DK2414369T3 - Imidazo [2,1-b] [1,3,4] thiadiazole derivatives - Google Patents

Info

Publication number

DK2414369T3

DK2414369T3 DK10715318.1T DK10715318T DK2414369T3 DK 2414369 T3 DK2414369 T3 DK 2414369T3 DK 10715318 T DK10715318 T DK 10715318T DK 2414369 T3 DK2414369 T3 DK 2414369T3

Authority

DK

Denmark

Prior art keywords

imidazo

phenyl

optionally substituted

pyridin

thiadiazol

Prior art date

2009-04-02

Links

• Espacenet
• Global Dossier
• Discuss

• UVNXNSUKKOLFBM-UHFFFAOYSA-N imidazo[2,1-b][1,3,4]thiadiazole Chemical class N1=CSC2=NC=CN21 UVNXNSUKKOLFBM-UHFFFAOYSA-N 0.000 title claims description 4
• 150000001875 compounds Chemical class 0.000 claims description 195
• 125000001424 substituent group Chemical group 0.000 claims description 126
• 125000001072 heteroaryl group Chemical group 0.000 claims description 69
• 125000003118 aryl group Chemical group 0.000 claims description 59
• -1 5-methoxy-pyridin-3-yl Chemical group 0.000 claims description 57
• 125000000217 alkyl group Chemical group 0.000 claims description 51
• 229910052739 hydrogen Inorganic materials 0.000 claims description 50
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 48
• 239000001257 hydrogen Substances 0.000 claims description 46
• 125000005842 heteroatom Chemical group 0.000 claims description 37
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 35
• 238000000034 method Methods 0.000 claims description 34
• 201000010099 disease Diseases 0.000 claims description 33
• 150000002148 esters Chemical class 0.000 claims description 32
• 206010028980 Neoplasm Diseases 0.000 claims description 30
• 238000011282 treatment Methods 0.000 claims description 29
• 150000001408 amides Chemical class 0.000 claims description 28
• 125000001153 fluoro group Chemical group F* 0.000 claims description 28
• 229910052757 nitrogen Inorganic materials 0.000 claims description 27
• 125000005843 halogen group Chemical group 0.000 claims description 25
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
• 125000004429 atom Chemical group 0.000 claims description 24
• 150000003839 salts Chemical class 0.000 claims description 24
• 201000011510 cancer Diseases 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
• 125000004122 cyclic group Chemical group 0.000 claims description 20
• 125000002950 monocyclic group Chemical group 0.000 claims description 20
• 229910052760 oxygen Inorganic materials 0.000 claims description 20
• 125000002619 bicyclic group Chemical group 0.000 claims description 18
• 239000003814 drug Substances 0.000 claims description 16
• 208000035475 disorder Diseases 0.000 claims description 15
• 239000012453 solvate Substances 0.000 claims description 15
• 238000002360 preparation method Methods 0.000 claims description 14
• 230000008569 process Effects 0.000 claims description 14
• 229910052717 sulfur Inorganic materials 0.000 claims description 14
• 150000002431 hydrogen Chemical class 0.000 claims description 13
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
• 239000002671 adjuvant Substances 0.000 claims description 12
• 239000003085 diluting agent Substances 0.000 claims description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• 229940124597 therapeutic agent Drugs 0.000 claims description 10
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
• 230000002062 proliferating effect Effects 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 7
• 201000001320 Atherosclerosis Diseases 0.000 claims description 7
• 208000020084 Bone disease Diseases 0.000 claims description 6
• 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 6
• 230000004663 cell proliferation Effects 0.000 claims description 6
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
• 206010018364 Glomerulonephritis Diseases 0.000 claims description 5
• 206010003246 arthritis Diseases 0.000 claims description 5
• AKQNKCWKASWGJF-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-(2-methylsulfanylpyrimidin-5-yl)imidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C1=CN=C(SC)N=C1 AKQNKCWKASWGJF-UHFFFAOYSA-N 0.000 claims description 4
• RIEWWHCPDPFGRL-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-(2-piperazin-1-ylpyrimidin-5-yl)imidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C1=CN=C(N2CCNCC2)N=C1 RIEWWHCPDPFGRL-UHFFFAOYSA-N 0.000 claims description 4
• ZMXPAPWWMBZNTB-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-(6-methoxypyridin-3-yl)-6-methylimidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=NC(OC)=CC=C1C1=C(C)N=C2N1N=C(C=1C=C(OC)C(OC)=CC=1)S2 ZMXPAPWWMBZNTB-UHFFFAOYSA-N 0.000 claims description 4
• 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 4
• 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 4
• 206010061218 Inflammation Diseases 0.000 claims description 4
• 208000009905 Neurofibromatoses Diseases 0.000 claims description 4
• 102100026379 Neurofibromin Human genes 0.000 claims description 4
• 201000004681 Psoriasis Diseases 0.000 claims description 4
• 208000026935 allergic disease Diseases 0.000 claims description 4
• 239000013066 combination product Substances 0.000 claims description 4
• 229940127555 combination product Drugs 0.000 claims description 4
• 208000027866 inflammatory disease Diseases 0.000 claims description 4
• 230000004054 inflammatory process Effects 0.000 claims description 4
• 201000004931 neurofibromatosis Diseases 0.000 claims description 4
• 208000015768 polyposis Diseases 0.000 claims description 4
• 208000005069 pulmonary fibrosis Diseases 0.000 claims description 4
• ADEIBKBMBBTEDS-UHFFFAOYSA-N tert-butyl 4-[4-[5-(2-aminopyrimidin-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-2-methoxyphenoxy]piperidine-1-carboxylate Chemical compound COC1=CC(C=2SC3=NC=C(N3N=2)C=2C=NC(N)=NC=2)=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 ADEIBKBMBBTEDS-UHFFFAOYSA-N 0.000 claims description 4
• SVHAYHRTCVVVHC-UHFFFAOYSA-N tert-butyl 4-[5-[2-(3,4-dimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyrimidin-2-yl]piperazine-1-carboxylate Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C1=CN=C(N2CCN(CC2)C(=O)OC(C)(C)C)N=C1 SVHAYHRTCVVVHC-UHFFFAOYSA-N 0.000 claims description 4
• VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 4
• 238000002054 transplantation Methods 0.000 claims description 4
• 230000002792 vascular Effects 0.000 claims description 4
• RWWQTLSCTIVVRI-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-(2-methylsulfinylpyrimidin-5-yl)imidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C1=CN=C(S(C)=O)N=C1 RWWQTLSCTIVVRI-UHFFFAOYSA-N 0.000 claims description 3
• HUTMTGYICXIPIA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-(3-fluoro-4-methylsulfonylphenyl)-6-methylimidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC(C)=C2C1=CC=C(S(C)(=O)=O)C(F)=C1 HUTMTGYICXIPIA-UHFFFAOYSA-N 0.000 claims description 3
• IAGZELQWGJLYMJ-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C1=CN=C(N2CCN(C)CC2)N=C1 IAGZELQWGJLYMJ-UHFFFAOYSA-N 0.000 claims description 3
• TYUAFSOVSKDGIB-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-[6-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C(C=C1C(F)(F)F)=CN=C1N1CCN(C)CC1 TYUAFSOVSKDGIB-UHFFFAOYSA-N 0.000 claims description 3
• OMOMOEILAGAXCG-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-[6-piperazin-1-yl-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C(C=C1C(F)(F)F)=CN=C1N1CCNCC1 OMOMOEILAGAXCG-UHFFFAOYSA-N 0.000 claims description 3
• RSNYNBZETHZDBU-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-6-methyl-5-pyridin-3-ylimidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC(C)=C2C1=CC=CN=C1 RSNYNBZETHZDBU-UHFFFAOYSA-N 0.000 claims description 3
• NWZFUZORNWLJOQ-UHFFFAOYSA-N 2-(3-methoxy-4-piperidin-4-yloxyphenyl)-5-(6-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=NC(OC)=CC=C1C1=CN=C2N1N=C(C=1C=C(OC)C(OC3CCNCC3)=CC=1)S2 NWZFUZORNWLJOQ-UHFFFAOYSA-N 0.000 claims description 3
• BRXLDWIKOGTBQT-UHFFFAOYSA-N 2-[4-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]-6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]-2-methoxyphenoxy]-n,n-dimethylacetamide Chemical compound C1=C(OCC(=O)N(C)C)C(OC)=CC(C=2SC3=NC(C)=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 BRXLDWIKOGTBQT-UHFFFAOYSA-N 0.000 claims description 3
• QWFJSMCERPTIKB-UHFFFAOYSA-N 5-[2-(3,4-dimethoxyphenyl)-6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1h-pyridin-2-one Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC(C)=C2C1=CC=C(O)N=C1 QWFJSMCERPTIKB-UHFFFAOYSA-N 0.000 claims description 3
• BYZDTGPFYDEWOP-UHFFFAOYSA-N 5-[2-(3,4-dimethoxyphenyl)-6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC(C)=C2C1=CN=C(N)C(C(F)(F)F)=C1 BYZDTGPFYDEWOP-UHFFFAOYSA-N 0.000 claims description 3
• AENJYOUQPLPPMH-UHFFFAOYSA-N 5-[2-(3,4-dimethoxyphenyl)-6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyridine-2-carbonitrile Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC(C)=C2C1=CC=C(C#N)N=C1 AENJYOUQPLPPMH-UHFFFAOYSA-N 0.000 claims description 3
