CN112313220B - Pd-l1拮抗剂化合物 - Google Patents
Pd-l1拮抗剂化合物 Download PDFInfo
- Publication number
- CN112313220B CN112313220B CN202080003296.6A CN202080003296A CN112313220B CN 112313220 B CN112313220 B CN 112313220B CN 202080003296 A CN202080003296 A CN 202080003296A CN 112313220 B CN112313220 B CN 112313220B
- Authority
- CN
- China
- Prior art keywords
- alkylene
- alkyl
- mmol
- compound
- group
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 331
- 229940123751 PD-L1 antagonist Drugs 0.000 title description 5
- 238000000034 method Methods 0.000 claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
- -1 C 1 -C 6 Alkyl Chemical group 0.000 claims description 154
- 229910052757 nitrogen Inorganic materials 0.000 claims description 64
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 206010028980 Neoplasm Diseases 0.000 claims description 38
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 37
- 201000010099 disease Diseases 0.000 claims description 37
- 239000000460 chlorine Substances 0.000 claims description 35
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 23
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 125000001188 haloalkyl group Chemical group 0.000 claims description 19
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 230000005764 inhibitory process Effects 0.000 claims description 14
- 125000004043 oxo group Chemical group O=* 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 229940124597 therapeutic agent Drugs 0.000 claims description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 208000023275 Autoimmune disease Diseases 0.000 claims description 6
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 208000036142 Viral infection Diseases 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 230000009385 viral infection Effects 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 239000004973 liquid crystal related substance Substances 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 3
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims description 3
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 1
- 102000008096 B7-H1 Antigen Human genes 0.000 claims 1
- 108010074708 B7-H1 Antigen Proteins 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 357
- 239000000543 intermediate Substances 0.000 description 200
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 195
- 239000000203 mixture Substances 0.000 description 167
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 143
- 239000007787 solid Substances 0.000 description 142
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 111
- 238000006243 chemical reaction Methods 0.000 description 110
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 102
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 101
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 99
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 94
- 239000012074 organic phase Substances 0.000 description 80
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 69
- 239000011541 reaction mixture Substances 0.000 description 68
- 238000003818 flash chromatography Methods 0.000 description 63
- 239000007788 liquid Substances 0.000 description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- 229910000027 potassium carbonate Inorganic materials 0.000 description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 48
- 239000000706 filtrate Substances 0.000 description 44
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 42
- 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 39
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 39
- 229960001153 serine Drugs 0.000 description 38
- 239000007864 aqueous solution Substances 0.000 description 36
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 32
- 150000003839 salts Chemical group 0.000 description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 30
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 30
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 30
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
- 125000004432 carbon atom Chemical group C* 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- 239000008346 aqueous phase Substances 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 239000012046 mixed solvent Substances 0.000 description 21
- 239000012071 phase Substances 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 19
- 238000012746 preparative thin layer chromatography Methods 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- 235000011056 potassium acetate Nutrition 0.000 description 16
- BCCSSBZYBJTLHZ-QMMMGPOBSA-N tert-butyl (2s)-2-amino-3-[(2-methylpropan-2-yl)oxy]propanoate Chemical compound CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C BCCSSBZYBJTLHZ-QMMMGPOBSA-N 0.000 description 16
- 125000000623 heterocyclic group Chemical group 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 208000035475 disorder Diseases 0.000 description 14
- 239000001632 sodium acetate Substances 0.000 description 14
- 235000017281 sodium acetate Nutrition 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 125000004122 cyclic group Chemical group 0.000 description 13
- 239000003937 drug carrier Substances 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 125000006413 ring segment Chemical group 0.000 description 12
- KJIODOACRIRBPB-UHFFFAOYSA-N 4-bromo-1h-indazole Chemical compound BrC1=CC=CC2=C1C=NN2 KJIODOACRIRBPB-UHFFFAOYSA-N 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 10
- 241000124008 Mammalia Species 0.000 description 10
- 239000004698 Polyethylene Substances 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 10
- 230000002441 reversible effect Effects 0.000 description 10
- 239000012453 solvate Substances 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 210000000056 organ Anatomy 0.000 description 9
- 238000004237 preparative chromatography Methods 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 8
- 238000009169 immunotherapy Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 108060001084 Luciferase Proteins 0.000 description 7
- 239000005089 Luciferase Substances 0.000 description 7
- 210000001744 T-lymphocyte Anatomy 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- GFOAHABINHRDKL-BYPYZUCNSA-N (5s)-5-(aminomethyl)pyrrolidin-2-one Chemical compound NC[C@@H]1CCC(=O)N1 GFOAHABINHRDKL-BYPYZUCNSA-N 0.000 description 5
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- XHUTYLPZWIBCIZ-UHFFFAOYSA-N 5-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=CN=CC(C#N)=C1 XHUTYLPZWIBCIZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 239000012190 activator Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 229940126179 compound 72 Drugs 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 125000004438 haloalkoxy group Chemical group 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 125000001041 indolyl group Chemical group 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- DETDCGYOOXTNBW-YFKPBYRVSA-N propan-2-yl (2s)-2-amino-3-hydroxypropanoate Chemical compound CC(C)OC(=O)[C@@H](N)CO DETDCGYOOXTNBW-YFKPBYRVSA-N 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 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 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- ZPCQHOKATFHJST-UHFFFAOYSA-N (2-amino-3-bromophenyl)methanol Chemical compound NC1=C(Br)C=CC=C1CO ZPCQHOKATFHJST-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- KDGFTIJXTPBJBP-UHFFFAOYSA-N 2-bromo-1-(bromomethyl)-3-iodobenzene Chemical compound BrCC1=CC=CC(I)=C1Br KDGFTIJXTPBJBP-UHFFFAOYSA-N 0.000 description 3
- GRJZJFUBQYULKL-UHFFFAOYSA-N 4-bromo-1h-indole Chemical compound BrC1=CC=CC2=C1C=CN2 GRJZJFUBQYULKL-UHFFFAOYSA-N 0.000 description 3
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 3
- JBHXSCWBUYDTDR-UHFFFAOYSA-N 5-(chloromethyl)pyridine-3-carbonitrile;hydrochloride Chemical compound Cl.ClCC1=CN=CC(C#N)=C1 JBHXSCWBUYDTDR-UHFFFAOYSA-N 0.000 description 3
- IPOSHVWRFQTHGK-UHFFFAOYSA-N 5-chloro-2,4-dihydroxybenzaldehyde Chemical compound OC1=CC(O)=C(C=O)C=C1Cl IPOSHVWRFQTHGK-UHFFFAOYSA-N 0.000 description 3
- MCMSJVMUSBZUCN-UHFFFAOYSA-N 9,10-dimethoxy-3-methyl-2-(2,4,6-trimethylphenyl)imino-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(C(N2C)=O)C1=CC2=NC1=C(C)C=C(C)C=C1C MCMSJVMUSBZUCN-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 3
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 3
- 230000001363 autoimmune Effects 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940127204 compound 29 Drugs 0.000 description 3
- 125000006165 cyclic alkyl group Chemical group 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 239000007972 injectable composition Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- 229960004618 prednisone Drugs 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- DAAXYQZSKBPJOX-FQEVSTJZSA-N (2S)-2-amino-3-[4-[5-[3-(4-hydroxyphenyl)-4-methoxyphenyl]-1,2,4-oxadiazol-3-yl]phenyl]propanoic acid Chemical compound COC1=C(C=C(C=C1)C2=NC(=NO2)C3=CC=C(C=C3)C[C@@H](C(=O)O)N)C4=CC=C(C=C4)O DAAXYQZSKBPJOX-FQEVSTJZSA-N 0.000 description 2
- LTNUFLTYJYKORX-GFCCVEGCSA-N (3R)-1-[3-(3-bromo-2-methylphenoxy)propyl]pyrrolidin-3-ol Chemical compound BrC=1C(=C(OCCCN2C[C@@H](CC2)O)C=CC=1)C LTNUFLTYJYKORX-GFCCVEGCSA-N 0.000 description 2
- IRPWVEBIMPXCAZ-UHFFFAOYSA-N 1,3-dibromo-2-chlorobenzene Chemical compound ClC1=C(Br)C=CC=C1Br IRPWVEBIMPXCAZ-UHFFFAOYSA-N 0.000 description 2
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 2
- JRALGBJRMAHOAX-UHFFFAOYSA-N 1-bromo-3-(3-chloropropyl)-2-methylbenzene Chemical compound CC1=C(Br)C=CC=C1CCCCl JRALGBJRMAHOAX-UHFFFAOYSA-N 0.000 description 2
- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 description 2
- 125000005955 1H-indazolyl group Chemical group 0.000 description 2
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- JXNPHMVNQPDXQI-UHFFFAOYSA-N 3-methylpyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)C1(C)CCNC1 JXNPHMVNQPDXQI-UHFFFAOYSA-N 0.000 description 2
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 2
- FNIFQOISPAAFQF-UHFFFAOYSA-N 4-(chloromethyl)benzaldehyde Chemical compound ClCC1=CC=C(C=O)C=C1 FNIFQOISPAAFQF-UHFFFAOYSA-N 0.000 description 2
- MVXAKOGJWVQPKC-UHFFFAOYSA-N 5-(3-ethynyl-5-fluorophenyl)-2-pyridin-2-yl-4,6,7,8-tetrahydro-[1,3]oxazolo[4,5-c]azepine Chemical compound FC1=CC(C#C)=CC(N2CC=3N=C(OC=3CCC2)C=2N=CC=CC=2)=C1 MVXAKOGJWVQPKC-UHFFFAOYSA-N 0.000 description 2
- ZDHQVQVNOIWLNX-UHFFFAOYSA-N 5-(7-chloro-10h-benzo[1,2]cyclohepta[2,4-c][1,3]thiazol-10-yl)-1-methyl-4-sulfanylidenepyrimidin-2-one Chemical compound S=C1NC(=O)N(C)C=C1C1C2=CC=C(Cl)C=C2C=CC2=C1N=CS2 ZDHQVQVNOIWLNX-UHFFFAOYSA-N 0.000 description 2
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 2
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- LPWKFUVWWQYLOD-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-methylphenyl)pyrido[2,3]thieno[2,4-d]pyrimidin-4-one Chemical compound C1=2C(N(C)C)=CN=CC=2SC(C2=O)=C1N=CN2C1=CC=C(C)C=C1 LPWKFUVWWQYLOD-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- 229940045513 CTLA4 antagonist Drugs 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 208000006332 Choriocarcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical class [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 230000006044 T cell activation Effects 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000005236 alkanoylamino group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 125000003277 amino group Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229960003852 atezolizumab Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229940126211 compound 54c Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000002601 intratumoral effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 2
- 150000002823 nitrates Chemical class 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000000160 oxazolidinyl group Chemical group 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000005406 washing Methods 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- BKMMTJMQCTUHRP-GSVOUGTGSA-N (2r)-2-aminopropan-1-ol Chemical compound C[C@@H](N)CO BKMMTJMQCTUHRP-GSVOUGTGSA-N 0.000 description 1
- XYDXDWXAAQXHLK-UHFFFAOYSA-N (3-bromo-2-methylphenyl)methanol Chemical compound CC1=C(Br)C=CC=C1CO XYDXDWXAAQXHLK-UHFFFAOYSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- QPMSJEFZULFYTB-PGMHMLKASA-N (3r)-pyrrolidin-3-ol;hydrochloride Chemical compound Cl.O[C@@H]1CCNC1 QPMSJEFZULFYTB-PGMHMLKASA-N 0.000 description 1
- JHHZLHWJQPUNKB-BYPYZUCNSA-N (3s)-pyrrolidin-3-ol Chemical compound O[C@H]1CCNC1 JHHZLHWJQPUNKB-BYPYZUCNSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- MWTUOSWPJOUADP-XDJHFCHBSA-N (5z)-5-(4-hydroxy-6-oxo-3-propan-2-ylcyclohexa-2,4-dien-1-ylidene)-4-(1-methylindol-5-yl)-1,2,4-triazolidin-3-one Chemical compound O=C1C=C(O)C(C(C)C)=C\C1=C\1N(C=2C=C3C=CN(C)C3=CC=2)C(=O)NN/1 MWTUOSWPJOUADP-XDJHFCHBSA-N 0.000 description 1
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 1
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- VQRBXYBBGHOGFT-UHFFFAOYSA-N 1-(chloromethyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1CCl VQRBXYBBGHOGFT-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- SPMVMDHWKHCIDT-UHFFFAOYSA-N 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC=1C=C(C)ON=1 SPMVMDHWKHCIDT-UHFFFAOYSA-N 0.000 description 1
- UZSYESYIKURHNI-JYQLQLLISA-N 1-[[4-[[2-bromo-3-[1-[4-[(3R)-3-hydroxypyrrolidin-1-yl]butyl]indazol-4-yl]phenyl]methoxy]-5-chloro-2-[(5-cyanopyridin-3-yl)methoxy]phenyl]methyl]-3-methylpyrrolidine-3-carboxylic acid Chemical compound BrC1=C(COC2=CC(=C(CN3CC(CC3)(C(=O)O)C)C=C2Cl)OCC=2C=NC=C(C=2)C#N)C=CC=C1C1=C2C=NN(C2=CC=C1)CCCCN1C[C@@H](CC1)O UZSYESYIKURHNI-JYQLQLLISA-N 0.000 description 1
- QXOGPTXQGKQSJT-UHFFFAOYSA-N 1-amino-4-[4-(3,4-dimethylphenyl)sulfanylanilino]-9,10-dioxoanthracene-2-sulfonic acid Chemical compound Cc1ccc(Sc2ccc(Nc3cc(c(N)c4C(=O)c5ccccc5C(=O)c34)S(O)(=O)=O)cc2)cc1C QXOGPTXQGKQSJT-UHFFFAOYSA-N 0.000 description 1
- RBLQMXTZTSXCJV-UHFFFAOYSA-N 1-bromo-3-(chloromethyl)-2-methylbenzene Chemical compound CC1=C(Br)C=CC=C1CCl RBLQMXTZTSXCJV-UHFFFAOYSA-N 0.000 description 1
- XDKMDDOCVPNVMB-UHFFFAOYSA-N 1-bromo-3-methyl-2-nitrobenzene Chemical compound CC1=CC=CC(Br)=C1[N+]([O-])=O XDKMDDOCVPNVMB-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- ASFQDNDZFGFMMP-UHFFFAOYSA-N 2,2-dimethyl-1,3-dioxan-5-one Chemical compound CC1(C)OCC(=O)CO1 ASFQDNDZFGFMMP-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical group OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 1
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- KEGQEFDADWTVBG-UHFFFAOYSA-N 2-bromo-1-iodo-3-methylbenzene Chemical compound CC1=CC=CC(I)=C1Br KEGQEFDADWTVBG-UHFFFAOYSA-N 0.000 description 1
- VJNUZLYTGSGDHR-UHFFFAOYSA-N 2-bromo-3-methylaniline Chemical compound CC1=CC=CC(N)=C1Br VJNUZLYTGSGDHR-UHFFFAOYSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- UTVCLUZQPSRKMY-UHFFFAOYSA-N 2-chloro-5-hydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1Cl UTVCLUZQPSRKMY-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 1
- ZDICHAGDCMMAKV-UHFFFAOYSA-N 3-bromo-2-chlorobenzaldehyde Chemical compound ClC1=C(Br)C=CC=C1C=O ZDICHAGDCMMAKV-UHFFFAOYSA-N 0.000 description 1
- LNURMIDMOXCNEH-UHFFFAOYSA-N 3-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Br)=C1Cl LNURMIDMOXCNEH-UHFFFAOYSA-N 0.000 description 1
- DUKKNDLIWRYBCT-UHFFFAOYSA-N 3-bromo-2-chlorophenol Chemical compound OC1=CC=CC(Br)=C1Cl DUKKNDLIWRYBCT-UHFFFAOYSA-N 0.000 description 1
- WPDXAMRGYMDTOV-UHFFFAOYSA-N 3-bromo-2-methylphenol Chemical compound CC1=C(O)C=CC=C1Br WPDXAMRGYMDTOV-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical class OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- DMBMXJJGPXADPO-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(C=O)C=C1 DMBMXJJGPXADPO-UHFFFAOYSA-N 0.000 description 1
- FGZYVGDEDFKTHO-UHFFFAOYSA-N 4-(chloromethyl)pyridine-2-carbonitrile Chemical compound ClCC1=CC=NC(C#N)=C1 FGZYVGDEDFKTHO-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- ZLHFILGSQDJULK-UHFFFAOYSA-N 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid Chemical compound C1=C(C(O)=O)C(OC)=CC(NC=2N=C3C4=CC=C(Cl)C=C4C(=NCC3=CN=2)C=2C(=CC=CC=2F)OC)=C1 ZLHFILGSQDJULK-UHFFFAOYSA-N 0.000 description 1
- MUQFMGBYYAOIJK-UHFFFAOYSA-N 4-bromo-1h-benzimidazole Chemical compound BrC1=CC=CC2=C1N=CN2 MUQFMGBYYAOIJK-UHFFFAOYSA-N 0.000 description 1
- DNJANJSHTMOQOV-UHFFFAOYSA-N 4-bromo-2h-benzotriazole Chemical compound BrC1=CC=CC2=C1N=NN2 DNJANJSHTMOQOV-UHFFFAOYSA-N 0.000 description 1
- QLPNZDSBEQBVBD-UHFFFAOYSA-N 4-bromo-3-methyl-2h-indazole Chemical group C1=CC(Br)=C2C(C)=NNC2=C1 QLPNZDSBEQBVBD-UHFFFAOYSA-N 0.000 description 1
- SCPUNJAMWFAYED-UHFFFAOYSA-N 4-chloro-3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(O)=C1 SCPUNJAMWFAYED-UHFFFAOYSA-N 0.000 description 1
- MDOJTZQKHMAPBK-UHFFFAOYSA-N 4-iodo-3-nitrobenzamide Chemical compound NC(=O)C1=CC=C(I)C([N+]([O-])=O)=C1 MDOJTZQKHMAPBK-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 description 1
- YJMXMAFOMRGHCU-UHFFFAOYSA-N 5-[[2-(aminomethyl)-5-[[4-[3-[[4-(aminomethyl)-2-chloro-5-[(5-cyanopyridin-3-yl)methoxy]phenoxy]methyl]-2-methylphenyl]indazol-1-yl]methyl]-4-chlorophenoxy]methyl]pyridine-3-carbonitrile Chemical compound NCC1=C(OCC=2C=NC=C(C#N)C=2)C=C(C(=C1)Cl)OCC1=C(C(=CC=C1)C1=C2C=NN(C2=CC=C1)CC1=C(C=C(C(=C1)OCC=1C=NC=C(C=1)C#N)CN)Cl)C YJMXMAFOMRGHCU-UHFFFAOYSA-N 0.000 description 1
- LUZXKYBQJCCUOB-UHFFFAOYSA-N 5-[[2-(aminomethyl)-5-[[4-[3-[[4-(aminomethyl)-2-chloro-5-methoxyphenoxy]methyl]-2-methylphenyl]indazol-1-yl]methyl]-4-chlorophenoxy]methyl]pyridine-3-carbonitrile Chemical compound NCC1=C(OCC=2C=NC=C(C#N)C=2)C=C(C(=C1)Cl)CN1N=CC2=C(C=CC=C12)C1=C(C(=CC=C1)COC1=C(C=C(C(=C1)OC)CN)Cl)C LUZXKYBQJCCUOB-UHFFFAOYSA-N 0.000 description 1
- HPPANHFMIGLWMV-WJOKGBTCSA-N 5-[[4-chloro-2-[[(1,3-dihydroxy-2-methylpropan-2-yl)amino]methyl]-5-[[4-[1-[3-[(3R)-3-hydroxypyrrolidin-1-yl]propyl]indazol-4-yl]indazol-1-yl]methyl]phenoxy]methyl]pyridine-3-carbonitrile Chemical compound ClC1=CC(=C(OCC=2C=NC=C(C#N)C=2)C=C1CN1N=CC=2C(=CC=CC1=2)C=1C=2C=NN(C=2C=CC=1)CCCN1C[C@@H](CC1)O)CNC(CO)(CO)C HPPANHFMIGLWMV-WJOKGBTCSA-N 0.000 description 1
- NQKFKCQGRHASLI-UHFFFAOYSA-N 5-[[4-chloro-5-[[4-[3-[[2-chloro-4-[(2-hydroxyethylamino)methyl]-5-methoxyphenoxy]methyl]-2-methylphenyl]indazol-1-yl]methyl]-2-[(2-hydroxyethylamino)methyl]phenoxy]methyl]pyridine-3-carbonitrile Chemical compound ClC1=CC(=C(OCC=2C=NC=C(C#N)C=2)C=C1CN1N=CC2=C(C=CC=C12)C1=C(C(=CC=C1)COC1=C(C=C(C(=C1)OC)CNCCO)Cl)C)CNCCO NQKFKCQGRHASLI-UHFFFAOYSA-N 0.000 description 1
- BCBXPQGKDOGIBL-JGCGQSQUSA-N 5-[[5-[[2-bromo-3-[1-[4-[(3R)-3-hydroxypyrrolidin-1-yl]butyl]indazol-4-yl]phenyl]methoxy]-4-chloro-2-(pyrrolidin-1-ylmethyl)phenoxy]methyl]pyridine-3-carbonitrile Chemical compound BrC1=C(COC=2C(=CC(=C(OCC=3C=NC=C(C#N)C=3)C=2)CN2CCCC2)Cl)C=CC=C1C1=C2C=NN(C2=CC=C1)CCCCN1C[C@@H](CC1)O BCBXPQGKDOGIBL-JGCGQSQUSA-N 0.000 description 1
- KONAGBRMAYSCTD-SSEXGKCCSA-N 5-[[5-[[2-bromo-3-[1-[4-[(3R)-3-hydroxypyrrolidin-1-yl]butyl]indazol-4-yl]phenyl]methoxy]-4-chloro-2-[(2-hydroxyethylamino)methyl]phenoxy]methyl]pyridine-3-carbonitrile Chemical compound BrC1=C(COC=2C(=CC(=C(OCC=3C=NC=C(C#N)C=3)C=2)CNCCO)Cl)C=CC=C1C1=C2C=NN(C2=CC=C1)CCCCN1C[C@@H](CC1)O KONAGBRMAYSCTD-SSEXGKCCSA-N 0.000 description 1
- YRLGXVINEHGBCE-ROJLCIKYSA-N 5-[[5-[[2-bromo-3-[1-[4-[(3R)-3-hydroxypyrrolidin-1-yl]butyl]indazol-4-yl]phenyl]methoxy]-4-chloro-2-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]phenoxy]methyl]pyridine-3-carbonitrile Chemical compound BrC1=C(COC=2C(=CC(=C(OCC=3C=NC=C(C#N)C=3)C=2)CN2C[C@@H](CC2)O)Cl)C=CC=C1C1=C2C=NN(C2=CC=C1)CCCCN1C[C@@H](CC1)O YRLGXVINEHGBCE-ROJLCIKYSA-N 0.000 description 1
- YRLGXVINEHGBCE-ZWXJPIIXSA-N 5-[[5-[[2-bromo-3-[1-[4-[(3R)-3-hydroxypyrrolidin-1-yl]butyl]indazol-4-yl]phenyl]methoxy]-4-chloro-2-[[(3S)-3-hydroxypyrrolidin-1-yl]methyl]phenoxy]methyl]pyridine-3-carbonitrile Chemical compound BrC1=C(COC=2C(=CC(=C(OCC=3C=NC=C(C#N)C=3)C=2)CN2C[C@H](CC2)O)Cl)C=CC=C1C1=C2C=NN(C2=CC=C1)CCCCN1C[C@@H](CC1)O YRLGXVINEHGBCE-ZWXJPIIXSA-N 0.000 description 1
- HLSGQSHEUKUFIY-MXBOTTGLSA-N 5-[[5-[[2-bromo-3-[1-[4-[(3R)-3-hydroxypyrrolidin-1-yl]butyl]indazol-4-yl]phenyl]methoxy]-4-chloro-2-[[[(2R)-1-hydroxypropan-2-yl]amino]methyl]phenoxy]methyl]pyridine-3-carbonitrile Chemical compound BrC1=C(COC=2C(=CC(=C(OCC=3C=NC=C(C#N)C=3)C=2)CN[C@@H](CO)C)Cl)C=CC=C1C1=C2C=NN(C2=CC=C1)CCCCN1C[C@@H](CC1)O HLSGQSHEUKUFIY-MXBOTTGLSA-N 0.000 description 1
- FYVUMWKOZOCQLY-AJQTZOPKSA-N 5-[[5-[[2-bromo-3-[1-[4-[(3R)-3-hydroxypyrrolidin-1-yl]butyl]indazol-4-yl]phenyl]methoxy]-4-chloro-2-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]phenoxy]methyl]pyridine-3-carbonitrile Chemical compound BrC1=C(COC=2C(=CC(=C(OCC=3C=NC=C(C#N)C=3)C=2)CNC[C@H]2NC(CC2)=O)Cl)C=CC=C1C1=C2C=NN(C2=CC=C1)CCCCN1C[C@@H](CC1)O FYVUMWKOZOCQLY-AJQTZOPKSA-N 0.000 description 1
