosphotransferase Human genes 0.000 description 7
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 7
• 238000003786 synthesis reaction Methods 0.000 description 7
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 7
• BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 6
• 235000019270 ammonium chloride Nutrition 0.000 description 6
• 230000015572 biosynthetic process Effects 0.000 description 6
• 230000005587 bubbling Effects 0.000 description 6
• VZSXFJPZOCRDPW-UHFFFAOYSA-N carbanide;trioxorhenium Chemical compound [CH3-].O=[Re](=O)=O VZSXFJPZOCRDPW-UHFFFAOYSA-N 0.000 description 6
• 210000004027 cell Anatomy 0.000 description 6
• 238000010168 coupling process Methods 0.000 description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
• PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 6
• 238000010926 purge Methods 0.000 description 6
• 238000004366 reverse phase liquid chromatography Methods 0.000 description 6
• 235000017557 sodium bicarbonate Nutrition 0.000 description 6
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
• SXJYSIBLFGQAND-UHFFFAOYSA-N 1-isocyanato-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(N=C=O)=C1 SXJYSIBLFGQAND-UHFFFAOYSA-N 0.000 description 5
• QOWSWEBLNVACCL-UHFFFAOYSA-N 4-Bromophenyl acetate Chemical compound OC(=O)CC1=CC=C(Br)C=C1 QOWSWEBLNVACCL-UHFFFAOYSA-N 0.000 description 5
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
• 208000007766 Kaposi sarcoma Diseases 0.000 description 5
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
• UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 5
• 201000004681 Psoriasis Diseases 0.000 description 5
• 239000007983 Tris buffer Substances 0.000 description 5
• 239000002253 acid Substances 0.000 description 5
• 230000002491 angiogenic effect Effects 0.000 description 5
• 239000008346 aqueous phase Substances 0.000 description 5
• 150000001499 aryl bromides Chemical class 0.000 description 5
• 238000004296 chiral HPLC Methods 0.000 description 5
• 230000008878 coupling Effects 0.000 description 5
• 238000005859 coupling reaction Methods 0.000 description 5
• 238000006880 cross-coupling reaction Methods 0.000 description 5
• 239000012972 dimethylethanolamine Substances 0.000 description 5
• 201000010099 disease Diseases 0.000 description 5
• 238000011068 loading method Methods 0.000 description 5
• 239000002245 particle Substances 0.000 description 5
• 238000005192 partition Methods 0.000 description 5
• 239000002244 precipitate Substances 0.000 description 5
• 206010039073 rheumatoid arthritis Diseases 0.000 description 5
• 239000011780 sodium chloride Substances 0.000 description 5
• 239000007858 starting material Substances 0.000 description 5
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
• 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 5
• VDUKDQTYMWUSAC-UHFFFAOYSA-N (4-methylsulfonylphenyl)boronic acid Chemical compound CS(=O)(=O)C1=CC=C(B(O)O)C=C1 VDUKDQTYMWUSAC-UHFFFAOYSA-N 0.000 description 4
• RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 4
• XPVICPGWIJBMIZ-UHFFFAOYSA-N 2,2,2-trichloroethyl n-(5-tert-butyl-1,2-oxazol-3-yl)carbamate Chemical compound CC(C)(C)C1=CC(NC(=O)OCC(Cl)(Cl)Cl)=NO1 XPVICPGWIJBMIZ-UHFFFAOYSA-N 0.000 description 4
• PNBIYFPZODYMOO-UHFFFAOYSA-N 2-(4-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(Br)C=C1F PNBIYFPZODYMOO-UHFFFAOYSA-N 0.000 description 4
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