CA2978170C - Pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives as cdk inhibitors - Google Patents

Info

Publication number

CA2978170C

CA2978170C CA2978170A CA2978170A CA2978170C CA 2978170 C CA2978170 C CA 2978170C CA 2978170 A CA2978170 A CA 2978170A CA 2978170 A CA2978170 A CA 2978170A CA 2978170 C CA2978170 C CA 2978170C

Authority

CA

Canada

Prior art keywords

amino

pyrazolo

methyl

phenyl

triazin

Prior art date

2015-03-09

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

Active

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title abstract description 25
• JUXWUYWPUDKPSD-UHFFFAOYSA-N pyrazolo[1,5-a][1,3,5]triazine Chemical compound N1=CN=CN2N=CC=C21 JUXWUYWPUDKPSD-UHFFFAOYSA-N 0.000 title abstract description 12
• LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical class N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 title abstract description 7
• 150000001875 compounds Chemical class 0.000 claims abstract description 342
• 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 claims abstract description 62
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 51
• 230000002103 transcriptional effect Effects 0.000 claims abstract description 43
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
• 108091007914 CDKs Proteins 0.000 claims abstract description 29
• 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 claims abstract description 24
• 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 claims abstract description 24
• 150000003839 salts Chemical class 0.000 claims abstract description 24
• 102100038111 Cyclin-dependent kinase 12 Human genes 0.000 claims abstract description 22
• 102100038114 Cyclin-dependent kinase 13 Human genes 0.000 claims abstract description 22
• 101000884345 Homo sapiens Cyclin-dependent kinase 12 Proteins 0.000 claims abstract description 22
• 101000884348 Homo sapiens Cyclin-dependent kinase 13 Proteins 0.000 claims abstract description 22
• 208000035475 disorder Diseases 0.000 claims abstract description 20
• 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 claims abstract 4
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 216
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 169
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 142
• -1 N-methyl4-piperidinyl Chemical group 0.000 claims description 89
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 46
• 125000000217 alkyl group Chemical group 0.000 claims description 43
• 201000010099 disease Diseases 0.000 claims description 31
• 206010028980 Neoplasm Diseases 0.000 claims description 28
• PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims description 27
• 229910052739 hydrogen Inorganic materials 0.000 claims description 26
• 239000001257 hydrogen Substances 0.000 claims description 26
• 210000004027 cell Anatomy 0.000 claims description 23
• 229910052757 nitrogen Inorganic materials 0.000 claims description 21
• IQHXABCGSFAKPN-UHFFFAOYSA-N pyrrolidine-3-carboxamide Chemical compound NC(=O)C1CCNC1 IQHXABCGSFAKPN-UHFFFAOYSA-N 0.000 claims description 21
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
• 125000005843 halogen group Chemical group 0.000 claims description 18
• NQQRXZOPZBKCNF-NSCUHMNNSA-N (e)-but-2-enamide Chemical compound C\C=C\C(N)=O NQQRXZOPZBKCNF-NSCUHMNNSA-N 0.000 claims description 17
• 125000003545 alkoxy group Chemical group 0.000 claims description 15
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
• XIMBESZRBTVIOD-UHFFFAOYSA-N piperidine-2-carboxamide Chemical compound NC(=O)C1CCCCN1 XIMBESZRBTVIOD-UHFFFAOYSA-N 0.000 claims description 13
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• KKCWBKUOPJMUQV-UHFFFAOYSA-N azetidine-2-carboxamide Chemical compound NC(=O)C1CCN1 KKCWBKUOPJMUQV-UHFFFAOYSA-N 0.000 claims description 11
• 125000001072 heteroaryl group Chemical group 0.000 claims description 11
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 125000003118 aryl group Chemical group 0.000 claims description 10
• 125000005842 heteroatom Chemical group 0.000 claims description 9
• BVOCPVIXARZNQN-UHFFFAOYSA-N nipecotamide Chemical compound NC(=O)C1CCCNC1 BVOCPVIXARZNQN-UHFFFAOYSA-N 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 201000011510 cancer Diseases 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
• 125000001424 substituent group Chemical group 0.000 claims description 8
• 229910003827 NRaRb Inorganic materials 0.000 claims description 7
• 125000003282 alkyl amino group Chemical group 0.000 claims description 7
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
• 125000001188 haloalkyl group Chemical group 0.000 claims description 7
• 229910052701 rubidium Inorganic materials 0.000 claims description 7