- KAXIYYPIORYZLB-UHFFFAOYSA-N 5-hydroxypyridine-3-carbonitrile Chemical compound OC1=CN=CC(C#N)=C1 KAXIYYPIORYZLB-UHFFFAOYSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- AVBARORPQMEWPR-UHFFFAOYSA-N 6-chloro-2-methoxypyridine-3-carbaldehyde Chemical compound COC1=NC(Cl)=CC=C1C=O AVBARORPQMEWPR-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 101150051188 Adora2a gene Proteins 0.000 description 1
- 101150078577 Adora2b gene Proteins 0.000 description 1
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 1
- 206010001413 Adult T-cell lymphoma/leukaemia Diseases 0.000 description 1
- 206010052613 Allergic bronchitis Diseases 0.000 description 1
- 206010049153 Allergic sinusitis Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 201000006107 Familial adenomatous polyposis Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282575 Gorilla Species 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 1
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 1
- 208000008051 Hereditary Nonpolyposis Colorectal Neoplasms Diseases 0.000 description 1
- 208000017095 Hereditary nonpolyposis colon cancer Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 1
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- 239000002139 L01XE22 - Masitinib Substances 0.000 description 1
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- 102000017578 LAG3 Human genes 0.000 description 1
- UCEQXRCJXIVODC-PMACEKPBSA-N LSM-1131 Chemical compound C1CCC2=CC=CC3=C2N1C=C3[C@@H]1C(=O)NC(=O)[C@H]1C1=CNC2=CC=CC=C12 UCEQXRCJXIVODC-PMACEKPBSA-N 0.000 description 1
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 201000005027 Lynch syndrome Diseases 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000009018 Medullary thyroid cancer Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 1
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000005927 Myosarcoma Diseases 0.000 description 1
- FOFDIMHVKGYHRU-UHFFFAOYSA-N N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide Chemical compound C12=CC=CC=C2OC2=C1N=CN=C2N(CC1)CCN1C(=S)NCC1=CC=C(OCO2)C2=C1 FOFDIMHVKGYHRU-UHFFFAOYSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- CXQHYVUVSFXTMY-UHFFFAOYSA-N N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 CXQHYVUVSFXTMY-UHFFFAOYSA-N 0.000 description 1
- JWCYXXDMTZOKNZ-CXNSMIOJSA-N N1(N=CC=2C(=CC=CC1=2)C=1C=2C=NN(C=2C=CC=1)CC1=CC(=C(C=C1Cl)CN[C@H](C(=O)O)CO)OCC=1C=NC=C(C=1)C#N)CC1=CC(=C(C=C1Cl)CN[C@H](C(=O)O)CO)OCC=1C=NC=C(C=1)C#N Chemical compound N1(N=CC=2C(=CC=CC1=2)C=1C=2C=NN(C=2C=CC=1)CC1=CC(=C(C=C1Cl)CN[C@H](C(=O)O)CO)OCC=1C=NC=C(C=1)C#N)CC1=CC(=C(C=C1Cl)CN[C@H](C(=O)O)CO)OCC=1C=NC=C(C=1)C#N JWCYXXDMTZOKNZ-CXNSMIOJSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 108010064641 ONX 0912 Proteins 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000012269 PD-1/PD-L1 inhibitor Substances 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- HZLFFNCLTRVYJG-WWGOJCOQSA-N Patidegib Chemical compound C([C@@]1(CC(C)=C2C3)O[C@@H]4C[C@H](C)CN[C@H]4[C@H]1C)C[C@H]2[C@H]1[C@H]3[C@@]2(C)CC[C@@H](NS(C)(=O)=O)C[C@H]2CC1 HZLFFNCLTRVYJG-WWGOJCOQSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 1
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 1
- 108091007744 Programmed cell death receptors Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007156 Spondylarthritis Diseases 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-AKLPVKDBSA-N Sulfur-35 Chemical compound [35S] NINIDFKCEFEMDL-AKLPVKDBSA-N 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 239000004012 Tofacitinib Substances 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 108091005906 Type I transmembrane proteins Proteins 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- MXZNUGFCDVAXLG-CHWSQXEVSA-N [(2S)-1-[(2R)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@@H](NC(=O)c1ccncc1)C(=O)N1CCC[C@@H]1B(O)O MXZNUGFCDVAXLG-CHWSQXEVSA-N 0.000 description 1
- FIHPGKCHMJNOAI-UHFFFAOYSA-N [3-bromo-2-(dimethylamino)phenyl]methanol Chemical compound CN(C)C1=C(C=CC=C1Br)CO FIHPGKCHMJNOAI-UHFFFAOYSA-N 0.000 description 1
- YWMGPWNJYAUMIO-UHFFFAOYSA-N [3-bromo-2-(methylamino)phenyl]methanol Chemical group CNC1=C(C=CC=C1Br)CO YWMGPWNJYAUMIO-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 150000001278 adipic acid derivatives Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229950009447 alisertib Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical class O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229950009545 amuvatinib Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 229960003982 apatinib Drugs 0.000 description 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
- 125000005239 aroylamino group Chemical group 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 150000001509 aspartic acid derivatives Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 150000004652 butanoic acids Chemical class 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 1
- 235000008207 calcium folinate Nutrition 0.000 description 1
- 239000011687 calcium folinate Substances 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical class [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical class CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229950009240 crenolanib Drugs 0.000 description 1
- DYNHJHQFHQTFTP-UHFFFAOYSA-N crenolanib Chemical compound C=1C=C2N(C=3N=C4C(N5CCC(N)CC5)=CC=CC4=CC=3)C=NC2=CC=1OCC1(C)COC1 DYNHJHQFHQTFTP-UHFFFAOYSA-N 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 229960002465 dabrafenib Drugs 0.000 description 1
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical class CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 1
- 229960001971 ebastine Drugs 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 150000002085 enols Chemical group 0.000 description 1
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229950008692 foretinib Drugs 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 201000007487 gallbladder carcinoma Diseases 0.000 description 1
- 229950004161 ganetespib Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002315 glycerophosphates Chemical class 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical class C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 239000002434 gonadorelin derivative Substances 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical class CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 102000048776 human CD274 Human genes 0.000 description 1
- 102000048362 human PDCD1 Human genes 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical class OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000004926 indolenyl group Chemical group 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 229950002133 iniparib Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 1
- 229960002014 ixabepilone Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical class OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960003784 lenvatinib Drugs 0.000 description 1
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 1
- 229960001508 levocetirizine Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229950002216 linifanib Drugs 0.000 description 1
- MPVGZUGXCQEXTM-UHFFFAOYSA-N linifanib Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C(N)=NNC=3C=CC=2)=C1 MPVGZUGXCQEXTM-UHFFFAOYSA-N 0.000 description 1
- PKCDDUHJAFVJJB-VLZXCDOPSA-N linsitinib Chemical compound C1[C@](C)(O)C[C@@H]1C1=NC(C=2C=C3N=C(C=CC3=CC=2)C=2C=CC=CC=2)=C2N1C=CN=C2N PKCDDUHJAFVJJB-VLZXCDOPSA-N 0.000 description 1
- 229950001762 linsitinib Drugs 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 229960004655 masitinib Drugs 0.000 description 1
- WJEOLQLKVOPQFV-UHFFFAOYSA-N masitinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3SC=C(N=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 WJEOLQLKVOPQFV-UHFFFAOYSA-N 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- JBVNBBXAMBZTMQ-CEGNMAFCSA-N megestrol Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 JBVNBBXAMBZTMQ-CEGNMAFCSA-N 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 201000002077 muscle cancer Diseases 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- SWZXEVABPLUDIO-WSZYKNRRSA-N n-[(2s)-3-methoxy-1-[[(2s)-3-methoxy-1-[[(2s)-1-[(2r)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]-2-methyl-1,3-thiazole-5-carboxamide Chemical compound N([C@@H](COC)C(=O)N[C@@H](COC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)[C@]1(C)OC1)C(=O)C1=CN=C(C)S1 SWZXEVABPLUDIO-WSZYKNRRSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- WPEWQEMJFLWMLV-UHFFFAOYSA-N n-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide Chemical compound C=1C=CN=C(NCC=2C=CN=CC=2)C=1C(=O)NC(C=C1)=CC=C1C1(C#N)CCCC1 WPEWQEMJFLWMLV-UHFFFAOYSA-N 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006070 nanosuspension Substances 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000006636 nicotinic acid Chemical class 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 description 1
- 229950011068 niraparib Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 229960002450 ofatumumab Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical class CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229950005750 oprozomib Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- YWWARDMVSMPOLR-UHFFFAOYSA-M oxolane;tetrabutylazanium;fluoride Chemical compound [F-].C1CCOC1.CCCC[N+](CCCC)(CCCC)CCCC YWWARDMVSMPOLR-UHFFFAOYSA-M 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 229940121653 pd-1/pd-l1 inhibitor Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 description 1
- 229960005330 pimecrolimus Drugs 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical class CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229960001131 ponatinib Drugs 0.000 description 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 201000003651 pulmonary sarcoidosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 238000003030 reporter gene method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229950006764 rigosertib Drugs 0.000 description 1
- OWBFCJROIKNMGD-BQYQJAHWSA-N rigosertib Chemical compound COC1=CC(OC)=CC(OC)=C1\C=C\S(=O)(=O)CC1=CC=C(OC)C(NCC(O)=O)=C1 OWBFCJROIKNMGD-BQYQJAHWSA-N 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 description 1
- 229950004707 rucaparib Drugs 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- 229960005569 saridegib Drugs 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010922 spray-dried dispersion Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- WOEQSXAIPTXOPY-UHFFFAOYSA-N tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1 WOEQSXAIPTXOPY-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229940126622 therapeutic monoclonal antibody Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 125000005403 thiohaloalkoxy group Chemical group 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- 229950005976 tivantinib Drugs 0.000 description 1
- 229960000940 tivozanib Drugs 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 1
- 229960000977 trabectedin Drugs 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
Abstract
本发明提供了一种式(I)化合物及其药物组合物,以及使用式(I)化合物预防和/或治疗免疫相关病症的方法。
Description
本申请要求于2019年2月21日提交中国专利局、申请号为201910130313.1、发明名称为“PD-L1拮抗剂化合物”,以及于2019年7月30日提交中国专利局、申请号为201910695768.8、发明名称为“PD-L1拮抗剂化合物”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种PD-L1拮抗剂化合物及使用其治疗/预防免疫相关病症的方法。
背景技术
肿瘤免疫治疗由于其卓越的疗效和创新性,在2013年被《科学》杂志评为年度最重要的科学突破。肿瘤免疫治疗有望成为继手术、化疗、放疗、靶向治疗后肿瘤治疗领域的一场革新。肿瘤免疫治疗是应用免疫学原理和方法,提高肿瘤细胞的免疫原性和对效应细胞杀伤的敏感性,激发和增强机体抗肿瘤免疫应答,并应用免疫细胞和效应分子输注宿主体内,协同机体免疫***杀伤肿瘤、抑制肿瘤生长。肿瘤免疫治疗近来备受关注,是肿瘤治疗领域的焦点。近几年,肿瘤免疫治疗的好消息不断,目前已在一些肿瘤类型如黑色素瘤,非小细胞肺癌等的治疗中展示出了强大的抗肿瘤活性,并已有肿瘤免疫治疗药物获得美国FDA(Food and Drug Administration,FDA)批准临床应用。
PD-1(程序性死亡受体1,programmed death 1)为CD28超家族成员。以PD-1为靶点的免疫调节在抗肿瘤、抗感染、抗自身免疫性疾病及器官移植存活等方面均有重要的意义。其配体PD-L1也可作为靶点,相应的抗体也可以起到相同的作用。PD-L1(程序性死亡受体-配体1,programmed cell death-Ligand 1)是大小为40kDa的第一型跨膜蛋白。正常情形下免疫***会对聚集在***或脾脏的外来抗原产生反应,促进具有抗原特异性的T细胞增殖。而PD-1与PD-L1结合,可以传导抑制性的信号,减低T细胞的增殖。
肿瘤细胞逃避T细胞摧毁的一种途径是通过在它表面产生PD-L1。当免疫细胞T细胞表面的PD-1识别PD-L1后,可以传导抑制性信号,T细胞就不能发现肿瘤细胞和向肿瘤细胞发出攻击信号。PD-1是通过解除肿瘤细胞逃避免疫***的新型免疫疗法。PD-1免疫疗法的作用机制是针对PD-1或PD-L1设计特定的蛋白质抗体,阻止PD-1和PD-L1的识别过程,部分恢复T细胞功能,从而使T细胞可以杀死肿瘤细胞。
PD-1表达于活化的T细胞,B细胞及髓系细胞,其有两个配体,即PD-L1和PD-L2。PD-L1/L2在抗原递呈细胞都表达,PD-L1在多种组织也有表达。PD-1与PD-L1的结合介导T细胞活化的共抑制信号,调节T细胞活化和增殖,起到类似于CTLA-4的负调节作用。华裔科学家陈列平实验室首先发现PD-L1在肿瘤组织高表达,而且调节肿瘤浸润CD8 T细胞的功能。因此,以PD-1/PD-L1为靶点的免疫调节对抗肿瘤有重要的意义。
多个靶向PD-1/PD-L1相互作用的治疗性单克隆抗体(mAbs)已被美国FDA批准上市。除了开发相关单克隆抗体之外,寻找方便癌症患者的口服小分子化合物用来靶向抑制免疫检查点也是肿瘤免疫疗法的前沿领域。小分子化合物能够穿过细胞膜作用于细胞内靶点,所以应用范围广泛。其次,小分子经化学修饰后往往具有良好的生物利用度和依从性,有效避免消化肠道中酶类的分解失活。最后,在生产工艺、剂型设计和给药方式等多种层面,小分子的研究也颇为成熟。
大多数单克隆抗体(mAbs)的使用途径是高剂量的静脉注射。小分子药物,其更适合口服给药,可以减少严重的免疫相关不良事件。与单克隆抗体相比,小分子药物抑制剂有很多其他好处,例如,制造成本更经济、稳定,且器官和肿瘤的渗透性更好。考虑到小分子药物动力学性质的众多优点,它将会在单一疗法或其它组合方案里体现出剂量上的灵活性。本发明的小分子化合物的可为患者和医生提供一个引人注目的治疗选择。
发明内容
本发明提供了一种式(I)化合物:
其中,
R1选自以下基团:
其中W1、W2、W3、W4各自独立地表示CRc或者N,Z1和Z2各自独立地表示氢、(C1-C6)烷基、(C3-C6)环烷基、卤代(C1-C6)烷基、卤素、-ORa、-C(O)ORa、(C1-C6)烷氧基、-NRaRb、-SO2Ra、氰基、硝基;
R2表示-(C0-C6亚烷基)NRARB或-O(C0-C6亚烷基)NRARB;
R3表示氢、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)卤代烷基、卤素、-ORa、-C(O)ORa、(C1-C6)烷氧基、-NRaRb、-SO2Ra、氰基或硝基;
X表示-(C0-C6亚烷基)-、-(C0-C6亚烷基)O-或-O(C0-C6亚烷基)-;
Y表示-(C0-C6亚烷基)(C6-C10芳基)、-(C0-C6亚烷基)(5-10元杂芳基)、-O(C1-C6)烷基、-O(C0-C6亚烷基)(C6-C10芳基)、-O(C0-C6亚烷基)(5-10元杂芳基)、-(C0-C6亚烷基)O(C6-C10芳基)、-(C0-C6亚烷基)O(5-10元杂芳基)、-O(C0-C6亚烷基)(C3-C6环烷基)或-O(C0-C6亚烷基)(3-6元杂环烷基);
对于上述Y定义中的亚烷基、烷基、环烷基、杂环烷基、芳基、杂芳基而言,其任选地被选自0、1、2或3个以下的取代基所取代:-ORa、氰基、氧代(=O)、卤素、C1-C6烷基、-(C1-C6亚烷基)ORa、C1-C6氰基烷基、C1-C6卤代烷基、C3-C8环烷基、
-C(O)Ra、-(C1-C6亚烷基)C(O)Ra、-C(O)ORa、-C1-C6烷基C(O)ORa、
-NRaRb、-(C1-C6亚烷基)NRaRb、-C(O)NRaRb、SO2Ra、
-C(O)NRaSO2Rb或者-NRaC(O)Rb;
或者Y表示-O(C0-C6亚烷基)CONRARB;
A表示-(C0-C6亚烷基)NRARB、-O(C0-C6亚烷基)NRARB、-C(O)(C0-C6亚烷基)NRARB、-(C0-C6亚烷基)(C3-C6环烷基)NRARB或-(3-6元杂环烷基)CHRARB;
或者A表示
其中,Q表示:-(C0-C6亚烷基)-、-(C0-C6亚烷基)O-或-O(C0-C6亚烷基)-;
W5表示CH或N;
R4表示:-(C0-C6亚烷基)NRARB、-O(C0-C6亚烷基)NRARB或-C(O)NRARB;
R5表示氢、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)卤代烷基、卤素、-ORa、-C(O)ORa、(C1-C6)烷氧基、-NRaRb、-SO2Ra、氰基、硝基;
R6表示氢、-(C0-C6亚烷基)(C6-C10芳基)、-(C0-C6亚烷基)(5-10元杂芳基)、-O(C1-C6)烷基、-O(C0-C6亚烷基)CONRARB、-O(C0-C6亚烷基)(C6-C10芳基)、-O(C0-C6亚烷基)(5-10元杂芳基)、-(C0-C6亚烷基)O(C6-C10芳基)、-(C0-C6亚烷基)O(5-10元杂芳基)、
-O(C0-C6亚烷基)(C3-C6环烷基)或-O(C0-C6亚烷基)(3-6元杂环烷基);
对于上述R6定义中的亚烷基、烷基、环烷基、杂环烷基、芳基、杂芳基而言,其可以任意地被0、1、2或3个选自以下取代基所取代:-ORa、氰基、卤素、C1-C6烷基、-(C1-C6亚烷基)ORa、C1-C6氰基烷基、C1-C6卤代烷基、C3-C8环烷基、-C(O)Ra、-(C1-C6亚烷基)C(O)Ra、-C(O)ORa、-(C1-C6烷基)C(O)ORa、-NRaRb、-(C1-C6亚烷基)NRaRb、-C(O)NRaRb、
-SO2Ra、-C(O)NRaSO2Rb和-NRaC(O)Rb;
表示任意地连接位置;
m、n、o、p选自0、1、2和3;
RA、RB分别独立地表示氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、-(C0-C6亚烷基)(C3-C6环烷基)、-(C0-C6亚烷基)(3-6元杂环烷基)、-(C0-C6亚烷基)(C6-C10芳基)、-(C0-C6亚烷基)(5-10元杂芳基)、-(C0-C6烷基)C(O)ORa、-SO2Ra、-SO2NRaRb或-C(O)NRaSO2Rb;
对于上述RA、RB定义中的亚烷基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基而言,其任选地被0、1、2或3个选自以下的取代基所取代:-ORa、氰基、氧代、卤素、C1-C6烷基、-(C1-C6亚烷基)ORa、C1-C6氰基烷基、C1-C6卤代烷基、C3-C8环烷基、-C(O)Ra、-(C1-C6亚烷基)C(O)Ra、-C(O)ORa、-(C1-C6烷基)C(O)ORa、-NRaRb、-(C1-C6亚烷基)NRaRb、-C(O)NRaRb、-SO2Ra、-C(O)NRaSO2Rb和-NRaC(O)Rb;
或者RA和RB一起和与之相连的原子共同环合形成5-7元环,并且该环还可以任意地具有0、1、2或3个选自O、N、S的杂原子,进一步地,该环还任选地被0、1、2或3个选自以下的取代基所取代:氧代、氰基、C1-C6烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、-ORa、-C(O)ORa、-(C1-C6)氰基烷基、(C1-C6)卤代烷基、-(C1-C6亚烷基)ORa、-C(O)Ra、-NRaRb、-(C1-C6亚烷基)NRaRb、-C(O)NRaRb、-(C1-C6亚烷基)C(O)NRaRb、-SO2Ra、-(C1-C6亚烷基)SO2Ra、-SO2NRaRb和-(C1-C6亚烷基)SO2NRaRb;
其中,Ra、Rb分别独立地表示氢、C1-C6烷基、-(C0-C6亚烷基)(C3-C6环烷基)、-(C0-C6亚烷基)(C3-C6杂环烷基)、-(C0-C6亚烷基)(C6-C10芳基)或-(C0-C6亚烷基)(5-10元杂芳基);
或者Ra、Rb一起和与之相连的原子共同环合形成5-7元环,并且该环还可以任意地具有0、1、2或3个选自O、N、S的杂原子,进一步地,该环还任选地被0、1、2或3个选自以下的取代基所取代:氧代、氰基、C1-C6烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、-ORd、-C(O)ORd、-(C1-C6)氰基烷基、(C1-C6)卤代烷基、-(C1-C6亚烷基)ORd、-C(O)Rd、-NRdRe、-(C1-C6亚烷基)NRdRe、-C(O)NRdRe、-(C1-C6亚烷基)C(O)NRdRe、-SO2Rd、-(C1-C6亚烷基)SO2Rd、-SO2NRdRe和-(C1-C6亚烷基)SO2NRdRe;
其中,Rc、Rd、Re分别独立地表示氢、C1-C6烷基或C3-C6环烷基。
除此之外,本发明还提供了一种具有如下式(II)结构的化合物:
其中,R2、R3、A、W1、Z1、Z2、Y、m、n、o如式(I)所定义。
除此之外,本发明还提供了一种具有如下式(III)结构的化合物:MP2021719P
其中,R2、R3、A、Z1、Z2、W1、Y、m、n、o如式(I)所定义。
除此之外,本发明还提供了一种具有如下式(IV)结构的化合物:
其中,R2、R3、A、Z1、Z2、W1、Y、m、n、o如式(I)所定义。
在本发明的化合物中,R2优选地选自-(C0-C6亚烷基)NRARB,其中RA、RB分别独立地表示氢或者表示被-ORa、-C(O)Ra或-C(O)ORa所取代的C1-C6烷基,其中Ra和Rb分别独立地表示氢或者C1-C6烷基。
在本发明的化合物中,Y优选地选自被-ORa、氰基、卤素、C1-C6烷基、-(C1-C6亚烷基)ORa、C1-C6氰基烷基、-C(O)ORa、-NRaRb、-C(O)NRaRb、SO2Ra、-C(O)NRaSO2Rb或者-NRaC(O)Rb所取代的-O(C1-C6)烷基、-O(C0-C6亚烷基)(C6-C10芳基)、-O(C0-C6亚烷基)(5-10元杂芳基)、-O(C1-C6)烷基、-(C0-C6亚烷基)O(C6-C10芳基)或-(C0-C6亚烷基)O(5-10元杂芳基),其中Ra、Rb分别独立地表示氢或者C1-C6烷基。
在本发明的化合物中,Y优选地选自-O-(C1-C6烷基),其中所述C1-C6烷基任选地被0、1或2个氰基、卤素、羟基、-C(O)NH2、氨基、磺酸基、羧基所取代,优选地,Y选自
在本发明的化合物中,Y优选地选自-O(C0-C6亚烷基)(3-6元杂环烷基),其中所述3-6元杂环烷基任选地被氧代、C1-C6烷基、羟基所取代,优选的Y选自
在本发明的化合物中,其中,Y优选地选自 其中W4和W5分别独立地表示CH或者N;p表示0、1、2或3;Z3表示氢、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)卤代烷基、卤素、-ORa、-C(O)ORa、(C1-C6)烷氧基、-NRaRb、-SO2Ra、氰基、硝基;Ra和Rb表示氢或者C1-C6烷基;优选地Y选自/>
在本发明的化合物中,Y优选地选自其中Z4表示氢、C1-C6烷基、氰基、氰甲基或C3-C6环烷基,优选地,Y选自/>
在本发明的化合物中,Y优选地选自-O(C0-C6亚烷基)CONRARB,其中RA和RB分别独立地表示氢或者任选地被-ORa、-NRaRb、-C(O)NRaRb所取代的C1-C6烷基,其中Ra、Rb分别独立地表示氢或者C1-C6烷基;优选地,Y选自
在本发明的化合物中,Y优选地选自-O(C0-C6亚烷基)CONRARB,其中RA和RB一起和与之相连的氮原子共同环合形成5-7元环,并且该环还可以任意地具有0、1、2或3个选自O、N、S的杂原子,进一步地,该环还任选地被0、1、2或3个选自以下的取代基所取代:氰基、C1-C6烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、-ORa、-C(O)ORa、-(C1-C6)氰基烷基、(C1-C6)卤代烷基、-(C1-C6亚烷基)ORa、-C(O)Ra和-NRaRb,其中,Ra、Rb分别独立地表示氢或者C1-C6烷基;优选地,Y选自
在本发明的化合物中,A优选地选自-(C0-C6亚烷基)NRARB,其中,RA、RB一起和与之相连的原子共同环合形成5-7元环,并且该环还任选地具有0、1、2或3个选自O、N、S的杂原子,进一步地,该环还可以任意地被0、1、2或3个选自以下的取代基所取代:氧代、氰基、C1-C6烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、-ORa、-C(O)ORa、-(C1-C6)氰基烷基、(C1-C6)卤代烷基、-(C1-C6亚烷基)ORa、-C(O)Ra、-NRaRb、-(C1-C6亚烷基)NRaRb、-C(O)NRaRb、-(C1-C6亚烷基)C(O)NRaRb、-SO2Ra、-(C1-C6亚烷基)SO2Ra、-SO2NRaRb和-(C1-C6亚烷基)SO2NRaRb,其中Ra、Rb分别独立地表示氢或者C1-C6烷基。
在本发明的化合物中,A优选地选自:
更优选选自
在本发明的化合物中,A还可以表示
其中,Q表示:-(C0-C6亚烷基)-、-(C0-C6亚烷基)O-、-O(C0-C6亚烷基)-;
W6表示CH或N;
R4表示:-(C0-C6亚烷基)NRARB,
其中,RA、RB分别独立地表示氢或者被-ORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-SO2Ra、-C(O)NRaSO2Rb或者-NRaC(O)Rb所取代的C1-C6烷基;
R5表示氢、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)卤代烷基、卤素、-ORa、-C(O)ORa、(C1-C6)烷氧基、-NRaRb、-SO2Ra、氰基、硝基;
R6表示氢或者被以下取代基所取代的-O(C1-C6)烷基、-O(C0-C6亚烷基)(C6-C10芳基)或-O(C0-C6亚烷基)(5-10元杂芳基):-ORa、氰基、卤素、C1-C6烷基、-(C1-C6亚烷基)ORa、C1-C6氰基烷基、-C(O)ORa、-NRaRb、-C(O)NRaRb、SO2Ra、-C(O)NRaSO2Rb或者-NRaC(O)Rb,其中,Ra和Rb分别独立地表示氢或者C1-C6烷基;
q表示0、1、2或3。
在本发明的化合物中,R2优选地选自
更优选选自/>
在本发明的化合物中,W5优选地为CH。
在本发明的化合物中,Z1或Z2表示氢、卤素、氰基、C1-C6烷基;其中卤素优选为氯或者溴。
具体地,本发明提供了具有如下结构的化合物:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
除此之外,本发明还提供了一种药物组合物,其包含本发明所述的化合物,并且任选地进一步包含另外的治疗剂和/或免疫检查点抑制剂。本发明的药物组合物可以包含可药用载体。
除此之外,本发明还提供了本发明的化合物或者含有本发明化合物的药物组合物在制备用于治疗可通过抑制PD-L1与PD-1结合来治疗的疾病或病症的药物中的应用。优选地,所述疾病选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
本发明还提供了本发明化合物或者含有本发明化合物的药物组合物在制备用于治疗对抑制PD-L1与PD-1之结合有响应的疾病或病症的药物中的应用。优选地,所述疾病或病症选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
除此之外,本发明还提供了一种治疗可通过抑制PD-L1与PD-1结合来治疗的疾病或病症(优选肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病)的方法,其包括向有此需要的哺乳动物施用本发明的化合物或者本发明的药物组合物。
本发明还提供了一种治疗对抑制PD-L1与PD-1之结合有响应的疾病或病症的方法,其包括向有此需要的哺乳动物施用本发明的化合物或者本发明的药物组合物。术语“对抑制PD-L1与PD-1之结合有响应的疾病或病症”意指这样的任何疾病或病症:通过抑制PD-L1与PD-1之结合可改变疾病进程,或可导致疾病、病症、障碍等的缓和、抑制、消除和改善效果或者可预防这样的疾病或病症。优选地,所述对抑制PD-L1与PD-1之结合有响应的疾病或病症选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
本发明还提供了一种抑制PD-L1和PD-1结合的方法,其包括使本发明化合物或者本发明的药物组合物暴露于所述的PD-L1和/或PD-1。
在上述涉及本发明的化合物、药物组合物以及利用本发明化合物或药物组合物的用途和方法的实施方案中,所述的本发明化合物尤其包括其药学上可接受的盐的形式。
炎症性疾病、自身免疫性疾病和免疫介导性疾病的代表性实例可包括但不限于,关节炎、类风湿性关节炎、脊柱关节炎、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节炎性病症、狼疮、***性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、过敏性皮肤炎、疼痛、肺病、肺部炎症、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎症性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注损伤、炎性肠病、克罗恩病、溃疡性结肠炎、肠易激综合征、哮喘、干燥综合征、自身免疫甲状腺疾病、荨麻疹(风疹)、多发性硬化、硬皮症、器官移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔兹海默病、糖尿病相关疾病、炎症、***性疾病、过敏性鼻炎、过敏性支气管炎、过敏性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、毛细胞白血病、何杰金氏病、非何杰金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤。
癌症或肿瘤的代表性实例可包括但不限于,皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、***癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、***瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
当将本发明化合物或其可药用盐与另外的用于治疗癌症或肿瘤的治疗剂或免疫检查点抑制剂组合施用时,本发明化合物或其可药用盐可提供增强的抗癌作用。
用于治疗癌症或肿瘤的治疗剂的代表性实例可包括但不限于细胞信号转导抑制剂、苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、***、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib、阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗、PI3K抑制剂、CSF1R抑制剂、A2A和/或A2B受体拮抗剂、IDO抑制剂、抗PD-1抗体、LAG3抗体、TIM-3抗体及抗CTLA-4抗体或其任意组合。
当将本发明化合物或其可药用盐与另外的用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂组合施用时,本发明化合物或其可药用盐可提供增强的治疗作用。
用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂的代表性实例可包括但不限于,甾体药物(例如,强的松、氢化***、甲基氢化***、可的松、羟基可的松、倍他米松、***等)、甲氨蝶呤、来氟米特、抗TNFα剂(例如,依那西普、英夫利昔单抗、阿达利单抗等)、钙调神经磷酸酶抑制剂(例如,他克莫司、吡美莫司等)和抗组胺药(例如,苯海拉明、羟嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等),并且选自其中的至少一种治疗剂可包含于本发明药物组合物中。
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用,其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至2,000mg/kg体重/天、优选1至1,000mg/kg体重/天,并且每天以单次或4次分次剂量,或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用频率和医生意见)进行调整。在某些情况下,小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。
除此之外,本发明还提供了一种抑制PD-L1的方法,其包含使本发明的所述的化合物、其药学上可接受的盐或者本发明所述的药物组合暴露于所述的PD-L1。
