ES2394759T3 - Pirrolopiridinas como inhibidores de quinasa - Google Patents

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Publication number

ES2394759T3

ES2394759T3 ES09700828T ES09700828T ES2394759T3 ES 2394759 T3 ES2394759 T3 ES 2394759T3 ES 09700828 T ES09700828 T ES 09700828T ES 09700828 T ES09700828 T ES 09700828T ES 2394759 T3 ES2394759 T3 ES 2394759T3

Authority

ES

Spain

Prior art keywords

mmol

pyrrolo

reaction

piperazin

phenyl

Prior art date

2008-01-08

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 150000005255 pyrrolopyridines Chemical class 0.000 title description 3
• 229940043355 kinase inhibitor Drugs 0.000 title description 2
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 149
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 88
• 150000002367 halogens Chemical group 0.000 claims abstract description 88
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 82
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 76
• 150000003839 salts Chemical class 0.000 claims abstract description 71
• 239000001257 hydrogen Substances 0.000 claims abstract description 68
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 68
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 50
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 41
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 29
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 26
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 24
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 13
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 8
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 6
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 5
• -1 2-isopropyl-1-oxa-3,4-diazol-5-yl Chemical group 0.000 claims description 209
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 69
• 125000000623 heterocyclic group Chemical group 0.000 claims description 39
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
• 229910052757 nitrogen Inorganic materials 0.000 claims description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims description 13
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
• 125000000217 alkyl group Chemical group 0.000 claims description 12
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 7
• 125000004429 atom Chemical group 0.000 claims description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 229910052703 rhodium Inorganic materials 0.000 claims description 6
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 4
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
• 229910052794 bromium Inorganic materials 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
• 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 3
• 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 3
• ZVXKYWHJBYIYNI-UHFFFAOYSA-N 1h-pyrazole-4-carboxamide Chemical compound NC(=O)C=1C=NNC=1 ZVXKYWHJBYIYNI-UHFFFAOYSA-N 0.000 claims description 2
• LNNDTIIAQNGGPA-UHFFFAOYSA-N 5-chloropyridine-3-carboxamide Chemical compound NC(=O)C1=CN=CC(Cl)=C1 LNNDTIIAQNGGPA-UHFFFAOYSA-N 0.000 claims description 2
• BCCUXBGEPLKSEX-UHFFFAOYSA-N 5-methylpyridine-3-carboxamide Chemical compound CC1=CN=CC(C(N)=O)=C1 BCCUXBGEPLKSEX-UHFFFAOYSA-N 0.000 claims description 2
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
• DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims 1
• 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 569
• 238000006243 chemical reaction Methods 0.000 description 329
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 216
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 192
• 239000000243 solution Substances 0.000 description 155
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 146
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 112
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 101
• 239000007787 solid Substances 0.000 description 86
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 82
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 82
• 239000000203 mixture Substances 0.000 description 81
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 73
• 238000000034 method Methods 0.000 description 67
• 238000003756 stirring Methods 0.000 description 65
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 60
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 59
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical group NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 56
• 235000019439 ethyl acetate Nutrition 0.000 description 54
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 52
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 46
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 46
• 238000011282 treatment Methods 0.000 description 45
• 238000004440 column chromatography Methods 0.000 description 43
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 42
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 41
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 39
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
• 201000010099 disease Diseases 0.000 description 32
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
• 239000012043 crude product Substances 0.000 description 31
• 239000003921 oil Substances 0.000 description 31
• 239000002253 acid Substances 0.000 description 29
• 125000004043 oxo group Chemical group O=* 0.000 description 29
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 29
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 28
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 28
• 235000005152 nicotinamide Nutrition 0.000 description 28
• 239000011570 nicotinamide Substances 0.000 description 28
• 229960003966 nicotinamide Drugs 0.000 description 28
• 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 28
• 238000005160 1H NMR spectroscopy Methods 0.000 description 27
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 27
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
• 206010028980 Neoplasm Diseases 0.000 description 27
• 238000004587 chromatography analysis Methods 0.000 description 27
• 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 26
• 239000003112 inhibitor Substances 0.000 description 26
• 241000124008 Mammalia Species 0.000 description 25
• 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 25
• UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 25
• 238000000746 purification Methods 0.000 description 24
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 23
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
• 210000004027 cell Anatomy 0.000 description 22
• GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 22
• 230000003463 hyperproliferative effect Effects 0.000 description 22
• 239000012044 organic layer Substances 0.000 description 22
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
• 239000000047 product Substances 0.000 description 22
