AU2006337626B2 - [4-(benzo [b] thiophen-2-yl) pyrimidin-2yl] -amine derivatives as IKK-beta inhibitors for the treatment of cancer and inflammatory diseases. - Google Patents

Info

Publication number

AU2006337626B2

AU2006337626B2 AU2006337626A AU2006337626A AU2006337626B2 AU 2006337626 B2 AU2006337626 B2 AU 2006337626B2 AU 2006337626 A AU2006337626 A AU 2006337626A AU 2006337626 A AU2006337626 A AU 2006337626A AU 2006337626 B2 AU2006337626 B2 AU 2006337626B2

Authority

AU

Australia

Prior art keywords

benzo

carboxylic acid

pyrimidin

mmol

thiophene

Prior art date

2005-11-18

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.)

Ceased

Links

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• 206010028980 Neoplasm Diseases 0.000 title claims abstract description 18
• 201000011510 cancer Diseases 0.000 title claims abstract description 18
• 208000027866 inflammatory disease Diseases 0.000 title claims abstract description 11
• 102000001284 I-kappa-B kinase Human genes 0.000 title description 2
• 108060006678 I-kappa-B kinase Proteins 0.000 title description 2
• VDEYQSOFDSCWMV-UHFFFAOYSA-N 4-(1-benzothiophen-2-yl)pyrimidin-2-amine Chemical class NC1=NC=CC(C=2SC3=CC=CC=C3C=2)=N1 VDEYQSOFDSCWMV-UHFFFAOYSA-N 0.000 title 1
• 239000003112 inhibitor Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 366
• 239000000203 mixture Substances 0.000 claims description 224
• 238000000034 method Methods 0.000 claims description 159
• -1 methylthio, aminosulfonyl Chemical group 0.000 claims description 123
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 83
• 229910052757 nitrogen Inorganic materials 0.000 claims description 48
• 125000000217 alkyl group Chemical group 0.000 claims description 45
• 150000003839 salts Chemical class 0.000 claims description 44
• 229910052739 hydrogen Inorganic materials 0.000 claims description 35
• 239000001257 hydrogen Substances 0.000 claims description 34
• 241000124008 Mammalia Species 0.000 claims description 23
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
• MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 18
• 150000002431 hydrogen Chemical group 0.000 claims description 12
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 11
• 125000003545 alkoxy group Chemical group 0.000 claims description 10
• 125000003386 piperidinyl group Chemical group 0.000 claims description 10
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 7
• 206010009944 Colon cancer Diseases 0.000 claims description 7
• 208000034578 Multiple myelomas Diseases 0.000 claims description 7
• 206010033128 Ovarian cancer Diseases 0.000 claims description 7
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 7
• 208000029742 colonic neoplasm Diseases 0.000 claims description 7
• 208000005017 glioblastoma Diseases 0.000 claims description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 206010023774 Large cell lung cancer Diseases 0.000 claims description 6
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 201000009546 lung large cell carcinoma Diseases 0.000 claims description 6
• 239000003085 diluting agent Substances 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 125000004193 piperazinyl group Chemical group 0.000 claims description 5
• 125000001424 substituent group Chemical group 0.000 claims description 4
• 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 3
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
• 239000003814 drug Substances 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 3
• 230000008569 process Effects 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 claims description 3
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
• 125000000623 heterocyclic group Chemical group 0.000 claims description 2
• 125000002883 imidazolyl group Chemical group 0.000 claims description 2
• 125000006301 indolyl methyl group Chemical group 0.000 claims description 2
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• 125000000335 thiazolyl group Chemical group 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
• 208000019693 Lung disease Diseases 0.000 claims 3
• 230000001684 chronic effect Effects 0.000 claims 3
• 238000009472 formulation Methods 0.000 claims 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 714
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 375
• 239000007787 solid Substances 0.000 description 313
• 239000000243 solution Substances 0.000 description 196
• 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 184
• 238000002360 preparation method Methods 0.000 description 161
• 239000012458 free base Substances 0.000 description 127
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 112
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 111