术语定义:
特别注意的是,在本文中,当提及具有特定结构式的“化合物”时,一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物,以及作为其替代性存在形式的可药用盐、溶剂合物、水合物等形式。本领域技术人员公知,一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式,它们都可以在一定条件下转化为所述化合物,因此,特别注意的是在本文中当提到一种化合物时,一般地还包括它的可药用盐,进而还包括其溶剂合物和水合物。
相似地,在本文中当提到一种化合物时,一般地还包括其前药、代谢产物和氮氧化物。
本发明所述的可药用盐或药学上可接受的盐可使用无机酸或有机酸而形成,所述的“可药用盐”或“药学上可接受的盐”是指这样的盐:在合理的医学判断范围内,其适用于接触人和较低等动物的组织,而没有不适当的毒性、刺激性、过敏反应等,称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐,或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐,如下概述。例如,游离碱可以与合适的酸反应。此外,当本发明的化合物带有酸性部分时,其合适的可药用盐可包括金属盐,例如碱金属盐(如钠盐或钾盐)和碱土金属盐(如钙盐或镁盐)。可药用的无毒酸加成盐的示例是氨基与无机酸(例如,盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如,醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐,或通过使用现有技术中的其他方法如离子交换形成的盐。其他可药用盐包括己二酸盐、海藻酸钠、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、hernisulfate、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。其他可药用盐包括(适当时)无毒铵盐、季铵盐和用反离子形成的铵阳离子,例如,卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐。
本发明的可药用盐可通过常规方法制备,例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)中,向其中添加过量的有机酸或无机酸水溶液,以使得盐从所得混合物中沉淀,从中除去溶剂和剩余的游离酸,然后分离所沉淀的盐。
本发明所述的前体或代谢物可以本领域公知的前体或代谢物,只要所述的前体或代谢物通过体内代谢转化形成化合物即可。例如“前药”是指本发明化合物的那些前药,在合理的医学判断范围内,其适用于接触人和更低等动物的组织,而没有不适当的毒性、刺激性、过敏反应等,称得上合理的受益/风险比并且对其预期用途有效。术语“前药”是指在体内迅速经转化产生上述式的母体化合物的化合物,例如通过在体内代谢,或本发明化合物的N-去甲基化。
本发明所述的“溶剂合物”意指本发明化合物与一个或更多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中,例如当一个或更多个溶剂分子纳入结晶固体的晶格中时,溶剂合物将能够被分离。溶剂合物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
本发明所述的“立体异构”分为构象异构和构型异构,构型异构还可分为顺反异构和旋光异构(即光学异构)。构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象,常见的有烷烃和环烷烃类化合物的结构,如环己烷结构中出现的椅式构象和船式构象。“立体异构体”是指当本发明化合物含有一个或更多个不对称中心,因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物可以有不对称中心,每个不对称中心会产生两个光学异构体,本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物可以以互变异构体形式存在,其通过一个或更多个双键位移而具有不同的氢的连接点。例如,酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。所有式(I)化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等,均包括在本发明范围中。
本发明的“同位素衍生物”是指在本专利中化合物被同位素标记的分子。通常用作同位素标记的同位素是:氢同位素:2H和3H;碳同位素:11C,13C和14C;氯同位素:35Cl和37Cl;氟同位素:18F;碘同位素:123I和125I;氮同位素:13N和15N;氧同位素:15O,17O和18O和硫同位素35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘2H和碳13C,由于它们容易标记且方便检测,运用更为广泛。某些重同位素,比如重氢(2H),的取代能增强代谢的稳定性,延长半衰期从而达到减少剂量的目而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始,用已知的合成技术象合成非同位素标记的化合物一样来完成其合成。
可根据常规方法中的任何一种将本发明化合物或药物组合物配制成用于口服施用或肠胃外施用(包括肌内、静脉内和皮下途径、瘤内注射)的剂型,例如片剂、颗粒、粉末、胶囊、糖浆、乳剂、微乳剂、溶液或混悬液。
用于口服施用的本发明药物组合物可通过将活性成分与例如以下的载体混合来制备:纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、右旋糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、助悬剂、乳化剂和稀释剂。在本发明的注射组合物中采用的载体的实例是水、盐溶液、葡萄糖溶液、葡萄糖样溶液(glucose-like solution)、醇、二醇、醚(例如,聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂和乳化剂。
本发明描述示例性实施方案的过程中,本发明的其它特征将变得显而易见,给出所述实施方案用于说明本发明而不意欲成为其限制,以下实施例使用本发明所公开的方法制备、分离和表征。
在本发明的技术方案中,其中表示任意地连接位置,举例说明:例如对于A-R1-X片段,其中R1选自以下基团:/>时,该A-R1-X既可以表示/>也可以表示/>
如果无另外说明,用于本发明申请(包括说明书和权利要求书)中的术语定义如下。必须注意,在说明书和所附的权利要求书中,如果文中无另外清楚指示,单数形式“一个”包括复数意义。如果无另外说明,使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中,如果无另外说明,使用“或”或“和”指“和/或”。
在说明书和权利要求书中,给定化学式或名称应涵盖所有立体和光学异构体及其中存在上述异构体的外消旋物。除非另外指明,否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C=C双键、C=N双键、环***等的许多几何异构体,且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体,且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时,其可通过常规方法(例如通过色谱或分段结晶)进行分离。取决于方法条件,以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如果需要的话,则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐;可将盐转化成游离化合物或另一种盐;可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在,其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是,可存在的所有互变异构体形式均包括在本发明内。
除非另有定义,本发明的取代基的定义是各自独立而非互相关联的,例如对于取代基中Ra(或者Rb)而言,其在不同的取代基的定义中是各自独立的。具体而言,对于Ra(或者Rb)在一种取代基中选择一种定义时,并不意味着该Ra(或者Rb)在其他取代基中都具有该相同的定义。更具体而言,例如(仅列举非穷举)对于NRaRb中,当Ra(或者Rb)的定义选自氢时,其并不意味着在-C(O)-NRaRb中,Ra(或者Rb)必然为氢。
除非另有定义,否则当取代基被标注为“任选取代的”时,所述取代基选自例如以下取代基,诸如烷基、环烷基、芳基、杂环基、卤素、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基团(其中两个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、磺酰氨基例如-SO2NH2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH2、取代的氨基甲酰基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有两个选自烷基、芳基或芳基烷基的取代基的情况、烷氧基羰基、芳基、取代的芳基、胍基、杂环基,例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等和取代的杂环基。
本文使用的术语“烷基”或“亚烷基”意欲包括具有指定碳原子数的支链和直链饱和脂族烃基团。例如,“C1-C6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基。
术语“烯基”表示含一个或更多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如,“C2-C6烯基”含有两个至六个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。
术语“炔基”表示含一个或更多个三键且通常长度为2至20个碳原子的直链或支链的烃基。例如,“C2-C6炔基”含有两个至六个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基等。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C1-C6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5、C6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地,“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基;例如甲基-S-和乙基-S-。
术语“羰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C=O)。
术语“芳基”,单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分,是指具有总计5至12个环成员的单环、二环或三环的环***,其中所述***中的至少一个环为芳族的且其中所述***中的每个环含有3至7个环成员。在本发明的某些实施方案中,“芳基”是指芳族环***,其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基。非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。例从环***中画出的虚线表明键可连接至任意合适的环原子。
术语“环烷基”是指单环或二环的环状烷基。单环的环状烷基指C3-C8的环状烷基,包括但不限于环丙基、环丁基、环戊基、环己基和降莰烷基。支化环烷基诸如1-甲基环丙基和2-甲基环丙基包括在“环烷基”的定义中。二环的环状烷基包括桥环、螺环或融合环的环烷基。
术语“环烯基”是指单环或二环的环状烯基。单环的环状烯基指C3-C8的环状烯基,包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和降莰烯基。支化环烯基诸如1-甲基环丙烯基和2-甲基环丙烯基包括在“环烯基”的定义中。二环的环状烯基包括桥环、螺环或稠合环的环状烯基。
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括意欲包括具有指定碳原子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子的经氧桥连接的如上文所定义的卤代烷基。例如,“C1-C6卤代烷氧基”意欲包括C1、C2、C3、C4、C5、C6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地,“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的卤代烷基;例如三氟甲基-S-和五氟乙基-S-。
本公开内容中,当提到一些取代基团时使用Cx1-Cx2的表述,这表示所述取代基团中的碳原子数可以是x1至x2个。例如,C0-C8表示所述基团含有0、1、2、3、4、5、6、7或8个碳原子,C1-C8表示所述基团含有1、2、3、4、5、6、7或8个碳原子,C2-C8表示所述基团含有2、3、4、5、6、7或8个碳原子,C3-C8表示所述基团含有3、4、5、6、7或8个碳原子,C4-C8表示所述基团含有4、5、6、7或8个碳原子,C0-C6表示所述基团含有0、1、2、3、4、5或6个碳原子,C1-C6表示所述基团含有1、2、3、4、5或6个碳原子,C2-C6表示所述基团含有2、3、4、5或6个碳原子,C3-C6表示所述基团含有3、4、5或6个碳原子。
本公开内容中,当提到环状基团(例如芳基、杂芳基、环烷基和杂环烷基)时使用“x1-x2元环”的表述,这表示该基团的环原子数可以是x1至x2个。例如,所述3-12元环状基团可以是3、4、5、6、7、8、9、10、11或12元环,其环原子数可以是3、4、5、6、7、8、9、10、11或12个;3-6元环表示该环状基团可以是3、4、5或6元环,其环原子数可以是3、4、5或6个;3-8元环表示该环状基团可以是3、4、5、6、7或8元环,其环原子数可以是3、4、5、6、7或8个;3-9元环表示该环状基团可以是3、4、5、6、7、8或9元环,其环原子数可以是3、4、5、6、7、8或9个;4-7元环表示该环状基团可以是4、5、6或7元环,其环原子数可以是4、5、6或7个;5-8元环表示该环状基团可以是5、6、7或8元环,其环原子数可以是5、6、7或8个;5-12元环表示该环状基团可以是5、6、7、8、9、10、11或12元环,其环原子数可以是5、6、7、8、9、10、11或12个;6-12元环表示该环状基团可以是6、7、8、9、10、11或12元环,其环原子数可以是6、7、8、9、10、11或12个。所述环原子可以是碳原子或杂原子,例如选自N、O和S的杂原子。当所述环是杂环时,所述杂环可以含有1、2、3、4、5、6、7、8、9、10或更多个环杂原子,例如选自N、O和S的杂原子。
本发明内容中,一个或更多个卤素可以各自独立地选自氟、氯、溴和碘。
术语“杂芳基”意指稳定的3元、4元、5元、6元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元芳香多环杂环,其为完全不饱和的、部分不饱和的,且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子;且包括任何以下多环基团,其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR,其中R为H或如果被定义,则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的,则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地,当杂环中S和O原子的总数超过1时,则这些杂原子彼此不相邻。优选地,杂环中S和O原子的总数不大于1。当使用术语“杂环”时,其意欲包括杂芳基。芳杂基的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”与单环“杂芳基”所形成的联芳基结构,例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基”、“-吡啶基联苯基”、“-吡啶基联嘧啶基-”、“-嘧啶基联苯基-”;其中本发明还包括含有例如上述杂环的稠环和螺环化合物。
本文使用的术语“杂环烷基”指的是一个单环杂环烷基体系,或为一个二环杂环烷基体系,同时还包括螺杂环或桥杂环烷基。单环的杂环烷基指的是3-8元、且至少含一个选自O、N、S、P的杂原子的饱和或不饱和但不为芳香性的环状烷基体系。二环杂环烷基体系指的是一个杂环烷基与一个苯基、或一个环烷基、或一个环烯基、或一个杂环烷基、或一个杂芳基稠合。
本文使用的术语“桥环烷基”指的是共用两个或两个以上碳原子的多环化合物。可分为二环桥环烃及多环桥环烃。前者由两个脂环共用两个以上碳原子所构成;后者是由三个以上的环组成的桥环烃。
本文使用的术语“螺环烷基”指的是单环之间共用一个碳原子(称螺原子)的多环烃。
本文使用的术语“桥环杂基”指的是共用两个或两个以上碳原子的多环化合物,该环中至少含一个选自O、N、S原子。可分为二环桥环杂环及多环桥杂环。
本文使用的术语“杂螺环基”指的是单环之间共用一个碳原子(称螺原子)的多环烃,该环中至少含一个选自O、N、S的杂原子。
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代,条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原子之间形成的双键(例如C=C、C=N或N=N)。
在本发明化合物上存在氮原子(例如胺)的情形下,可通过使用氧化剂(例如mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此,所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物以获得本发明衍生物。
当任何变量在化合物的任何组成或式中出现一次以上时,其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此,例如如果显示基团取代有0-3个R,则所述基团可任选地取代有至多三个R基团,且在每次出现时R独立地选自R的定义。此外,取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、***、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外,术语“治疗有效量”意指这样的量:与未接受上述量的相应受试者相比,所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用,或降低在疾病或病症的进展速度。有效量可以一个或更多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。
本文使用的术语“治疗”包括其广义上的含义,涵盖对对象的治疗性处理和/或预防性处理。具体而言,所述“治疗”包括导致病症、疾病、障碍等的缓和、抑制、消除和改善和/或预防的任何处理,例如减轻、减少、调节、改善、消除、预防、防止或改善其症状。所述治疗性处理包括缓和、抑制或改善疾病的症状或状况;抑制并发症的产生;改善潜在代谢综合征;抑制疾病或症状的产生,如控制疾病或情况的发展;减轻疾病或症状;使疾病或症状减退;减轻由疾病或症状引起的并发症,或治疗由疾病或症状引起的征兆。所述预防性处理包括事先处理以防止、阻断或延迟、减缓疾病或病症的发生或发展或者减弱疾病或病症的严重程度。
同样,“治疗剂”也包括对对象具有治疗性处理和/或预防性处理的药剂或试剂。
术语“药用”或“药学上可接受的”在本文中用于指如下那些化合物、物质、组合物和/或剂型:在合理医学判断的范围内,其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症,并与合理的益处/风险比相称。
特定药学及医学术语
术语“癌症”,如本文所用,指一种不能控制的细胞的异常生长,并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于,实体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、***、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。
术语“联合给药”或其类似术语,如本文所用,指将几种所选的治疗药物给一个病人用药,以相同或不同的给药方式在相同或不同的时间给药。
术语“增强”或“能增强”,如本文所用,指预期的结果能够在效价或是持续时间方面都有增加或延长。因此,在增强药物的治疗效果方面,术语“能增强”指药物在***中有提高或延长效价或持续时间的能力。本文所用的“增效值”,指在理想的***中,能够最大限度地的增强另外一个治疗药物的能力。
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。
术语“试剂盒”与“产品包装”是同义词。
术语“对象”、“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于,哺乳类:人、非人灵长类如猩猩、猿及猴类;农业动物如牛、马、山羊、绵羊、猪;家畜如兔、狗;实验动物包括啮齿类,如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于,鸟、鱼等。在一优选例中,所选哺乳动物是人。
如本文所用,某一化合物或药物组合物,给药后,可以使某一疾病、症状或情况得到改善,尤指其严重度得到改善,延迟发病,减缓病情进展,或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药,可以归因于或与给药有关的情况。
给药途径
适合的给药途径包括但不限于,口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、***给药、耳道给药、鼻腔给药及局部给药。此外,仅作举例说明,肠道外给药,包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、***内注射、及鼻内注射。
本发明化合物给药方式可以是局部的给药方式。在特定的具体实施例中,长效制剂通过植入给药(例如皮下或肌肉)或通过肌肉注射。此外,在另一具体化实施例中,药物通过靶向药物给药***来给药。例如,由器官特异性抗体包裹的脂质体。在这种具体实施例中,所述脂质体被选择性的导向特定器官并吸收。
药物组合物和剂量
本文使用的短语“可药用载体”意指药用物质、组合物或媒介物,诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质,其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。
术语“药物组合物”意指包含本发明化合物与任选的其它可药用载体的组合物。“可药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质,包括(即)佐剂、赋形剂或媒介物,诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂,这取决于给药模式和剂型的性质。
本发明的药用组合物可包含治疗有效量的与任选的一种或多种可药用载体(添加剂)和/或稀释剂一起配制的一种或多种本发明的化合物,以及任选的一种或多种其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途,例如口服,诸如片剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液;经舌下;含服;经肠胃外,诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式);经鼻,包括向鼻膜给药,诸如通过吸入喷雾;局部,诸如以乳膏剂或软膏剂形式;或经直肠,诸如以栓剂形式;或经瘤内注射。它们可单独给药,但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。
根据本领域技术人员认识范围内的诸多因素来调配可药用载体。这些因素包括,但不限于:所调配活性剂的类型和性质;含有活性剂的组合物所要给药的受试者;组合物的预期给药途径;及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体剂型。
上述载体可包括除活性剂外的诸多不同成分和添加剂,上述其它成分出于本领域技术人员公知的各种原因包括于制剂中,例如稳定活性剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源,例如Allen L.V.Jr.etal.Remington:The Science and Practice of Pharmacy(2Volumes),22nd Edition(2012),Pharmaceutical Press。
当然,本发明化合物的剂量方案取决于已知因素而有所变化,诸如具体药剂的药效学特性及其给药模式和途径;接受者的物种、年龄、性别、健康状况、医学病状和重量;症状的性质和程度;同时治疗的种类;治疗频率;给药途径、患者的肾和肝功能及期望效应。根据一般指导,当用于指定效应时,各活性成分的日口服剂量应为约0.001mg/天至约10-5000mg/天,优选地为约0.01mg/天至约1000mg/天,且最优选地为约0.1mg/天至约250mg/天。在恒速输注期间,静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日剂量给药,或可以每日两次、三次或四次的分开剂量给药总日剂量。
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。
适于给药的剂型(药物组合物)可含有约1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中,以组合物的总重量计,活性成分通常将以约0.1-95重量%的量存在。
用于口服给药的典型胶囊剂含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使该混合物穿过60目网筛,并包装成1号明胶胶囊。
典型的可注射制剂可如下制备:以无菌方式将至少一种本发明化合物(250mg)置于瓶中、以无菌方式冻干并密封。为进行使用,将瓶内容物与2mL生理盐水混合,以产生可注射制剂。
本发明范围包括(单独或与可药物载体组合)包含治疗有效量的至少一种本发明化合物作为活性成分的药物组合物。任选地,本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。
不考虑所选择的给药路径,通过本领域技术人员已知的常规方法来将本发的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。
可改变活性成分在本发明的药物组合物中的实际剂量水平,从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。
选定的剂量水平会取决于多种因素,包括所用的本发明的特定化合物或其酯、盐或酰胺的活性;给药路径;给药时间;所用的特定化合物的***速率;吸收速率和程度;治疗的持续时间;与所用的特定化合物组合使用的其它药物、化合物和/或物质;所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如,为了达到所期望的治疗效果,医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量,并逐步增加剂量直至实现所期望的效果。通常,合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常,口服、静脉内、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约50mg/kg体重/天。如果需要的话,有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药,任选地呈单位剂型形式。在本发明的某些方面中,服药为每天一次给药。
虽然本发明化合物可单独给药,但优选以药物制剂(组合物)形式给予化合物。
试剂盒/产品包装
为了用于上述适应症的治疗,试剂盒/产品包装也在此进行描述。这些试剂盒可以由输送器、药包或容器盒组成,容器盒可被划分成多格,以容纳一种或多种容器,如管形瓶、试管及类似物等,每个容器中包含所述方法中的单独一种成分。合适的容器包括瓶子,管形瓶,注射器和试管等。容器由可接受的玻璃或塑料等材料制作而成。
举例来讲,容器可装有一种或多种在此所述的化合物,化合物可能以药物组分形式存在,也可能与在本文中所述的其它成分组成混合物体存在。容器可有一个无菌输出口(例如容器可为静脉输液包或瓶,瓶塞可被皮下注射器针头刺破)。这样的试剂盒可带有一种化合物,及本文中所述的使用方法的说明、标签或操作说明。
一个典型的试剂盒可包括一种或多种容器,为适应商业推广和使用者对化合物使用的需求,每个容器装有一种或多种材料(如试剂,也可以是浓缩的母液,和/或器械)。这些材料包括但不局限于缓冲液,稀释液,滤器,针头,注射器,输送器,包,容器,瓶和/或试管,附有内容清单和/或使用说明书,内置包装也附有说明书。整套的说明都要包括在内。
标签可显示在容器上或与容器紧密相关。标签出现在容器上即指标签字母、数字或其它特征被粘贴、铸模、刻在容器上;标签也可出现在装有多种容器的容器盒或运输盒内,如在产品插页中。一个标签可用来提示内容物的某种特定治疗用途。标签也可标示内容物使用说明,诸如在上述方法中描述的。
在本说明书中被描述的所有特征(包括任何所述的权利要求、摘要和图),和/或任何方法或过程中涉及的所有步骤,均有可能以任意一种组合存在,除非某些特征或步骤在同一组合中是相互排斥的。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的,例如是指在100毫升的溶液中溶质的重量。除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
具体实施例:
本发明中一些中间体的合成方法如下:
中间体I1:
中间体I1的合成路线如下:
第一步:将2-溴-3-甲基苯胺(31.5g,169.32mmol)加入到浓盐酸(100mL)中,室温下搅拌20分钟,向体系中加入250g碎冰。冰浴下缓慢加入亚硝酸钠(26.25g,380.43mmol),控制反应液温度低于5℃。加完后保持冰浴搅拌1小时,之后冰浴下缓慢加入碘化钾(112.89g,679.99mmol)。反应液持续搅拌2小时,缓慢升至室温,之后60℃下搅拌1小时。反应液冷却至室温,用200mL亚硫酸氢钠溶液淬灭,用石油醚(3x200mL)萃取,合并有机相,用200mL饱和碳酸氢钠洗一次,再用150mL饱和食盐水洗一次。有机相用无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到2-溴-3-甲基碘苯(36.0g,121.23mmol),淡黄色液体,收率71.6%。
第二步:将2-溴-3-甲基碘苯(33.0g,111.14mmol)溶于四氯化碳(400mL),加入N-溴代丁二酰亚胺(39.6g,222.27mmol)和过氧苯甲酰(5.0g,20.66mmol)。反应混合物在氮气氛围下回流过夜。然后过滤,浓缩滤液,粗产品用快速过柱机分离得到2-溴-3-溴甲基碘苯(28.0g,74.50mmol),淡黄色液体,收率67.0%。
第三步:将2-溴-3-溴甲基碘苯(14.0g,37.25mmol)和5-氯-2,4-二羟基苯甲醛(6.43g,37.25mmol)溶于乙腈(150mL)中,加入碳酸氢钠(10.0g,119.05mmol)。反应混合物搅拌回流过夜。将反应液冷却至室温,搅拌下加入150mL水,持续搅拌20分钟,过滤,滤饼用20mL水洗涤三次,干燥,得到中间体I1(17.0g,36.36mmol),白色固体,收率97.6%。MS(ESI):m/z 464.9(M-H)-.
中间体I2:
中间体I2的合成路线如下:
MP2021719P
将中间体I1(1.3g,3.68mmol)加入到甲醇(10mL)中,加入原甲酸三甲酯(1.96g,18.42mmol)和对甲苯磺酸(31.73mg,0.184mmol),反应混合物在50℃下搅拌过夜。直接浓缩反应液,将残留物溶于N,N-二甲基甲酰胺(10mL)中,加入碳酸钾(1.53g,11.05mmol),碘化钾(61.17mg,0.368mmol)和4-氯甲基-2-氰基吡啶(1.3g,3.68mmol),反应混合物在70℃下搅拌6小时。将反应液冷却至室温,加入4mol/L盐酸(5mL),持续搅拌20分钟,过滤,滤饼10mL用水洗三次,用10mL乙酸乙酯洗两次,干燥,得到中间体I2(0.97g,2.07mmol),淡黄色固体,收率56.1%。MS(ESI):m/z 583.3(M+H)+.
中间体I3:
中间体I3的合成路线如下:
将中间体I1(10.5g,29.53mmol)溶于N,N-二甲基甲酰胺(100mL),加入碳酸钾(12.24g,88.58mmol),碘化钾(0.49g,2.95mmol)和5-氯甲基-3-氰基吡啶(5.41g,35.43mmol),反应混合物在70℃下搅拌6小时。将反应液冷却至室温,加入100mL水,持续搅拌20分钟,过滤,滤饼用50mL水洗三次,用20mL乙酸乙酯洗两次,干燥,得到中间体I3(13.0g,27.56mmol),淡黄色固体,收率93.3%。MS(ESI):m/z 583.3(M+H)+.
中间体I4:
/>
中间体I4的合成路线如下:
第一步:将3-溴-2-甲基苯甲醇(10.0g,50.00mmol)溶于二氯甲烷(100mL)中,加入4mol/L盐酸二氧六环溶液(1.25mL,5.00mmol),冰浴下加入氯化亚砜(11.8g,100.00mmol)。反应混合物在50℃下搅拌3小时。反应液直接浓缩,残留物用快速过柱机分离得到3-氯甲基-2-甲基溴苯(10.05g,46.10mmol),淡黄色固体,产率92.2%。
第二步:将3-氯甲基-2-甲基溴苯(10.05g,46.10mmol)和5-氯-2,4-二羟基苯甲醛(7.93g,46.10mmol)溶于乙腈(200mL)中,加入碳酸氢钠(11.62g,119.05mmol)。反应混合物搅拌回流过夜。将反应液冷却至室温,搅拌下加入200mL水,持续搅拌20分钟,过滤,滤饼用20mL水洗涤三次,用20mL乙酸乙酯洗涤两次,干燥,得到中间体I4(14.71g,41.56mmol),白色固体,收率90.2%。MS(ESI):m/z353.2(M-H)-.
中间体I5:
中间体I5的合成路线如下:
将中间体I4(10.0g,28.25mmol)溶于N,N-二甲基甲酰胺(100mL),加入碳酸钾(11.7g,84.75mmol),碘化钾(0.47g,2.83mmol)和5-氯甲基-3-氰基吡啶(5.15g,33.90mmol),反应混合物在70℃下搅拌6小时。将反应液冷却至室温,加入100mL水,持续搅拌20分钟,过滤,滤饼用50mL水洗三次,用20mL乙酸乙酯洗两次,干燥,得到中间体I5(12.4g,26.45mmol),淡黄色固体,收率93.6%。MS(ESI):m/z 471.2(M+H)+.
中间体I6:
中间体I6的合成路线如下:
第一步:将1-溴-3-氯丙烷(5.99g,38.06mmol)和4-溴-1H-吲唑(5.0g,25.38mmol)溶于乙腈(50mL)中,加入碳酸钾(7.01g,50.75mmol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,过滤,浓缩。残留物用快速过柱机分离得到4-溴-1-(4-氯丙基)-1H-吲唑(3.0g,10.97mmol),淡黄色液体,收率43.2%。MS(ESI):m/z 273.4(M+H)+.
第二步:将4-溴-1-(4-氯丙基)-1H-吲唑(1.5g,5.48mmol)和(R)-3-羟基吡咯烷(955.42mg,10.97mmol)溶于乙腈(20mL)中,加入碳酸钾(3.03g,21.93mmol)和碘化钾(0.25g,1.48mmol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,过滤,滤液浓缩后加入50mL乙酸乙酯,用20mL水洗三次,再用20mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。得到(R)-1-(4-(4-溴-1H-吲唑-1-基)丙基)吡咯烷-3-醇(1.78g,5.49mmol),淡黄色液体,收率100%。MS(ESI):m/z 324.4(M+H)+.
第三步:将(R)-1-(4-(4-溴-1H-吲唑-1-基)丙基)吡咯烷-3-醇(1.78g,5.49mmol)和双联硼酸频那醇酯(2.09g,8.24mmol)溶于1,4-二氧六环(20mL)中,加入醋酸钾(1.62g,16.47mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(401.72mg,0.549mmol)。反应混合物在氮气氛围下90℃搅拌过夜。将反应液冷却至室温,加入100mL乙酸乙酯,经硅藻土过滤,滤液用50mL水洗三次,50mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到中间体I6(1.38g,3.74mmol),淡黄色液体,收率68.1%。MS(ESI):m/z372.4(M+H)+.中间体I7~I17:
/>
中间体I7~I17的合成方法同中间体I6。
中间体I18:
中间体I18的合成路线如下:
第一步:将1,4-二氧杂螺环[4,5]癸基-8-甲磺酸酯(7.5g,31.74mmol)和4-溴-1H-吲唑(4.17g,21.16mmol)溶于N,N-二甲基甲酰胺(60mL)中,加入碳酸钾(5.85g,42.32mmol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,加入400mL乙酸乙酯,用100mL水洗涤三次,100mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I18-a(2.5g,7.41mmol),无色油状液体,收率35.0%。MS(ESI):m/z337.4(M+H)+.
第二步:将化合物I18-a(2.3g,6.82mmol)溶于四氢呋喃(10mL)中,加入4.0mol/L盐酸(10mL),室温下搅拌2小时。反应混合物用饱和碳酸氢钠调节pH值到7左右,减压除去四氢呋喃,用20mL乙酸乙酯萃取三次,有机相用20mL水洗一次,20mL饱和食盐水洗一次,无水硫酸钠干燥,浓缩得到化合物I18-b(1.6g,5.46mmol),白色固体,收率80.0%。MS(ESI):m/z293.5(M+H)+.
第三步:将化合物I18-b(150mg,511.67umol)和(R)-3-羟基吡咯烷(89.15mg,1.02mmol)溶于1,2-二氯乙烷(5mL)中,加入乙酸(0.05mL)。反应混合物于25℃下搅拌1小时,之后加入三乙酰氧基硼氢化钠(325.33mg,1.54mmol),室温搅拌过夜。向反应液中加入20mL水,用20mL二氯甲烷萃取两次,合并有机相,用20mL水洗一次,20mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I18-c(150mg,411.77umol),淡黄色液体,收率80.5%。MS(ESI):m/z 364.5(M+H)+.
第四步:将化合物I18-c(1.3g,3.57mmol)和双联硼酸频那醇酯(1.36g,5.35mmol)溶于1,4-二氧六环(15mL),加入醋酸钾(1.05g,10.71mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(261.12mg,0.36mmol)。反应混合物在氮气氛围下90℃搅拌过夜。将反应液冷却至室温,加入80mL乙酸乙酯,经硅藻土过滤,滤液用30mL水洗三次,30mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到中间体I18(1.0g,2.43mmol),淡黄色液体,收率68.1%。MS(ESI):m/z 412.3(M+H)+.
中间体I19:
中间体I19的合成路线如下:
第一步:将4-((甲基磺酰基)氧基)哌啶-1-甲酸叔丁酯(6.38g,22.84mmol)和4-溴-1H-吲唑(3.0g,15.23mmol)溶于N,N-二甲基甲酰胺(40mL)中,加入碳酸钾(6.31g,45.68mmol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,加入100mL乙酸乙酯,用50mL水洗涤三次,50mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I-19a(3.2g,8.41mmol),无色液体,收率55.3%。MS(ESI):m/z 380.6(M+H)+.
第二步:将化合物I-19a(3.2g,8.41mmol)溶于1,4-二氧六环(10mL)中,加入4.0mol/L盐酸1,4-二氧六环溶液(10mL),室温下搅拌2小时。反应浓缩得到化合物I-19b(2.6g,8.41mmol),白色固体,收率100%。MS(ESI):m/z 280.6(M+H)+.
第三步:将化合物I-19b(1.2g,4.28mmol)和2,2-二甲基-1,3-二氧六环-5-酮(668.91mg,5.14mmol)溶于1,2-二氯乙烷(10mL)中,加入乙酸钾(1.26g,12.85mmol)。反应混合物于25℃下搅拌1小时,之后加入三乙酰氧基硼氢化钠(2.72g,12.85mmol),室温搅拌过夜。向反应液中加入20mL水,用20mL二氯甲烷萃取两次,合并有机相,用20mL水洗一次,20mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I-19c(1.1g,2.79mmol),淡黄色液体,收率65.1%。MS(ESI):m/z 394.4(M+H)+.
第四步:将化合物I-19c(1.1g,2.79mmol)和双联硼酸频那醇酯(1.06g,4.18mmol)溶于1,4-二氧六环(10mL)中,加入醋酸钾(821.35mg,8.37mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(127mg,0.17mmol)。反应混合物在氮气氛围下90℃搅拌过夜。将反应液冷却至室温,加入70mL乙酸乙酯,经硅藻土过滤,滤液用20mL水洗三次,20mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I-19(900mg,2.04mmol),淡黄色液体,收率73.1%。MS(ESI):m/z 442.6(M+H)+.
中间体I20和I21:
/>
中间体I20和I21的合成路线如下:
第一步:将1,4-二氧杂螺环[4,5]癸基-8-甲基甲磺酸酯(7.93g,31.74mmol)和4-溴-1H-吲唑(4.17g,21.16mmol)溶于N,N-二甲基甲酰胺(60mL)中,加入碳酸钾(5.85g,42.32mmol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,加入100mL乙酸乙酯,用50mL水洗涤三次,50mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I20-a(3.16g,9.03mmol),无色液体,收率42.7%。MS(ESI):m/z 351.4(M+H)+.
第二步:将化合物I20-a(3.16g,9.03mmol)溶于四氢呋喃(10mL),加入4.0mol/L盐酸(10mL),室温下搅拌2小时。反应混合物用饱和碳酸氢钠调节pH值到7左右,减压除去四氢呋喃,用50mL乙酸乙酯萃取三次,有机相用50mL水洗一次,50mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩得到化合物I20-b(2.76g,9.03mmol),白色固体,收率100%。MS(ESI):m/z 307.6(M+H)+.
第三步:将化合物I20-b(2.5g,8.14mmol)和(R)-3-羟基吡咯烷(1.06g,12.21mmol)溶于1,2-二氯乙烷(20mL),加入乙酸(1.47g,24.42mmol)。反应混合物于25℃下搅拌1小时,之后加入三乙酰氧基硼氢化钠(5.17g,24.42mmol),室温搅拌过夜。向反应液中加入水,用20mL二氯甲烷萃取两次,合并有机相,用20mL水洗一次,20mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I20-c(1.63g,4.32mmol),淡黄色液体,收率53.1%;I21-c(1.14g,3.02mmol),淡黄色液体,收率37.1%。MS(ESI):m/z378.7(M+H)+.
第四步:将化合物I20-c(1.63g,4.32mmol)和双联硼酸频那醇酯(2.19g,8.64mmol)溶于1,4-二氧六环(20mL),加入醋酸钾(1.27g,12.96mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(163mg,0.22mmol)。反应混合物在氮气氛围下90℃搅拌过夜。将反应液冷却至室温,加入50mL乙酸乙酯,经硅藻土过滤,滤液用20mL水洗三次,20mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I20(1.30g,3.05mmol),淡黄色液体,收率70.6%。MS(ESI):m/z 426.7(M+H)+.用同样的方法可得到化合物I21(1.02g,2.40mmol),淡黄色油状液体,收率79.5%。MS(ESI):m/z426.7(M+H)+.
中间体I22:
中间体I22的合成路线如下:
第一步:将1-溴-3-氯丙烷(101.01g,641.60mmol)和3-溴-2-甲基苯酚(80.0g,427.73mmol)溶于乙腈(800mL)中,加入碳酸钾(177.35g,1.28mol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,过滤,滤液浓缩后得到1-溴-3-(3-氯丙基)-2-甲基苯(112.5g,427.73mmol),淡黄色液体,收率100%。
第二步:将化合物1-溴-3-(3-氯丙基)-2-甲基苯(110g,417.37mmol)和(R)-3-羟基吡咯烷(54.54g,626.05mmol)溶于乙腈(1500mL)中,加入碳酸钾(173.05g,1.25mol)和碘化钾(6.93g,41.74mmol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,过滤,滤液浓缩后加入1000mL乙酸乙酯,用200mL水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤浓缩得到(R)-1-(3-(3-溴-2-甲基苯氧基)丙基)吡咯烷-3-醇(130.0g,413.73mmol),淡黄色液体,收率99.1%。MS(ESI):m/z 314.6(M+H)+.