• LQKQKJIRALJYEC-UHFFFAOYSA-N 5-[2-(3,4-dimethoxyphenyl)-6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyrimidin-2-amine Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC(C)=C2C1=CN=C(N)N=C1 LQKQKJIRALJYEC-UHFFFAOYSA-N 0.000 claims description 3
• NJNVCRQDBBXSPC-UHFFFAOYSA-N 5-[2-(3,4-dimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyridine-2-carbonitrile Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C1=CC=C(C#N)N=C1 NJNVCRQDBBXSPC-UHFFFAOYSA-N 0.000 claims description 3
• ZOLVBLFHQQAYHY-UHFFFAOYSA-N 5-[2-(3-methoxy-4-piperidin-4-yloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyrimidin-2-amine Chemical compound COC1=CC(C=2SC3=NC=C(N3N=2)C=2C=NC(N)=NC=2)=CC=C1OC1CCNCC1 ZOLVBLFHQQAYHY-UHFFFAOYSA-N 0.000 claims description 3
• WTNIEFBGQTVEOI-UHFFFAOYSA-N 5-[2-(3-morpholin-4-ylsulfonylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=CN=C2N1N=C(C=1C=C(C=CC=1)S(=O)(=O)N1CCOCC1)S2 WTNIEFBGQTVEOI-UHFFFAOYSA-N 0.000 claims description 3
• IADDDQNVAOFGGG-UHFFFAOYSA-N 5-[2-(4-morpholin-4-ylsulfonylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=CN=C2N1N=C(C=1C=CC(=CC=1)S(=O)(=O)N1CCOCC1)S2 IADDDQNVAOFGGG-UHFFFAOYSA-N 0.000 claims description 3
• OCSQYJPBIKNLOZ-UHFFFAOYSA-N 5-[2-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]-6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound COC1=CC(C=2SC3=NC(C)=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=CC=C1OCCN1CCOCC1 OCSQYJPBIKNLOZ-UHFFFAOYSA-N 0.000 claims description 3
• UAQOVZOKHHGSKX-UHFFFAOYSA-N 5-[5-(4-methylsulfonylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CN=C2N1N=C(C=1C=C(C(N)=NC=1)C(F)(F)F)S2 UAQOVZOKHHGSKX-UHFFFAOYSA-N 0.000 claims description 3
• USYWDCIKSBYJOL-UHFFFAOYSA-N 5-[5-(6-fluoropyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C(S1)=NN2C1=NC=C2C1=CC=C(F)N=C1 USYWDCIKSBYJOL-UHFFFAOYSA-N 0.000 claims description 3
• 208000012124 AIDS-related disease Diseases 0.000 claims description 3
• 208000023275 Autoimmune disease Diseases 0.000 claims description 3
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 3
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 3
• 208000035473 Communicable disease Diseases 0.000 claims description 3
• 206010062016 Immunosuppression Diseases 0.000 claims description 3
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 3
• 208000012902 Nervous system disease Diseases 0.000 claims description 3
• 230000006044 T cell activation Effects 0.000 claims description 3
• 108090000190 Thrombin Proteins 0.000 claims description 3
• 208000036142 Viral infection Diseases 0.000 claims description 3
• 230000030833 cell death Effects 0.000 claims description 3
• 208000015114 central nervous system disease Diseases 0.000 claims description 3
• 230000001066 destructive effect Effects 0.000 claims description 3
• 206010012601 diabetes mellitus Diseases 0.000 claims description 3
• 239000005556 hormone Substances 0.000 claims description 3
• 229940088597 hormone Drugs 0.000 claims description 3
• 230000001506 immunosuppresive effect Effects 0.000 claims description 3
• 208000019423 liver disease Diseases 0.000 claims description 3
• WJBBQRAWMLWHGB-UHFFFAOYSA-N methyl 4-[2-[6-amino-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-2-methoxybenzoate Chemical compound C1=C(OC)C(C(=O)OC)=CC=C1C1=CN=C2N1N=C(C=1C=C(C(N)=NC=1)C(F)(F)F)S2 WJBBQRAWMLWHGB-UHFFFAOYSA-N 0.000 claims description 3
• UJAVCRZZTZJNJN-UHFFFAOYSA-N n-[[3-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazol-2-yl]phenyl]methyl]methanesulfonamide Chemical compound CS(=O)(=O)NCC1=CC=CC(C=2SC3=NC=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 UJAVCRZZTZJNJN-UHFFFAOYSA-N 0.000 claims description 3
• 210000000056 organ Anatomy 0.000 claims description 3
• 230000001575 pathological effect Effects 0.000 claims description 3
• 208000037803 restenosis Diseases 0.000 claims description 3
• 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 3
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
• DHYKYBOWIVIKSA-UHFFFAOYSA-N tert-butyl n-[2-[4-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]-6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]-2-methoxyphenoxy]ethyl]carbamate Chemical compound C1=C(OCCNC(=O)OC(C)(C)C)C(OC)=CC(C=2SC3=NC(C)=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 DHYKYBOWIVIKSA-UHFFFAOYSA-N 0.000 claims description 3
• 229960004072 thrombin Drugs 0.000 claims description 3
• 230000009385 viral infection Effects 0.000 claims description 3
• 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 2
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
• QXVYXFLTVOHZHN-UHFFFAOYSA-N 5-[2-(3-methoxy-4-piperidin-4-yloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound COC1=CC(C=2SC3=NC=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=CC=C1OC1CCNCC1 QXVYXFLTVOHZHN-UHFFFAOYSA-N 0.000 claims description 2
• 208000024827 Alzheimer disease Diseases 0.000 claims description 2
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 2
• 206010019842 Hepatomegaly Diseases 0.000 claims description 2
• 208000029462 Immunodeficiency disease Diseases 0.000 claims description 2
• 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 7
• 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 3
• 208000017701 Endocrine disease Diseases 0.000 claims 2
• 125000002843 carboxylic acid group Chemical group 0.000 claims 2
• 238000003776 cleavage reaction Methods 0.000 claims 2
• 208000030172 endocrine system disease Diseases 0.000 claims 2
• 208000015181 infectious disease Diseases 0.000 claims 2
• 208000030159 metabolic disease Diseases 0.000 claims 2
• 230000004060 metabolic process Effects 0.000 claims 2
• 230000000414 obstructive effect Effects 0.000 claims 2
• 208000023504 respiratory system disease Diseases 0.000 claims 2
• 230000007017 scission Effects 0.000 claims 2
• YBPINIBANNZBJJ-UHFFFAOYSA-N 2,4-difluoro-n-[2-methoxy-5-(5-pyridazin-4-ylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyridin-3-yl]benzenesulfonamide Chemical compound COC1=NC=C(C=2SC3=NC=C(N3N=2)C=2C=NN=CC=2)C=C1NS(=O)(=O)C1=CC=C(F)C=C1F YBPINIBANNZBJJ-UHFFFAOYSA-N 0.000 claims 1
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 1
• 208000004403 Prostatic Hyperplasia Diseases 0.000 claims 1
• KDUXFZBQLUGABF-UHFFFAOYSA-N n-[3-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazol-2-yl]phenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC(C=2SC3=NC=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 KDUXFZBQLUGABF-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 200
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 189
• 229910052796 boron Inorganic materials 0.000 description 104
• 239000000203 mixture Substances 0.000 description 97
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 94
• 239000000047 product Substances 0.000 description 93
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 90
• 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 81
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 69
• 239000002904 solvent Substances 0.000 description 66
• 239000007787 solid Substances 0.000 description 65
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 60
• 238000005160 1H NMR spectroscopy Methods 0.000 description 60
• 238000006243 chemical reaction Methods 0.000 description 58
• 239000011541 reaction mixture Substances 0.000 description 46
• 235000019439 ethyl acetate Nutrition 0.000 description 40
• 239000000543 intermediate Substances 0.000 description 39
• 108091007960 PI3Ks Proteins 0.000 description 36
• 229910000027 potassium carbonate Inorganic materials 0.000 description 33
• 239000012044 organic layer Substances 0.000 description 32
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
• 102000038030 PI3Ks Human genes 0.000 description 31
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
• 235000015320 potassium carbonate Nutrition 0.000 description 27
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
• 238000004440 column chromatography Methods 0.000 description 24
• 239000000243 solution Substances 0.000 description 24
• MQVHKBWFJUMWBG-UHFFFAOYSA-N 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole Chemical compound IC1=CN=C2SC(Br)=NN21 MQVHKBWFJUMWBG-UHFFFAOYSA-N 0.000 description 23
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 21
• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 21
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
• 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 20
• OQZKROYNCVLJKM-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN=C(N)C(C(F)(F)F)=C1 OQZKROYNCVLJKM-UHFFFAOYSA-N 0.000 description 20
• 229910002666 PdCl2 Inorganic materials 0.000 description 20
• 108091000080 Phosphotransferase Proteins 0.000 description 20
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
• 230000000694 effects Effects 0.000 description 20
• PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 20
• 102000020233 phosphotransferase Human genes 0.000 description 20
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
• 230000015572 biosynthetic process Effects 0.000 description 16
• 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 16
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 15
• 239000001301 oxygen Substances 0.000 description 15
• 239000000725 suspension Substances 0.000 description 15
• 238000003786 synthesis reaction Methods 0.000 description 15
• 239000000706 filtrate Substances 0.000 description 14
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
• 239000000651 prodrug Substances 0.000 description 13
• 229940002612 prodrug Drugs 0.000 description 13
• 102000004169 proteins and genes Human genes 0.000 description 13
• 108090000623 proteins and genes Proteins 0.000 description 13
• 229910000029 sodium carbonate Inorganic materials 0.000 description 13
• BOXRDDIXJOUZLV-UHFFFAOYSA-N 2h-imidazo[4,5-d]thiadiazole Chemical class N1SC2=NC=NC2=N1 BOXRDDIXJOUZLV-UHFFFAOYSA-N 0.000 description 12
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
• 238000002953 preparative HPLC Methods 0.000 description 12
• 230000002829 reductive effect Effects 0.000 description 12
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
• 102000001253 Protein Kinase Human genes 0.000 description 11
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 11
• YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 11
• 108060006633 protein kinase Proteins 0.000 description 11
• 238000006722 reduction reaction Methods 0.000 description 11
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
• 238000004128 high performance liquid chromatography Methods 0.000 description 10
• 150000002632 lipids Chemical class 0.000 description 10
• 230000009467 reduction Effects 0.000 description 10
• 239000011593 sulfur Substances 0.000 description 10
• 238000012360 testing method Methods 0.000 description 10
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 9
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• 125000000753 cycloalkyl group Chemical group 0.000 description 9
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
• 239000012074 organic phase Substances 0.000 description 9
• 230000000144 pharmacologic effect Effects 0.000 description 9
• 125000004076 pyridyl group Chemical group 0.000 description 9
• 238000010992 reflux Methods 0.000 description 9
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
• TXCCSQJYENKQNU-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-iodo-6-methylimidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC(C)=C2I TXCCSQJYENKQNU-UHFFFAOYSA-N 0.000 description 8
• BVTNVSLXXCQKQZ-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-iodoimidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2I BVTNVSLXXCQKQZ-UHFFFAOYSA-N 0.000 description 8
• 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 8
• 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 8
• 239000002253 acid Substances 0.000 description 8
• 238000003556 assay Methods 0.000 description 8
• 239000002585 base Substances 0.000 description 8
• 210000004027 cell Anatomy 0.000 description 8
• 238000009472 formulation Methods 0.000 description 8
• 239000002244 precipitate Substances 0.000 description 8
• 125000006239 protecting group Chemical group 0.000 description 8
• 238000010898 silica gel chromatography Methods 0.000 description 8
• 239000000126 substance Substances 0.000 description 8
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
• 239000003153 chemical reaction reagent Substances 0.000 description 7
• 239000003112 inhibitor Substances 0.000 description 7
• UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 7
• 235000011181 potassium carbonates Nutrition 0.000 description 7
• 238000000746 purification Methods 0.000 description 7
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 239000012267 brine Substances 0.000 description 6
• 150000001721 carbon Chemical group 0.000 description 6
• 238000004587 chromatography analysis Methods 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• 238000003818 flash chromatography Methods 0.000 description 6
• 125000000524 functional group Chemical group 0.000 description 6
• 230000005764 inhibitory process Effects 0.000 description 6
• 230000001105 regulatory effect Effects 0.000 description 6
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
• 238000003756 stirring Methods 0.000 description 6
• RCVDPBFUMYUKPB-UHFFFAOYSA-N (3,4-dimethoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1OC RCVDPBFUMYUKPB-UHFFFAOYSA-N 0.000 description 5
• JFHCFWOCRFEOAG-UHFFFAOYSA-N 2-bromoimidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=CN=C2SC(Br)=NN21 JFHCFWOCRFEOAG-UHFFFAOYSA-N 0.000 description 5
• QTPSMGSUMWXIEM-UHFFFAOYSA-N 4-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]-6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC(C=2SC3=NC(C)=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 QTPSMGSUMWXIEM-UHFFFAOYSA-N 0.000 description 5
• 102000004190 Enzymes Human genes 0.000 description 5
• 108090000790 Enzymes Proteins 0.000 description 5
• 229910052786 argon Inorganic materials 0.000 description 5
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
• 239000003054 catalyst Substances 0.000 description 5
• 230000003197 catalytic effect Effects 0.000 description 5
• 239000003638 chemical reducing agent Substances 0.000 description 5
• 125000001309 chloro group Chemical group Cl* 0.000 description 5
• 238000005859 coupling reaction Methods 0.000 description 5
• 239000012043 crude product Substances 0.000 description 5
• 229940088598 enzyme Drugs 0.000 description 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
• 239000011777 magnesium Substances 0.000 description 5
• 125000002757 morpholinyl group Chemical group 0.000 description 5
• 208000015122 neurodegenerative disease Diseases 0.000 description 5
• 238000007911 parenteral administration Methods 0.000 description 5
• 125000000714 pyrimidinyl group Chemical group 0.000 description 5
• 238000004809 thin layer chromatography Methods 0.000 description 5
• MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 4
• FPEOMUHJNJUHPT-UHFFFAOYSA-N 2-bromo-6-methylimidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C(Br)SC2=NC(C)=CN21 FPEOMUHJNJUHPT-UHFFFAOYSA-N 0.000 description 4
• DRMSMLJUCQEKBY-UHFFFAOYSA-N 5-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C(S1)=NN2C1=NC=C2I DRMSMLJUCQEKBY-UHFFFAOYSA-N 0.000 description 4
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
• 150000001299 aldehydes Chemical class 0.000 description 4
• 150000001412 amines Chemical class 0.000 description 4
• 239000007864 aqueous solution Substances 0.000 description 4
• 230000027455 binding Effects 0.000 description 4
• 125000001246 bromo group Chemical group Br* 0.000 description 4
• 125000004432 carbon atom Chemical group C* 0.000 description 4
• 230000008878 coupling Effects 0.000 description 4
• 238000010168 coupling process Methods 0.000 description 4
• 238000010511 deprotection reaction Methods 0.000 description 4
• 229940093499 ethyl acetate Drugs 0.000 description 4
• 238000001727 in vivo Methods 0.000 description 4
• 125000001041 indolyl group Chemical group 0.000 description 4
• 125000002346 iodo group Chemical group I* 0.000 description 4
• 239000010410 layer Substances 0.000 description 4
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
• 125000006574 non-aromatic ring group Chemical group 0.000 description 4
• 125000002098 pyridazinyl group Chemical group 0.000 description 4
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 4
• 229920006395 saturated elastomer Polymers 0.000 description 4
• 239000000741 silica gel Substances 0.000 description 4
• 229910002027 silica gel Inorganic materials 0.000 description 4
• 239000007858 starting material Substances 0.000 description 4
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
• XYENNOOASGKRJJ-UHFFFAOYSA-N 2-(1-ethylpyrazol-4-yl)-5-iodoimidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=NN(CC)C=C1C(S1)=NN2C1=NC=C2I XYENNOOASGKRJJ-UHFFFAOYSA-N 0.000 description 3
• KNPMFXCEPAWHLV-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-6-methylimidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC(C)=C2 KNPMFXCEPAWHLV-UHFFFAOYSA-N 0.000 description 3
• BLGFHDGQGXOTOI-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2 BLGFHDGQGXOTOI-UHFFFAOYSA-N 0.000 description 3
• QLGIAWPYHKGABK-UHFFFAOYSA-N 2-methoxy-4-(6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)phenol Chemical compound C1=C(O)C(OC)=CC(C=2SC3=NC(C)=CN3N=2)=C1 QLGIAWPYHKGABK-UHFFFAOYSA-N 0.000 description 3
• WLNIAGIPNUEVIF-UHFFFAOYSA-N 5-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxypyridin-3-amine Chemical compound C1=C(N)C(OC)=NC=C1C(S1)=NN2C1=NC=C2I WLNIAGIPNUEVIF-UHFFFAOYSA-N 0.000 description 3