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
• 201000011510 cancer Diseases 0.000 description 21
• 229910052938 sodium sulfate Inorganic materials 0.000 description 21
• 235000011152 sodium sulphate Nutrition 0.000 description 21
• 239000012265 solid product Substances 0.000 description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
• 150000001413 amino acids Chemical class 0.000 description 20
• 125000003118 aryl group Chemical group 0.000 description 20
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
• 235000019341 magnesium sulphate Nutrition 0.000 description 18
• 125000006239 protecting group Chemical group 0.000 description 18
• 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 18
• 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 17
• 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 17
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
• 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 17
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
• 238000002360 preparation method Methods 0.000 description 17
• 239000010410 layer Substances 0.000 description 16
• 150000002431 hydrogen Chemical group 0.000 description 15
• 238000000926 separation method Methods 0.000 description 15
• 229910000029 sodium carbonate Inorganic materials 0.000 description 15
• 235000017550 sodium carbonate Nutrition 0.000 description 15
• 239000007832 Na2SO4 Substances 0.000 description 14
• 208000035475 disorder Diseases 0.000 description 14
• 150000002148 esters Chemical class 0.000 description 14
• OVPLZYJGTGDFNB-UHFFFAOYSA-N propan-2-yl carbamate Chemical compound CC(C)OC(N)=O OVPLZYJGTGDFNB-UHFFFAOYSA-N 0.000 description 14
• 239000002904 solvent Substances 0.000 description 14
• GQWRBNJRKSPGTF-CQSZACIVSA-N (2s)-2-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N(C(C)C)C[C@@H](C(O)=O)C1=CC=C(Cl)C=C1 GQWRBNJRKSPGTF-CQSZACIVSA-N 0.000 description 13
• 238000001914 filtration Methods 0.000 description 13
• 239000011541 reaction mixture Substances 0.000 description 13
• 238000003786 synthesis reaction Methods 0.000 description 13
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
• 125000000068 chlorophenyl group Chemical group 0.000 description 12
• 238000005859 coupling reaction Methods 0.000 description 12
• 239000003814 drug Substances 0.000 description 12
• 239000000543 intermediate Substances 0.000 description 12
• 239000003153 chemical reaction reagent Substances 0.000 description 11
• 238000010168 coupling process Methods 0.000 description 11
• 229910000027 potassium carbonate Inorganic materials 0.000 description 11
• 230000015572 biosynthetic process Effects 0.000 description 10
• 125000000753 cycloalkyl group Chemical group 0.000 description 10
• 235000015320 potassium carbonate Nutrition 0.000 description 10
• 125000003226 pyrazolyl group Chemical group 0.000 description 10
• 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 9
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 9
• 206010025323 Lymphomas Diseases 0.000 description 9
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 9
• 150000001412 amines Chemical class 0.000 description 9
• 239000003795 chemical substances by application Substances 0.000 description 9
• 230000008878 coupling Effects 0.000 description 9
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
• 238000010992 reflux Methods 0.000 description 9
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 8
• 201000009030 Carcinoma Diseases 0.000 description 8
• 108091000080 Phosphotransferase Proteins 0.000 description 8
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
• 208000009956 adenocarcinoma Diseases 0.000 description 8
• GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 8
• HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 8
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
• 102000020233 phosphotransferase Human genes 0.000 description 8
• 239000000377 silicon dioxide Substances 0.000 description 8
• 125000001424 substituent group Chemical group 0.000 description 8
• 230000002159 abnormal effect Effects 0.000 description 7
• 238000004458 analytical method Methods 0.000 description 7
• 229910052681 coesite Inorganic materials 0.000 description 7
• 229910052906 cristobalite Inorganic materials 0.000 description 7
• 239000010779 crude oil Substances 0.000 description 7
• 239000000706 filtrate Substances 0.000 description 7
• 235000012239 silicon dioxide Nutrition 0.000 description 7
• 229910052682 stishovite Inorganic materials 0.000 description 7
• 239000000725 suspension Substances 0.000 description 7
• XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 7
• 229910052905 tridymite Inorganic materials 0.000 description 7
• MBYQIHCBCCZXDZ-UHFFFAOYSA-N 3-methyl-5-phenyl-4-piperazin-1-yl-1h-pyrrolo[2,3-b]pyridine Chemical compound C1CNCCN1C1=C2C(C)=CNC2=NC=C1C1=CC=CC=C1 MBYQIHCBCCZXDZ-UHFFFAOYSA-N 0.000 description 6
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
• 206010039491 Sarcoma Diseases 0.000 description 6
• 150000001336 alkenes Chemical class 0.000 description 6
• 125000006242 amine protecting group Chemical group 0.000 description 6
• 238000005984 hydrogenation reaction Methods 0.000 description 6
• 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 6
• KYKDOARTYFGHPC-UHFFFAOYSA-N n-propan-2-ylpropanamide Chemical compound CCC(=O)NC(C)C KYKDOARTYFGHPC-UHFFFAOYSA-N 0.000 description 6
• JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 6
• 150000003141 primary amines Chemical class 0.000 description 6
• 230000002829 reductive effect Effects 0.000 description 6
• 206010041823 squamous cell carcinoma Diseases 0.000 description 6
• HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 6
• 238000004809 thin layer chromatography Methods 0.000 description 6
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
• JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 5
• 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 5
• UBBFOEJAGGJZDA-UHFFFAOYSA-N 5-phenyl-4-piperazin-1-yl-1h-pyrrolo[2,3-b]pyridine;dihydrochloride Chemical compound Cl.Cl.C1CNCCN1C1=C(C=2C=CC=CC=2)C=NC2=C1C=CN2 UBBFOEJAGGJZDA-UHFFFAOYSA-N 0.000 description 5
• 239000002841 Lewis acid Substances 0.000 description 5
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
• 230000010261 cell growth Effects 0.000 description 5
• 229940126214 compound 3 Drugs 0.000 description 5
• 238000010511 deprotection reaction Methods 0.000 description 5
• 206010073071 hepatocellular carcinoma Diseases 0.000 description 5
• 230000007062 hydrolysis Effects 0.000 description 5
• 238000006460 hydrolysis reaction Methods 0.000 description 5
• 230000002401 inhibitory effect Effects 0.000 description 5
• 150000007517 lewis acids Chemical class 0.000 description 5
• 238000004519 manufacturing process Methods 0.000 description 5
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