第三步:将(R)-1-(3-(3-溴-2-甲基苯氧基)丙基)吡咯烷-3-醇(130.0g,413.73mmol)和双联硼酸频那醇酯(157.59g,620.59mmol)溶于1,4-二氧六环(500mL)中,加入醋酸钾(104.26g,1.24mol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(15.14g,20.69mmol)。反应混合物在氮气氛围下90℃搅拌过夜。将反应液冷却至室温,加入500mL乙酸乙酯,经硅藻土过滤,滤液用100mL水洗三次,100mL饱和食盐水洗一次次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到中间体I22(63.7g,176.32mmol),淡黄色液体,收率42.6%。MS(ESI):m/z362.6(M+H)+.
中间体I23:
中间体I23的合成路线同中间体I22。
中间体I24:
中间体I24的合成路线如下:
第一步:将中间体I1(2.0g,4.28mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(1.39g,6.42mmol)和醋酸(256.91mg,4.28mmol),反应混合物在25℃下搅拌过夜之后,再加入三乙酰氧基硼氢化钠(906.73mg,4.28mmol),继续搅拌3小时,加水淬灭,用50mL乙酸乙酯萃取三次,合并有机相,用30mL水洗两次,30mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I24-a(2.8g,4.19mmol),白色固体,收率97.9%。MS(ESI):m/z 668.6(M+H)+.
第二步:将化合物I24-a(2.8g,4.19mmol)溶于二氯甲烷(20mL)中,冰浴下加入二碳酸二叔丁酯(1.01g,4.61mmol,1.06mL),反应混合物缓慢升至室温并持续搅拌过夜。反应液加入50mL二氯甲烷,用20mL水洗两次,20mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I24(3.0g,3.90mmol),白色固体,收率93.2%。MS(ESI):m/z 768.4(M+H)+.
中间体I25:
/>
中间体I25的合成路线如下:
第一步:将中间体I24(1.0g,1.30mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入溴乙酸甲酯(298.43mg,1.95mmol)和碳酸钾(539.25mg,3.90mmol),反应混合物在50℃下搅拌6小时,加入60mL乙酸乙酯,用20mL水洗三次,20mL饱和食盐水洗一次,干燥,过滤,滤液浓缩得到化合物I25-a(1.09g,1.30mmol),淡黄色液体,收率100%。MS(ESI):m/z 840.4(M+H)+.
第二步:将化合物I25-a(1.09g,1.30mmol)溶于四氢呋喃(4mL),甲醇(4mL)和水(4mL)的混合溶剂中,加入氢氧化锂(108.88mg,2.59mmol),反应混合物在25℃下搅拌3小时。反应液用饱和柠檬酸调节至酸性,用30mL乙酸乙酯萃取三次,合并有机相,用30mL水洗两次,30mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩得到中间体I25(1.0g,1.21mmol),淡黄色液体,收率93.3%。MS(ESI):m/z826.5(M+H)+.
中间体I26:
中间体I26的合成路线如下:
第一步:将2-氯-5-羟基苯甲酸(29.0g,168.05mmol)溶于四氢呋喃(100mL)中,在氮气氛围和冰浴下滴加1.0mol/L硼烷四氢呋喃溶液(336.10mL,336.10mmol)。滴加完毕,反应液升至室温搅拌16小时。TLC(PE:EA=4:1,Rf=0.2)检测原料消耗完全,冰浴下向反应液中滴加甲醇淬灭反应,直至不再有气泡冒出。浓缩溶剂得到化合物I26-a(26.6g,167.74mmol),淡黄色固体,收率99.8%。1H NMR(500MHz,d6-DMSO)δ9.59(s,1H),7.15(d,J=8.5Hz,1H),6.99(d,J=3.0Hz,1H),6.64(dd,J=8.5,3.0Hz,1H),5.32(t,J=6.0Hz,1H),4.47(d,J=6.0Hz,2H).
第二步:将化合物I26-a(26.6g,167.74mmol)和咪唑(11.53g,169.41mmol)溶于二氯甲烷(300mL)中,在0℃条件下分批加入TBSCl(25.53g,169.41mmol,29.35mL)的二氯甲烷(100mL)溶液。混合物升温至30℃搅拌16小时。用50mL水淬灭反应,水相用二氯甲烷萃取(100mL x 2)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到I26-b(33.4g,122.79mmol),淡黄色液体,收率73.0%。1H NMR(500MHz,d6-DMSO)δ9.66(s,1H),7.17(d,J=8.5Hz,1H),6.97(s,1H),6.67(d,J=8.5Hz,1H),4.66(s,2H),0.93(s,9H),0.11(s,6H).
第三步:将I26-b(8.0g,29.32mmol)溶于乙腈(100mL)中,加入三乙胺(14.83g,146.60mmol),接着加入氯化镁(5.58g,58.64mmol)和多聚甲醛(8.80g,293.21mmol)。混合物在氮气氛围下加热至90℃剧烈搅拌20小时。向反应液中加入100mL水稀释,用饱和柠檬酸水溶液调节pH=3-4,然后用乙酸乙酯萃取(2x200mL)。合并有机相,用100mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到I26-c(5.0g,16.67mmol),白色固体,收率56.7%。1H NMR(500MHz,d6-DMSO)δ10.97(s,1H),10.23(s,1H),7.58(s,1H),7.25(s,1H),4.72(s,2H),0.96(s,9H),0.14(s,6H).
第四步:将5-氯甲基-3-氰基吡啶盐酸盐(3.2g,16.95mmol)溶于N,N-二甲基甲酰胺(40mL)中,在冰浴下加入N,N-二异丙基乙胺(5.48g,42.38mmol)和碳酸钾(5.86g,42.38mmol)。搅拌10分钟后加入I26-c(4.25g,14.13mmol)和碘化钾(234.50mg,1.41mmol)。混合物在冰浴下搅拌30分钟,然后升至50℃搅拌16小时。将反应液在冰浴下冷却,加入100mL水稀释直至不再有固体析出,过滤固体,用水洗涤,干燥,然后用快速过柱机分离得到I26-d(5.0g,11.99mmol),白色固体,收率84.9%。MS(ESI):m/z 417.2(M+H)+.
第五步:将I26-d(5.0g,11.99mmol)溶于甲苯(10mL)中,加入乙二醇(14.89g,239.82mmol,13.29mL)和对甲苯磺酸(228.09mg,1.20mmol)。然后滴加原甲酸三甲酯(2.55g,23.98mmol,2.62mL)。混合物在氮气氛围下加热至80℃搅拌16小时。反应液在冰浴下冷却,用30mL饱和碳酸氢钠水溶液淬灭,用30mL水稀释,水溶液用乙酸乙酯萃取(2x50mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到I26-e(5.5g,11.93mmol),白色固体,收率99.5%。MS(ESI):m/z 461.2(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.99(d,J=2.0Hz,1H),8.91(d,J=2.0Hz,1H),8.37(s,1H),7.39(s,1H),7.15(s,1H),6.06(s,1H),5.30(s,2H),4.68(s,2H),4.04–4.01(m,2H),3.94–3.91(m,2H),0.87(s,9H),0.06(s,6H).
第六步:将I26-e(2.2g,4.77mmol)溶于四氢呋喃(10mL)中,加入1mol/L四丁基氟化铵的四氢呋喃溶液(7.16mL,7.16mmol),反应液在30℃搅拌半小时。用10mL水稀释,水溶液用乙酸乙酯萃取(2x50mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用乙酸乙酯和石油醚混合液(3%EA,20mL)打浆,过滤得到I26-f(1.58g,4.57mmol),淡黄色固体,收率95.5%。MS(ESI):m/z347.2(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.00(d,J=2.0Hz,1H),8.96(d,J=2.0Hz,1H),8.40(d,J=2.0Hz,1H),7.37(s,1H),7.30(s,1H),6.05(s,1H),5.51(t,J=5.5Hz,1H),5.28(s,2H),4.53(d,J=5.5Hz,2H),4.03–4.0(m,2H),3.93–3.90(m,2H).
第七步:将I26-f(1.5g,4.33mmol)溶于二氯甲烷(30mL)中,加入N,N-二异丙基乙胺(1.68g,12.98mmol,2.26mL),在0℃氮气氛围下加入甲磺酸酐(1.51g,8.65mmol)。然后加入N,N-二异丙基乙胺(1.68g,12.98mmol,2.26mL)和盐酸二氧六环(4M,1.62mL)的二氯甲烷(10mL)混合液。反应液在25℃搅拌16小时。用20mL水淬灭反应,水溶液用二氯甲烷萃取(2x50mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到I26-g(1.4g,3.85mmol),淡黄色固体,收率88.6%。MS(ESI):m/z365.2(M+H)+.
第八步:将I26-g(1.36g,3.72mmol),4-溴-1H-吲唑(733.72mg,3.72mmol)和碳酸钾(1.03g,7.45mmol)溶于N,N-二甲基甲酰胺(20mL)中。混合物在50℃下搅拌16小时。反应液在冰浴下冷却,用水稀释直至固体不再析出,过滤,用水洗涤,干燥,再用快速过柱机分离得到中间体I26(1.08g,2.06mmol),淡黄色固体,收率55.2%。MS(ESI):m/z 525.0(M+H)+.1HNMR(500MHz,d6-DMSO)δ8.96(d,J=2.0Hz,1H),8.82(s,1H),8.27(s,1H),8.05(s,1H),7.70(d,J=8.5Hz,1H),7.45(s,1H),7.40(d,J=7.5Hz,1H),7.32(t,J=7.5Hz,1H),6.91(s,1H),6.04(s,1H),5.71(s,2H),5.16(s,2H),4.04–4.01(m,2H),3.97–3.89(m,2H).
中间体I27:
中间体I27的合成路线如下:
将中间体I26(0.1g,190.19umol)溶于四氢呋喃(5mL)中,加入4.0mol/L盐酸水溶液(1mL)。混合物在30℃下搅拌1小时。然后用10mL饱和碳酸氢钠水溶液中和,用10mL水稀释,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用10mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到化合物I27(0.09g,186.83umol),淡黄色固体,收率98.2%。MS(ESI):m/z481.0(M+H)+.
中间体I28:
中间体I28的合成方法与中间体I27相似,只是在I26的合成方法中用碘甲烷替代5-氯甲基-3-氰基吡啶盐酸盐,然后将由此得到的中间体按I27的合成方法进行同样水解处理。
中间体I29:
中间体I29的合成路线如下:
将中间体I26(1.0g,912.93umol),联硼酸频那醇酯(695.48mg,2.74mmol),醋酸钾(537.58mg,5.48mmol)和Pd(dppf)Cl2(66.80mg,91.29umol)混合于二氧六环(20mL)中。混合物在氮气氛围下加热至100℃搅拌16小时。待反应液冷却至室温,用50mL乙酸乙酯稀释,硅藻土过滤,在用50mL乙酸乙酯洗涤,浓缩滤液。残留物用快速过柱机分离得到中间体I29(0.28g,489.51umol),淡黄色固体,收率53.5%。MS(ESI):m/z 573.2(M+H)+.
中间体I30:
中间体I30的合成路线如下:
第一步:将4-氯-3-羟基苯甲酸(5.5g,31.87mmol)溶于四氢呋喃(50mL)中,在氮气氛围和冰浴下滴加1.0mol/L硼烷四氢呋喃溶液(63.74mL,63.74mmol)。滴加完毕,反应液升至室温搅拌过夜。用30mL甲醇淬灭反应,浓缩溶剂,残留物用快速过柱机分离得到化合物I30-a(4.7g,29.75mmol),白色固体,收率93.0%。MS(ESI):m/z 157.1(M-H)-.
第二步:将化合物I30-a(1.0g,6.31mmol)溶于乙腈(20mL)中,加入N-碘代丁二酰亚胺(1.70g,7.57mmol)。混合物在室温下搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x20mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I30-b(1.1g,3.87mmol),白色固体,收率58.5%。MS(ESI):m/z283.3(M-H)-.
第三步:将化合物I30-b(850mg,2.99mmol)溶于无水N,N-二甲基甲酰胺(10mL)中,在冰浴下加入N,N-二异丙基乙胺(1.93g,14.9mmol)。再加入TBSCl(1.35g,8.96mmol),混合物在室温下搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x20mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I30-c(1.2g,2.34mmol),油状液体,收率78.3%。
第四步:将化合物I30-c(1.0g,1.95mmol)溶于超干四氢呋喃(10mL)中,冷却至-78℃,滴加2.5M正丁基锂正己烷溶液(0.94mL,2.35mmol)。搅拌30分钟后,向反应液中慢慢滴加N,N-二甲基甲酰胺的四氢呋喃(5mL)溶液。滴加完毕后,反应液缓慢升至室温并搅拌2小时。用20mL饱和氯化铵水溶液淬灭反应,并且室温搅拌过夜。水溶液用乙酸乙酯萃取(3x20mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I30-d(300mg,1.00mmol),油状液体,收率51.2%。
第五步:将化合物I30-d(500mg,1.66mmol)溶于乙腈(10mL)中,加入碳酸钾(344.5mg,2.49mmol)和2-溴-1-溴甲基-3-碘苯(749.5mg,1.99mmol)。将混合物加热至70℃反应3小时。冷却至室温后,加入10mL水,沉淀析出,过滤固体并用水洗涤,干燥固体。固体再用乙酸乙酯洗涤,干燥后得到化合物I30-e(820mg,1.38mmol),白色固体,收率82.8%。
第六步:将化合物I30-e(500mg,0.84mmol)溶于四氢呋喃(10mL)中,加入1mol/L四丁基氟化铵的四氢呋喃溶液(4.2mL,4.2mmol)。混合物在室温下搅拌2小时,然后加入10mL水淬灭,沉淀析出,过滤固体并用水洗涤,干燥固体。固体再用乙酸乙酯洗涤,干燥后得到化合物I30-f(275mg,0.57mmol),白色固体,收率68.1%。
第七步:将化合物I30-f(100mg,207.68umol)溶于四氢呋喃(5mL)中,冰浴冷却至0℃,加入三乙胺(42mg,415.36umol)和甲磺酸酐(54.20mg,311.52umol)。混合物在0℃下搅拌2小时,TLC检测反应结束。加入20mL水淬灭反应,水溶液用乙酸乙酯萃取(3x20mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩得到白色固体。将该白色固体溶于乙腈(5mL)中,加入5-羟基-3-氰基吡啶(29.93mg,249.22umol)和N,N-二异丙基乙胺(53.58mg,415.36umol)。将混合物加热至80℃继续搅拌2小时。然后加入10mL水淬灭,沉淀析出,过滤固体并用水洗涤,干燥固体。固体再用乙酸乙酯洗涤,干燥后得到中间体I30(59mg,101.37umol),白色固体,收率48.7%。MS(ESI):m/z 583.3(M+H)+.
中间体I31:
中间体I31的合成路线如下:
第一步:将中间体I4(3.36g,9.45mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入碳酸钾(1.96g,14.17mmol)和碘甲烷(1.61g,11.34mmol,705.85uL),混合物在室温下搅拌1小时。然后加入30mL水淬灭,沉淀析出,过滤,水洗,干燥得到化合物I31-a(3.4g,9.20mmol),淡黄色固体,收率97.4%。
第二步:将化合物I31-a(3.4g,9.20mmol),联硼酸频那醇酯(3.04g,11.96mmol),醋酸钾(2.71g,27.59mmol)和Pd(dppf)Cl2(336.52mg,459.91umol)混合于二氧六环(40mL)中。混合物在氮气氛围下加热至100℃搅拌16小时。待反应液冷却至室温,用50mL乙酸乙酯稀释,硅藻土过滤,在用50mL乙酸乙酯洗涤,浓缩滤液。残留物用快速过柱机分离得到中间体I31(3.74g,8.98mmol),淡黄色固体,收率97.6%。MS(ESI):m/z 417.2(M+H)+.
中间体I32:
中间体I32的合成路线如下:
将中间体I31(1.0g,2.40mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入L-丝氨酸异丙酯(424mg,2.88mmol)和乙酸(288mg,4.80mmol)。混合物在室温下搅拌2小时。然后向混合物中加入三乙酰氧基硼氢化钠(1.53g,7.20mmol),反应在室温下搅拌过夜。然后加入50mL水淬灭,水溶液用乙酸乙酯萃取(2x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用薄层层析分离得到中间体I32(1.1g,2.01umol),淡黄色固体,收率83.8%。MS(ESI):m/z 548.3(M+H)+.
中间体I33:
中间体I33的合成方法基本同中间体I32,不同之处在于用O-叔丁基-L-丝氨酸叔丁酯替代L-丝氨酸异丙酯。
中间体I34:
中间体I34的合成路线如下:
将中间体I27(0.14g,290.62umol)溶于N,N-二甲基甲酰胺(3mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(69.47mg,319.68umol)和乙酸(34.90mg,581.24umol,33.24uL)。混合物在30℃下搅拌1小时。然后向混合物中加入三乙酰氧基硼氢化钠(246.38mg,1.16mmol),反应在30℃下搅拌1小时。然后加入20mL水淬灭,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用10mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用薄层层析分离得到中间体I34(0.12g,175.69umol),淡黄色固体,收率60.5%。MS(ESI):m/z 682.1(M+H)+.中间体I35:
中间体I35的合成方法基本同中间体I34,不同之处在于用L-丝氨酸异丙酯替代O-叔丁基-L-丝氨酸叔丁酯。
中间体I36:
中间体I36的合成路线如下:
第一步:将中间体I5(1.0g,2.13mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(554.04mg,2.55mmol)和乙酸(255.6mg,4.62mmol)。混合物在室温下搅拌2小时。然后向混合物中加入三乙酰氧基硼氢化钠(2.16g,10.2mmol),反应在室温下搅拌过夜。然后加入50mL水淬灭,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I36-a(1.16g,1.73mmol),淡黄色固体,收率81.2%。MS(ESI):m/z 672.1(M+H)+.
第二步:将化合物I36-a(1.16g,1.73mmol),联硼酸频那醇酯(878.84mg,3.46mmol),醋酸钾(508.62mg,5.19mmol)和Pd(dppf)Cl2(126.46mg,0.173mmol)混合于二氧六环(20mL)中。混合物在氮气氛围下加热至100℃搅拌16小时。待反应液冷却至室温,用50mL乙酸乙酯稀释,硅藻土过滤,在用50mL乙酸乙酯洗涤,浓缩滤液。残留物用快速过柱机分离得到中间体I36(978mg,1.36mmol),淡黄色固体,收率78.6%。MS(ESI):m/z 720.2(M+H)+.
中间体I37:
中间体I37的合成方法基本同中间体I36,不同之处在于用L-丝氨酸异丙酯替代O-叔丁基-L-丝氨酸叔丁酯。
中间体I38:
中间体I38的合成路线如下:
将中间体I5(2.0g,4.26mmol),联硼酸频那醇酯(1.3g,5.11mmol),醋酸钾(1.25g,12.78mmol)和Pd(dppf)Cl2(314mg,0.43mmol)混合于二氧六环(30mL)中。混合物在氮气氛围下加热至100℃搅拌16小时。待反应液冷却至室温,用50mL乙酸乙酯稀释,硅藻土过滤,在用50mL乙酸乙酯洗涤,浓缩滤液。残留物用快速过柱机分离得到中间体I38(1.7g,1.36mmol),淡黄色固体,收率76.9%。MS(ESI):m/z 519.4(M+H)+.
中间体I39:
中间体I39的合成路线如下:
第一步:将化合物I26-c(1.0g,3.32mmol)和盐酸羟胺(354mg,4.99mmol)溶于乙醇(15mL)中。混合物在50℃下搅拌30分钟。接着,浓盐酸(1.1mL,13.28mmol)和锌粉(436mg,6.65mmol)缓慢加入到反应液中。混合物在50℃下搅拌15分钟,然后向该悬浊液中慢慢滴加2mL 30%氨水,并在室温下搅拌15分钟。混合液用二氯甲烷萃取,无水硫酸钠干燥,过滤,浓缩。得到化合物I39-a(540mg,2.89mmol),淡黄色液体,收率87.0%。
第二步:将化合物I39-a(1.0g,5.33mmol)溶于无水甲醇(25mL)中,冰浴冷却至0℃。加入碳酸二叔丁酯(1.40g,6.40mmol,1.47mL)和4-二甲氨基吡啶(32.56mg,266.49umol),混合物在室温下搅拌过夜。然后加入50mL饱和氯化铵水溶液淬灭,水溶液用乙酸乙酯萃取(4x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到化合物I39-b(900mg,3.13mmol),淡黄色液体,收率58.7%。MS(ESI):m/z 310.3(M+Na)+.1H NMR(500MHz,d6-DMSO)δ9.70(s,1H),7.23(s,1H),7.02(d,J=4.5Hz,2H),5.31(t,J=5.5Hz,1H),4.45(d,J=5.5Hz,2H),4.05(d,J=6.0Hz,2H),1.21(s,9H).
第三步:化合物I39-b(900mg,3.13mmol)溶于N,N-二甲基甲酰胺(8mL)中,加入碳酸钾(1.30g,9.38mmol)。然后加入5-氯甲基-3-氰基吡啶(572.70mg,3.75mmol),混合物加热至50℃搅拌1小时。然后加入50mL饱和氯化铵水溶液淬灭,水溶液用乙酸乙酯萃取(4x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到I39-c(1.2g,2.97mmol),白色固体,收率94.9%。MS(ESI):m/z 404.4(M+H)+.
第四步:将I39-c(1.0g,2.48mmol)溶于二氯甲烷(15mL)中,在0℃氮气氛围下加入甲磺酸酐(862.66mg,4.95mmol)。然后加入N,N-二异丙基乙胺(1.92g,14.86mmol,2.59mL)和盐酸二氧六环(4M,1.24mL)的二氯甲烷(5mL)混合液。反应液在25℃搅拌12小时。用20mL水淬灭反应,水溶液用二氯甲烷萃取(2x50mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到I39-d(900mg,2.13mmol),淡黄色固体,收率86.1%。MS(ESI):m/z 422.2(M+H)+.
第五步:将I39-d(900mg,2.13mmol),4-溴-1H-吲唑(419.91mg,2.13mmol)和碳酸钾(441.82mg,3.20mmol)溶于N,N-二甲基甲酰胺(15mL)中。混合物在50℃下搅拌16小时。然后加入50mL饱和氯化铵水溶液淬灭,水溶液用乙酸乙酯萃取(4x100mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到中间体I39(0.6g,1.03mmol),白色固体,收率48.1%。MS(ESI):m/z 584.4(M+H)+.
中间体I40:
中间体I40的合成路线如下:
第一步:将5-氯-2,4-二羟基苯甲醛(5.0g,29.07mmol)溶于四氢呋喃(50mL)中,加入N,N-二异丙基乙胺(5.62g,43.60mmol),冰浴冷却至0℃。然后慢慢滴加2-(三甲基硅烷基)乙氧甲基氯(5.79g,34.88mmol)。反应液慢慢升至室温,并在室温下搅拌3小时。加入100mL水淬灭,水溶液用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I40-a(5.5g,18.21mmol),淡黄色液体,收率62.6%。
第二步:将化合物I40-a(5.5g,18.21mmol)溶于N,N-二甲基甲酰胺(50mL)中,加入碳酸钾(5.03g,36.42mmol),碘化钾(3.02g,18.21mmol)和5-氯甲基-3-氰基吡啶(3.32g,21.85mmol)。混合物加热至80℃搅拌2小时。待反应冷却至室温,加入60mL水,沉淀析出,过滤固体并用水洗涤,干燥固体。固体再用乙酸乙酯洗涤,干燥后得到化合物I40-b(7.0g,16.75mmol),白色固体,收率92.0%。MS(ESI):m/z 419.4(M+H)+.
第三步:将化合物I40-b(4.0g,9.57mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(2.49g,11.48mmol)和醋酸(1.15g,19.14mmol),反应混合物在室温下搅拌3小时,再加入三乙酰氧基硼氢化钠(6.09g,28.71mmol),继续在室温下搅拌过夜。加入50mL水淬灭,用乙酸乙酯萃取(3x50mL),合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I40-c(5.57g,8.99mmol),淡黄色液体,收率94.0%。MS(ESI):m/z 620.4(M+H)+.
第四步:将化合物I40-c(5.57g,8.99mmol)溶于四氢呋喃(50mL)中,加入三乙胺(2.72g,26.97mmol),冰浴冷却至0℃。再分批加入碳酸二叔丁酯(3.92g,17.98mmol),混合物在室温下搅拌过夜。加入60mL水淬灭,用乙酸乙酯萃取(3x50mL),合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物I40-d(4.31g,5.99mmol),淡黄色液体,收率66.7%。MS(ESI):m/z 720.5(M+H)+.
第五步:将化合物I40-d(4.31g,5.99mmol)溶于四氢呋喃(40mL)中,加入1.0mol/L四丁基氟化铵四氢呋喃溶液(29.95mL,29.95mmol)。混合物加热至50℃搅拌过夜。待反应液冷却至室温,加入100mL饱和氯化铵水溶液淬灭,水相用乙酸乙酯萃取(3x60mL),合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到中间体I40(1.81g,3.07mmol),淡黄色固体,收率51.2%。MS(ESI):m/z 590.3(M+H)+.
中间体I41:
中间体I41的合成路线如下:
第一步:将3-溴-2-氯苯酚(3.0g,14.46mmol),联硼酸频哪醇酯(4.41g,17.35mmol),醋酸钾(4.26g,43.38mmol)和Pd(dppf)Cl2(529.06mg,723.06umol)混合于二氧六环(30mL)中。混合物在氮气氛围下加热至90℃搅拌过夜。待反应液冷却至室温,用100mL乙酸乙酯稀释,硅藻土过滤,再用100mL乙酸乙酯洗涤,浓缩滤液。残留物用快速过柱机分离(PE/EA=5/1)得到化合物I41-a(3.17g,12.45mmol),白色固体,收率86.1%。MS(ESI):m/z 253.2(M-H)-.
第二步:将6-氯-2-甲氧基-3-吡啶甲醛(500mg,2.91mmol)和化合物I41-a(890.02mg,3.50mmol)溶于二氧六环(10mL)和水(2mL)的混合溶剂中,加入碳酸钾(1.21g,8.74mmol)和Pd(dppf)Cl2(106.61mg,145.70umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用100mL水淬灭反应,水相用乙酸乙酯萃取(2x100mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离(PE/EA=2/1)得到化合物I41-b(565mg,2.14mmol),淡黄色固体,收率73.5%。MS(ESI):m/z 262.1(M-H)-.1H NMR(500MHz,DMSO-d6)δ10.39(s,1H),10.29(s,1H),8.17(d,J=7.7Hz,1H),7.40(d,J=7.7Hz,1H),7.27(t,J=7.8Hz,1H),7.13–7.05(m,2H),4.03(s,3H).
第三步:将化合物I41-b(950mg,3.60mmol)溶于无水二氯甲烷(20mL)中,氮气氛围下依次加入吡啶(740.97mg,9.37mmol)、4-二甲氨基吡啶(44.02mg,360.29umol)和三乙胺(765.61mg,7.57mmol,1.05mL)。干冰浴冷却至-78℃,再向反应液中慢慢滴加三氟甲磺酸酐(1.17g,4.14mmol,695.83uL),滴加完毕后搅拌15分钟,再渐渐升至室温,继续搅拌1小时。然后反应液用200mL乙酸乙酯稀释,用100mL柠檬酸水溶液洗涤。有机相无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离(PE/EA=4/1)得到化合物I41-c(1.1g,2.78mmol),淡黄色固体,收率77.2%。MS(ESI):m/z 396.3(M+H)+.1H NMR(500MHz,DMSO-d6)δ10.30(s,1H),8.25(d,J=7.6Hz,1H),7.84(dd,J=7.7,1.5Hz,1H),7.79(dd,J=8.3,1.5Hz,1H),7.70(t,J=8.0Hz,1H),7.51(d,J=7.7Hz,1H),4.06(s,3H).
第四步:将化合物I41-c(500mg,1.26mmol),联硼酸频哪醇酯(385.01mg,1.52mmol),醋酸钾(371.99mg,3.79mmol)和Pd(dppf)Cl2(92.45mg,126.35umol)混合于二氧六环(10mL)中。混合物在氮气氛围下加热至90℃搅拌过夜。待反应液冷却至室温,用50mL乙酸乙酯稀释,硅藻土过滤,再用50mL乙酸乙酯洗涤,浓缩滤液。残留物用快速过柱机分离(PE/EA=3/1)得到中间体I41(225mg,602.19umol),淡黄色固体,收率47.7%。MS(ESI):m/z374.2(M+H)+.
中间体I42:
中间体I42的合成路线如下:
第一步:将4-甲酰基苯硼酸频哪醇酯(4.5g,19.39mmol)和1,3-二溴-2-氯苯(10.48g,38.78mmol)溶于二氧六环(50mL)和水(10mL)的混合溶剂中,加入碳酸钾(8.04g,58.17mmol)和Pd(dppf)Cl2(1.42g,1.94mmol)。混合物在氮气氛围下加热至80℃搅拌3小时。用100mL水淬灭反应,水相用乙酸乙酯萃取(2x200mL)。合并有机相,用100mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离(PE/EA=4/1)得到化合物I42-a(3.7g,12.52mmol),白色固体,收率64.6%。
第二步:将化合物I42-a(700mg,2.37mmol),联硼酸频哪醇酯(721.71mg,2.84mmol),醋酸钾(697.3mg,7.11mmol)和Pd(dppf)Cl2(173.3mg,236.84umol)混合于二氧六环(15mL)中。混合物在氮气氛围下加热至90℃搅拌过夜。待反应液冷却至室温,用50mL乙酸乙酯稀释,硅藻土过滤,再用50mL乙酸乙酯洗涤,浓缩滤液。残留物用快速过柱机分离(PE/EA=5/1)得到中间体I42(615mg,1.79mmol),白色固体,收率75.8%。
中间体I43:
中间体I43的合成路线如下:
将中间体I3(1.0g,1.71mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(600mg,2.76mmol)和醋酸(1.05g,17.49mmol),反应混合物在室温下搅拌过夜,再加入三乙酰氧基硼氢化钠(1.0g,4.72mmol),继续在室温下1小时。加入100mL水淬灭,用乙酸乙酯萃取(2x100mL),合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离(PE/EA=1/1)得到中间体I43(800mg,1.02mmol),淡黄色液体,收率59.5%。MS(ESI):m/z 784.4(M+H)+.