• VYORVLCXRAKNEG-UHFFFAOYSA-N 5-imidazo[2,1-b][1,3,4]thiadiazol-2-yl-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C(S1)=NN2C1=NC=C2 VYORVLCXRAKNEG-UHFFFAOYSA-N 0.000 description 3
• 125000006164 6-membered heteroaryl group Chemical group 0.000 description 3
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
• 201000009030 Carcinoma Diseases 0.000 description 3
• 206010025323 Lymphomas Diseases 0.000 description 3
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
• 239000004480 active ingredient Substances 0.000 description 3
• 239000000908 ammonium hydroxide Substances 0.000 description 3
• 238000004458 analytical method Methods 0.000 description 3
• 239000008346 aqueous phase Substances 0.000 description 3
• 230000008901 benefit Effects 0.000 description 3
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 3
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
• 229910000024 caesium carbonate Inorganic materials 0.000 description 3
• 150000001735 carboxylic acids Chemical class 0.000 description 3
• 230000003915 cell function Effects 0.000 description 3
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
• 238000001035 drying Methods 0.000 description 3
• 125000000623 heterocyclic group Chemical group 0.000 description 3
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
• 208000032839 leukemia Diseases 0.000 description 3
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 3
• 230000004048 modification Effects 0.000 description 3
• 238000012986 modification Methods 0.000 description 3
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
• 125000003226 pyrazolyl group Chemical group 0.000 description 3
• ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 3
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
• 239000012047 saturated solution Substances 0.000 description 3
• 238000000926 separation method Methods 0.000 description 3
• 230000011664 signaling Effects 0.000 description 3
• BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
• 235000019345 sodium thiosulphate Nutrition 0.000 description 3
• 239000000758 substrate Substances 0.000 description 3
• WYQSHXOVIQEQIP-UHFFFAOYSA-N tert-butyl 4-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]piperidine-1-carboxylate Chemical compound COC1=CC(B2OC(C)(C)C(C)(C)O2)=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 WYQSHXOVIQEQIP-UHFFFAOYSA-N 0.000 description 3
• RFAOJXRLJAOHPA-UHFFFAOYSA-N tert-butyl 4-[4-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxyphenoxy]piperidine-1-carboxylate Chemical compound COC1=CC(C=2SC3=NC=C(I)N3N=2)=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 RFAOJXRLJAOHPA-UHFFFAOYSA-N 0.000 description 3
• BYYFETDDCXAWBR-UHFFFAOYSA-N tert-butyl 4-[4-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-2-methoxyphenoxy]piperidine-1-carboxylate Chemical compound COC1=CC(C=2SC3=NC=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 BYYFETDDCXAWBR-UHFFFAOYSA-N 0.000 description 3
• MSBSEHDGEZAQRG-UHFFFAOYSA-N tert-butyl 4-[5-[2-(3,4-dimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxylate Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C(C=C1C(F)(F)F)=CN=C1N1CCN(C(=O)OC(C)(C)C)CC1 MSBSEHDGEZAQRG-UHFFFAOYSA-N 0.000 description 3
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
• 230000001225 therapeutic effect Effects 0.000 description 3
• 238000001665 trituration Methods 0.000 description 3
• XDBHWPLGGBLUHH-UHFFFAOYSA-N (3-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(C#N)=C1 XDBHWPLGGBLUHH-UHFFFAOYSA-N 0.000 description 2
• ASXFMIDIRZPCGK-UHFFFAOYSA-N (4-methylpyridin-3-yl)boronic acid Chemical compound CC1=CC=NC=C1B(O)O ASXFMIDIRZPCGK-UHFFFAOYSA-N 0.000 description 2
• DHADXDMPEUWEAS-UHFFFAOYSA-N (6-methoxypyridin-3-yl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=N1 DHADXDMPEUWEAS-UHFFFAOYSA-N 0.000 description 2
• 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 2
• LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
• ZUQBOFLJCDUPLL-UHFFFAOYSA-N 2,5-bis(3,4-dimethoxyphenyl)-6-methylimidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC(C)=C2C1=CC=C(OC)C(OC)=C1 ZUQBOFLJCDUPLL-UHFFFAOYSA-N 0.000 description 2
• RSFFPCCWMHUQLL-UHFFFAOYSA-N 2,5-bis(3,4-dimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C1=CC=C(OC)C(OC)=C1 RSFFPCCWMHUQLL-UHFFFAOYSA-N 0.000 description 2
• LZOMSHMFRHDKIM-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-(5-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazole Chemical compound COC1=CN=CC(C=2N3N=C(SC3=NC=2)C=2C=C(OC)C(OC)=CC=2)=C1 LZOMSHMFRHDKIM-UHFFFAOYSA-N 0.000 description 2
• PZUXOIHEQQTURR-UHFFFAOYSA-N 2-amino-5-[2-(3,4-dimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyridine-3-carbonitrile Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C1=CN=C(N)C(C#N)=C1 PZUXOIHEQQTURR-UHFFFAOYSA-N 0.000 description 2
• QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 2
• WFSJROCEOJANPD-UHFFFAOYSA-N 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound C1=C(O)C(OC)=CC(B2OC(C)(C)C(C)(C)O2)=C1 WFSJROCEOJANPD-UHFFFAOYSA-N 0.000 description 2
• UWARFAZJBCXUAH-UHFFFAOYSA-N 3-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazol-2-yl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2SC3=NC=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 UWARFAZJBCXUAH-UHFFFAOYSA-N 0.000 description 2
• VCDSWCOJROIKSV-UHFFFAOYSA-N 3-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazol-2-yl]benzonitrile Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=CN=C2N1N=C(C=1C=C(C=CC=1)C#N)S2 VCDSWCOJROIKSV-UHFFFAOYSA-N 0.000 description 2
• HENXUFOAGXNWKH-UHFFFAOYSA-N 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=CN=CC(B2OC(C)(C)C(C)(C)O2)=C1 HENXUFOAGXNWKH-UHFFFAOYSA-N 0.000 description 2
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
• DNQYSWLVAPMRQL-UHFFFAOYSA-N 4-(5-iodo-6-methylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC(C=2SC3=NC(C)=C(I)N3N=2)=C1 DNQYSWLVAPMRQL-UHFFFAOYSA-N 0.000 description 2
• ZLGCWMNOSMWIIN-UHFFFAOYSA-N 4-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazol-2-yl]benzonitrile Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=CN=C2N1N=C(C=1C=CC(=CC=1)C#N)S2 ZLGCWMNOSMWIIN-UHFFFAOYSA-N 0.000 description 2
• YDATXJNKCGEXCJ-UHFFFAOYSA-N 5-(2-pyridin-3-ylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=CN=C2N1N=C(C=1C=NC=CC=1)S2 YDATXJNKCGEXCJ-UHFFFAOYSA-N 0.000 description 2
• IXTBQKLZPOYJFJ-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(C#N)N=C1 IXTBQKLZPOYJFJ-UHFFFAOYSA-N 0.000 description 2
• BPQVMIDUTRJYSC-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN=C(N)N=C1 BPQVMIDUTRJYSC-UHFFFAOYSA-N 0.000 description 2
• KZGFUDRECRXYET-UHFFFAOYSA-N 5-[2-(1-ethylpyrazol-4-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=NN(CC)C=C1C(S1)=NN2C1=NC=C2C1=CN=C(N)C(C(F)(F)F)=C1 KZGFUDRECRXYET-UHFFFAOYSA-N 0.000 description 2
• KWRFIVPQEUSIQV-UHFFFAOYSA-N 5-[2-(3-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound COC1=CC=CC(C=2SC3=NC=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 KWRFIVPQEUSIQV-UHFFFAOYSA-N 0.000 description 2
• QWSACUPFDITMLU-UHFFFAOYSA-N 5-[2-(3-methylsulfonylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound CS(=O)(=O)C1=CC=CC(C=2SC3=NC=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 QWSACUPFDITMLU-UHFFFAOYSA-N 0.000 description 2
• LJYVZFARGSUJCH-UHFFFAOYSA-N 5-[2-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=CC(OC)=CC=C1C(S1)=NN2C1=NC=C2C1=CN=C(N)C(C(F)(F)F)=C1 LJYVZFARGSUJCH-UHFFFAOYSA-N 0.000 description 2
• COZZXMRJMOFWRL-UHFFFAOYSA-N 5-[2-(4-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound CC1=CC=NC=C1C(S1)=NN2C1=NC=C2C1=CN=C(N)C(C(F)(F)F)=C1 COZZXMRJMOFWRL-UHFFFAOYSA-N 0.000 description 2
• UPYPASZOSPAMEB-UHFFFAOYSA-N 5-[2-(5-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound COC1=CN=CC(C=2SC3=NC=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 UPYPASZOSPAMEB-UHFFFAOYSA-N 0.000 description 2
• IPSDTCAVEMBNQA-UHFFFAOYSA-N 5-[2-(6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=NC(C)=CC=C1C(S1)=NN2C1=NC=C2C1=CN=C(N)C(C(F)(F)F)=C1 IPSDTCAVEMBNQA-UHFFFAOYSA-N 0.000 description 2
• LLSSEDSCHHDSLG-UHFFFAOYSA-N 5-[2-[3-(dimethylamino)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound CN(C)C1=CC=CC(C=2SC3=NC=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 LLSSEDSCHHDSLG-UHFFFAOYSA-N 0.000 description 2
• JNIZCLWHOMQGII-UHFFFAOYSA-N 5-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazol-2-yl]spiro[1h-indole-3,4'-piperidine]-2-one Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=CN=C2N1N=C(C=1C=C3C4(CCNCC4)C(=O)NC3=CC=1)S2 JNIZCLWHOMQGII-UHFFFAOYSA-N 0.000 description 2
• GLYQQFBHCFPEEU-UHFFFAOYSA-N 5-bromo-1,3,4-thiadiazol-2-amine Chemical compound NC1=NN=C(Br)S1 GLYQQFBHCFPEEU-UHFFFAOYSA-N 0.000 description 2
• 125000006163 5-membered heteroaryl group Chemical group 0.000 description 2
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
• OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 2
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
• 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
• 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
• 208000017604 Hodgkin disease Diseases 0.000 description 2
• 206010020751 Hypersensitivity 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 compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
• 241000124008 Mammalia Species 0.000 description 2
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
• 238000005481 NMR spectroscopy Methods 0.000 description 2
• 206010029260 Neuroblastoma Diseases 0.000 description 2
• 208000031481 Pathologic Constriction Diseases 0.000 description 2
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
• 102000001708 Protein Isoforms Human genes 0.000 description 2
• 108010029485 Protein Isoforms Proteins 0.000 description 2
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
• 241000700605 Viruses Species 0.000 description 2
• YZQQHZXHCXAJAV-UHFFFAOYSA-N [3-(dimethylamino)phenyl]boronic acid Chemical compound CN(C)C1=CC=CC(B(O)O)=C1 YZQQHZXHCXAJAV-UHFFFAOYSA-N 0.000 description 2
• 230000002159 abnormal effect Effects 0.000 description 2
• 230000001154 acute effect Effects 0.000 description 2
• 230000010933 acylation Effects 0.000 description 2
• 238000005917 acylation reaction Methods 0.000 description 2
• 125000003158 alcohol group Chemical group 0.000 description 2
• 230000029936 alkylation Effects 0.000 description 2
• 238000005804 alkylation reaction Methods 0.000 description 2
• 125000002947 alkylene group Chemical group 0.000 description 2
• 230000007815 allergy Effects 0.000 description 2
• 229910021529 ammonia Inorganic materials 0.000 description 2
• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 2
• 239000012300 argon atmosphere Substances 0.000 description 2
• 230000006399 behavior Effects 0.000 description 2
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
• 230000033228 biological regulation Effects 0.000 description 2
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
• 229910052794 bromium Inorganic materials 0.000 description 2
• XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Inorganic materials [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
• 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
• 125000002837 carbocyclic group Chemical group 0.000 description 2
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
• 125000005518 carboxamido group Chemical group 0.000 description 2
• 230000010261 cell growth Effects 0.000 description 2
• 210000003169 central nervous system Anatomy 0.000 description 2
• 239000000460 chlorine Chemical group 0.000 description 2
• 229910052801 chlorine Inorganic materials 0.000 description 2
• BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 2
• 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
• 238000002648 combination therapy Methods 0.000 description 2
• 238000009833 condensation Methods 0.000 description 2
• 230000005494 condensation Effects 0.000 description 2
• 238000007796 conventional method Methods 0.000 description 2
• 238000001816 cooling Methods 0.000 description 2
• 239000013058 crude material Substances 0.000 description 2
• 230000003831 deregulation Effects 0.000 description 2
• 238000013461 design Methods 0.000 description 2
• 238000011161 development Methods 0.000 description 2
• 229960004132 diethyl ether Drugs 0.000 description 2
• 238000007876 drug discovery Methods 0.000 description 2
• 235000019253 formic acid Nutrition 0.000 description 2
• 238000001640 fractional crystallisation Methods 0.000 description 2
• 239000000417 fungicide Substances 0.000 description 2
• 125000002541 furyl group Chemical group 0.000 description 2
• 201000005787 hematologic cancer Diseases 0.000 description 2
• 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
• 125000002883 imidazolyl group Chemical group 0.000 description 2
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
• 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 2
• 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 2
• 238000002955 isolation Methods 0.000 description 2
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
• 125000000842 isoxazolyl group Chemical group 0.000 description 2
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
• 229910052749 magnesium Inorganic materials 0.000 description 2
• 230000003211 malignant effect Effects 0.000 description 2
• 239000003550 marker Substances 0.000 description 2
• 201000001441 melanoma Diseases 0.000 description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
• CVYIUOGLNQBYDK-UHFFFAOYSA-N n-[3-[5-[6-amino-5-(trifluoromethyl)pyridin-3-yl]imidazo[2,1-b][1,3,4]thiadiazol-2-yl]phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC(C=2SC3=NC=C(N3N=2)C=2C=C(C(N)=NC=2)C(F)(F)F)=C1 CVYIUOGLNQBYDK-UHFFFAOYSA-N 0.000 description 2
• CSFCUJPBEQKNTG-UHFFFAOYSA-N n-[5-[2-(3,4-dimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]pyrimidin-2-yl]-n',n'-dimethylethane-1,2-diamine Chemical compound C1=C(OC)C(OC)=CC=C1C(S1)=NN2C1=NC=C2C1=CN=C(NCCN(C)C)N=C1 CSFCUJPBEQKNTG-UHFFFAOYSA-N 0.000 description 2
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
• 125000001624 naphthyl group Chemical group 0.000 description 2
• 230000004770 neurodegeneration Effects 0.000 description 2
• 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
• 239000003921 oil Substances 0.000 description 2
• 230000003287 optical effect Effects 0.000 description 2
• 125000002524 organometallic group Chemical group 0.000 description 2
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
• 125000002971 oxazolyl group Chemical group 0.000 description 2
• 230000003647 oxidation Effects 0.000 description 2
• 238000007254 oxidation reaction Methods 0.000 description 2
• 244000045947 parasite Species 0.000 description 2
• 230000008506 pathogenesis Effects 0.000 description 2
• 239000012660 pharmacological inhibitor Substances 0.000 description 2
• 210000003800 pharynx Anatomy 0.000 description 2
• 150000003905 phosphatidylinositols Chemical class 0.000 description 2
• 229910052698 phosphorus Inorganic materials 0.000 description 2
• 239000011574 phosphorus Chemical group 0.000 description 2
• 125000003386 piperidinyl group Chemical group 0.000 description 2
• 125000003367 polycyclic group Chemical group 0.000 description 2
• 230000002265 prevention Effects 0.000 description 2
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
• 239000003909 protein kinase inhibitor Substances 0.000 description 2
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
• 125000003373 pyrazinyl group Chemical group 0.000 description 2
• 125000000168 pyrrolyl 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
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
• 238000006268 reductive amination reaction Methods 0.000 description 2
• 239000002002 slurry Substances 0.000 description 2
• 208000000587 small cell lung carcinoma Diseases 0.000 description 2
• 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
• 206010041823 squamous cell carcinoma Diseases 0.000 description 2
• 238000010561 standard procedure Methods 0.000 description 2
• 230000036262 stenosis Effects 0.000 description 2
• 208000037804 stenosis Diseases 0.000 description 2
• 238000006467 substitution reaction Methods 0.000 description 2
• 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 2
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
• ANQPPOBCQWNEMU-UHFFFAOYSA-N tert-butyl 4-[2-methoxy-4-[5-(6-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]phenoxy]piperidine-1-carboxylate Chemical compound C1=NC(OC)=CC=C1C1=CN=C2N1N=C(C=1C=C(OC)C(OC3CCN(CC3)C(=O)OC(C)(C)C)=CC=1)S2 ANQPPOBCQWNEMU-UHFFFAOYSA-N 0.000 description 2
• 125000003831 tetrazolyl group Chemical group 0.000 description 2
• 125000000335 thiazolyl group Chemical group 0.000 description 2
• 125000001544 thienyl group Chemical group 0.000 description 2
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
• 210000001685 thyroid gland Anatomy 0.000 description 2
• 230000009466 transformation Effects 0.000 description 2
• PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
• GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
• 230000003612 virological effect Effects 0.000 description 2
• CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
• IBTSWKLSEOGJGJ-UHFFFAOYSA-N (3-acetamidophenyl)boronic acid Chemical compound CC(=O)NC1=CC=CC(B(O)O)=C1 IBTSWKLSEOGJGJ-UHFFFAOYSA-N 0.000 description 1
• WDGWHKRJEBENCE-UHFFFAOYSA-N (3-carbamoylphenyl)boronic acid Chemical compound NC(=O)C1=CC=CC(B(O)O)=C1 WDGWHKRJEBENCE-UHFFFAOYSA-N 0.000 description 1
• RJKFNKNDTBNEST-UHFFFAOYSA-N (3-fluoro-4-methylsulfonylphenyl)boronic acid Chemical compound CS(=O)(=O)C1=CC=C(B(O)O)C=C1F RJKFNKNDTBNEST-UHFFFAOYSA-N 0.000 description 1