• 230000001594 aberrant effect Effects 0.000 claims description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 6
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 6
• YPSPPJRTCRMQGD-UHFFFAOYSA-N morpholine-3-carboxamide Chemical compound NC(=O)C1COCCN1 YPSPPJRTCRMQGD-UHFFFAOYSA-N 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 206010025323 Lymphomas Diseases 0.000 claims description 5
• 239000003795 chemical substances by application Substances 0.000 claims description 5
• 230000001404 mediated effect Effects 0.000 claims description 5
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 5
• 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 4
• 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 4
• 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
• 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 4
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
• 239000002246 antineoplastic agent Substances 0.000 claims description 4
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 208000027866 inflammatory disease Diseases 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
• HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 3
• 201000009030 Carcinoma Diseases 0.000 claims description 3
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 3
• 125000002947 alkylene group Chemical group 0.000 claims description 3
• 230000001028 anti-proliverative effect Effects 0.000 claims description 3
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 201000000050 myeloid neoplasm Diseases 0.000 claims description 3
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
• 210000001685 thyroid gland Anatomy 0.000 claims description 3
• 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 2
• 206010003571 Astrocytoma Diseases 0.000 claims description 2
• 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
• 208000035473 Communicable disease Diseases 0.000 claims description 2
• LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
• 201000008808 Fibrosarcoma Diseases 0.000 claims description 2
• 208000032612 Glial tumor Diseases 0.000 claims description 2
• 206010018338 Glioma Diseases 0.000 claims description 2
• 208000017604 Hodgkin disease Diseases 0.000 claims description 2
• 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 2
• 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
• 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
• 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 2
• 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 2
• 206010029260 Neuroblastoma Diseases 0.000 claims description 2
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
• 201000010208 Seminoma Diseases 0.000 claims description 2
• 206010042971 T-cell lymphoma Diseases 0.000 claims description 2
• 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 2
• 230000001154 acute effect Effects 0.000 claims description 2
• 229940127089 cytotoxic agent Drugs 0.000 claims description 2
• 230000003325 follicular Effects 0.000 claims description 2
• 229960003444 immunosuppressant agent Drugs 0.000 claims description 2
• 239000003018 immunosuppressive agent Substances 0.000 claims description 2
• 208000015181 infectious disease Diseases 0.000 claims description 2
• 210000003734 kidney Anatomy 0.000 claims description 2
• 208000032839 leukemia Diseases 0.000 claims description 2
• 210000004185 liver Anatomy 0.000 claims description 2
• 201000001441 melanoma Diseases 0.000 claims description 2
• 208000007538 neurilemmoma Diseases 0.000 claims description 2
• 201000008968 osteosarcoma Diseases 0.000 claims description 2
• 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 2
• 208000001608 teratocarcinoma Diseases 0.000 claims description 2
• GPDBJFPOOGCXPZ-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpyrrolidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(CC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1 GPDBJFPOOGCXPZ-UHFFFAOYSA-N 0.000 claims 2
• MPRGZJIDIZHMNQ-UHFFFAOYSA-N N-[3-[[[2-[(3-hydroxycyclohexyl)amino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpyrrolidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(CC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CC(CCC1)O MPRGZJIDIZHMNQ-UHFFFAOYSA-N 0.000 claims 2
• XVCFTTIVYZTNOY-UHFFFAOYSA-N N-[3-[[[2-[(3-hydroxycyclohexyl)amino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-(prop-2-enoylamino)cyclohexane-1-carboxamide Chemical compound C(C=C)(=O)NC1CCC(CC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CC(CCC1)O XVCFTTIVYZTNOY-UHFFFAOYSA-N 0.000 claims 2
• JVAPFLBAEURREJ-JOCHJYFZSA-N (2R)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylazetidine-2-carboxamide Chemical compound C(C=C)(=O)N1[C@H](CC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1 JVAPFLBAEURREJ-JOCHJYFZSA-N 0.000 claims 1