中间体I44:
中间体I44的合成方法基本同化合物I26-g,不同之处在于用碘甲烷替代5-氯甲基-3-氰基吡啶盐酸盐。
中间体I45:
中间体I45的合成路线如下:
将中间体I34(1g,1.46mmol),联硼酸频哪醇酯(557.67mg,2.20mmol),醋酸钾(431.06mg,4.39mmol)和Pd(dppf)Cl2(107.13mg,146.41umol)混合于二氧六环(15mL)中。混合物在氮气氛围下加热至90℃搅拌过夜。待反应液冷却至室温,用100mL乙酸乙酯稀释,硅藻土过滤,再用100mL乙酸乙酯洗涤,浓缩滤液。残留物用快速过柱机分离(DCM/MeOH=20/1)得到中间体I45(600mg,821.81umol),淡黄色固体,收率56.1%。MS(ESI):m/z 730.7(M+H)+.
本发明中实施例化合物的合成方法如下:
实施例1:
(4-((2-bromo-3-(1-(3-((R)-3-hydroxypyrrolidin-1-yl)propyl)-1H-indazol-4-yl)benzyl)oxy)-5-chloro-2-((2-cyanopyridin-4-yl)methoxy)benzyl)-L-se rine
第一步:将中间体I2(200mg,0.34mmol)与中间体I6(190.86mg,0.51mmol)溶于1,4-二氧六环(5mL)中,加入碳酸钾(94.73mg,0.68mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(25.08mg,0.034mmol),反应混合物在氮气气氛95℃下搅拌过夜。将反应液冷却至室温,加入30mL乙酸乙酯,经硅藻土过滤,滤液用10mL水洗三次,10mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物1a(80mg,0.11mmol),收率33.3%,淡黄色固体。MS(ESI):m/z 700.3(M+H)+.
第二步:将化合物1a(80mg,0.11mmol)溶于N,N-二甲基甲酰胺(3mL)和醋酸(0.2mL)的混合物中,加入L-丝氨酸(23.99mg,0.23mmol),反应混合物在45℃下搅拌过夜。之后加入三乙酰氧基硼氢化钠(90.67mg,0.43mmol),继续搅拌3小时。将反应液冷却至室温滴入水淬灭,过滤,滤液用反向制备色谱提纯得到化合物1(4.6mg,5.82umol),收率5.1%,白色固体。MS(ESI):m/z 789.3(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.75(d,J=5.0Hz,1H),8.17(s,1H),7.89(d,J=5.0Hz,1H),7.74(d,J=8.5Hz,1H),7.70(d,J=10.0Hz,2H),7.56(q,J=7.0,5.5Hz,2H),7.53–7.43(m,2H),7.09(d,J=7.0Hz,1H),7.04(s,1H),5.39(d,J=4.5Hz,2H),5.33(s,2H),4.83(s,1H),4.49(s,3H),4.21(s,1H),4.03(s,2H),3.77–3.60(m,2H),3.21(s,1H),2.72(d,J=7.5Hz,3H),2.36(s,1H),2.10–1.91(m,5H),1.59(s,1H).
实施例2:
(4-((2-bromo-3-(1-(3-((R)-3-hydroxypyrrolidin-1-yl)propyl)-1H-indazol-4-yl)benzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-se rine
第一步:将中间体I3(200mg,0.34mmol)与中间体I6(190.86mg,0.51mmol)溶于1,4-二氧六环(5mL)中,加入碳酸钾(94.73mg,0.68mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(25.08mg,0.034mmol),反应混合物在氮气气氛95℃下搅拌过夜。将反应液冷却至室温,加入30mL乙酸乙酯,经硅藻土过滤,滤液用10mL水洗三次,10mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物2a(130mg,0.18mmol),收率53.1%,淡黄色固体。MS(ESI):m/z 700.3(M+H)+.
第二步:将化合物2a(130mg,0.18mmol)溶于N,N-二甲基甲酰胺(3mL)和醋酸(0.2mL)的混合物中,加入L-丝氨酸(58.47mg,0.56mmol),反应混合物在45℃下搅拌过夜。之后加入三乙酰氧基硼氢化钠(157.21mg,0.74mmol),继续搅拌3小时。将反应液冷却至室温滴入水淬灭,过滤,滤液用反向制备色谱提纯得到化合物2(20mg,25.31umol),收率13.7%,白色固体。MS(ESI):m/z 789.3(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.01(t,J=2.5Hz,2H),8.51(s,1H),7.76–7.66(m,3H),7.60–7.52(m,2H),7.51–7.41(m,2H),7.15–7.02(m,2H),5.43–5.25(m,4H),4.49(t,J=7.0Hz,2H),4.20(q,J=7.0,5.5Hz,1H),3.97(s,2H),3.69(dd,J=11.0,4.5Hz,1H),3.61(dd,J=11.0,6.5Hz,1H),3.16(d,J=6.0Hz,1H),2.71(dd,J=10.0,6.0Hz,1H),2.66–2.57(m,1H),2.43–2.35(m,3H),2.28(d,J=7.0Hz,1H),2.17(s,1H),2.05–1.96(m,3H),1.57(s,1H).
下列化合物由中间体I3、对应的硼酸酯中间体I6-I21以及氨基酸类衍生物出发,采用实施例2相同的合成方法得到。
/>
/>
/>
/>
/>
/>
/>
/>
/>
实施例22:
(4-((2-bromo-3-(1-(1-(1,3-dihydroxypropan-2-yl)piperidin-4-yl)-1H-inda zol-4-yl)benzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
将粗品化合物17(260mg,307.27umol)溶于四氢呋喃(3mL)中,加入4.0mol/L盐酸(3mL),反应混合物在25℃下搅拌3小时。之后加入碳酸氢钠调节pH至弱酸性,浓缩除去溶剂,滤渣用3mL N,N-二甲基甲酰胺浸泡,搅拌1小时,过滤,滤液用反向制备色谱提纯得到化合物22(29.7mg,36.84umol),收率12.0%,白色固体。MS(ESI):m/z 821.3(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.00(d,J=23.2Hz,2H),8.52(s,1H),8.24(s,2H),7.80(d,J=8.8Hz,1H),7.76–7.68(m,2H),7.56–7.49(m,2H),7.47(dd,J=13.6,7.2Hz,2H),7.16–7.05(m,2H),5.36(d,J=7.6Hz,4H),4.64(s,1H),4.02–3.90(m,2H),3.63(s,1H),3.56(dd,J=10.8,6.5Hz,2H),3.50(dd,J=10.8,5.8Hz,2H),3.00(d,J=10.3Hz,2H),2.77(t,J=11.2Hz,2H),2.64(d,J=6.8Hz,1H),2.17(s,4H),1.95(s,3H),1.35(s,1H),1.30(s,1H).
实施例23:
(4-(4-(2-bromo-3-((4-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)phenyl)-1H-indazol-1-yl)butyl)-L-proline
第一步:将中间体I3(260mg,331.25umol)与中间体I14(173.33mg,369.25umol)溶于1,4-二氧六环(4mL)和水(0.4mL)中的混合物,加入碳酸钾(137.35mg,993.75umol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(24.24mg,33.13umol),反应混合物在氮气气氛80℃下搅拌过夜。将反应液冷却至室温,加入30mL乙酸乙酯,经硅藻土过滤,滤液用10mL水洗三次,10mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物23a(110mg,109.95umol),收率33.2%,淡黄色固体。MS(ESI):m/z 798.6(M+H)+.
第二步:将化合物23a(110mg,109.95umol)溶于N,N-二甲基甲酰胺(3mL)和醋酸(0.2mL)的混合物,加入L-丝氨酸(58.47mg,556.34umol),反应混合物在45℃下搅拌过夜。之后加入三乙酰氧基硼氢化钠(157.26mg,741.79umol),继续搅拌3小时。将反应液冷却至室温加入水,过滤,滤渣直接用水洗两次得到粗产品23b,淡黄色固体。MS(ESI):m/z 887.6(M+H)+.
第三步:将粗产品23b溶于四氢呋喃(3mL),加入4.0mol/L盐酸(3mL),反应混合物在50℃下搅拌过夜。直接加入醋酸钠将pH调至弱酸性,浓缩混合物,得到的固体残渣用3mLN,N-二甲基甲酰胺浸泡,过滤,滤液用反向制备色谱提纯得到化合物23(5mg,6.01umol),收率15.0%,白色固体。MS(ESI):m/z 833.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.01(s,2H),8.51(s,1H),8.30(s,2H),7.77(d,J=8.5Hz,1H),7.75–7.65(m,2H),7.60–7.54(m,1H),7.53–7.43(m,2H),7.10(d,J=7.0Hz,2H),5.47–5.22(m,4H),4.54–4.41(m,2H),3.60–3.57(m,1H),3.09–2.99(m,3H),2.94–2.83(m,2H),2.81–2.66(m,2H),2.16–2.05(m,2H),1.96–1.80(m,4H),1.72–1.50(m,4H).
实施例24:
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-cyclopropyl-3-(1-(3-((R)-3-hydroxypyrrolidin-1-yl)propyl)-1H-indazol-4-yl)benzyl)oxy)benzyl)-L-serine
第一步:将化合物2a(100mg,142.65umol)与环丙基硼酸(15mg,174umol)溶于1,4-二氧六环(4mL)和水(0.4mL)的混合物,加入碳酸钾(62mg,450umol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10.9mg,15.00umol),反应混合物在氮气气氛80℃下搅拌过夜。将反应液冷却至室温,加入30mL乙酸乙酯,经硅藻土过滤,滤液用10mL水洗三次,10mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物24a(53.09mg,80.32umol),收率56.3%,淡黄色固体。MS(ESI):m/z 662.8(M+H)+.
第二步:将化合物24a(53.09mg,80.32umol)溶于N,N-二甲基甲酰胺(3mL)和醋酸(0.2mL)的混合物,加入L-丝氨酸(58.47mg,556.34umol),反应混合物在45℃下搅拌过夜。之后加入三乙酰氧基硼氢化钠(157.26mg,741.79umol),继续搅拌3小时。将反应液冷却至室温滴入水淬灭,过滤,滤液用反向制备色谱提纯得到化合物24(2.2mg,2.93umol),收率3.7%,白色固体。MS(ESI):m/z 751.8(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.04–9.00(m,2H),8.52(s,1H),8.30(s,1H),7.74(s,1H),7.66(d,J=8.6Hz,1H),7.56(d,J=7.3Hz,1H),7.52(s,1H),7.45(t,J=7.8Hz,1H),7.39(t,J=7.4Hz,2H),7.34(d,J=7.6Hz,1H),7.11–7.05(m,2H),5.49(s,2H),5.36(d,J=6.6Hz,2H),4.48(t,J=6.8Hz,2H),4.17(s,2H),3.93(s,2H),3.62(s,2H),2.28(d,J=6.6Hz,3H),2.06–1.93(m,6H),1.53(s,1H).
下列化合物由中间体I5、对应的硼酸酯中间体I6和I12以及氨基酸类衍生物出发,采用实施例2相同的合成方法得到。
/>
实施例28:
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(1-(4-((R)-3-hydroxyp yrrolidin-1-yl)butyl)-1H-indazol-4-yl)-2-nitrobenzyl)oxy)benzyl)-L-serin e
第一步:将2-硝基-3-甲基溴苯(1.0g,4.65mmol)溶于四氯化碳(10mL),加入N-溴代丁二酰亚胺(928mg,6.98mmol)和过氧苯甲酰(225mg,0.93mmol)。反应混合物在氮气氛围下回流过夜。然后过滤,浓缩滤液,粗产品用快速过柱机分离得到化合物28a(609mg,2.08mmol),淡黄色固体,收率44.7%。
第二步:将中间体I40(200mg,338.92umol)溶于乙腈(5mL)中,加入碳酸钾(94mg,677.84umol)和化合物28a(120mg,406.71umol)。将混合物加热至50℃反应3小时。冷却至室温后,加入20mL水淬灭,水溶液用乙酸乙酯萃取(3x20mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物28b(140mg,174.10umol),淡黄色固体,收率51.5%。MS(ESI):m/z 803.2(M+H)+.
第三步:将化合物28b(140mg,174.10umol)和中间体I7(81mg,208.92umol)溶于二氧六环(6mL)和水(1mL)的混合溶剂中,加入碳酸钾(73mg,522.31umol)和Pd(dppf)Cl2(13mg,17.41umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x20mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物28c(123mg,125.18umol),淡黄色固体,收率71.9%。MS(ESI):m/z982.2(M+H)+.
第四步:将化合物28c(50mg,50.97umol)溶于四氢呋喃(1mL)中,加入6.0mol/L盐酸水溶液(1mL)。混合物加热至50℃过夜。冷却至室温,加入醋酸钠(493mg),减压蒸去溶剂,加入3mL N,N-二甲基甲酰胺。过滤固体,用1mL N,N-二甲基甲酰胺洗涤固体一次,滤液直接用反向制备色谱分离得到化合物28(23.21mg,30.18umol),白色固体,收率59.2%。MS(ESI):m/z 770.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.03(d,J=2.0Hz,1H),9.01(d,J=2.0Hz,1H),8.52(s,1H),7.88(d,J=7.5Hz,1H),7.85–7.78(m,3H),7.74(d,J=7.5Hz,1H),7.50(s,1H),7.49–7.44(m,1H),7.09(s,1H),7.04(d,J=7.0Hz,1H),5.42(s,2H),5.35(d,J=12.5Hz,1H),5.31(d,J=12.5Hz,1H),4.47(t,J=7.0Hz,2H),4.22–4.17(m,1H),3.96(s,2H),3.68(dd,J=11.5,4.5Hz,1H),3.60(dd,J=11.0,6.5Hz,1H),3.16–3.11(m,1H),2.77(dd,J=10.0,5.5Hz,1H),2.69–2.63(m,1H),2.57–2.53(m,3H),2.45(d,J=8.0Hz,1H),2.01–1.93(m,1H),1.91–1.83(m,2H),1.61–1.53(m,1H),1.49–1.42(m,2H).
实施例29:
(4-((2-amino-3-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-seri ne
第一步:将(2-氨基-3-溴苯基)甲醇(80mg,395.95umol)和三苯基膦(125mg,475.13umol)溶于超干四氢呋喃(5mL)中,加入中间体I40(234mg,395.95umol)的四氢呋喃(2mL)溶液。冰浴冷却至0℃,在氮气氛围下慢慢滴加偶氮二甲酸异丙酯(96mg,475.13umol)。反应混合物慢慢升至室温,搅拌过夜。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x20mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物29a(88mg,113.67umol),淡黄色液体,收率28.7%。MS(ESI):m/z 773.2(M+H)+.
第二步:将化合物29a(88mg,113.67umol)和中间体I7(53mg,136.40umol)溶于二氧六环(5mL)和水(1mL)的混合溶剂中,加入碳酸钾(47mg,341.02umol)和Pd(dppf)Cl2(13mg,11.37umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x20mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物29b(48mg,50.39umol),淡黄色固体,收率44.3%。MS(ESI):m/z 952.2(M+H)+.
第四步:将化合物29b(48mg,50.39umol)溶于二氯甲烷(1mL)中,加入二氯甲烷和三氟乙酸混合溶液(v/v=2mL/1mL)。混合物在室温下搅拌过夜。减压蒸去反应溶剂,加入3mL乙腈,滴加2滴三乙胺,直接用反向制备色谱分离得到化合物29(12.03mg,16.28umol),白色固体,收率32.3%。MS(ESI):m/z 740.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.03(d,J=2.0Hz,1H),9.01(d,J=2.0Hz,1H),8.52(s,1H),7.88(d,J=7.5Hz,1H),7.74(d,J=7.5Hz,1H),7.50(s,1H),7.49–7.44(m,1H),7.09(s,1H),7.04(d,J=7.0Hz,1H),7.02–6.96(m,3H),5.35(d,J=12.5Hz,1H),5.31(d,J=12.5Hz,1H),5.42(s,2H),5.02(s,2H),4.47(t,J=7.0Hz,2H),4.22–4.17(m,1H),3.96(s,2H),3.68(dd,J=11.5,4.5Hz,1H),3.60(dd,J=11.0,6.5Hz,1H),3.16–3.11(m,1H),2.77(dd,J=10.0,5.5Hz,1H),2.69(dd,J=16.0,8.0Hz,1H),2.57–2.53(m,3H),2.45(d,J=8.0Hz,1H),2.01–1.93(m,1H),1.91–1.83(m,2H),1.61–1.53(m,1H),1.49–1.42(m,2H).
实施例30:
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)-2-(methylamino)benzyl)oxy)benzyl)-L-serine
化合物30的合成基本同化合物29,不同之处在于用将(3-溴-2-(甲基氨基)苯基)甲醇替代(2-氨基-3-溴苯基)甲醇。MS(ESI):m/z 754.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.03(d,J=2.0Hz,1H),9.01(d,J=2.0Hz,1H),8.52(s,1H),7.88(d,J=7.5Hz,1H),7.74(d,J=7.5Hz,1H),7.50(s,1H),7.49–7.44(m,1H),7.09(s,1H),7.04(d,J=7.0Hz,1H),7.02–6.96(m,3H),5.35(d,J=12.5Hz,1H),5.31(d,J=12.5Hz,1H),5.42(s,2H),4.96(s,1H),4.47(t,J=7.0Hz,2H),4.22–4.17(m,1H),3.96(s,2H),3.68(dd,J=11.5,4.5Hz,1H),3.60(dd,J=11.0,6.5Hz,1H),3.16–3.11(m,1H),2.77(dd,J=10.0,5.5Hz,1H),2.69(dd,J=16.0,8.0Hz,1H),2.64(s,3H),2.57–2.53(m,3H),2.45(d,J=8.0Hz,1H),2.01–1.93(m,1H),1.91–1.83(m,2H),1.61–1.53(m,1H),1.49–1.42(m,2H).
实施例31:
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2-(dimethylamino)-3-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)benzyl)-L-serine
化合物31的合成基本同化合物29,不同之处在于用(3-溴-2-(二甲氨基)苯基)甲醇替代(2-氨基-3-溴苯基)甲醇。MS(ESI):m/z 768.7(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.13–9.04(m,2H),8.58(s,1H),7.82(s,1H),7.76(d,J=8.5Hz,1H),7.67–7.63(m,1H),7.61(s,1H),7.58–7.52(m,1H),7.36–7.27(m,2H),7.12–7.03(m,2H),5.45–5.31(m,4H),4.54(t,J=7.0Hz,2H),4.28–4.22(m,1H),4.04(s,2H),3.83–3.74(m,1H),3.69(dd,J=11.0,6.0Hz,1H),3.24–3.20(m,1H),2.79–2.71(m,1H),2.66–2.61(m,2H),2.54–2.50(m,2H),2.49(s,6H),2.44–2.38(m,1H),2.06–1.93(m,3H),1.64–1.57(m,1H),1.53–1.45(m,2H).
实施例32:
(4-((2-bromo-3-(1-(3-((R)-3-hydroxypyrrolidin-1-yl)propyl)-1H-indazol-4-yl)benzyl)oxy)-5-chloro-2-(((5-cyanopyridin-3-yl)oxy)methyl)benzyl)-L-serine
第一步:将中间体I30(115mg,197.05umol)和中间体I6(90mg,236.45umol)溶于二氧六环(6mL)和水(1mL)的混合溶剂中,加入碳酸钾(81.7mg,591.15umol)和Pd(dppf)Cl2(14.4mg,19.7umol)。混合物在氮气氛围下加热至80℃搅拌过夜。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x20mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物32a(100mg,143.06umol),油状液体,收率72.6%。MS(ESI):m/z 700.2(M+H)+.
第二步:将化合物32a(75mg,106.99umol)溶于N,N-二甲基甲酰胺(5mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(28mg,128.39umol)和乙酸(12.85mg,213.98umol,12.24uL)。混合物在室温下搅拌4小时。然后向混合物中加入三乙酰氧基硼氢化钠(90.70mg,427.96umol),反应在室温下搅拌过夜。然后加入50mL水淬灭,水溶液用乙酸乙酯萃取(3x20mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物32b(76mg,84.44umol),油状液体,收率78.7%。MS(ESI):m/z 901.2(M+H)+.
第三步:将化合物32b(50mg,55.41umol)溶于四氢呋喃(3mL)中,加入6.0mol/L盐酸水溶液(3mL)。混合物加热至50℃过夜。冷却至室温,加入醋酸钠(1.48g),减压蒸去溶剂,加入3mL N,N-二甲基甲酰胺。过滤固体,用1mL N,N-二甲基甲酰胺洗涤固体一次,滤液直接用反向制备色谱分离得到化合物32(22.45mg,28.49umol),白色固体,收率51.3%。MS(ESI):m/z 789.2(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.69(d,J=2.5Hz,1H),8.64(s,1H),8.10(s,1H),7.74(d,J=8.5Hz,1H),7.70(d,J=7.5Hz,1H),7.68(s,1H),7.63(s,1H),7.56(t,J=7.5Hz,1H),7.51–7.43(m,3H),7.09(d,J=7.0Hz,1H),5.39(s,2H),5.35(s,2H),4.49(t,J=6.5Hz,2H),4.22–4.19(m,1H),3.97(d,J=13.0Hz,1H),3.84(d,J=13.5Hz,1H),3.66–3.59(m,3H),3.22–3.19(m,1H),2.75–2.70(m,1H),2.66–2.60(m,1H),2.45–2.36(m,4H),2.04–1.97(m,3H),1.60–1.55(m,1H).
实施例33:
(4-((2-bromo-3-(1-(3-((R)-3-hydroxypyrrolidin-1-yl)propyl)-1H-indazol-4-yl)benzyl)oxy)-5-chloro-2-(((5-cyanopyridin-3-yl)oxy)methyl)benzyl)-L-serine
化合物33的合成基本同化合物32,不同之处在于用甲基丝氨醇替代O-叔丁基-L-丝氨酸叔丁酯。MS(ESI):m/z 789.3(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.66(d,J=2.5Hz,1H),8.62(s,1H),8.08(s,1H),7.73(d,J=8.5Hz,1H),7.67(s,2H),7.58–7.51(m,2H),7.51–7.45(m,1H),7.43(d,J=7.5Hz,1H),7.39(d,J=6.5Hz,1H),7.08(d,J=7.0Hz,1H),5.36(d,J=11.5Hz,2H),5.32(s,2H),4.47(d,J=6.5Hz,2H),4.20(s,2H),3.73(d,J=9.5Hz,2H),3.67(d,J=7.0Hz,1H),3.31(d,J=4.5Hz,3H),2.72(d,J=9.5Hz,1H),2.66–2.56(m,2H),2.36(s,3H),2.06–1.93(m,3H),1.57(d,J=6.5Hz,1H),0.98–0.91(m,3H).
实施例34:
(4-((2-bromo-3-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)-5-chloro-2-(cyanomethoxy)benzyl)-L-serine
第一步:将中间体I24(130mg,169.07umol)溶于N,N-二甲基甲酰胺(5mL),加入溴乙腈(46.18mg,350.04umol)和碳酸钾(70.10mg,507.22umol),反应混合物在50℃下搅拌6小时,加入30mL乙酸乙酯,用10mL水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,滤液浓缩的到化合物34a(137mg,169.07umol),收率100%,淡黄色液体。MS(ESI):m/z 807.3(M+H)+.
第二步:将中间体34a(220mg,310.81umol)与中间体I7(131.73mg,341.89umol)溶于1,4-二氧六环(4mL)和水(0.4mL)的混合物,加入碳酸钾(128.87mg,932.44umol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(22.74mg,31.08umol),反应混合物在氮气气氛80℃下搅拌过夜。将反应液冷却至室温,加入30mL乙酸乙酯,经硅藻土过滤,滤液用10mL水洗三次,10mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物34b(260mg,309.80umol),收率99.7%,淡黄色固体。MS(ESI):m/z 938.3(M+H)+.
第三步:将化合物34b(260mg,309.80umol)溶于四氢呋喃(3mL),加入4.0mol/L盐酸(3mL),反应混合物在50℃下搅拌过夜。用醋酸钠将反应液调至弱酸性,直接浓缩,得到的残渣用3mL N,N-二甲基甲酰胺浸泡,过滤,滤液用反向制备色谱提纯得到化合物34(40mg,55.02umol),收率17.8%,白色固体。MS(ESI):m/z 725.3(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.26(s,1H),7.76–7.74(m,2H),7.69(s,1H),7.60–7.55(m,2H),7.50–7.44(m,2H),7.19(s,1H),7.10(d,J=7.0Hz,1H),5.38(s,2H),5.30(s,2H),4.46(t,J=6.8Hz,2H),4.27–4.23(m,1H),3.94–386(m,2H),3.70(dd,J=11.0,4.5Hz,1H),3.64(dd,J=11.0,6.0Hz,1H),3.18(t,J=5.0Hz,1H),2.94–2.86(m,2H),2.77–2.70(m,3H),2.64(dd,J=10.5,2.0Hz,1H),2.04–1.96(m,1H),1.92–1.85(m,2H),1.67–1.62(m,1H),1.56–1.49(m,2H).
下列化合物由中间体I24出发,采用实施例34相同的合成方法得到。
/>
/>
/>
/>
/>
/>
实施例49:
(4-((2-bromo-3-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)-5-chloro-2-(2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxoethox y)benzyl)-L-serine
第一步:将中间体I25(85mg,102.79umol)和(R)-3-羟基吡咯烷(13.43mg,154.18umol)溶于N,N-二甲基甲酰胺(3mL),先后加入三乙胺(31.20mg,308.37umol)和2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(58.63mg,154.18umol),反应混合物在25℃下搅拌30分钟。向反应混合物中加水淬灭,用20mL乙酸乙酯萃取三次,合并有机相,用10mL水洗一次,10mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物49a(90mg,100.44umol),收率97.7%,淡黄色固体。MS(ESI):m/z895.3(M+H)+.
第二步:将中间体49a(90mg,100.44umol)与中间体I7(38.70mg,100.44umol)溶于1,4-二氧六环(4mL)和水(0.4mL)的混合物,加入碳酸钾(41.65mg,301.33umol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(7.35mg,10.04umol),反应混合物在氮气气氛80℃下搅拌过夜。将反应液冷却至室温,加入30mL乙酸乙酯,经硅藻土过滤,滤液用10mL水洗三次,10mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物49b(100mg,97.33umol),收率96.9%,淡黄色固体。MS(ESI):m/z 1025.7(M+H)+.
第三步:将化合物49b(100mg,97.33umol)溶于四氢呋喃(3mL),加入4.0mol/L盐酸(3mL),反应混合物在50℃下搅拌过夜。用醋酸钠将反应液调至弱酸性,直接浓缩,得到的残渣用3mL N,N-二甲基甲酰胺浸泡,过滤,滤液用反向制备色谱提纯得到化合物49(15mg,18.40umol),收率18.9%,白色固体。MS(ESI):m/z 814.1(M+H)+.1H NMR(500MHz,d6-DMSO)δ7.73(d,J=8.5Hz,1H),7.70(d,J=7.5Hz,1H),7.66(s,1H),7.55(t,J=7.5Hz,1H),7.50–7.46(m,2H),7.45–7.42(m,1H),7.08–7.04(m,2H),5.31(s,2H),4.96(s,1H),4.93–4.88(m,1H),4.44(t,J=7.0Hz,2H),4.31(s,1H),4.22(s,1H),4.17(s,1H),4.08–4.04(m,1H),4.00–3.97(m,1H),3.73–3.70(m,1H),3.65–3.60(m,1H),3.55–3.53(m,2H),3.43–3.31(m,2H),3.29–3.27(m,1H),3.21–3.19(m,1H),2.79–2.73(m,1H),2.71–2.66(m,1H),2.55–2.53(m,3H),2.46–2.43(m,1H),2.00–1.93(m,1H),1.91–1.85(m,3H),1.60–1.54(m,1H),1.50–1.44(m,2H).
下列化合物由中间体I25出发,采用实施例49相同的合成方法得到。
/>
/>
实施例54:
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4-(3-(3-((R)-3-hydroxyp yrrolidin-1-yl)propoxy)-2-methylphenyl)-1H-indazol-1-yl)methyl)benzyl)-L-serine
/>
第一步:将中间体I26(1.5g,912.93umol),中间体I22(494.74mg,1.37mmol),碳酸钾(630.88mg,4.56mmol)和Pd(dppf)Cl2(66.80mg,91.29umol)混合于二氧六环(10mL)和水(2mL)的混合溶剂中。混合物在氮气氛围下加热至100℃搅拌3小时。待反应液冷却至室温,用20mL水稀释,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到粗品化合物54a(0.62g,913.10umol),淡黄色固体,收率100%。MS(ESI):m/z680.3(M+H)+.
第二步:将化合物54a(0.6g,882.11umol)溶于四氢呋喃(10mL)中,加入4.0mol/L盐酸水溶液(1.85mL)。混合物在25℃下搅拌半小时。然后用10mL饱和碳酸氢钠水溶液中和,用10mL水稀释,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用10mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到化合物54b(0.56g,881.19umol),淡黄色固体,收率99.8%。MS(ESI):m/z 636.3(M+H)+.
第三步:将化合物54b(0.1g,157.20umol)溶于N,N-二甲基甲酰胺(2mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(0.09g,414.17umol)和乙酸(262.50mg,4.37mmol,0.25mL)。混合物在30℃下搅拌2小时。然后向混合物中加入三乙酰氧基硼氢化钠(199.90mg,943.19umol),反应在30℃下搅拌1小时。然后加入20mL水淬灭,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用10mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物54c(0.09g,107.66umol),淡黄色固体,收率68.4%。MS(ESI):m/z837.6(M+H)+.
第四步:将化合物54c(0.08g,95.53umol)溶于四氢呋喃(6mL)中,加入6.0mol/L盐酸水溶液(6mL)。混合物加热至50℃搅拌3小时。冷却至室温,加入醋酸钠调节pH=4-5,减压蒸去溶剂,加入3mL N,N-二甲基甲酰胺。过滤固体,用1mL N,N-二甲基甲酰胺洗涤固体一次,滤液直接用反向制备色谱分离得到化合物54(20mg,27.62umol),白色固体,收率28.9%。MS(ESI):m/z 725.9(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.95(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.34(s,1H),7.69(s,1H),7.65(d,J=8.5Hz,1H),7.55(s,1H),7.44(dd,J=8.5,7.0Hz,1H),7.26(t,J=8.0Hz,1H),7.01(t,J=7.5Hz,2H),6.91(d,J=7.5Hz,1H),6.86(s,1H),5.70(s,2H),5.15–5.05(m,2H),4.21(s,1H),4.08(t,J=6.0Hz,2H),3.94(d,J=14.0Hz,1H),3.87(d,J=14.0Hz,1H),3.64–3.57(m,3H),3.16–3.12(m,1H),2.81–2.76(m,1H),2.72–2.60(m,3H),2.58–2.52(m,1H),2.46–2.34(m,2H),2.05–1.85(m,6H),1.61–1.53(m,1H).