• YCXPWNGIPLGCOJ-UHFFFAOYSA-N (3-methoxy-4-methoxycarbonylphenyl)boronic acid Chemical compound COC(=O)C1=CC=C(B(O)O)C=C1OC YCXPWNGIPLGCOJ-UHFFFAOYSA-N 0.000 description 1
• NLLGFYPSWCMUIV-UHFFFAOYSA-N (3-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC(B(O)O)=C1 NLLGFYPSWCMUIV-UHFFFAOYSA-N 0.000 description 1
• HZFFUMBZBGETES-UHFFFAOYSA-N (3-methylsulfonylphenyl)boronic acid Chemical compound CS(=O)(=O)C1=CC=CC(B(O)O)=C1 HZFFUMBZBGETES-UHFFFAOYSA-N 0.000 description 1
• VDUKDQTYMWUSAC-UHFFFAOYSA-N (4-methylsulfonylphenyl)boronic acid Chemical compound CS(=O)(=O)C1=CC=C(B(O)O)C=C1 VDUKDQTYMWUSAC-UHFFFAOYSA-N 0.000 description 1
• BRRALDPVXKGEEE-UHFFFAOYSA-N (4-morpholin-4-ylsulfonylphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1S(=O)(=O)N1CCOCC1 BRRALDPVXKGEEE-UHFFFAOYSA-N 0.000 description 1
• OJBYZWHAPXIJID-UHFFFAOYSA-N (6-fluoropyridin-3-yl)boronic acid Chemical compound OB(O)C1=CC=C(F)N=C1 OJBYZWHAPXIJID-UHFFFAOYSA-N 0.000 description 1
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
• GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
• RUAOUHQNNBBMGS-UHFFFAOYSA-N 1,1,1,2-tetrachloro-2,2-diiodoethane Chemical compound ClC(Cl)(Cl)C(Cl)(I)I RUAOUHQNNBBMGS-UHFFFAOYSA-N 0.000 description 1
• JNVXRQOSRUDXDY-UHFFFAOYSA-N 1,1-diiodoethane Chemical compound CC(I)I JNVXRQOSRUDXDY-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
• 125000005943 1,2,3,6-tetrahydropyridyl group Chemical group 0.000 description 1
• 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
• 125000004511 1,2,3-thiadiazolyl 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
• 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
• QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
• NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
• 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
• 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
• IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
• JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
• FLOJNXXFMHCMMR-UHFFFAOYSA-N 1,3-dithiolanyl Chemical group [CH]1SCCS1 FLOJNXXFMHCMMR-UHFFFAOYSA-N 0.000 description 1
• 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
• HKDFRDIIELOLTJ-UHFFFAOYSA-N 1,4-dithianyl Chemical group [CH]1CSCCS1 HKDFRDIIELOLTJ-UHFFFAOYSA-N 0.000 description 1
• ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
• VHADYSUJZAPXOW-UHFFFAOYSA-N 1h-indol-5-ylboronic acid Chemical compound OB(O)C1=CC=C2NC=CC2=C1 VHADYSUJZAPXOW-UHFFFAOYSA-N 0.000 description 1
• MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 1
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
• KRNXYPYYVHFVQS-UHFFFAOYSA-N 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN=C(N)C(C#N)=C1 KRNXYPYYVHFVQS-UHFFFAOYSA-N 0.000 description 1
• ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
• KYYKGOURQXPERA-UHFFFAOYSA-N 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine Chemical compound C1=C(N)C(OC)=NC=C1B1OC(C)(C)C(C)(C)O1 KYYKGOURQXPERA-UHFFFAOYSA-N 0.000 description 1
• BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
• JEECGGXGHJUYMN-UHFFFAOYSA-N 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound C1=NC(C)=CC=C1B1OC(C)(C)C(C)(C)O1 JEECGGXGHJUYMN-UHFFFAOYSA-N 0.000 description 1
• AFKIHRZPPIRQCI-UHFFFAOYSA-N 2-methylsulfanyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine Chemical compound C1=NC(SC)=NC=C1B1OC(C)(C)C(C)(C)O1 AFKIHRZPPIRQCI-UHFFFAOYSA-N 0.000 description 1
• AZYTZQYCOBXDGY-UHFFFAOYSA-N 2-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=CC=N1 AZYTZQYCOBXDGY-UHFFFAOYSA-N 0.000 description 1
• UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
• NBJHDLKSWUDGJG-UHFFFAOYSA-N 4-(2-chloroethyl)morpholin-4-ium;chloride Chemical compound Cl.ClCCN1CCOCC1 NBJHDLKSWUDGJG-UHFFFAOYSA-N 0.000 description 1
• GVGODOIZAKSPFC-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NN=C1 GVGODOIZAKSPFC-UHFFFAOYSA-N 0.000 description 1
• 125000004606 5,6,7,8-tetrahydroisoquinolinyl group Chemical group C1(=NC=CC=2CCCCC12)* 0.000 description 1
• 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 description 1
• CDOCFVINRHGATH-UHFFFAOYSA-N 6-(3,4-dimethoxyphenyl)-3-iodo-2-methylimidazo[1,2-b]pyridazine Chemical compound C1=C(OC)C(OC)=CC=C1C1=NN2C(I)=C(C)N=C2C=C1 CDOCFVINRHGATH-UHFFFAOYSA-N 0.000 description 1
• 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 1
• 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
• 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
• 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
• 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
• 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
• 208000003200 Adenoma Diseases 0.000 description 1
• 206010001233 Adenoma benign Diseases 0.000 description 1
• 206010003571 Astrocytoma Diseases 0.000 description 1
• 208000003950 B-cell lymphoma Diseases 0.000 description 1
• 229910015845 BBr3 Inorganic materials 0.000 description 1
• 206010005003 Bladder cancer Diseases 0.000 description 1
• ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
• 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
• JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
• 208000005623 Carcinogenesis Diseases 0.000 description 1
• 208000010667 Carcinoma of liver and intrahepatic biliary tract Diseases 0.000 description 1
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
• 108091007958 Class I PI3Ks Proteins 0.000 description 1
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
• 201000008808 Fibrosarcoma Diseases 0.000 description 1
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
• 208000032612 Glial tumor Diseases 0.000 description 1
• 206010018338 Glioma Diseases 0.000 description 1
• 239000007818 Grignard reagent Substances 0.000 description 1
• 239000007995 HEPES buffer Substances 0.000 description 1
• 206010073069 Hepatic cancer Diseases 0.000 description 1
• 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
• 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
• 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
• 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 1
• QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 1
• 241000764238 Isis Species 0.000 description 1
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
• 208000007766 Kaposi sarcoma Diseases 0.000 description 1
• 206010023347 Keratoacanthoma Diseases 0.000 description 1
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• 241001465754 Metazoa Species 0.000 description 1
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
• 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
• 208000025966 Neurological disease Diseases 0.000 description 1
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
• 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
• 208000027771 Obstructive airways disease Diseases 0.000 description 1
• 102000043276 Oncogene Human genes 0.000 description 1
• 108700020796 Oncogene Proteins 0.000 description 1
• 229910019142 PO4 Inorganic materials 0.000 description 1
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
• 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
• 102000052575 Proto-Oncogene Human genes 0.000 description 1
• 108700020978 Proto-Oncogene Proteins 0.000 description 1
• 206010038389 Renal cancer Diseases 0.000 description 1
• 102000014400 SH2 domains Human genes 0.000 description 1
• 108050003452 SH2 domains Proteins 0.000 description 1
• 206010039491 Sarcoma Diseases 0.000 description 1
• 201000010208 Seminoma Diseases 0.000 description 1
• 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
• XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
• 206010041067 Small cell lung cancer Diseases 0.000 description 1
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
• 208000006011 Stroke Diseases 0.000 description 1
• 239000005864 Sulphur Substances 0.000 description 1
• 206010042971 T-cell lymphoma Diseases 0.000 description 1
• 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
• PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 1
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
• 201000006083 Xeroderma Pigmentosum Diseases 0.000 description 1
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
• XUIQQIRLFMCWLN-UHFFFAOYSA-N [3-(methanesulfonamido)phenyl]boronic acid Chemical compound CS(=O)(=O)NC1=CC=CC(B(O)O)=C1 XUIQQIRLFMCWLN-UHFFFAOYSA-N 0.000 description 1
• FJSWJJOLFPIDER-UHFFFAOYSA-N [3-(methanesulfonamidomethyl)phenyl]boronic acid Chemical compound CS(=O)(=O)NCC1=CC=CC(B(O)O)=C1 FJSWJJOLFPIDER-UHFFFAOYSA-N 0.000 description 1
• 238000009825 accumulation Methods 0.000 description 1
• 238000005903 acid hydrolysis reaction Methods 0.000 description 1
• 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
• 239000008186 active pharmaceutical agent Substances 0.000 description 1
• 150000001266 acyl halides Chemical class 0.000 description 1
• 208000009956 adenocarcinoma Diseases 0.000 description 1
• 150000001340 alkali metals Chemical group 0.000 description 1