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
• 239000000741 silica gel Substances 0.000 description 96
• 229910002027 silica gel Inorganic materials 0.000 description 96
• 239000000725 suspension Substances 0.000 description 95
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 81
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 77
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 73
• 239000003921 oil Substances 0.000 description 65
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
• HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 description 58
• 238000006243 chemical reaction Methods 0.000 description 55
• 238000003756 stirring Methods 0.000 description 51
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
• 239000011369 resultant mixture Substances 0.000 description 45
• 238000004587 chromatography analysis Methods 0.000 description 44
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 43
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 43
• 235000019439 ethyl acetate Nutrition 0.000 description 42
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 38
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 38
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
• 239000000047 product Substances 0.000 description 35
• 239000011541 reaction mixture Substances 0.000 description 35
• 239000012044 organic layer Substances 0.000 description 33
• 239000002253 acid Substances 0.000 description 31
• 238000001914 filtration Methods 0.000 description 31
• 230000002829 reductive effect Effects 0.000 description 29
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 28
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
• 239000012043 crude product Substances 0.000 description 24
• AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 24
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 20
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 20
• 239000011734 sodium Substances 0.000 description 20
• 239000000543 intermediate Substances 0.000 description 19
• RGUABPVONIGVAT-UHFFFAOYSA-N 3-(4-methylpiperazin-1-yl)propan-1-amine Chemical compound CN1CCN(CCCN)CC1 RGUABPVONIGVAT-UHFFFAOYSA-N 0.000 description 18
• 238000011097 chromatography purification Methods 0.000 description 18
• 239000007789 gas Substances 0.000 description 17
• GSQDFHSGLFZEMW-UHFFFAOYSA-N n-cyclopropyl-2-(2,5-dichloropyrimidin-4-yl)-1-benzothiophene-4-carboxamide Chemical compound ClC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 GSQDFHSGLFZEMW-UHFFFAOYSA-N 0.000 description 17
• 239000012299 nitrogen atmosphere Substances 0.000 description 17
• 238000000746 purification Methods 0.000 description 17
• 229920006395 saturated elastomer Polymers 0.000 description 16
• 239000002904 solvent Substances 0.000 description 16
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• VTBWLEIOWRFORL-UHFFFAOYSA-N cyclopropanamine;trihydrochloride Chemical compound Cl.Cl.Cl.NC1CC1 VTBWLEIOWRFORL-UHFFFAOYSA-N 0.000 description 15
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 15
• UKPGHGAXQOFBCE-UHFFFAOYSA-N n-cyclopropyl-1-benzothiophene-4-carboxamide;trihydrochloride Chemical compound Cl.Cl.Cl.C=1C=CC=2SC=CC=2C=1C(=O)NC1CC1 UKPGHGAXQOFBCE-UHFFFAOYSA-N 0.000 description 15
• 239000012258 stirred mixture Substances 0.000 description 15
• IEXCRLAGBWKVPW-UHFFFAOYSA-N 2-[5-chloro-2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-n-cyclopropyl-1-benzothiophene-4-carboxamide;trihydrochloride Chemical compound Cl.Cl.Cl.C1CN(C)CCN1CCCNC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 IEXCRLAGBWKVPW-UHFFFAOYSA-N 0.000 description 14
• UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 14
• 229910002091 carbon monoxide Inorganic materials 0.000 description 14
• 239000013058 crude material Substances 0.000 description 14
• 238000001035 drying Methods 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 14
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
• 239000010410 layer Substances 0.000 description 13
• IPFMYOITZSJUNI-UHFFFAOYSA-N n-cyclopropyl-1-benzothiophene-4-carboxamide;dihydrochloride Chemical compound Cl.Cl.C=1C=CC=2SC=CC=2C=1C(=O)NC1CC1 IPFMYOITZSJUNI-UHFFFAOYSA-N 0.000 description 13
• 239000011780 sodium chloride Substances 0.000 description 13
• NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 13
• FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 12
• CGVKBSGIGZOHFS-UHFFFAOYSA-N 2-[5-chloro-2-[2-(1-methylpiperidin-4-yl)ethylamino]pyrimidin-4-yl]-1-benzothiophene-4-carboxamide;dihydrochloride Chemical compound Cl.Cl.C1CN(C)CCC1CCNC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(N)=O)=N1 CGVKBSGIGZOHFS-UHFFFAOYSA-N 0.000 description 12