实施例55:
(4-((4-(2-bromo-3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)phenyl)-1H-indazol-1-yl)methyl)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
化合物55的合成基本同化合物54,不同之处在于用将中间体I23替代中间体I22。MS(ESI):m/z 790.0(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.95(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.34(s,1H),8.21(s,1H),7.73–7.65(m,2H),7.55(s,1H),7.48–7.41(m,2H),7.18(dd,J=8.5,1.0Hz,1H),7.06(d,J=7.0Hz,1H),7.03(dd,J=7.5,1.0Hz,1H),6.82(s,1H),5.71(s,2H),5.13–5.04(m,2H),4.20(s,1H),4.16(t,J=6.0Hz,2H),3.94(d,J=14.5Hz,1H),3.86(d,J=14.5Hz,1H),3.64(dd,J=11.0,4.0Hz,1H),3.58(dd,J=11.0,6.0Hz,1H),3.16–3.12(m,1H),2.76(s,1H),2.70–2.60(m,3H),2.40(s,1H),2.03–1.90(m,3H),1.56(s,1H).
实施例56:
(4-((3-(1-(4-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)benzyl)-1H-indazol-4-yl)-2-methylbenzyl)oxy)-5-chloro-2-methoxybenzyl)-L-serine
第一步:将中间体I26(0.45g,855.87umol),I31(0.4g,959.92umol),碳酸钾(354.87mg,2.57mmol)和Pd(dppf)Cl2(31.31mg,42.79umol)混合于二氧六环(10mL)和水(2mL)的混合溶剂中。混合物在氮气氛围下加热至100℃搅拌16小时。待反应液冷却至室温,用20mL水稀释,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物56a(0.38g,516.58umol),淡黄色固体,收率60.4%。MS(ESI):m/z 736.2(M+H)+.
第四步:将化合物56a(0.38g,516.58umol)溶于四氢呋喃(5mL)中,加入4.0mol/L盐酸水溶液(1mL)。混合物在30℃下搅拌1小时。然后用10mL饱和碳酸氢钠水溶液中和,用10mL水稀释,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用10mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到化合物56b(0.35g,506.10umol),淡黄色固体,收率98.0%。MS(ESI):m/z 691.7(M+H)+.
第五步:将化合物56b(0.35g,506.10umol)溶于N,N-二甲基甲酰胺(5mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(241.95mg,1.11mmol)和乙酸(121.57mg,2.02mmol,115.78uL)。混合物在30℃下搅拌16小时。然后向混合物中加入三乙酰氧基硼氢化钠(429.05mg,2.02mmol),反应在30℃下搅拌1小时。然后加入20mL水淬灭,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用10mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到化合物56c(0.35g,319.88umol),淡黄色液体,收率63.2%。MS(ESI):m/z 548.6(M/2+H)+.
第六步:将化合物56c(0.35g,319.88umol)溶于四氢呋喃(2mL)中,加入6.0mol/L盐酸水溶液(2mL)。混合物加热至50℃搅拌3小时。冷却至室温,加入醋酸钠调节pH=4-5,减压蒸去溶剂,加入3mL N,N-二甲基甲酰胺。过滤固体,用1mL N,N-二甲基甲酰胺洗涤固体一次,滤液直接用反向制备色谱分离得到化合物56(0.11g,126.47umol),白色固体,收率39.5%。MS(ESI):m/z 869.7(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.96(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.35(s,1H),8.16(HCOOH,s,0.3H),7.68(d,J=10.5Hz,2H),7.63(d,J=6.0Hz,1H),7.57(s,1H),7.50–7.46(m,2H),7.42–7.32(m,2H),7.06(d,J=7.0Hz,1H),7.04(s,1H),6.88(s,1H),5.73(s,2H),5.36(s,2H),5.12(q,J=12.5Hz,2H),4.07–3.81(m,7H),3.74–3.59(m,4H),3.22–3.15(m,2H),2.18(s,3H).
实施例57:
(4-((3-(1-(4-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)benzyl)-1H-indazol-4-yl)-2-methylbenzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
第一步:将中间体I34(0.12g,175.69umol),中间体I36(151.81mg,210.82umol),碳酸钾(72.84mg,527.06umol)和Pd(dppf)Cl2(12.86mg,17.57umol)混合于二氧六环(10mL)和水(2mL)的混合溶剂中。混合物在氮气氛围下加热至100℃搅拌16小时。待反应液冷却至室温,用20mL水稀释,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用薄层层析分离得到化合物57a(0.13g,108.67umol),淡黄色液体,收率61.9%。MS(ESI):m/z 598.0(M/2+H)+.
第二步:化合物57a(0.13g,108.67umol)溶于四氢呋喃(3mL)中,加入6.0mol/L盐酸水溶液(3mL)。混合物加热至50℃搅拌16小时。冷却至室温,加入醋酸钠调节pH=4-5,减压蒸去溶剂,加入3mL N,N-二甲基甲酰胺。过滤固体,用1mL N,N-二甲基甲酰胺洗涤固体一次,滤液直接用反向制备色谱分离得到化合物57(0.025g,25.72umol),白色固体,收率23.7%。MS(ESI):m/z 971.7(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.03(dd,J=5.0,1.5Hz,2H),8.95(d,J=2.0Hz,1H),8.86(s,1H),8.53(s,1H),8.35(s,1H),8.27(HCCOH,s,1H),7.70–7.68(m,2H),7.58(dd,J=6.0,3.0Hz,1H),7.55(s,1H),7.51(s,1H),7.48(t,J=6.0Hz,1H),7.40–7.34(m,2H),7.17(s,1H),7.06(d,J=7.0Hz,1H),6.87(s,1H),5.72(s,2H),5.42–5.31(m,4H),5.18–5.06(m,2H),3.95–3.84(m,4H),3.63–3.57(m,4H),3.13–3.07(m,2H),2.17(s,3H).
实施例58:
(4-((4-(2-bromo-3-((4-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)phenyl)-1H-in dazol-1-yl)methyl)benzyl)-L-serine
第一步:将4-氯甲基苯甲醛(1.0g,6.47mmol),4-溴-1H-吲唑(1.2g,6.09mmol)和碳酸钾(1.01g,6.09mmol)溶于乙腈(10mL)中。混合物在70℃下搅拌18小时。然后加入50mL水淬灭,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物58a(800mg,2.54mmol),淡黄色固体,收率41.7%。MS(ESI):m/z 315.2(M+H)+.
第二步:将化合物58a(400mg,1.27mmol),联硼酸频那醇酯(386.75mg,1.52mmol),醋酸钾(374.17mg,3.81mmol)和Pd(dppf)Cl2(92.87mg,126.92umol)混合于二氧六环(10mL)中。混合物在氮气氛围下加热至100℃搅拌16小时。待反应液冷却至室温,用50mL乙酸乙酯稀释,硅藻土过滤,在用50mL乙酸乙酯洗涤,浓缩滤液。残留物用快速过柱机分离得到化合物58b(300mg,828.21umol),淡黄色固体,收率65.3%。MS(ESI):m/z 363.2(M+H)+.
第三步:将化合物58b(150mg,414.10umol),中间体I3(230mg,394.11umol),碳酸钾(163.41mg,1.18mmol)和Pd(dppf)Cl2(28.84mg,39.41umol)混合于二氧六环(10mL)和水(2mL)的混合溶剂中。混合物在氮气氛围下加热至80℃搅拌16小时。待反应液冷却至室温,用20mL水稀释,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用薄层层析分离得到化合物58c(140mg,202.33umol),淡黄色固体,收率51.3%。MS(ESI):m/z 691.2(M+H)+.
第四步:将化合物58c(110mg,158.97umol)溶于N,N-二甲基甲酰胺(3mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(103.63mg,476.91umol)和乙酸(105.00mg,1.75mmol,0.1mL)。混合物在30℃下搅拌2小时。然后向混合物中加入三乙酰氧基硼氢化钠(200mg,943.66umol),反应在30℃下搅拌1小时。然后加入20mL水淬灭,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用10mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到化合物58d(120mg,109.63umol),淡黄色液体,收率69.0%。MS(ESI):m/z 547.1(M/2+H)+.
第五步:将化合物58d(120mg,109.63umol)溶于四氢呋喃(3mL)中,加入6mol/L盐酸水溶液(3mL)。混合物加热至50℃搅拌3小时。冷却至室温,加入醋酸钠调节pH=4-5,减压蒸去溶剂,加入3mL N,N-二甲基甲酰胺。过滤固体,用1mL N,N-二甲基甲酰胺洗涤固体一次,滤液直接用反向制备色谱分离得到化合物58(5mg,5.75umol),白色固体,收率5.2%。MS(ESI):m/z 869.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.94(s,1H),8.91(s,1H),8.44(s,1H),7.70(d,J=8.5Hz,1H),7.65(d,J=7.6Hz,2H),7.51–7.45(m,2H),7.42–7.36(m,2H),7.30(d,J=7.7Hz,2H),7.21(d,J=7.8Hz,2H),7.03(s,1H),7.02(s,1H),5.62(s,2H),5.32–5.26(m,4H),3.94–3.79(m,9H),3.08(s,1H),3.02(s,1H).
实施例59:
(4-((4-(2-bromo-3-((4-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)phenyl)-1H-indazol-1-yl)methyl)-3-chlorobenzyl)-L-serine
化合物59的合成方法同化合物58。MS(ESI):m/z 903.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.03–8.96(m,2H),8.49(s,1H),8.20(s,0.5H),7.74(t,J=4.0Hz,2H),7.70(d,J=7.5Hz,1H),7.57–7.53(m,3H),7.50–7.45(m,2H),7.25(d,J=8.0Hz,1H),7.11(d,J=8.0Hz,2H),6.91(d,J=8.0Hz,1H),5.75(s,2H),5.40–5.28(m,4H),3.98(t,J=14.0Hz,2H),3.90(d,J=13.5Hz,2H),3.80(d,J=14.0Hz,2H),3.15(s,2H),3.09(s,2H).
实施例60:
(R)-5-((4-chloro-2-(((1,3-dihydroxy-2-methylpropan-2-yl)amino)methyl)-5-((1'-(3-(3-hydroxypyrrolidin-1-yl)propyl)-1H,1'H-[4,4'-biindazol]-1-yl)methyl)phenoxy)methyl)nicotinonitrile
化合物60的合成基本同化合物54,不同之处在于用中间体I6替代中间体I22,并将2-氨基-2-甲基-1,3-丙二醇替代O-叔丁基-L-丝氨酸叔丁酯。MS(ESI):m/z 735.5(M+H)+.1HNMR(500MHz,d6-DMSO)δ8.94(s,1H),8.86(s,1H),8.32(s,1H),8.04(d,J=6.0Hz,2H),7.77(d,J=8.5Hz,1H),7.72(d,J=8.5Hz,1H),7.61–7.50(m,3H),7.48–7.40(m,2H),6.88(s,1H),5.75(s,2H),5.13(s,2H),4.53(t,J=6.5Hz,2H),4.21(s,2H),3.79(s,2H),3.70–3.63(m,2H),2.76–2.73(m,1H),2.68–2.63(m,1H),2.47–2.40(m,3H),2.06–1.96(m,3H),1.62–1.56(m,1H),0.95(s,3H).
实施例61:
(2S,2'S)-2,2'-((((1H,1'H-[4,4'-biindazole]-1,1'-diylbis(methylene))bis(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxypropanoic acid)
第一步:将中间体I26(0.3g,572.52umol),中间体I29(0.39g,687.02umol),碳酸钾(158.7mg,1.15mmol)和Pd(dppf)Cl2(41.67mg,0.057mmol)混合于二氧六环(10mL)和水(2mL)的混合溶剂中。混合物在氮气氛围下加热至100℃搅拌3小时。待反应液冷却至室温,用20mL水稀释,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到粗品化合物61a(413mg,464.31umol),黑色固体,收率81.1%。MS(ESI):m/z891.2(M+H)+.
第二步:将化合物61a(413mg,464.31umol)溶于四氢呋喃(5mL)中,加入4.0mol/L盐酸水溶液(1mL)。混合物在25℃下搅拌半小时。然后用10mL饱和碳酸氢钠水溶液中和,用10mL水稀释,水溶液用乙酸乙酯萃取(2x30mL)。合并有机相,用10mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到化合物61b(359mg,447.59umol),淡黄色固体,收率96.4%。MS(ESI):m/z 803.8(M+H)+.
第三步:将化合物61b(359mg,447.59umol)溶于N,N-二甲基甲酰胺(5mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(242.82mg,1.12mmol)和乙酸(107.42mg,1.79mmol)。混合物在25℃下搅拌2小时。然后向混合物中加入三乙酰氧基硼氢化钠(379.56mg,1.79mmol),反应在25℃下搅拌半小时。再补加三乙酰氧基硼氢化钠(379.56mg,1.79mmol),并在25℃下继续搅拌半小时。然后加入20mL水淬灭,水溶液用乙酸乙酯萃取(3x50mL)。合并有机相,用20mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物61c(0.25g,207.64umol),淡黄色固体,收率46.4%。MS(ESI):m/z 603.2(M/2+H)+.
第十三步:将化合物61c(0.2g,165.80umol)溶于四氢呋喃(5mL)中,加入6.0mol/L盐酸水溶液(5mL)。混合物加热至50℃搅拌4小时。冷却至室温,加入醋酸钠调节pH=4-5,减压蒸去溶剂,加入5mL N,N-二甲基甲酰胺。过滤固体,用1mL N,N-二甲基甲酰胺洗涤固体一次,滤液直接用反向制备色谱分离得到化合物61(25mg,25.51umol),白色固体,收率15.4%。MS(ESI):m/z 981.3(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.92(d,J=1.5Hz,2H),8.83(s,2H),8.32(s,2H),8.21(HCOOH,s,0.27H),8.07(s,2H),7.73(d,J=8.5Hz,2H),7.65–7.51(m,4H),7.47(d,J=7.0Hz,2H),6.87(s,2H),5.75(s,4H),5.20–5.06(m,4H),3.97(d,J=14.5Hz,2H),3.89(d,J=14.5Hz,2H),3.66(dd,J=11.0,4.5Hz,2H),3.62–3.59(m,2H),3.17(d,J=5.0Hz,2H).
实施例62:
isopropyl
(5-chloro-4-((3-(1-(2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-((((S)-3-hydroxy-1-isopropoxy-1-oxopropan-2-yl)amino)methyl)benzyl)-1H-indazol-4-yl)-2-methylbenzyl)oxy)-2-methoxybenzyl)-L-serinate
/>
将中间体I35(200mg,327.33umol)和中间体I32(215mg,392.80umol)溶于二氧六环(10mL)和水(2mL)的混合溶剂中,加入碳酸钾(90mg,654.66umol)和Pd(dppf)Cl2(24mg,32.73umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用反向制备色谱分离得到化合物62(153mg,160.71umol),白色固体,收率49.1%。MS(ESI):m/z 953.8(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.96(d,J=1.5Hz,1H),8.84(d,J=1.5Hz,1H),8.32(t,J=1.5Hz,1H),7.68(t,J=4.0Hz,2H),7.61(d,J=7.0Hz,1H),7.52–7.45(m,2H),7.39–7.31m,3H),7.05(d,J=7.0Hz,1H),6.97(s,1H),6.87(s,1H),5.71(s,2H),5.32(s,2H),5.14–5.07(m,2H),4.85–4.81(m,2H),3.84(s,3H),3.77(d,J=14.5Hz,1H),3.66–3.62(m,2H),3.57–3.53(m,5H),3.21–3.17(m,2H),2.18(s,3H),1.17–1.15(m,6H),1.11(d,J=6.0Hz,3H),1.08(d,J=6.0Hz,3H).
实施例63:
isopropyl
(5-chloro-4-((3-(1-(2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-((((S)-3-hydroxy-1-isopropoxy-1-oxopropan-2-yl)amino)methyl)benzyl)-1H-indazol-4-yl)-2-methylbenzyl)oxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serinate
化合物63的合成基本同化合物62,不同之处在于用中间体I37替代中间体I32。MS(ESI):m/z 1055.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.02(d,J=2.0Hz,1H),8.98(d,J=2.0Hz,1H),8.94(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.44(t,J=2.0Hz,1H),8.34(t,J=2.0Hz,1H),7.68–7.66(m,2H),7.60–7.55(m,1H),7.53(s,1H),7.50–7.44(m,1H),7.40–7.32(m,3H),7.12(s,1H),7.05(d,J=6.5Hz,1H),6.85(s,1H),5.72(s,2H),5.32–5.30(m,4H),5.13–5.07(m,2H),4.88–4.83(m,2H),3.90–3.83(m,2H),3.74–3.71(m,1H),3.60–3.53(m,4H),3.20(t,J=5.0Hz,2H),3.06–3.04(m,1H),2.17(s,3H),1.13–1.10(m,12H).
实施例64:
(5-chloro-4-((4-(3-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-((((S)-3-hydroxy-1-isopropoxy-1-oxopropan-2-yl)amino)methyl)phenoxy)meth yl)-2-methylphenyl)-1H-indazol-1-yl)methyl)-2-((5-cyanopyridin-3-yl)m ethoxy)benzyl)-L-serine
第一步:将中间体I34(200mg,293.68umol)和中间体I37(229mg,352.42umol)溶于二氧六环(10mL)和水(2mL)的混合溶剂中,加入碳酸钾(81mg,587.36umol)和Pd(dppf)Cl2(22mg,29.37umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物64a(185mg,164.59umol),淡黄色固体,收率56.0%。MS(ESI):m/z563.4(M/2+H)+.
第二步:将化合物64a(185mg,164.59umol)溶于四氢呋喃(2mL)中,加入6.0mol/L盐酸水溶液(2mL)。混合物加热至50℃过夜。冷却至室温,加入醋酸钠(986mg),减压蒸去溶剂,加入4mL N,N-二甲基甲酰胺。过滤固体,用2mL N,N-二甲基甲酰胺洗涤固体一次,滤液直接用反向制备色谱分离得到化合物64(124mg,122.53umol),白色固体,收率74.4%。MS(ESI):m/z 1013.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.02(d,J=2.0Hz,1H),8.98(d,J=2.0Hz,1H),8.94(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.44(t,J=2.0Hz,1H),8.34(t,J=2.0Hz,1H),7.68–7.66(m,2H),7.60–7.55(m,1H),7.53(s,1H),7.50–7.44(m,1H),7.40–7.32(m,3H),7.12(s,1H),7.05(d,J=6.5Hz,1H),6.85(s,1H),5.72(s,2H),5.32–5.30(m,4H),5.13–5.07(m,2H),4.88–4.83(m,1H),3.90–3.83(m,2H),3.74–3.71(m,1H),3.60–3.53(m,5H),3.20(t,J=5.0Hz,1H),3.06–3.04(m,1H),2.17(s,3H),1.13–1.10(m,6H).
实施例65:
(5-chloro-4-((3-(1-(2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-((((S)-3-hydroxy-1-isopropoxy-1-oxopropan-2-yl)amino)methyl)benzyl)-1H-indazol-4-yl)-2-methylbenzyl)oxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
化合物65的合成基本同化合物64,不同之处在于用中间体I35和中间体I36分别替代中间体I34和中间体I37。MS(ESI):m/z 1013.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.03(d,J=2.0Hz,1H),9.02(d,J=2.0Hz,1H),8.95(d,J=2.0Hz,1H),8.83(d,J=2.0Hz,1H),8.52(t,J=2.0Hz,1H),8.30(t,J=2.0Hz,1H),7.69–7.66(m,2H),7.57(dd,J=7.0,2.0Hz,1H),7.52(s,1H),7.50–7.44(m,2H),7.38–7.32(m,2H),7.17(s,1H),7.05(d,J=7.0Hz,1H),6.86(s,1H),5.71(s,2H),5.41–5.28(m,4H),5.09(s,2H),4.83(q,J=6.0Hz,1H),3.96(s,2H),3.79–3.76(m,1H),3.70–3.58(m,3H),3.54(d,J=5.5Hz,2H),3.19(t,J=5.5Hz,1H),3.15(t,J=5.5Hz,1H),2.17(s,3H),1.11(d,J=6.0Hz,3H),1.08(d,J=6.0Hz,3H).
实施例66:
(4-((3-(1-(4-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-2-chloro-5-methoxybenzyl)-1H-indazol-4-yl)-2-methylbenzyl)oxy)-5-chloro-2-methoxybenzyl)-L-serine
第一步:将中间体I28(200mg,529.10umol)和中间体I31(264mg,634.92umol)溶于二氧六环(10mL)和水(2mL)的混合溶剂中,加入碳酸钾(147mg,1.06mmol)和Pd(dppf)Cl2(39mg,52.91umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物66a(203mg,345.24umol),淡黄色固体,收率65.3%。MS(ESI):m/z589.4(M+H)+.
第二步:将化合物66a(203mg,345.24umol)溶于N,N-二甲基甲酰胺(5mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(180mg,828.58umol)和醋酸(83mg,1.38mmol),反应混合物在室温下搅拌3小时,再加入三乙酰氧基硼氢化钠(439mg,2.07mmol),继续在室温下搅拌过夜。加入50mL水淬灭,用乙酸乙酯萃取(3x50mL),合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物66b(310mg,313.13umol),淡黄色固体,收率90.7%。MS(ESI):m/z 991.4(M+H)+.
第三步:将化合物66b(100mg,101.01umol)溶于四氢呋喃(5mL)中,加入6.0mol/L盐酸水溶液(5mL)。混合物加热至50℃过夜。冷却至室温,加入醋酸钠(2.47g),减压蒸去溶剂,加入6mL N,N-二甲基甲酰胺。过滤固体,用2mL N,N-二甲基甲酰胺洗涤固体一次,滤液直接用反向制备色谱分离得到化合物66(23.24mg,30.34umol),白色固体,收率30.0%。MS(ESI):m/z 767.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ7.72(d,J=8.5Hz,1H),7.67(s,1H),7.59(d,J=7.5Hz,1H),7.51–7.47(m,2H),7.47–7.44(m,1H),7.37–7.28(m,2H),7.03(d,J=7.0Hz,1H),7.01(s,1H),6.68(s,1H),5.72(s,2H),5.33(s,2H),3.91–3.79(m,7H),3.71–3.59(m,7H),3.14(t,J=5.5Hz,2H),2.14(s,3H).
实施例67:
(4-((4-(3-((4-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)phenoxy)methyl)-2-methylphenyl)-1H-indazol-1-yl)methyl)-5-chloro-2-methoxybenzyl)-L-serine
化合物67的合成基本同化合物66,不同之处在于用中间体I38替代中间体I31。MS(ESI):m/z 869.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.02(dd,J=4.5,1.9Hz,2H),8.53(d,J=2.0Hz,1H),7.74(d,J=8.5Hz,1H),7.71(s,1H),7.59–7.55(m,1H),7.54–7.49(m,3H),7.37–7.31(m,2H),7.17(s,1H),7.06(d,J=7.0Hz,1H),6.70(s,1H),5.74(s,2H),5.39–5.30(m,4H),4.02–3.95(m,2H),3.91–3.86(m,1H),3.83–3.78(m,1H),3.72–3.60(m,7H),3.16(q,J=6.0Hz,2H),2.16(s,3H).
实施例68:
5-((4-chloro-5-((4-(3-((2-chloro-4-(((2-hydroxyethyl)amino)methyl)-5-methoxyphenoxy)methyl)-2-methylphenyl)-1H-indazol-1-yl)methyl)-2-(((2-hydroxyethyl)amino)methyl)phenoxy)methyl)nicotinonitrile
将化合物56b(100mg,144.93umol)溶于N,N-二甲基甲酰胺(5mL)中,加入乙醇胺(22mg,347.83umol)和醋酸(35mg,579.72mmol),反应混合物在室温下搅拌3小时,再加入三乙酰氧基硼氢化钠(184mg,869.58umol),继续在室温下搅拌过夜。加入50mL水淬灭,用乙酸乙酯萃取(3x50mL),合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用反向制备色谱分离得到化合物68(25.63mg,32.86umol),白色固体,收率22.7%。MS(ESI):m/z 781.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.04(d,J=2.0Hz,1H),8.92(d,J=2.0Hz,1H),8.39(s,1H),7.81–7.74(m,2H),7.70(d,J=7.5Hz,1H),7.61–7.53(m,2H),7.52–7.38(m,3H),7.13(d,J=7.0Hz,1H),7.08(s,1H),6.95(s,1H),5.80(s,2H),5.42(s,2H),5.19(s,2H),3.95(s,3H),3.83(s,2H),3.80(s,2H),3.60–3.58(m,2H),3.57–3.54(m,2H),2.76–2.70(m,2H),2.70–2.64(m,2H),2.26(s,3H).
实施例69:
5-((4-chloro-5-((4-(3-((2-chloro-5-methoxy-4-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)phenoxy)methyl)-2-methylphenyl)-1H-indazol-1-yl)methyl)-2-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)phenoxy)methyl)nicotinonitrile
化合物69的合成基本同化合物68,不同之处在于用(S)-5-(氨甲基)-2-吡咯烷酮替代乙醇胺。MS(ESI):m/z 887.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.96(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.35(s,1H),7.81(s,2H),7.68(d,J=10.5Hz,2H),7.63(d,J=6.0Hz,1H),7.57(s,1H),7.50–7.46(m,2H),7.42–7.32(m,2H),7.06(d,J=7.0Hz,1H),7.04(s,1H),6.88(s,1H),5.73(s,2H),5.36(s,2H),5.12(q,J=12.5Hz,2H),4.07–3.81(m,8H),3.74–3.59(m,5H),3.22–3.15(m,4H),2.18(s,3H),2.01–1.91(m,4H).
实施例70:
1-(4-((3-(1-(4-((3-carboxy-3-methylpyrrolidin-1-yl)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)benzyl)-1H-indazol-4-yl)-2-methylbenzyl)oxy)-5-chloro-2-methoxybenzyl)-3-methylpyrrolidine-3-carboxylic acid
化合物70的合成基本同化合物68,不同之处在于用3-甲基吡咯烷-3-甲酸替代乙醇胺。MS(ESI):m/z 917.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.96(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.35(s,1H),7.68(d,J=10.5Hz,2H),7.63(d,J=6.0Hz,1H),7.57(s,1H),7.50–7.46(m,2H),7.42–7.32(m,2H),7.06(d,J=7.0Hz,1H),7.04(s,1H),6.88(s,1H),5.73(s,2H),5.36(s,2H),5.12(q,J=12.5Hz,2H),4.07–3.81(m,8H),3.74(s,3H),2.40–2.30(m,4H),2.18(s,3H),1.89–1.74(m,4H),1.27(s,6H).
实施例71:
5-((4-chloro-5-((3-(1-(2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-(((2-hydroxyethyl)amino)methyl)benzyl)-1H-indazol-4-yl)-2-methylbenzyl)ox y)-2-(((2-hydroxyethyl)amino)methyl)phenoxy)methyl)nicotinonitrile
第一步:将中间体I27(100mg,208.33umol)和中间体I38(130mg,250.00umol)溶于二氧六环(10mL)和水(2mL)的混合溶剂中,加入碳酸钾(58mg,416.66umol)和Pd(dppf)Cl2(15mg,20.83umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物71a(121mg,152.78umol),淡黄色固体,收率73.3%。MS(ESI):m/z793.4(M+H)+.
第二步:将化合物71a(50mg,63.13umol)溶于N,N-二甲基甲酰胺(5mL)中,加入乙醇胺(10mg,151.51umol)和醋酸(15mg,252.52mmol),反应混合物在室温下搅拌3小时,再加入三乙酰氧基硼氢化钠(81mg,378.78umol),继续在室温下搅拌过夜。加入50mL水淬灭,用乙酸乙酯萃取(3x50mL),合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用反向制备色谱分离得到化合物71(16.54mg,18.75umol),白色固体,收率29.7%。MS(ESI):m/z883.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.03(dd,J=5.0,1.5Hz,2H),8.95(d,J=2.0Hz,1H),8.86(s,1H),8.53(s,1H),8.35(s,1H),7.68(d,J=10.5Hz,2H),7.63(d,J=6.0Hz,1H),7.57(s,1H),7.50–7.46(m,2H),7.42–7.32(m,2H),7.06(d,J=7.0Hz,1H),7.04(s,1H),6.88(s,1H),5.73(s,2H),5.36(s,2H),5.12(q,J=12.5Hz,2H),4.07–3.81(m,8H),3.74–3.59(m,5H),3.22–3.15(m,2H),2.18(s,3H).
实施例72:
5-((2-(aminomethyl)-5-((4-(3-((4-(aminomethyl)-2-chloro-5-methoxyphenoxy)methyl)-2-methylphenyl)-1H-indazol-1-yl)methyl)-4-chlorophenox y)methyl)nicotinonitrile
第一步:将中间体I39(200mg,344.23umol)和中间体I31(172mg,413.08umol)溶于二氧六环(10mL)和水(2mL)的混合溶剂中,加入碳酸钾(95mg,688.46umol)和Pd(dppf)Cl2(25mg,34.42umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物72a(236mg,298.36umol),淡黄色固体,收率86.7%。MS(ESI):m/z792.4(M+H)+.
第二步:将化合物72a(100mg,126.42umol)溶于N,N-二甲基甲酰胺(5mL)中,加入7.0mol/L氨甲醇溶液(0.2mL,1.26mmol)和无水硫酸镁(76mg,632.10mmol),反应混合物在室温下搅拌3小时,再加入三乙酰氧基硼氢化钠(81mg,379.26umol),继续在室温下搅拌过夜。加入50mL水淬灭,用乙酸乙酯萃取(3x50mL),合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物72b(32mg,40.40umol),白色固体,收率29.7%。MS(ESI):m/z 793.4(M+H)+.
第三步:将化合物72b(32mg,40.40umol)溶于二氯甲烷(1mL)中,加入二氯甲烷和三氟乙酸混合溶液(v/v=2mL/1mL)。混合物在室温下搅拌过夜。减压蒸去反应溶剂,加入3mL乙腈,滴加2滴三乙胺,直接用反向制备色谱分离得到化合物72(10.51mg,15.19umol),白色固体,收率37.6%。MS(ESI):m/z 693.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.95(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.35–8.34(m,1H),7.68–7.65(m,2H),7.61(d,J=7.0Hz,1H),7.54(s,1H),7.48(d,J=7.5Hz,1H),7.46–7.44(m,1H),7.39–7.33(m,2H),7.07–7.03(m,2H),6.89(s,1H),5.72(s,2H),5.37(s,2H),5.13(s,2H),3.90(s,3H),3.88(s,2H),3.84(s,2H),2.17(s,3H).