• 125000003342 alkenyl group Chemical group 0.000 description 1
• 125000005907 alkyl ester group Chemical group 0.000 description 1
• 125000000304 alkynyl group Chemical group 0.000 description 1
• 235000019270 ammonium chloride Nutrition 0.000 description 1
• 230000000844 anti-bacterial effect Effects 0.000 description 1
• 208000006673 asthma Diseases 0.000 description 1
• 239000012298 atmosphere Substances 0.000 description 1
• CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
• 125000002393 azetidinyl group Chemical group 0.000 description 1
• 125000004069 aziridinyl group Chemical group 0.000 description 1
• 239000003899 bactericide agent Substances 0.000 description 1
• 230000004888 barrier function Effects 0.000 description 1
• 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
• 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
• 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
• 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
• 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
• MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
• SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
• 201000001531 bladder carcinoma Diseases 0.000 description 1
• 230000037396 body weight Effects 0.000 description 1
• 210000000988 bone and bone Anatomy 0.000 description 1
• 239000004327 boric acid Substances 0.000 description 1
• 210000000133 brain stem Anatomy 0.000 description 1
• 210000000481 breast Anatomy 0.000 description 1
• 239000000872 buffer Substances 0.000 description 1
• 230000036952 cancer formation Effects 0.000 description 1
• 239000002775 capsule Substances 0.000 description 1
• 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
• 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
• XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical group NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 1
• 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 1
• 150000003857 carboxamides Chemical class 0.000 description 1
• 231100000504 carcinogenesis Toxicity 0.000 description 1
• 210000004413 cardiac myocyte Anatomy 0.000 description 1
• 210000000170 cell membrane Anatomy 0.000 description 1
• 230000001413 cellular effect Effects 0.000 description 1
• 210000003679 cervix uteri Anatomy 0.000 description 1
• 230000008859 change Effects 0.000 description 1
• 239000012069 chiral reagent Substances 0.000 description 1
• 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
• 210000001072 colon Anatomy 0.000 description 1
• 239000013078 crystal Substances 0.000 description 1
• 125000000392 cycloalkenyl group Chemical group 0.000 description 1
• KFGVRWGDTLZAAO-UHFFFAOYSA-N cyclopenta-1,3-diene dicyclohexyl(cyclopenta-1,3-dien-1-yl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.C1CCC(CC1)P(C1CCCCC1)c1ccc[cH-]1 KFGVRWGDTLZAAO-UHFFFAOYSA-N 0.000 description 1
• 230000001086 cytosolic effect Effects 0.000 description 1
• 239000012024 dehydrating agents‎ Substances 0.000 description 1
• 238000006297 dehydration reaction Methods 0.000 description 1
• 238000001212 derivatisation Methods 0.000 description 1
• 230000001627 detrimental effect Effects 0.000 description 1
• 229910052805 deuterium Inorganic materials 0.000 description 1
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
• 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
• 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
• 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
• 229940043279 diisopropylamine Drugs 0.000 description 1
• 238000010790 dilution Methods 0.000 description 1
• 239000012895 dilution Substances 0.000 description 1
• 125000000532 dioxanyl group Chemical group 0.000 description 1
• 125000005879 dioxolanyl group Chemical group 0.000 description 1
• 239000001177 diphosphate Substances 0.000 description 1
• KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
• 125000005883 dithianyl group Chemical group 0.000 description 1
• 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
• 239000002552 dosage form Substances 0.000 description 1
• 231100000673 dose–response relationship Toxicity 0.000 description 1
• 239000003937 drug carrier Substances 0.000 description 1
• 239000012039 electrophile Substances 0.000 description 1
• 230000007368 endocrine function Effects 0.000 description 1
• 210000002889 endothelial cell Anatomy 0.000 description 1
• 238000006911 enzymatic reaction Methods 0.000 description 1
• 210000003238 esophagus Anatomy 0.000 description 1
• 125000004185 ester group Chemical group 0.000 description 1
• 230000032050 esterification Effects 0.000 description 1
• 238000005886 esterification reaction Methods 0.000 description 1
• 238000006266 etherification reaction Methods 0.000 description 1
• DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
• 230000005284 excitation Effects 0.000 description 1
• 238000002474 experimental method Methods 0.000 description 1
• 239000000284 extract Substances 0.000 description 1
• 239000011737 fluorine Chemical group 0.000 description 1
• 229910052731 fluorine Inorganic materials 0.000 description 1
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
• 230000003325 follicular Effects 0.000 description 1
• 239000012458 free base Substances 0.000 description 1
• 238000004108 freeze drying Methods 0.000 description 1
• 230000006870 function Effects 0.000 description 1
• 210000000232 gallbladder Anatomy 0.000 description 1
• 208000005017 glioblastoma Diseases 0.000 description 1
• 150000004795 grignard reagents Chemical class 0.000 description 1
• 210000004524 haematopoietic cell Anatomy 0.000 description 1
• 230000026030 halogenation Effects 0.000 description 1
• 238000005658 halogenation reaction Methods 0.000 description 1
• 238000010438 heat treatment Methods 0.000 description 1
• 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
• 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
• 239000004009 herbicide Substances 0.000 description 1
• 125000004474 heteroalkylene group Chemical group 0.000 description 1
• 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
• 102000034345 heterotrimeric G proteins Human genes 0.000 description 1
• 108091006093 heterotrimeric G proteins Proteins 0.000 description 1
• 210000003630 histaminocyte Anatomy 0.000 description 1
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
• 239000005457 ice water Substances 0.000 description 1
• 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
• 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 description 1
• 125000002632 imidazolidinyl group Chemical group 0.000 description 1
• 125000002636 imidazolinyl group Chemical group 0.000 description 1
• 208000026278 immune system disease Diseases 0.000 description 1
• 238000000099 in vitro assay Methods 0.000 description 1
• 238000005462 in vivo assay Methods 0.000 description 1
• 230000001939 inductive effect Effects 0.000 description 1
• 230000004968 inflammatory condition Effects 0.000 description 1
• 239000007924 injection Substances 0.000 description 1
• 238000002347 injection Methods 0.000 description 1
• 150000007529 inorganic bases Chemical class 0.000 description 1
• CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical group O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
• 238000012739 integrated shape imaging system Methods 0.000 description 1
• 230000010354 integration Effects 0.000 description 1
• QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
• 230000031146 intracellular signal transduction Effects 0.000 description 1
• 230000004068 intracellular signaling Effects 0.000 description 1
• 238000007918 intramuscular administration Methods 0.000 description 1
• 229910052740 iodine Inorganic materials 0.000 description 1
• 239000003456 ion exchange resin Substances 0.000 description 1
• 229920003303 ion-exchange polymer Polymers 0.000 description 1
• 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
• 238000006317 isomerization reaction Methods 0.000 description 1
• 230000000155 isotopic effect Effects 0.000 description 1
• 210000003734 kidney Anatomy 0.000 description 1
• 229940043355 kinase inhibitor Drugs 0.000 description 1
• 208000003849 large cell carcinoma Diseases 0.000 description 1
• 210000002429 large intestine Anatomy 0.000 description 1
• 210000000867 larynx Anatomy 0.000 description 1
• 231100001231 less toxic Toxicity 0.000 description 1
• 239000003446 ligand Substances 0.000 description 1
• 125000005647 linker group Chemical group 0.000 description 1
• 210000000088 lip Anatomy 0.000 description 1
• 229910052744 lithium Inorganic materials 0.000 description 1
• JCIVHYBIFRUGKO-UHFFFAOYSA-N lithium;2,2,6,6-tetramethylpiperidine Chemical compound [Li].CC1(C)CCCC(C)(C)N1 JCIVHYBIFRUGKO-UHFFFAOYSA-N 0.000 description 1
• 210000004185 liver Anatomy 0.000 description 1
• 201000002250 liver carcinoma Diseases 0.000 description 1
• 210000004072 lung Anatomy 0.000 description 1
