CA3018907A1

CA3018907A1 - Fused pentacyclic imidazole derivatives as modulators of tnf activity

Fused pentacyclic imidazole derivatives as modulators of tnf activity Download PDF

Info

Publication number: CA3018907A1
Authority: CA; Canada
Prior art keywords: alkyl; formula; heteroaryl; optionally substituted; compound
Prior art date: 2016-04-01
Legal status : Pending

Application number

CA3018907A

Other languages

English (en)

French (fr)

Inventor

Jag Paul Heer

Jean KEYAERTS

Current Assignee

UCB Biopharma SRL

Original Assignee

UCB Biopharma SRL

Sanofi SA

Priority date

2016-04-01

Filing date

2017-03-31

Publication date

2017-10-05

2017-03-31 Application filed by UCB Biopharma SRL, Sanofi SA filed Critical UCB Biopharma SRL

2017-10-05 Publication of CA3018907A1 publication Critical patent/CA3018907A1/en

Status Pending legal-status Critical Current

Links

229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title abstract description 8
150000002460 imidazoles Chemical class 0.000 title abstract description 7
230000000694 effects Effects 0.000 title description 7
238000011282 treatment Methods 0.000 claims abstract description 62
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
208000035475 disorder Diseases 0.000 claims abstract description 29
208000023275 Autoimmune disease Diseases 0.000 claims abstract description 17
230000002265 prevention Effects 0.000 claims abstract description 15
208000027866 inflammatory disease Diseases 0.000 claims abstract description 13
208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 11
208000012902 Nervous system disease Diseases 0.000 claims abstract description 11
208000022873 Ocular disease Diseases 0.000 claims abstract description 11
208000030159 metabolic disease Diseases 0.000 claims abstract description 11
208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 11
230000000926 neurological effect Effects 0.000 claims abstract description 11
230000000771 oncological effect Effects 0.000 claims abstract description 11
208000002193 Pain Diseases 0.000 claims abstract description 10
230000003040 nociceptive effect Effects 0.000 claims abstract description 10
-1 nitro, hydroxy Chemical group 0.000 claims description 521
150000001875 compounds Chemical class 0.000 claims description 231
229910052739 hydrogen Inorganic materials 0.000 claims description 169
239000001257 hydrogen Substances 0.000 claims description 169
238000000034 method Methods 0.000 claims description 119
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 111
125000001424 substituent group Chemical group 0.000 claims description 75
229910052736 halogen Inorganic materials 0.000 claims description 59
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 57
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 49
150000002367 halogens Chemical group 0.000 claims description 48
125000001072 heteroaryl group Chemical group 0.000 claims description 47
125000003118 aryl group Chemical group 0.000 claims description 43
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 41
150000003839 salts Chemical class 0.000 claims description 34
150000001204 N-oxides Chemical class 0.000 claims description 26
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 24
125000004093 cyano group Chemical group *C#N 0.000 claims description 24
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 23
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 20
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
229910052757 nitrogen Inorganic materials 0.000 claims description 16
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
230000002757 inflammatory effect Effects 0.000 claims description 12
125000000753 cycloalkyl group Chemical group 0.000 claims description 11
125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 10
125000005215 cycloalkylheteroaryl group Chemical group 0.000 claims description 6
239000003814 drug Substances 0.000 claims description 6
125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 6
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
125000000623 heterocyclic group Chemical group 0.000 claims description 5
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 5
125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 4
125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims description 4
239000004480 active ingredient Substances 0.000 claims description 3
125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
238000002560 therapeutic procedure Methods 0.000 claims description 3
125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
125000002877 alkyl aryl group Chemical group 0.000 claims description 2
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
150000002431 hydrogen Chemical group 0.000 claims 5
125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 1
125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims 1
125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
230000001363 autoimmune Effects 0.000 abstract description 7
208000025966 Neurological disease Diseases 0.000 abstract description 5
230000003389 potentiating effect Effects 0.000 abstract description 3
230000008901 benefit Effects 0.000 abstract description 2
125000000217 alkyl group Chemical group 0.000 description 184
239000000543 intermediate Substances 0.000 description 161
238000006243 chemical reaction Methods 0.000 description 64
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 57
239000002904 solvent Substances 0.000 description 50
230000008569 process Effects 0.000 description 48
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 41
239000000203 mixture Substances 0.000 description 41
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
239000011541 reaction mixture Substances 0.000 description 38
239000000243 solution Substances 0.000 description 34
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 31
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
108700012920 TNF Proteins 0.000 description 30
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
239000002585 base Substances 0.000 description 28
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 25
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 24
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
125000001153 fluoro group Chemical group F* 0.000 description 22
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 21
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
238000004128 high performance liquid chromatography Methods 0.000 description 19
239000012267 brine Substances 0.000 description 18
238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 18
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
239000012071 phase Substances 0.000 description 17
125000004432 carbon atom Chemical group C* 0.000 description 16
125000005843 halogen group Chemical group 0.000 description 16
238000002360 preparation method Methods 0.000 description 15
239000010410 layer Substances 0.000 description 14
229910052943 magnesium sulfate Inorganic materials 0.000 description 14
235000019341 magnesium sulphate Nutrition 0.000 description 14
239000007787 solid Substances 0.000 description 14
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
125000003545 alkoxy group Chemical group 0.000 description 13
125000001309 chloro group Chemical group Cl* 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