• OQIMJOXSDVGEBU-UHFFFAOYSA-N 6-bromo-1-benzothiophene Chemical compound BrC1=CC=C2C=CSC2=C1 OQIMJOXSDVGEBU-UHFFFAOYSA-N 0.000 description 12
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
• 150000001412 amines Chemical class 0.000 description 12
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• 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 12
• 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 11
• 239000006260 foam Substances 0.000 description 11
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
• 235000019341 magnesium sulphate Nutrition 0.000 description 11
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 11
• 239000012071 phase Substances 0.000 description 11
• 230000002441 reversible effect Effects 0.000 description 11
• OPQRMLFPDZPBKA-UHFFFAOYSA-N 2-(5-bromo-2-chloropyrimidin-4-yl)-n-cyclopropyl-1-benzothiophene-4-carboxamide Chemical compound ClC1=NC=C(Br)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 OPQRMLFPDZPBKA-UHFFFAOYSA-N 0.000 description 10
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
• 238000001816 cooling Methods 0.000 description 10
• 125000000753 cycloalkyl group Chemical group 0.000 description 10
• 125000005843 halogen group Chemical group 0.000 description 10
• QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical class Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 description 10
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
• XSGXZJPLDGFVCT-UHFFFAOYSA-N 2-(2-chloro-5-methylpyrimidin-4-yl)-n-cyclopropyl-1-benzothiophene-4-carboxamide Chemical compound CC1=CN=C(Cl)N=C1C1=CC2=C(C(=O)NC3CC3)C=CC=C2S1 XSGXZJPLDGFVCT-UHFFFAOYSA-N 0.000 description 9
• XBTPQBZYBXHPGX-UHFFFAOYSA-N 4-(1-benzothiophen-2-yl)-n-[3-(4-methylpiperazin-1-yl)propyl]pyrimidin-2-amine;trihydrochloride Chemical compound Cl.Cl.Cl.C1CN(C)CCN1CCCNC1=NC=CC(C=2SC3=CC=CC=C3C=2)=N1 XBTPQBZYBXHPGX-UHFFFAOYSA-N 0.000 description 9
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 9
• 101100508533 Drosophila melanogaster IKKbeta gene Proteins 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 125000006308 propyl amino group Chemical group 0.000 description 9
• ODQTWTGPDQOEFJ-UHFFFAOYSA-N 2-(2,5-dichloropyrimidin-4-yl)-1-benzothiophene-4-carboxylic acid Chemical compound C=1C=2C(C(=O)O)=CC=CC=2SC=1C1=NC(Cl)=NC=C1Cl ODQTWTGPDQOEFJ-UHFFFAOYSA-N 0.000 description 8
• YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 8
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
• KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
• 239000000463 material Substances 0.000 description 8
• HFCUTESXGRGMSQ-UHFFFAOYSA-N n-cyclopropyl-1-benzothiophene-4-carboxamide Chemical compound C=1C=CC=2SC=CC=2C=1C(=O)NC1CC1 HFCUTESXGRGMSQ-UHFFFAOYSA-N 0.000 description 8
• LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 8
• 238000010898 silica gel chromatography Methods 0.000 description 8
• GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 7
• DTAJKPICAHMNKN-UHFFFAOYSA-N 2-(2-chloro-5-fluoropyrimidin-4-yl)-n-cyclopropyl-1-benzothiophene-4-carboxamide Chemical compound FC1=CN=C(Cl)N=C1C1=CC2=C(C(=O)NC3CC3)C=CC=C2S1 DTAJKPICAHMNKN-UHFFFAOYSA-N 0.000 description 7
• IZXMGGLFJGYNBW-UHFFFAOYSA-N 3-(4-propan-2-ylpiperazin-1-yl)propan-1-amine Chemical compound CC(C)N1CCN(CCCN)CC1 IZXMGGLFJGYNBW-UHFFFAOYSA-N 0.000 description 7
• HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 7
• 150000002148 esters Chemical class 0.000 description 7
• 239000000377 silicon dioxide Substances 0.000 description 7
• 239000012279 sodium borohydride Substances 0.000 description 7
• 229910000033 sodium borohydride Inorganic materials 0.000 description 7
• DQLCYLFCLQPLSY-UHFFFAOYSA-N tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CCCN)CC1 DQLCYLFCLQPLSY-UHFFFAOYSA-N 0.000 description 7
• HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 6
• BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 6
• VLNGTGPAHWKGHA-UHFFFAOYSA-N 2-(2,5-dichloropyrimidin-4-yl)-n-methyl-1-benzothiophene-4-carboxamide Chemical compound C=1C=2C(C(=O)NC)=CC=CC=2SC=1C1=NC(Cl)=NC=C1Cl VLNGTGPAHWKGHA-UHFFFAOYSA-N 0.000 description 6
• KGUNSXVWZTYNES-CQSZACIVSA-N 2-[5-chloro-2-[3-[(2r)-2-methylpiperazin-1-yl]propylamino]pyrimidin-4-yl]-n-methyl-1-benzothiophene-4-carboxamide Chemical compound C=1C=2C(C(=O)NC)=CC=CC=2SC=1C(C(=CN=1)Cl)=NC=1NCCCN1CCNC[C@H]1C KGUNSXVWZTYNES-CQSZACIVSA-N 0.000 description 6
• 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 6
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 6
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
• 230000005587 bubbling Effects 0.000 description 6
• 238000010511 deprotection reaction Methods 0.000 description 6
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