实施例73:
(4-((3-(1-(4-(aminomethyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)be nzyl)-1H-indazol-4-yl)-2-methylbenzyl)oxy)-5-chloro-2-methoxybenzyl)-L-serine
化合物73的合成基本同化合物72,不同之处在于用中间体I33替代中间体I31。MS(ESI):m/z 781.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.96(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.35(s,1H),7.68(d,J=10.5Hz,2H),7.63(d,J=6.0Hz,1H),7.57(s,1H),7.50–7.46(m,2H),7.42–7.32(m,2H),7.06(d,J=7.0Hz,1H),7.04(s,1H),6.88(s,1H),5.73(s,2H),5.36(s,2H),5.12(q,J=12.5Hz,2H),4.07–3.81(m,5H),3.74–3.59(m,3H),3.22–3.15(m,2H),2.18(s,3H).
实施例74:
(4-((4-(3-((4-(aminomethyl)-2-chloro-5-methoxyphenoxy)methyl)-2-methylphenyl)-1H-indazol-1-yl)methyl)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
化合物74的合成基本同化合物72,不同之处在于用中间体I34替代中间体I39。MS(ESI):m/z 781.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.96(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.35(s,1H),8.16(HCOOH,s,0.3H),7.68(d,J=10.5Hz,2H),7.63(d,J=6.0Hz,1H),7.57(s,1H),7.50–7.46(m,2H),7.42–7.32(m,2H),7.06(d,J=7.0Hz,1H),7.04(s,1H),6.88(s,1H),5.73(s,2H),5.36(s,2H),5.12(q,J=12.5Hz,2H),4.07–3.81(m,6H),3.74–3.59(m,2H),3.22–3.15(m,2H),2.18(s,3H).
实施例75:
5-((2-(aminomethyl)-5-((3-(1-(4-(aminomethyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)benzyl)-1H-indazol-4-yl)-2-methylbenzyl)oxy)-4-chlorophenoxy)methyl)nicotinonitrile
化合物75的合成基本同化合物72,不同之处在于用中间体I38替代中间体I31。MS(ESI):m/z 795.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.03(dd,J=5.0,1.5Hz,2H),8.95(d,J=2.0Hz,1H),8.86(s,1H),8.53(s,1H),8.35(s,1H),7.70–7.68(m,2H),7.58(dd,J=6.0,3.0Hz,1H),7.55(s,1H),7.51(s,1H),7.48(t,J=6.0Hz,1H),7.40–7.34(m,2H),7.17(s,1H),7.06(d,J=7.0Hz,1H),6.87(s,1H),5.72(s,2H),5.42–5.31(m,4H),5.18–5.06(m,2H),3.95–3.84(m,2H),3.63–3.57(m,1H),3.13–3.07(m,1H),2.17(s,3H).
实施例76:
(5-chloro-4-((4-(2-chloro-3-(6-methoxy-5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)pyridin-2-yl)phenyl)-1H-indazol-1-yl)methyl)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
第一步:将中间体I34(70mg,102.48umol)和中间体I41(45.95mg,122.98umol)溶于二氧六环(2mL)和水(0.4mL)的混合溶剂中,加入碳酸钾(28.33mg,204.97umol)和Pd(dppf)Cl2(7.50mg,10.25umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离(DCM/MeOH=10/1)得到化合物76a(75mg,88.26umol),黄色固体,收率86.1%。MS(ESI):m/z 849.8(M+H)+.
第二步:将化合物76a(75mg,88.26umol)溶于N,N-二甲基甲酰胺(5mL)中,依次加入(S)-5-氨甲基-2-吡咯烷酮(12.09mg,105.91umol)和醋酸(6.35mg,105.91umol)。混合物在室温下搅拌过夜,然后加入三乙酰氧基硼氢化钠(37.41mg,176.51umol)。反应液在室温下继续搅拌3小时,用50mL饱和碳酸氢钠水溶液淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离(DCM/MeOH=10/1)得到化合物76b(47mg,49.58umol),黄色液体,收率56.2%。MS(ESI):m/z 947.1(M+H)+.
第三步:将化合物76b(47mg,49.58umol)溶于二氯甲烷(1mL)中,加入二氯甲烷(1mL)和三氟乙酸(2mL)的混合溶液。混合物在25℃搅拌4小时。减压蒸去所有溶剂,残留物用反向高效液相制备色谱分离得到化合物76(17.96mg,21.49umol),白色固体,收率43.3%。MS(ESI):m/z 835.8(M+H)+.1H NMR(500MHz,DMSO-d6)δ8.96(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.34(d,J=2.0Hz,1H),7.87–7.81(m,2H),7.74–7.70(m,2H),7.67(dd,J=7.0,2.5Hz,1H),7.60–7.54(m,3H),7.51–7.46(m,1H),7.32(d,J=7.5Hz,1H),7.18(d,J=7.0Hz,1H),6.86(s,1H),5.73(s,2H),5.15–5.07(m,2H),3.96(d,J=14.5Hz,1H),3.92(s,3H),3.89(d,J=14.5Hz,1H),3.73(d,J=3.5Hz,2H),3.68–3.63(m,2H),3.60(dd,J=11.0,6.0Hz,1H),3.17(t,J=5.5Hz,1H),2.57(d,J=6.0Hz,2H),2.16–2.06(m,3H),1.74–1.66(m,1H).
实施例77:
(5-chloro-4-((4-(2-chloro-4'-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1'-biphenyl]-3-yl)-1H-indazol-1-yl)methyl)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
化合物77的合成基本同化合物76,不同之处在于用中间体I42替代中间体I41。MS(ESI):m/z 804.7(M+H)+.1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),8.84(s,1H),8.33(s,1H),7.87(s,1H),7.73–7.67(m,2H),7.56–7.42(m,9H),7.20–7.15(m,1H),6.83(s,1H),5.72(s,2H),5.13–5.05(m,2H),3.93–3.85(m,2H),3.81–3.73(m,2H),3.65–3.55(m,3H),3.08–3.04(m,1H),2.56–2.54(m,2H),2.16–2.04(m,3H),1.75–1.65(m,1H).
实施例78:
(4-((3-(1-(4-((((S)-1-carboxy-2-hydroxyethyl)amino)methyl)-2-chloro-5-((5-cyanopyridin-3-yl)methoxy)benzyl)-3-methyl-1H-indazol-4-yl)-2-methylbenzyl)oxy)-5-chloro-2-methoxybenzyl)-L-serine
化合物78的合成基本同化合物56,不同之处在于在中间体I26合成的步骤中用4-溴-3-甲基-1H-吲唑替代4-溴-1H-吲唑。MS(ESI):m/z 883.5(M+H)+.1H NMR(500MHz,d6-DMSO)δ9.04(d,J=2.0Hz,1H),8.90(d,J=2.0Hz,1H),8.41(s,1H),8.25(HCOOH,s,0.59H),7.72–7.66(m,2H),7.64(s,1H),7.53(s,1H),7.49(t,J=7.5Hz,1H),7.43(t,J=7.5Hz,1H),7.34(d,J=7.5Hz,1H),7.08(s,1H),6.98(d,J=7.0Hz,1H),6.83(d,J=7.0Hz,1H),5.74–5.64(m,2H),5.43(s,2H),5.20-5.14(m,2H),4.07–3.93(m,7H),3.82–3.75(m,2H),3.74–3.68(m,2H),3.29–3.24(m,2H),2.09(s,3H),1.84(s,3H).
实施例79:
5-((5-((2-bromo-3-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)-4-chloro-2-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)nicotinonitrile
化合物79由中间体I3、对应的硼酸酯中间体I7以及(S)-3-吡咯烷醇出发,采用实施例2相同的合成方法得到。MS(ESI):m/z 785.1(M+H)+.1H NMR(500MHz,DMSO-d6)δ9.00(d,J=14.5Hz,2H),8.44(s,1H),7.79–7.69(m,3H),7.58(t,J=7.5Hz,1H),7.52–7.44(m,2H),7.41(s,1H),7.10(d,J=7.5Hz,2H),5.34(d,J=5.5Hz,4H),4.47(t,J=7.0Hz,2H),4.30–4.18(m,2H),3.64(q,J=13.5Hz,2H),2.99–2.87(m,2H),2.85–2.60(m,7H),2.44–2.40(m,1H),2.05–1.97(m,2H),1.93–1.85(m,2H),1.69–1.52(m,4H).
实施例80:
(R)-5-((5-((2-bromo-3-(1-(4-(3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)-4-chloro-2-(((2-hydroxyethyl)amino)methyl)phenoxy)methyl)nicotinonitrile
化合物80由中间体I3、对应的硼酸酯中间体I7以及乙醇胺出发,采用实施例2相同的合成方法得到。MS(ESI):m/z 759.9(M+H)+.1H NMR(500MHz,DMSO-d6)δ9.02(dd,J=9.0,2.0Hz,2H),8.49(t,J=2.0Hz,1H),7.76(d,J=8.5Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.69(s,1H),7.57(t,J=7.5Hz,1H),7.53(s,1H),7.52–7.45(m,2H),7.15–7.09(m,2H),5.36(d,J=9.5Hz,4H),4.47(t,J=7.0Hz,2H),4.27–4.18(m,1H),3.92(s,2H),3.56(t,J=5.5Hz,2H),2.91–2.84(m,1H),2.84–2.73(m,3H),2.72–2.60(m,3H),2.60–2.54(m,1H),2.05–1.94(m,1H),1.94–1.84(m,2H),1.67–1.57(m,1H),1.56–1.46(m,2H).
实施例81:
5-((5-((2-bromo-3-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)-4-chloro-2-((((R)-1-hydroxypropan-2-yl)amino)methyl)phenoxy)methyl)nicotinonitrile
化合物81由中间体I3、对应的硼酸酯中间体I7以及(R)-2-氨基丙醇出发,采用实施例2相同的合成方法得到。MS(ESI):m/z 773.8(M+H)+.1H NMR(500MHz,DMSO-d6)δ9.02(dd,J=6.5,2.0Hz,2H),8.53–8.48(m,1H),7.78–7.72(m,2H),7.69(s,1H),7.60–7.53(m,2H),7.53–7.45(m,2H),7.17–7.08(m,2H),5.36(d,J=16.5Hz,4H),4.47(t,J=7.0Hz,2H),4.24(s,1H),3.92(q,J=13.5Hz,2H),3.52–3.42(m,1H),3.41–3.31(m,1H),3.00–2.79(m,3H),2.78–2.64(m,3H),2.62–2.57(m,1H),2.05–1.95(m,1H),1.95–1.82(m,2H),1.67–1.60(m,1H),1.59–1.44(m,2H),1.04(d,J=6.5Hz,3H).
实施例82:
5-((5-((2-bromo-3-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)-4-chloro-2-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenoxy)methyl)nicotinonitrile
化合物82由中间体I3、对应的硼酸酯中间体I7以及(R)-3-吡咯烷醇出发,采用实施例2相同的合成方法得到。MS(ESI):m/z 784.9(M+H)+.1H NMR(500MHz,DMSO-d6)δ9.01(d,J=2.0Hz,1H),8.98(d,J=2.0Hz,1H),8.43(t,J=2.0Hz,1H),7.77–7.72(m,2H),7.70(s,1H),7.57(t,J=7.5Hz,1H),7.52–7.48(m,1H),7.47–7.44(m,1H),7.42(s,1H),7.10(d,J=7.0Hz,2H),5.34(d,J=7.0Hz,4H),4.47(t,J=7.0Hz,2H),4.32–4.25(m,1H),4.25–4.18(m,1H),3.67(q,J=13.5Hz,2H),3.04–2.91(m,2H),2.88–2.75(m,4H),2.75–2.66(m,2H),2.60–2.52(m,1H),2.47–2.42(m,1H),2.07–1.96(m,2H),1.94–1.85(m,2H),1.72–1.64(m,1H),1.63–1.51(m,3H).
实施例83:
5-((5-((2-bromo-3-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)-4-chloro-2-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)phenoxy)methyl)nicotinonitrile
化合物83由中间体I3、对应的硼酸酯中间体I7以及(S)-5-氨甲基-2-吡咯烷酮出发,采用实施例2相同的合成方法得到。MS(ESI):m/z 812.6(M+H)+.1H NMR(500MHz,DMSO-d6)δ9.02(s,1H),8.99(s,1H),8.44(s,1H),7.77(d,J=8.5Hz,1H),7.75–7.71(m,2H),7.70(s,1H),7.57(t,J=7.5Hz,1H),7.50(t,J=8.0Hz,1H),7.47–7.44(m,2H),7.12–7.08(m,2H),5.35(s,2H),5.33(s,2H),4.47(t,J=7.0Hz,2H),4.25(dp,J=6.3,2.8Hz,1H),3.77–3.67(m,2H),3.66–3.59(m,1H),2.96–2.85(m,2H),2.80–2.68(m,3H),2.67–2.61(m,1H),2.57–2.52(m,2H),2.15–1.99(m,4H),1.94–1.83(m,2H),1.70–1.61(m,2H),1.58–1.47(m,2H).
实施例84:
1-(4-((2-bromo-3-(1-(4-((R)-3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-3-methylpyrrolidine-3-carboxylic acid
化合物84由中间体I3、对应的硼酸酯中间体I7以及3-甲基吡咯烷-3-甲酸出发,采用实施例2相同的合成方法得到。MS(ESI):m/z829.6(M+H)+.1H NMR(500MHz,DMSO-d6)δ9.01(s,1H),8.98(s,1H),8.42(s,1H),7.78–7.72(m,2H),7.69(s,1H),7.57(t,J=7.5Hz,1H),7.51–7.44(m,2H),7.38(s,1H),7.11–7.08(m,2H),5.34(s,2H),5.33(s,2H),4.46(t,J=7.0Hz,2H),4.22–4.17(m,1H),3.64–3.51(m,2H),2.91(d,J=9.0Hz,1H),2.82–2.75(m,1H),2.74–2.67(m,1H),2.61–2.53(m,5H),2.48–2.44(m,1H),2.32–2.24(m,2H),2.01–1.93(m,1H),1.91–1.83(m,2H),1.60–1.52(m,2H),1.50–1.43(m,2H),1.22(s,3H).
实施例85:
(R)-5-((5-((2-bromo-3-(1-(4-(3-hydroxypyrrolidin-1-yl)butyl)-1H-indazol-4-yl)benzyl)oxy)-4-chloro-2-(pyrrolidin-1-ylmethyl)phenoxy)methyl)nicotinonitrile
化合物85由中间体I3、对应的硼酸酯中间体I7以及四氢吡咯出发,采用实施例2相同的合成方法得到。MS(ESI):m/z 769.6(M+H)+.1H NMR(500MHz,DMSO-d6)δ9.01(s,1H),8.98(s,1H),8.44(s,1H),7.78–7.72(m,2H),7.69(s,1H),7.57(t,J=7.5Hz,1H),7.51–7.45(m,2H),7.38(s,1H),7.12–7.08(m,2H),5.34(s,4H),4.46(t,J=7.0Hz,2H),4.21–4.17(m,1H),3.60(s,2H),2.79–2.74(m,1H),2.71–2.65(m,1H),2.55–2.52(m,5H),2.49–2.47(m,2H),2.45–2.41(m,1H),2.00–1.93(m,1H),1.91–1.85(m,2H),1.74–1.70(m,4H),1.60–1.53(m,1H),1.50–1.43(m,2H).
实施例86:
(4-((2-bromo-3-(1-(4-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)butyl)-1H-indazol-4-yl)benzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
第一步:将4-溴-1H-吲唑(2.5g,12.69mmol)和1-溴-4-氯丁烷(4.35g,25.38mmol)溶于乙腈(15mL)中,加入碳酸钾(5.26g,38.06mmol)。反应混合物于70℃下搅拌过夜。将反应液冷却至室温,过滤,浓缩。残留物用快速过柱机分离得到化合物86a(1.9g,6.61mmol),淡黄色液体,收率52.1%。MS(ESI):m/z 287.4(M+H)+.
第二步:将化合物86a(380mg,1.32mmol)和(S)-5-氨甲基-2-吡咯烷酮(301.65mg,2.64mmol)溶于N,N-二甲基甲酰胺(5mL)中,加入碳酸钾(364.32mg,2.64mmol)和碘化钾(219.35mg,1.32mmol)。反应混合物于50℃下搅拌过夜。将反应液冷却至室温,加入50mL水,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到化合物86b(450mg,1.23mmol),淡黄色液体,收率93.2%。MS(ESI):m/z 365.4(M+H)+.
第三步:将化合物86b(450mg,1.23mmol)溶于二氯甲烷(10mL)中,依次加入三乙胺(249.32mg,2.46mmol)和二碳酸二叔丁酯(268.88mg,1.23mmol)。混合物在室温下搅拌过夜。反应液用100mL二氯甲烷稀释,有机相依次用50mL水和50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离(DCM/MeOH=10/1)得到化合物86c(500mg,1.07mmol),黄色液体,收率87.2%。MS(ESI):m/z 465.5(M+H)+.
第四步:将化合物86c(500mg,1.07mmol)和双联硼酸频那醇酯(409.24mg,1.61mmol)溶于1,4-二氧六环(10mL)中,加入醋酸钾(316.32mg,3.22mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(78.61mg,107.44umol)。反应混合物在氮气氛围下100℃搅拌5小时。将反应液冷却至室温,加入100mL乙酸乙酯,经硅藻土过滤,滤饼用100mL乙酸乙酯洗涤,浓缩滤液。残留物用快速过柱机分离(DCM/MeOH=85/15)得到化合物86d(280mg,546.40umol),黄色液体,收率50.9%。MS(ESI):m/z 513.4(M+H)+.
第五步:将中间体I43(150mg,191.11umol)和化合物86d(100mg,200.63umol)溶于二氧六环(5mL)和水(0.5mL)的混合溶剂中,加入碳酸钾(83.19mg,601.90umol)和Pd(dppf)Cl2(14.68mg,20.06umol)。混合物在氮气氛围下加热至80℃搅拌过夜。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到化合物86e(180mg,174.85umol),黄色液体,收率87.2%。MS(ESI):m/z 1042.8(M+H)+.
第六步:将化合物86e(180mg,174.85umol)溶于二氯甲烷(1mL)中,加入二氯甲烷(1mL)和三氟乙酸(2mL)的混合溶液。混合物在25℃搅拌4小时。减压蒸去所有溶剂,残留物用反向高效液相制备色谱分离得到化合物86(14.14mg,17.30umol),白色固体,收率9.9%。MS(ESI):m/z 830.7(M+H)+.1H NMR(500MHz,DMSO-d6)δ9.04–8.97(m,2H),8.56–8.44(m,1H),7.85(t,J=15.5Hz,1H),7.79–7.66(m,3H),7.59–7.55(m,2H),7.52–7.44(m,2H),7.17–7.06(m,2H),5.44–5.30(m,4H),4.47(s,2H),4.03(s,2H),3.71(s,2H),3.68–3.61(m,1H),3.21(s,1H),2.79–2.69(m,4H),2.14–2.06(m,3H),1.93–1.87(m,2H),1.72–1.62(m,1H),1.57–1.49(m,2H).
实施例87:
(4-((2-bromo-3-(1-(3-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)propyl)-1H-indazol-4-yl)benzyl)oxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
化合物87的合成基本同化合物86,不同之处在于用1-溴-3-氯丙烷替代1-溴-4-氯丁烷。MS(ESI):m/z 816.4(M+H)+.1H NMR(500MHz,DMSO-d6)δ9.06–8.98(m,2H),8.56–8.44(m,1H),7.79–7.70(m,4H),7.61–7.54(m,2H),7.50(t,J=8.0Hz,1H),7.47–7.41(m,1H),7.16–7.07(m,2H),5.40–5.31(m,4H),4.53(t,J=6.5Hz,2H),4.01(s,2H),3.74–3.62(m,3H),3.19(s,1H),2.70–2.59(m,4H),2.14–2.04(m,5H),1.73–1.63(m,1H).
实施例88:
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4-(3-(3-((R)-3-hydroxyp yrrolidin-1-yl)propoxy)-2-methylphenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl)benzyl)-L-serine
化合物88的合成基本同化合物54,不同之处在于在合成中间体I26的过程中用4-溴-1H-吡唑并[3,4-b]吡啶替代4-溴-1H-吲唑。MS(ESI):m/z 726.6(M+H)+.1H NMR(500MHz,DMSO-d6)δ8.92(d,J=2.0Hz,1H),8.82(d,J=2.0Hz,1H),8.59(d,J=4.5Hz,1H),8.32(t,J=2.0Hz,1H),7.88(s,1H),7.53(s,1H),7.30(t,J=8.0Hz,1H),7.15(d,J=4.5Hz,1H),7.07(d,J=8.0Hz,1H),6.96(d,J=7.5Hz,1H),6.89(s,1H),5.74(s,2H),5.13–5.05(m,2H),4.26–4.17(m,1H),4.08(t,J=6.0Hz,2H),3.96–3.84(m,2H),3.66–3.55(m,2H),3.14(t,J=5.5Hz,1H),2.89–2.82(m,1H),2.82–2.68(m,3H),2.67–2.59(m,1H),2.56–2.49(m,1H),2.01(s,3H),1.99–1.93(m,3H),1.63–1.56(m,1H).
实施例89:
(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((4-(3-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-2-methylphenyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)methyl)benzyl)-L-serine
化合物89的合成基本同化合物54,不同之处在于在合成中间体I26的过程中用4-溴-1H-吡唑并[3,4-c]吡啶替代4-溴-1H-吲唑。MS(ESI):m/z 726.6(M+H)+.1H NMR(500MHz,DMSO-d6)δ9.20(s,1H),8.96(d,J=2.0Hz,1H),8.90(d,J=2.0Hz,1H),8.40(t,J=2.0Hz,1H),8.14(s,1H),7.91(s,1H),7.55(s,1H),7.29(t,J=8.0Hz,1H),7.11–7.04(m,2H),6.94(d,J=7.5Hz,1H),5.85(s,2H),5.21–5.14(m,2H),4.23–4.16(m,1H),4.08(t,J=6.0Hz,2H),3.96–3.82(m,2H),3.62–3.54(m,2H),3.10(t,J=5.5Hz,1H),2.73(dd,J=9.5,6.0Hz,1H),2.65–2.56(m,3H),2.47–2.44(m,1H),2.36(dd,J=9.5,3.5Hz,1H),1.99(s,3H),1.98–1.90(m,3H),1.58–1.51(m,1H).
实施例90:
(5-chloro-4-((4-(2-chloro-3-((4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)benzyl)oxy)phenyl)-1H-indazol-1-yl)methyl)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
第一步:将化合物90a(260mg,1.02mmol)溶于乙腈(10mL)中,加入碳酸钾(282.37mg,2.04mmol),4-氯甲基苯甲醛(189.51mg,1.23mmol)和碘化钾(67.83mg,408.62umol)。混合物加热至70℃搅拌过夜。用100mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离(PE/EA=5/1)得到化合物90b(207mg,555.48umol),白色固体,收率54.4%。
第二步:将中间体I34(50mg,73.20umol)和化合物90b(32.73mg,87.84umol)溶于二氧六环(5mL)和水(1mL)的混合溶剂中,加入碳酸钾(20.23mg,146.41umol)和Pd(dppf)Cl2(5.36mg,7.32umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离(PE/EA=2/1)得到化合物90c(53mg,62.44umol),黄色液体,收率85.3%。MS(ESI):m/z 848.4(M+H)+.
第三步:将化合物90c(53mg,62.44umol)溶于N,N-二甲基甲酰胺(2mL)中,依次加入(R)-3-吡咯烷醇盐酸盐(23.15mg,187.32umol)和乙酸钠(15.36mg,187.32umol)。混合物在室温下搅拌过夜,然后加入三乙酰氧基硼氢化钠(42.31mg,374.64umol)。反应液在室温下搅拌2小时,用50mL饱和碳酸氢钠水溶液淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离(DCM/MeOH=10/1)得到化合物90d(19mg,20.65umol),黄色液体,收率33.1%。MS(ESI):m/z919.8(M+H)+.
第四步:将化合物90d(19mg,20.65umol)溶于四氢呋喃(1mL)中,加入6mol/L盐酸水溶液(1mL)。混合物在50℃下搅拌过夜。待反应冷却至室温,反应液用醋酸钠(500mg)中和,减压蒸去所有溶剂,残留物用反向高效液相制备色谱分离得到化合物90(5.31mg,6.57umol),白色固体,收率31.8%。MS(ESI):m/z 807.5(M+H)+.1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),8.84(s,1H),8.33(t,J=2.0Hz,1H),7.75–7.73(m,1H),7.71–7.66(m,1H),7.53(s,1H),7.48–7.44(m,4H),7.44–7.40(m,1H),7.37–7.32(m,3H),7.13–7.08(m,2H),5.74–5.68(m,2H),5.25(s,2H),5.13–5.05(m,2H),4.21–4.15(m,1H),3.77–3.72(m,1H),3.63–3.51(m,6H),2.70–2.63(m,2H),2.44–2.35(m,1H),2.33–2.28(m,1H),2.02–1.95(m,1H),1.57–1.49(m,1H).
实施例91:
(5-chloro-4-((4-(2-chloro-4'-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1'-biphenyl]-3-yl)-1H-indol-1-yl)methyl)-2-methoxybenzyl)-L-serine
/>
第一步:将中间体I44(268.43mg,1.02mmol),4-溴吲哚(200mg,1.02mmol)和碳酸钾(281.99mg,2.04mmol)溶于N,N-二甲基甲酰胺(5mL)中。混合物在60℃下搅拌3小时。待反应液冷却至室温,加入100mL水淬灭,水相用乙酸乙酯萃取(2x100mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物91a(120mg,283.89umol),淡黄色固体,收率27.8%。MS(ESI):m/z 422.1(M+H)+.
第二步:将化合物91a(120mg,283.89umol)溶于四氢呋喃(3mL)中,加入4.0mol/L盐酸水溶液(1mL)。混合物在30℃下搅拌1小时。然后用50mL饱和碳酸氢钠水溶液中和,用50mL水稀释,水溶液用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。得到化合物91b(100mg,264.10umol),淡黄色固体,收率93.0%。MS(ESI):m/z 378.3(M+H)+.
第三步:将化合物91b(100mg,264.10umol)溶于N,N-二甲基甲酰胺(3mL)中,加入O-叔丁基-L-丝氨酸叔丁酯(68.87mg,316.92umol)和乙酸(19.02mg,316.92umol)。混合物在室温下搅拌1小时。然后向混合物中加入三乙酰氧基硼氢化钠(447.78mg,2.11mmol),反应在室温下搅拌1小时。然后加入50mL水淬灭,水溶液用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物91c(86mg,148.29umol),黄色液体,收率56.1%。MS(ESI):m/z 579.1(M+H)+.
第四步:将化合物91c(86mg,148.29umol)和中间体I42(60.97mg,177.95umol)溶于二氧六环(5mL)和水(0.5mL)的混合溶剂中,加入碳酸钾(40.93mg,296.58umol)和Pd(dppf)Cl2(10.84mg,14.83umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物91d(76mg,106.04umol),黄色固体,收率71.5%。MS(ESI):m/z 716.5(M+H)+.
第五步:将化合物91d(76mg,106.04umol)溶于N,N-二甲基甲酰胺(5mL)中,依次加入(S)-5-氨甲基-2-吡咯烷酮(18.16mg,159.06umol)和醋酸(9.54mg,159.06umol)。混合物在室温下搅拌过夜,然后加入三乙酰氧基硼氢化钠(44.95mg,212.08umol)。反应液在室温下继续搅拌3小时,用50mL饱和碳酸氢钠水溶液淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物91e(45mg,55.29umol),黄色液体,收率52.1%。MS(ESI):m/z 813.1(M+H)+.
第六步:将化合物91e(45mg,55.29umol)溶于二氯甲烷(1mL)中,加入二氯甲烷(1mL)和三氟乙酸(2mL)的混合溶液。混合物在25℃搅拌4小时。减压蒸去所有溶剂,残留物用反向高效液相制备色谱分离得到化合物91(13.75mg,19.60umol),白色固体,收率35.4%。MS(ESI):m/z 701.6(M+H)+.1H NMR(500MHz,DMSO-d6)δ7.68(s,H),7.55(d,J=2.0Hz,1H),7.50–7.40(m,10H),7.22(t,J=8.0Hz,1H),7.04(d,J=8.0Hz,1H),6.22(t,J=3.0Hz,1H),5.50(s,2H),3.77(m,2H),3.65–3.63(m,5H),3.55–3.53(m,3H),1.71–1.68(m,1H).
实施例92:
(5-chloro-4-((4-(2-chloro-4'-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1'-biphenyl]-3-yl)-1H-benzo[d][1,2,3]triazol-1-yl)methyl)-2-m ethoxybenzyl)-L-serine
化合物92的合成基本同化合物91,不同之处在于用4-溴-1H-苯并三氮唑替代4-溴吲哚。MS(ESI):m/z 703.4(M+H)+.1H NMR(500MHz,DMSO-d6)δ7.86(d,J=8.4Hz,1H),7.68(s,1H),7.64(t,J=7.7Hz,1H),7.55–7.52(m,3H),7.49–7.45(m,5H),7.41(d,J=7.1Hz,1H),7.11(s,1H),6.05(s,2H),3.89(d,J=14.5Hz,1H),3.84–3.77(m,3H),3.74(s,3H),3.67–3.64(m,2H),3.62–3.58(m,1H),3.18–3.15(m,1H),2.59(d,J=6.1Hz,2H),2.14–2.08(m,3H),1.73–1.68(m,1H).
实施例93:
(5-chloro-4-((4-(2-chloro-4'-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)-[1,1'-biphenyl]-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-methoxybenzyl)-L-serine
化合物93的合成基本同化合物91,不同之处在于用4-溴-1H-苯并咪唑替代4-溴吲哚。MS(ESI):m/z 702.7(M+H)+.1H NMR(500MHz,DMSO-d6)δ8.32(s,1H),7.67(s,1H),7.62(d,J=8.0Hz,1H),7.52(s,1H),7.47–7.41(m,7H),7.32(t,J=7.5Hz,1H),7.21(d,J=7.0Hz,1H),7.05(s,1H),5.58(s,2H),3.90–3.85(m,1H),3.81–3.75(m,3H),3.71(s,3H),3.66–3.59(m,3H),3.14(s,1H),2.56(d,J=6.0Hz,2H),2.13–2.08(m,3H),1.72–1.68(m,1H).
实施例94:
(5-chloro-4-((4-(2-chloro-3-((9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-1H-indazol-1-yl)methyl)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
第一步:将化合物94a(200mg,786.26umol)溶于二氯甲烷(3mL)中,加入3-溴-2-氯苯甲醛(224.32mg,1.02mmol)和乙酸(94.43mg,1.57mmol)。混合物在室温下搅拌过夜。然后向混合物中加入三乙酰氧基硼氢化钠(666.56mg,3.15mmol),反应在室温下搅拌3小时。然后加入50mL水淬灭,水溶液用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物94b(200mg,436.84umol),黄色液体,收率55.6%。MS(ESI):m/z 457.4(M+H)+.