239000002253 acid Substances 0.000 description 12
125000001246 bromo group Chemical group Br* 0.000 description 12
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
239000003054 catalyst Substances 0.000 description 11
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 11
238000000746 purification Methods 0.000 description 11
230000002829 reductive effect Effects 0.000 description 11
229910052723 transition metal Inorganic materials 0.000 description 11
210000004027 cell Anatomy 0.000 description 10
150000003624 transition metals Chemical class 0.000 description 10
239000003643 water by type Substances 0.000 description 10
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
125000003282 alkyl amino group Chemical group 0.000 description 9
239000000284 extract Substances 0.000 description 9
239000000706 filtrate Substances 0.000 description 9
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
239000012044 organic layer Substances 0.000 description 9
125000000714 pyrimidinyl group Chemical group 0.000 description 9
230000009467 reduction Effects 0.000 description 9
229920006395 saturated elastomer Polymers 0.000 description 9
125000003107 substituted aryl group Chemical group 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
102000018594 Tumour necrosis factor Human genes 0.000 description 8
108050007852 Tumour necrosis factor Proteins 0.000 description 8
238000003556 assay Methods 0.000 description 8
125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 8
238000002347 injection Methods 0.000 description 8
239000007924 injection Substances 0.000 description 8
208000032839 leukemia Diseases 0.000 description 8
238000005160 1H NMR spectroscopy Methods 0.000 description 7
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
125000004656 alkyl sulfonylamino group Chemical group 0.000 description 7
SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 7
150000002148 esters Chemical group 0.000 description 7
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 7
230000006870 function Effects 0.000 description 7
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
239000007800 oxidant agent Substances 0.000 description 7
239000000047 product Substances 0.000 description 7
238000003756 stirring Methods 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
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
101150041968 CDC13 gene Proteins 0.000 description 6
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
125000003806 alkyl carbonyl amino group Chemical group 0.000 description 6
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
239000003638 chemical reducing agent 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
239000013058 crude material Substances 0.000 description 6
239000012043 crude product Substances 0.000 description 6
CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
238000010828 elution Methods 0.000 description 6
239000012065 filter cake Substances 0.000 description 6
238000002875 fluorescence polarization Methods 0.000 description 6
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 6
239000003921 oil Substances 0.000 description 6
229910000027 potassium carbonate Inorganic materials 0.000 description 6
239000000377 silicon dioxide Substances 0.000 description 6
229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
235000017557 sodium bicarbonate Nutrition 0.000 description 6
JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 6
238000004809 thin layer chromatography Methods 0.000 description 6
125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 5
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 5
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
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 5
206010028980 Neoplasm Diseases 0.000 description 5
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
239000005864 Sulphur Chemical group 0.000 description 5
GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 5
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
239000013078 crystal Substances 0.000 description 5
125000005842 heteroatom Chemical group 0.000 description 5
239000007788 liquid Substances 0.000 description 5
125000004043 oxo group Chemical group O=* 0.000 description 5
239000001301 oxygen Substances 0.000 description 5
229910052760 oxygen Inorganic materials 0.000 description 5
125000003386 piperidinyl group Chemical group 0.000 description 5
125000004076 pyridyl group Chemical group 0.000 description 5
108020003175 receptors Proteins 0.000 description 5
102000005962 receptors Human genes 0.000 description 5
239000000725 suspension Substances 0.000 description 5
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
125000003831 tetrazolyl group Chemical group 0.000 description 5
CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 4
RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
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 4
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
208000030760 Anaemia of chronic disease Diseases 0.000 description 4
206010025323 Lymphomas Diseases 0.000 description 4
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 4
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
230000002378 acidificating effect Effects 0.000 description 4
125000004457 alkyl amino carbonyl group Chemical group 0.000 description 4
125000004448 alkyl carbonyl group Chemical group 0.000 description 4
235000011114 ammonium hydroxide Nutrition 0.000 description 4
238000004458 analytical method Methods 0.000 description 4
239000008346 aqueous phase Substances 0.000 description 4
125000002393 azetidinyl group Chemical group 0.000 description 4
230000009286 beneficial effect Effects 0.000 description 4
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 4
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
229910000024 caesium carbonate Inorganic materials 0.000 description 4
201000011510 cancer Diseases 0.000 description 4
238000004587 chromatography analysis Methods 0.000 description 4
MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 4
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
230000014759 maintenance of location Effects 0.000 description 4
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 4
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 4
230000037361 pathway Effects 0.000 description 4
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 4
125000006239 protecting group Chemical group 0.000 description 4
238000003571 reporter gene assay Methods 0.000 description 4
230000002441 reversible effect Effects 0.000 description 4
230000011664 signaling Effects 0.000 description 4
239000011780 sodium chloride Substances 0.000 description 4
239000012312 sodium hydride Substances 0.000 description 4
229910000104 sodium hydride Inorganic materials 0.000 description 4
239000012453 solvate Substances 0.000 description 4
238000010561 standard procedure Methods 0.000 description 4
125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 4
238000004704 ultra performance liquid chromatography Methods 0.000 description 4
229910052727 yttrium Inorganic materials 0.000 description 4
UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 4
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
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