• 201000005249 lung adenocarcinoma Diseases 0.000 description 1
• 229910001629 magnesium chloride Inorganic materials 0.000 description 1
• 235000019341 magnesium sulphate Nutrition 0.000 description 1
• 238000004949 mass spectrometry Methods 0.000 description 1
• 230000007721 medicinal effect Effects 0.000 description 1
• 239000012528 membrane Substances 0.000 description 1
• 230000003340 mental effect Effects 0.000 description 1
• 230000002503 metabolic effect Effects 0.000 description 1
• 230000007102 metabolic function Effects 0.000 description 1
• 229910052751 metal Inorganic materials 0.000 description 1
• 239000002184 metal Substances 0.000 description 1
• BRWZPVRDOUWXKE-UHFFFAOYSA-N methylsulfanylmethane;trifluoroborane Chemical compound CSC.FB(F)F BRWZPVRDOUWXKE-UHFFFAOYSA-N 0.000 description 1
• 230000005012 migration Effects 0.000 description 1
• 238000013508 migration Methods 0.000 description 1
• 239000002808 molecular sieve Substances 0.000 description 1
• 239000012452 mother liquor Substances 0.000 description 1
• 210000000214 mouth Anatomy 0.000 description 1
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
• 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
• 208000007538 neurilemmoma Diseases 0.000 description 1
• QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
• 238000006396 nitration reaction Methods 0.000 description 1
• 150000002825 nitriles Chemical group 0.000 description 1
• 239000012299 nitrogen atmosphere Substances 0.000 description 1
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
• 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
• 239000012038 nucleophile Substances 0.000 description 1
• 238000005580 one pot reaction Methods 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
• 125000003566 oxetanyl group Chemical group 0.000 description 1
• 239000007800 oxidant agent Substances 0.000 description 1
• 125000000466 oxiranyl group Chemical group 0.000 description 1
• 229910052763 palladium Inorganic materials 0.000 description 1
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
• 210000000496 pancreas Anatomy 0.000 description 1
• 230000003071 parasitic effect Effects 0.000 description 1
• 210000001428 peripheral nervous system Anatomy 0.000 description 1
• 239000012071 phase Substances 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
• 239000010452 phosphate Substances 0.000 description 1
• 150000003906 phosphoinositides Chemical class 0.000 description 1
• UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
• 230000026731 phosphorylation Effects 0.000 description 1
• 238000006366 phosphorylation reaction Methods 0.000 description 1
• 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
• 125000004193 piperazinyl group Chemical group 0.000 description 1
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
• 229960005235 piperonyl butoxide Drugs 0.000 description 1
• 239000003880 polar aprotic solvent Substances 0.000 description 1
• 238000002600 positron emission tomography Methods 0.000 description 1
• 229910052700 potassium Inorganic materials 0.000 description 1
• 239000011591 potassium Substances 0.000 description 1
• IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
• 230000003389 potentiating effect Effects 0.000 description 1
• 239000002243 precursor Substances 0.000 description 1
• 150000003140 primary amides Chemical class 0.000 description 1
• 150000003141 primary amines Chemical class 0.000 description 1
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
• VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
• 238000011321 prophylaxis Methods 0.000 description 1
• 210000002307 prostate Anatomy 0.000 description 1
• 230000029983 protein stabilization Effects 0.000 description 1
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
• 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
• 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
• 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
• 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
• 125000001422 pyrrolinyl group Chemical group 0.000 description 1
• 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
• 102000005962 receptors Human genes 0.000 description 1
• 108020003175 receptors Proteins 0.000 description 1
• 230000007115 recruitment Effects 0.000 description 1
• 238000001953 recrystallisation Methods 0.000 description 1
• 210000000664 rectum Anatomy 0.000 description 1
• 201000010174 renal carcinoma Diseases 0.000 description 1
• 238000011160 research Methods 0.000 description 1
• 239000013557 residual solvent Substances 0.000 description 1
• 230000004044 response Effects 0.000 description 1
• 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
• 150000003335 secondary amines Chemical class 0.000 description 1
• 230000019491 signal transduction Effects 0.000 description 1
• 239000010703 silicon Substances 0.000 description 1
• 229910052710 silicon Inorganic materials 0.000 description 1
• 239000000377 silicon dioxide Substances 0.000 description 1
• 210000003491 skin Anatomy 0.000 description 1
• 208000000649 small cell carcinoma Diseases 0.000 description 1
• 210000000813 small intestine Anatomy 0.000 description 1
• 229910052708 sodium Inorganic materials 0.000 description 1
• 239000011734 sodium Substances 0.000 description 1
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
• 235000017557 sodium bicarbonate Nutrition 0.000 description 1
• WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
• 239000012312 sodium hydride Substances 0.000 description 1
• 229910000104 sodium hydride Inorganic materials 0.000 description 1
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
• 230000003595 spectral effect Effects 0.000 description 1
• 125000003003 spiro group Chemical group 0.000 description 1
• 239000008174 sterile solution Substances 0.000 description 1
• 210000002784 stomach Anatomy 0.000 description 1
• 125000000547 substituted alkyl group Chemical group 0.000 description 1
• 125000003107 substituted aryl group Chemical group 0.000 description 1
• 229940124530 sulfonamide Drugs 0.000 description 1
• 125000000565 sulfonamide group Chemical group 0.000 description 1
• 150000003456 sulfonamides Chemical class 0.000 description 1
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
• 150000003461 sulfonyl halides Chemical class 0.000 description 1
• 238000005694 sulfonylation reaction Methods 0.000 description 1
• DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
• 239000000829 suppository Substances 0.000 description 1
• 230000004083 survival effect Effects 0.000 description 1
• 238000003419 tautomerization reaction Methods 0.000 description 1
• 208000001608 teratocarcinoma Diseases 0.000 description 1
• NINUNQDOTKZDNJ-UHFFFAOYSA-N tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=NC=C(B2OC(C)(C)C(C)(C)O2)C=C1C(F)(F)F NINUNQDOTKZDNJ-UHFFFAOYSA-N 0.000 description 1
• YODSUBUWTUTLAZ-UHFFFAOYSA-N tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=NC=C(B2OC(C)(C)C(C)(C)O2)C=N1 YODSUBUWTUTLAZ-UHFFFAOYSA-N 0.000 description 1
• PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
• TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 description 1
• 210000001550 testis Anatomy 0.000 description 1
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
• 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
• 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
• 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
• 238000002560 therapeutic procedure Methods 0.000 description 1
• 230000004797 therapeutic response Effects 0.000 description 1
• 125000001113 thiadiazolyl group Chemical group 0.000 description 1
• 125000002053 thietanyl group Chemical group 0.000 description 1
• 125000001730 thiiranyl group Chemical group 0.000 description 1
• 125000001166 thiolanyl group Chemical group 0.000 description 1
• 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
• 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
• 210000001519 tissue Anatomy 0.000 description 1
• 238000003354 tissue distribution assay Methods 0.000 description 1
• 238000004448 titration Methods 0.000 description 1
• 210000002105 tongue Anatomy 0.000 description 1
• 230000001988 toxicity Effects 0.000 description 1
• 231100000419 toxicity Toxicity 0.000 description 1
• 238000006478 transmetalation reaction Methods 0.000 description 1
• 125000001425 triazolyl group Chemical group 0.000 description 1
• IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
• JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
• BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
• 239000001226 triphosphate Substances 0.000 description 1
• 125000005455 trithianyl group Chemical group 0.000 description 1
• 208000010576 undifferentiated carcinoma Diseases 0.000 description 1
• 238000011144 upstream manufacturing Methods 0.000 description 1
• 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1