第二步:将化合物94b(200mg,436.84umol)溶于二氯甲烷(3mL)中,加入4.0mol/L盐酸二氧六环溶液(436.84uL,1.75mmol)。混合物在室温下3小时。然后浓缩反应液得到化合物94c(172mg,436.35umol),黄色固体,收率99.9%。MS(ESI):m/z 357.4(M+H)+.
第三步:将化合物94c(172mg,436.35umol)溶于甲醇(5mL)中,加入***(141.66mg,1.75mmol,129.96uL)和乙酸(52.41mg,872.71umol)。混合物在室温下搅拌1小时。然后向混合物中加入三乙酰氧基硼氢化钠(369.92mg,1.75mmol),反应在室温下搅拌3小时。然后加入50mL水淬灭,水溶液用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物94d(160mg,430.41umol),黄色液体,收率98.6%。MS(ESI):m/z 371.2(M+H)+.
第四步:将化合物94d(32.66mg,87.84umol)和中间体I45(50mg,73.20umol)溶于二氧六环(3mL)和水(0.3mL)的混合溶剂中,加入碳酸钾(30.35mg,219.61umol)和Pd(dppf)Cl2(5.36mg,7.32umol)。混合物在氮气氛围下加热至80℃搅拌3小时。用50mL水淬灭反应,水相用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层层析分离得到化合物94e(20mg,22.35umol),黄色液体,收率30.5%。MS(ESI):m/z895.0(M+H)+.
第五步:将化合物94e(20mg,22.35umol)溶于二氯甲烷(1mL)中,加入二氯甲烷(1mL)和三氟乙酸(2mL)的混合溶液。混合物在25℃搅拌4小时。减压蒸去所有溶剂,残留物用反向高效液相制备色谱分离得到化合物94(5mg,6.39umol),白色固体,收率28.6%。MS(ESI):m/z 782.7(M+H)+.1H NMR(500MHz,DMSO-d6)δ8.94(d,J=1.9Hz,1H),8.84(d,J=2.1Hz,1H),8.32(t,J=2.2Hz,1H),7.74–7.65(m,2H),7.58(dd,J=7.6,1.9Hz,1H),7.54(s,1H),7.45(t,J=7.6Hz,2H),7.39(dd,J=7.6,1.8Hz,1H),7.10(d,J=7.0Hz,1H),6.80(s,1H),5.70(s,2H),5.14–5.02(m,2H),3.95–3.88(m,2H),3.65(s,2H),3.60–3.55(m,2H),3.15–3.09(m,1H),2.61–2.54(m,2H),2.48–2.41(m,5H),2.39–2.26(m,4H),1.55–1.43(m,8H).
实施例95:
(5-chloro-4-((4-(2-chloro-3-(9-methyl-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-1H-indazol-1-yl)methyl)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
第一步:将化合物94a(200mg,786.26umol)和3-溴-2-氯苯甲酸(240.68mg,1.02mmol)溶于N,N-二甲基甲酰胺(6mL)中,依次加入N,N-二异丙基乙胺(263.16mg,2.04mmol)和HATU(298.96mg,786.26umol)。混合物在室温下搅拌过夜。然后向混合物中加入三乙酰氧基硼氢化钠(666.56mg,3.15mmol),反应在室温下搅拌3小时。然后加入50mL水淬灭,水溶液用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物95a(240mg,508.67umol),黄色液体,收率64.7%。MS(ESI):m/z 471.3(M+H)+.
第二步至第五步与化合物94的步骤类似。最终得到化合物95(7mg,8.79umol),白色固体。MS(ESI):m/z 796.7(M+H)+.1H NMR(500MHz,DMSO-d6)δ8.94(d,J=2.1Hz,1H),8.83(d,J=2.1Hz,1H),8.32(s,1H),7.76(s,1H),7.72(d,J=8.5Hz,1H),7.58–7.49(m,3H),7.48–7.41(m,2H),7.15(d,J=7.0Hz,1H),6.79(s,1H),5.72(s,2H),5.08(d,J=3.9Hz,2H),3.92–3.85(m,2H),3.73–3.70(m,2H),3.57–3.56(m,2H),3.21–3.19(m,2H),3.05–3.03(m,1H),2.36–2.30(m,4H),2.19(s,3H),1.50–1.38(m,8H).
实施例96:
(5-chloro-4-((4-(2-chloro-3-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)-1H-indazol-1-yl)methyl)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)-L-serine
第一步:将化合物94a(200mg,786.26umol)和1,3-二溴-2-氯苯(212.57mg,786.26umol)溶于甲苯(3mL)中,依次加入Pd2(dba)3(36.00mg,39.31umol)和叔丁醇钠(75.56mg,786.26umol)。混合物在氮气氛围下加热至100℃搅拌过夜。然后加入50mL水淬灭,水溶液用乙酸乙酯萃取(3x50mL)。合并有机相,用50mL饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物96a(250mg,563.31umol),黄色液体,收率71.6%。MS(ESI):m/z 443.3(M+H)+.
第二步至第五步与化合物94的步骤类似。最终得到化合物96(10mg,13.01umol),白色固体。MS(ESI):m/z 782.7(M+H)+.1H NMR(500MHz,DMSO-d6)δ8.95(d,J=2.1Hz,2H),8.84(d,J=2.0Hz,1H),8.32(t,J=2.1Hz,1H),7.72(s,1H),7.67(d,J=8.5Hz,1H),7.54(s,1H),7.48–7.36(m,2H),7.27(dd,J=8.2,1.6Hz,1H),7.16–7.06(m,2H),6.78(s,1H),5.71(s,2H),5.13–5.03(m,2H),3.97–3.73(m,2H),3.65–3.55(m,2H),3.15–3.09(m,1H),3.00(t,J=5.5Hz,4H),2.50–2.38(m,4H),2.32–2.24(m,3H),1.64–1.49(m,8H).
细胞水平PD-1/PD-L1信号抑制的生物活性检测
本检测方法用于本发明所述化合物的细胞水平生物学活性评价。
实验原理
本检测方法采用荧光素酶报告基因法检测化合物对细胞水平PD-1/PD-L1信号抑制的生物活性。PD-1/NFAT-Reporter-Jurkat细胞稳定表达人PD-1,且表达由NFAT元件调控的荧光素酶报告基因;TCR activator/PD-L1-CHO细胞稳定表达人PD-L1和TCR激活元件。当两株细胞共培养时,PD-1/PD-L1的结合会抑制TCR信号通路,从而抑制下游NFAT控制的荧光素酶报告基因表达。当加入PD-1/PD-L1抗体或者抑制剂,这种抑制作用被反转,荧光素酶表达,从而可以检测PD-1/PD-L1抑制剂对荧光素酶活性影响。
实验材料与设备
PD-1/NFAT-Reporter-Jurkat细胞(货号60535)以及TCR activator/PD-L1-CHO细胞(货号60536)购自BPS Bioscience公司;PD-L1抗体(Atezolizumab,货号A2004)购自Selleck公司;荧光素酶检测试剂(ONE-GloTMLuciferase Assay System,货号E6120)购自Promega公司;多功能微孔板检测仪(型号SpectraMax i3x)购自Molecular Devices公司。
实验主要过程
按常规细胞培养实验操作流程培养PD-1/NFAT-Reporter-Jurkat细胞和TCRactivator/PD-L1-CHO细胞。
收集TCR activator/PD-L1-CHO细胞并按照35000个/每孔,接种到96孔培养板中,培养基体积为100微升,37℃孵育过夜。第二天,弃去培养基,加入化合物孵育30分钟,同时设置溶剂对照(二甲基亚砜,DMSO,终浓度0.1%)和PD-L1抗体(Atezolizumab,终浓度约10nM)阳性对照。再加入PD-1/NFAT-reporter-Jurkat细胞。继续培养6小时后,按荧光素酶检测试剂说明书检测荧光素酶活性。
以PD-L1抗体作为阳性对照,计算测试化合物的PD-1/PD-L1结合抑制率(%)=(化合物处理孔化学发光值/溶剂对照孔化学发光值平均值–1)/(PD-L1抗体孔化学发光值平均值/溶剂对照孔化学发光值平均值–1)×100%。
根据上述检测方法,对本发明所述化合物进行细胞水平生物学活性评价。
数据小结见下表。
本发明的化合物的活性数据如下:
/>
/>
由上述结果可见,本发明的化合物可有效抑制PD-1和PD-L1结合,具有良好的PD-1/PD-L1结合抑制活性。
Claims (29)
1.化合物,具有如下式(II)结构、式(III)结构或式(IV)结构:
其中,W1表示CRc或者N;Z1和Z2各自独立地表示氢、(C1-C6)烷基、(C3-C6)环烷基、卤代(C1-C6)烷基、卤素、-ORa、-C(O)ORa、
(C1-C6)烷氧基、-NRaRb、-SO2Ra、氰基、硝基;
R2表示-(C0-C6亚烷基)NRARB或-O(C0-C6亚烷基)NRARB;
R3表示氢、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)卤代烷基、卤素、-ORa、-C(O)ORa、(C1-C6)烷氧基、-NRaRb、-SO2Ra、氰基、硝基;
Y表示-(C0-C6亚烷基)(C6-C10芳基)、-(C0-C6亚烷基)(5-10元杂芳基)、-O(C1-C6)烷基、-O(C0-C6亚烷基)(C6-C10芳基)、-O(C0-C6亚烷基)(5-10元杂芳基)、-(C0-C6亚烷基)O(C6-C10芳基)、-(C0-C6亚烷基)O(5-10元杂芳基)、-O(C0-C6亚烷基)(C3-C6环烷基)或-O(C0-C6亚烷基)(3-6元杂环烷基);
对于上述Y定义中的亚烷基、烷基、环烷基、杂环烷基、杂芳基而言,其任选地被0、1、2或3个选自以下的取代基所取代:-ORa、氰基、氧代(=O)、卤素、C1-C6烷基、-(C1-C6亚烷基)ORa、C1-C6氰基烷基、C1-C6卤代烷基、C3-C8环烷基、
-C(O)Ra、-(C1-C6亚烷基)C(O)Ra、-C(O)ORa、-(C1-C6烷基)C(O)ORa、-NRaRb、-(C1-C6亚烷基)NRaRb、-C(O)NRaRb、SO2Ra、-C(O)NRaSO2Rb或者-NRaC(O)Rb;
或者Y表示-O(C0-C6亚烷基)CONRARB;
A表示-(C0-C6亚烷基)NRARB、-O(C0-C6亚烷基)NRARB、
-C(O)(C0-C6亚烷基)NRARB、-(C0-C6亚烷基)(C3-C6环烷基)NRARB或-(3-6元杂环烷基)CHRARB;
或者A表示
其中,Q表示-(C0-C6亚烷基)-、-(C0-C6亚烷基)O-或-O(C0-C6亚烷基)-;
W5表示CH或N;
R4表示-(C0-C6亚烷基)NRARB、-O(C0-C6亚烷基)NRARB或-C(O)NRARB;
R5表示氢、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)卤代烷基、卤素、-ORa、-C(O)ORa、(C1-C6)烷氧基、-NRaRb、-SO2Ra、氰基或硝基;
R6表示氢、-(C0-C6亚烷基)(C6-C10芳基)、-(C0-C6亚烷基)(5-10元杂芳基)、-O(C1-C6)烷基、-O(C0-C6亚烷基)CONRARB、
-O(C0-C6亚烷基)(C6-C10芳基)、-O(C0-C6亚烷基)(5-10元杂芳基)、-(C0-C6亚烷基)O(C6-C10芳基)、-(C0-C6亚烷基)O(5-10元杂芳基)、-O(C0-C6亚烷基)(C3-C6环烷基)或-O(C0-C6亚烷基)(3-6元杂环烷基);
对于上述R6定义中的亚烷基、烷基、环烷基、芳基、杂芳基而言,其任选地被0、1、2或3个选自以下的取代基所取代:-ORa、氰基、卤素、C1-C6烷基、-(C1-C6亚烷基)ORa、C1-C6氰基烷基、C1-C6卤代烷基、C3-C8环烷基、-C(O)Ra、-(C1-C6亚烷基)C(O)Ra、-C(O)ORa、
-(C1-C6烷基)C(O)ORa、-NRaRb、-(C1-C6亚烷基)NRaRb、
-C(O)NRaRb、-SO2Ra、-C(O)NRaSO2Rb或者-NRaC(O)Rb;
表示任意地连接位置;
m、n、o、p选自0、1、2和3;
RA、RB分别独立地表示氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、-(C0-C6亚烷基)(C3-C6环烷基)、-(C0-C6亚烷基)(3-6元杂环烷基)、-(C0-C6亚烷基)(C6-C10芳基)、-(C0-C6亚烷基)(5-10元杂芳基)、-(C0-C6烷基)C(O)ORa、-SO2Ra、-SO2NRaRb或-C(O)NRaSO2Rb;
对于上述RA、RB定义中的亚烷基、烷基、烯基、炔基、环烷基、芳基、杂芳基而言,其任选地被0、1、2或3个选自以下的取代基所取代:-ORa、氰基、氧代、卤素、C1-C6烷基、-(C1-C6亚烷基)ORa、C1-C6氰基烷基、C1-C6卤代烷基、C3-C8环烷基、-C(O)Ra、-(C1-C6亚烷基)C(O)Ra、-C(O)ORa、-(C1-C6烷基)C(O)ORa、-NRaRb、-(C1-C6亚烷基)NRaRb、-C(O)NRaRb、-SO2Ra、-C(O)NRaSO2Rb或者-NRaC(O)Rb;
或者RA和RB一起和与之相连的原子共同环合形成5-7元环,并且该环还任选地具有0、1、2或3个选自O、N、S的杂原子,进一步地,该环还任选地被0、1、2或3个选自以下的取代基所取代:氧代、氰基、C1-C6烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、-ORa、-C(O)ORa、-(C1-C6)氰基烷基、(C1-C6)卤代烷基、-(C1-C6亚烷基)ORa、-C(O)Ra、-NRaRb、-(C1-C6亚烷基)NRaRb、-C(O)NRaRb、-(C1-C6亚烷基)C(O)NRaRb、-SO2Ra、-(C1-C6亚烷基)SO2Ra、-SO2NRaRb或者-(C1-C6亚烷基)SO2NRaRb;
Ra、Rb分别独立地表示氢、C1-C6烷基、-(C0-C6亚烷基)(C3-C6环烷基)、-(C0-C6亚烷基)(C3-C6杂环烷基)、-(C0-C6亚烷基)(C6-C10芳基)或-(C0-C6亚烷基)(5-10元杂芳基);
或者Ra、Rb一起和与之相连的原子共同环合形成5-7元环,并且该环还任选地具有0、1、2或3个选自O、N、S的杂原子,进一步地,该环还任选地被0、1、2或3个选自以下的取代基所取代:氧代、氰基、C1-C6烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、-ORd、-C(O)ORd、-(C1-C6)氰基烷基、(C1-C6)卤代烷基、-(C1-C6亚烷基)ORd、-C(O)Rd、-NRdRe、-(C1-C6亚烷基)NRdRe、-C(O)NRdRe、-(C1-C6亚烷基)C(O)NRdRe、-SO2Rd、-(C1-C6亚烷基)SO2Rd、-SO2NRdRe或者-(C1-C6亚烷基)SO2NRdRe;
其中,Rc、Rd、Re分别独立地表示氢、C1-C6烷基或C3-C6环烷基。
2.如权利要求1所述的化合物,其中R2表示-(C0-C6亚烷基)NRARB,其中RA、RB分别独立地表示氢或者表示被-ORa、-C(O)Ra、-C(O)ORa所取代的C1-C6烷基,其中Ra和Rb分别独立地表示氢或者C1-C6烷基。
3.如权利要求1所述的化合物,其中Y表示被-ORa、氰基、卤素、C1-C6烷基、-(C1-C6亚烷基)ORa、C1-C6氰基烷基、-C(O)ORa、-NRaRb、-C(O)NRaRb、SO2Ra、-C(O)NRaSO2Rb或者-NRaC(O)Rb所取代的-O(C1-C6)烷基、-O(C0-C6亚烷基)(C6-C10芳基)、-O(C0-C6亚烷基)(5-10元杂芳基)、-O(C1-C6)烷基、-(C0-C6亚烷基)O(C6-C10芳基)或-(C0-C6亚烷基)O(5-10元杂芳基),其中Ra、Rb分别独立地表示氢或者C1-C6烷基。
4.如权利要求1-3任一项所述的化合物,其中Y选自-O-(C1-C6烷基),其中所述C1-C6烷基任选地被0、1或2个氰基、卤素、羟基、-C(O)NH2、氨基、磺酸基、羧基所取代。
5.如权利要求1-3任一项所述的化合物,其中Y选自
6.如权利要求1-3任一项所述的化合物,其中Y选自-O(C0-C6亚烷基)(3-6元杂环烷基),其中所述3-6元杂环烷基任选地被氧代、C1-C6烷基、羟基所取代。
7.如权利要求1-3任一项所述的化合物,其中Y选自
8.如权利要求1-3任一项所述的化合物,其中Y选自 其中W4和W5分别独立地表示CH或者N;p表示0、1、2或3;Z3表示氢、(C1-C6)烷基、(C3-C6)环烷基、卤代(C1-C6)烷基、卤素、-ORa、-C(O)ORa、(C1-C6)烷氧基、-NRaRb、-SO2Ra、氰基或硝基;Ra和Rb表示氢或者C1-C6烷基。
9.如权利要求1-3任一项所述的化合物,其中Y选自
10.如权利要求1-3任一项所述的化合物,其中Y选自其中Z4表示氢、C1-C6烷基、氰基、氰甲基或C3-C6环烷基。
11.如权利要求1-3任一项所述的化合物,其中Y选自
12.如权利要求1-3任一项所述的化合物,其中Y表示-O(C0-C6亚烷基)CONRARB,其中RA和RB分别独立地表示氢或者任意地被-ORa、-NRaRb、-C(O)NRaRb所取代的C1-C6烷基,其中Ra、Rb分别独立地表示氢或者C1-C6烷基。
13.如权利要求1-3任一项所述的化合物,其中Y选自
14.如权利要求1-3任一项所述的化合物,其中Y表示-O(C0-C6亚烷基)CONRARB,其中RA和RB一起和与之相连的氮原子共同环合形成5-7元环,并且该环还任选地具有0、1、2或3个选自O、N、S的杂原子,进一步地,该环还任选地被0、1、2或3个选自以下的取代基所取代:氰基、C1-C6烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、-ORa、-C(O)ORa、-(C1-C6)氰基烷基、(C1-C6)卤代烷基、-(C1-C6亚烷基)ORa、-C(O)Ra、-NRaRb,其中,Ra、Rb分别独立地表示氢或者C1-C6烷基。
15.如权利要求1-3任一项所述的化合物,其中Y选自
16.如权利要求1-3任一项所述的化合物,其中A表示-(C0-C6亚烷基)NRARB,其中,RA、RB一起和与之相连的原子共同环合形成5-7元环,并且该环还任选地具有0、1、2或3个选自O、N、S的杂原子,进一步地,该环还可以任意地被0、1、2或3个选自以下的取代基所取代:氧代、氰基、C1-C6烷基、C3-C6环烷基、C2-C6烯基、C2-C6炔基、-ORa、-C(O)ORa、-(C1-C6)氰基烷基、(C1-C6)卤代烷基、-(C1-C6亚烷基)ORa、-C(O)Ra、-NRaRb、-(C1-C6亚烷基)NRaRb、-C(O)NRaRb、-(C1-C6亚烷基)C(O)NRaRb、-SO2Ra、-(C1-C6亚烷基)SO2Ra、-SO2NRaRb或者-(C1-C6亚烷基)SO2NRaRb,其中Ra、Rb分别独立地表示氢或者C1-C6烷基。
17.如权利要求1-3任一项所述的化合物,其中A选自:
18.如权利要求1-3任一项所述的化合物,其中A选自:
19.如权利要求1-3任一项所述的化合物,其中A表示
其中,
Q表示-(C0-C6亚烷基)-、-(C0-C6亚烷基)O-或-O(C0-C6亚烷基)-;W6表示CH或N;
R4表示-(C0-C6亚烷基)NRARB,
其中,RA、RB分别独立地表示氢或者被-ORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-SO2Ra、-C(O)NRaSO2Rb或者-NRaC(O)Rb所取代的C1-C6烷基;
R5表示氢、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)卤代烷基、卤素、-ORa、-C(O)ORa、(C1-C6)烷氧基、-NRaRb、-SO2Ra、氰基或硝基;
R6表示氢或者被下述基团取代的-O(C1-C6)烷基、-O(C0-C6亚烷基)(C6-C10芳基)或-O(C0-C6亚烷基)(5-10元杂芳基):-ORa、氰基、卤素、C1-C6烷基、-(C1-C6亚烷基)ORa、C1-C6氰基烷基、-C(O)ORa、-NRaRb、-C(O)NRaRb、SO2Ra、-C(O)NRaSO2Rb或者-NRaC(O)Rb;
其中,Ra和Rb分别独立地表示氢或者C1-C6烷基;
q表示0、1、2或3。
20.如权利要求1-3任一项所述的化合物,其中,R2选自
21.如权利要求1-3任一项所述的化合物,其中,R2选自
22.如权利要求1-3任一项所述的化合物,其中W5表示CH。
23.如权利要求1-3任一项所述的化合物,其中Z1或Z2表示氢、卤素、氰基或C1-C6烷基。
24.如权利要求1-3任一项所述的化合物,其中Z1或Z2表示氯或者溴。
25.化合物,其具有如下结构之一:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
26.药物组合物,其包含权利要求1-25任一项所述的化合物,并且任选地进一步包含另外的治疗剂和/或免疫检查点抑制剂。
27.如权利要求1-25任一项所述的化合物或者权利要求26所述的药物组合物在制备对抑制PD-L1与PD-1结合有响应的疾病或病症的药物中的应用。
28.如权利要求27所述的应用,其中所述疾病或病症选自肿瘤、病毒感染、炎症相关疾病和自身免疫性疾病。
29.如权利要求27所述的应用,其中所述疾病或病症选自癌症。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110060670.2A CN112876458B (zh) | 2019-02-21 | 2020-02-20 | 细胞程序性死亡-配体-1拮抗剂化合物 |
CN202110060679.3A CN112876463B (zh) | 2019-02-21 | 2020-02-20 | 一种制备pd-l1拮抗剂的中间体及其制备方法 |
CN202110060576.7A CN112876411A (zh) | 2019-02-21 | 2020-02-20 | 化合物及其在合成pdl1拮抗剂类药物分子中的应用 |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2019101303131 | 2019-02-21 | ||
CN201910130313 | 2019-02-21 | ||
CN201910695768 | 2019-07-30 | ||
CN2019106957688 | 2019-07-30 | ||
PCT/CN2020/075938 WO2020169058A1 (zh) | 2019-02-21 | 2020-02-20 | Pd-l1拮抗剂化合物 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110060576.7A Division CN112876411A (zh) | 2019-02-21 | 2020-02-20 | 化合物及其在合成pdl1拮抗剂类药物分子中的应用 |
CN202110060679.3A Division CN112876463B (zh) | 2019-02-21 | 2020-02-20 | 一种制备pd-l1拮抗剂的中间体及其制备方法 |
CN202110060670.2A Division CN112876458B (zh) | 2019-02-21 | 2020-02-20 | 细胞程序性死亡-配体-1拮抗剂化合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112313220A CN112313220A (zh) | 2021-02-02 |
CN112313220B true CN112313220B (zh) | 2023-11-03 |
Family
ID=72143312
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110060679.3A Active CN112876463B (zh) | 2019-02-21 | 2020-02-20 | 一种制备pd-l1拮抗剂的中间体及其制备方法 |
CN202110060670.2A Active CN112876458B (zh) | 2019-02-21 | 2020-02-20 | 细胞程序性死亡-配体-1拮抗剂化合物 |
CN202110060576.7A Pending CN112876411A (zh) | 2019-02-21 | 2020-02-20 | 化合物及其在合成pdl1拮抗剂类药物分子中的应用 |
CN202080003296.6A Active CN112313220B (zh) | 2019-02-21 | 2020-02-20 | Pd-l1拮抗剂化合物 |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110060679.3A Active CN112876463B (zh) | 2019-02-21 | 2020-02-20 | 一种制备pd-l1拮抗剂的中间体及其制备方法 |
CN202110060670.2A Active CN112876458B (zh) | 2019-02-21 | 2020-02-20 | 细胞程序性死亡-配体-1拮抗剂化合物 |
CN202110060576.7A Pending CN112876411A (zh) | 2019-02-21 | 2020-02-20 | 化合物及其在合成pdl1拮抗剂类药物分子中的应用 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20220227733A1 (zh) |
EP (1) | EP3929188A4 (zh) |
JP (1) | JP7281834B2 (zh) |
CN (4) | CN112876463B (zh) |
TW (1) | TW202045487A (zh) |
WO (1) | WO2020169058A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20220121254A (ko) * | 2019-12-26 | 2022-08-31 | 애들레이 노르티 바이오파마 컴퍼니 리미티드 | Pd-l1 길항제 화합물 |
WO2023104744A1 (en) | 2021-12-06 | 2023-06-15 | Helmholtz-Zentrum Dresden-Rossendorf E.V. | 3-((3-([1,1'-biphenyl]-3-ylmethoxy)phenoxy)methyl)benzonitrile derivatives and the use thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018009505A1 (en) * | 2016-07-08 | 2018-01-11 | Bristol-Myers Squibb Company | 1,3-dihydroxy-phenyl derivatives useful as immunomodulators |
WO2018195321A1 (en) * | 2017-04-20 | 2018-10-25 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
CN109665968A (zh) * | 2017-10-16 | 2019-04-23 | 四川科伦博泰生物医药股份有限公司 | 并环化合物及其制备方法和用途 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2693377A1 (en) * | 2007-07-21 | 2009-01-29 | Albany Molecular Research, Inc. | 5-pyridinone substituted indazoles |
AU2014315457B2 (en) * | 2013-09-04 | 2018-05-10 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
US9850225B2 (en) * | 2014-04-14 | 2017-12-26 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
JP6905053B2 (ja) * | 2016-05-23 | 2021-07-21 | 中国医学科学院薬物研究所Institute Of Materia Medica, Chinese Academy Of Medical Sciences | ベンジルフェニルエーテル誘導体、その調製方法、並びにその医薬組成物及び使用 |
WO2018119263A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Heterocyclic compounds derivatives as pd-l1 internalization inducers |
-
2020
- 2020-02-20 CN CN202110060679.3A patent/CN112876463B/zh active Active
- 2020-02-20 CN CN202110060670.2A patent/CN112876458B/zh active Active
- 2020-02-20 TW TW109105556A patent/TW202045487A/zh unknown
- 2020-02-20 JP JP2021517249A patent/JP7281834B2/ja active Active
- 2020-02-20 EP EP20760039.6A patent/EP3929188A4/en active Pending
- 2020-02-20 CN CN202110060576.7A patent/CN112876411A/zh active Pending
- 2020-02-20 US US17/281,251 patent/US20220227733A1/en active Pending
- 2020-02-20 WO PCT/CN2020/075938 patent/WO2020169058A1/zh unknown
- 2020-02-20 CN CN202080003296.6A patent/CN112313220B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018009505A1 (en) * | 2016-07-08 | 2018-01-11 | Bristol-Myers Squibb Company | 1,3-dihydroxy-phenyl derivatives useful as immunomodulators |
WO2018195321A1 (en) * | 2017-04-20 | 2018-10-25 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
CN109665968A (zh) * | 2017-10-16 | 2019-04-23 | 四川科伦博泰生物医药股份有限公司 | 并环化合物及其制备方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
CN112876463A (zh) | 2021-06-01 |
US20220227733A1 (en) | 2022-07-21 |
EP3929188A4 (en) | 2022-10-12 |
WO2020169058A1 (zh) | 2020-08-27 |
CN112876463B (zh) | 2022-11-11 |
JP2022501397A (ja) | 2022-01-06 |
JP7281834B2 (ja) | 2023-05-26 |
CN112876458B (zh) | 2022-10-04 |
EP3929188A1 (en) | 2021-12-29 |
CN112313220A (zh) | 2021-02-02 |
CN112876458A (zh) | 2021-06-01 |
CN112876411A (zh) | 2021-06-01 |
TW202045487A (zh) | 2020-12-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2944573T3 (es) | Antagonistas de TLR7/8 y usos de los mismos | |
TWI827641B (zh) | Tlr7/8拮抗劑及其用途 | |
US20200369648A1 (en) | Tlr7/8 antagonists and uses thereof | |
CN111548343B (zh) | 一种高活性csf1r抑制剂化合物的制备方法 | |
WO2019158070A1 (zh) | A2a和/或a2b受体拮抗剂 | |
CN116348469A (zh) | 一种高活性Wnt通路抑制剂化合物 | |
CN112313220B (zh) | Pd-l1拮抗剂化合物 | |
CN115066423B (zh) | Pd-l1拮抗剂化合物 | |
US20230399327A1 (en) | High activity hpk1 kinase inhibitor | |
JP7436630B2 (ja) | アデノシン受容体拮抗薬 | |
TWI768781B (zh) | 轉化生長因子-β受體抑制劑 | |
CN112592354B (zh) | 一种异噁唑并嘧啶类杂环化合物的制备方法 | |
LU505117B1 (en) | A pan-KRAS inhibitor compound | |
CN118047799A (zh) | 一种pan-KRAS抑制剂化合物 | |
CN116348117A (zh) | Hpk1激酶抑制剂化合物 | |
CN117903169A (zh) | 一种pan-KRAS抑制剂化合物 | |
CN117396482A (zh) | 一种Wnt通路抑制剂化合物 | |
CN116806220A (zh) | 一种Wnt通路抑制剂化合物 | |
CN117534685A (zh) | 一种pan-KRAS抑制剂化合物 | |
CN116848103A (zh) | 高活性hpk1激酶抑制剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
TA01 | Transfer of patent application right | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20211125 Address after: 361000 floor 3-5, No. 188, Pingcheng South Road, Haicang street, Haicang District, Xiamen City, Fujian Province Applicant after: Xiamen Baotai Biotechnology Co.,Ltd. Address before: 311100 Building 8, 1008 Xiangxiang street, Cangqian street, Yuhang District, Hangzhou City, Zhejiang Province Applicant before: Hangzhou Arnold Biomedical Technology Co.,Ltd. |
|
GR01 | Patent grant | ||
GR01 | Patent grant |