• JVAPFLBAEURREJ-QFIPXVFZSA-N (2S)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylazetidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)[C@@H]4CCN4C(=O)C=C)=C3)N2N=C1 JVAPFLBAEURREJ-QFIPXVFZSA-N 0.000 claims 1
• DSFZZUGNNOOUNN-AATRIKPKSA-N (E)-1-[4-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]piperidin-1-yl]-4-pyrrolidin-1-ylbut-2-en-1-one Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NCC1CCN(CC1)C(\C=C\CN1CCCC1)=O)NC1CCOCC1 DSFZZUGNNOOUNN-AATRIKPKSA-N 0.000 claims 1
• QUZBDSGIBSWWNQ-QPJJXVBHSA-N (E)-4-(3,3-difluoropyrrolidin-1-yl)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]but-2-enamide Chemical compound FC1(CN(CC1)C/C=C/C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1)F QUZBDSGIBSWWNQ-QPJJXVBHSA-N 0.000 claims 1
• RYXVGPSBEVUZKD-WEVVVXLNSA-N (E)-4-(3-fluoropiperidin-1-yl)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]but-2-enamide Chemical compound FC1CN(CCC1)C/C=C/C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1 RYXVGPSBEVUZKD-WEVVVXLNSA-N 0.000 claims 1
• LNUBFZYACACGRH-QPJJXVBHSA-N (E)-4-(3-fluoropyrrolidin-1-yl)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]but-2-enamide Chemical compound FC1CN(CC1)C/C=C/C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1 LNUBFZYACACGRH-QPJJXVBHSA-N 0.000 claims 1
• XCMLHSLRNSDRPI-RMKNXTFCSA-N (E)-4-(4-ethylpiperazin-1-yl)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]but-2-enamide Chemical compound C(C)N1CCN(CC1)C/C=C/C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1 XCMLHSLRNSDRPI-RMKNXTFCSA-N 0.000 claims 1
• WOQRHKUMXBMOER-RMKNXTFCSA-N (E)-4-(dimethylamino)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]but-2-enamide Chemical compound CN(C/C=C/C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1)C WOQRHKUMXBMOER-RMKNXTFCSA-N 0.000 claims 1
• CEVVVWYWRZPQBX-AATRIKPKSA-N (E)-4-(dimethylamino)-N-[3-fluoro-5-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]but-2-enamide Chemical compound CN(C/C=C/C(=O)NC1=CC(=CC(=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1)F)C CEVVVWYWRZPQBX-AATRIKPKSA-N 0.000 claims 1
• WZFYDJKZVZOZQQ-QPJJXVBHSA-N (E)-4-morpholin-4-yl-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]but-2-enamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)\C=C\CN4CCOCC4)=C3)N2N=C1 WZFYDJKZVZOZQQ-QPJJXVBHSA-N 0.000 claims 1
• QKKNVJXKZQGYTA-JXMROGBWSA-N (E)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-piperidin-1-ylbut-2-enamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)\C=C\CN4CCCCC4)=C3)N2N=C1 QKKNVJXKZQGYTA-JXMROGBWSA-N 0.000 claims 1
• TWWNLNFZVDCVGK-RMKNXTFCSA-N (E)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-pyrrolidin-1-ylbut-2-enamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)\C=C\CN4CCCC4)=C3)N2N=C1 TWWNLNFZVDCVGK-RMKNXTFCSA-N 0.000 claims 1
• NQNCIKDFGVCZFY-UHFFFAOYSA-N 1-(2-methylprop-2-enoyl)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]azetidine-2-carboxamide Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NCC=1C=C(C=CC=1)NC(=O)C1N(CC1)C(C(=C)C)=O)NC1CCOCC1 NQNCIKDFGVCZFY-UHFFFAOYSA-N 0.000 claims 1
• HVOCJQXJUFXWCM-UHFFFAOYSA-N 1-(3-methylbut-2-enoyl)-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]azetidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4CCN4C(=O)C=C(C)C)=C3)N2N=C1 HVOCJQXJUFXWCM-UHFFFAOYSA-N 0.000 claims 1
• JDKUPKQKIILYPG-RMKNXTFCSA-N 1-[(E)-4-(dimethylamino)but-2-enoyl]-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]pyrrolidine-3-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4CCN(C4)C(=O)\C=C\CN(C)C)=C3)N2N=C1 JDKUPKQKIILYPG-RMKNXTFCSA-N 0.000 claims 1
• VODRZEHGMHREHX-AATRIKPKSA-N 1-[(E)-4-(dimethylamino)but-2-enoyl]-N-[3-fluoro-5-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]pyrrolidine-3-carboxamide Chemical compound CN(C/C=C/C(=O)N1CC(CC1)C(=O)NC1=CC(=CC(=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1)F)C VODRZEHGMHREHX-AATRIKPKSA-N 0.000 claims 1
• SDHIXASQHYFOME-VMPITWQZSA-N 1-[(E)-4-methoxybut-2-enoyl]-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]pyrrolidine-3-carboxamide Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NCC=1C=C(C=CC=1)NC(=O)C1CN(CC1)C(\C=C\COC)=O)NC1CCOCC1 SDHIXASQHYFOME-VMPITWQZSA-N 0.000 claims 1
• JWIHJXRBJGVIJK-GQCTYLIASA-N 1-[(E)-but-2-enoyl]-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]azetidine-2-carboxamide Chemical compound C(\C=C\C)(=O)N1C(CC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1 JWIHJXRBJGVIJK-GQCTYLIASA-N 0.000 claims 1
• MYIKYBZQJIHUDS-UHFFFAOYSA-N 2-methyl-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-2-(prop-2-enoylamino)propanamide Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NCC=1C=C(C=CC=1)NC(C(C)(C)NC(C=C)=O)=O)NC1CCOCC1 MYIKYBZQJIHUDS-UHFFFAOYSA-N 0.000 claims 1
• XSUXGZNZLGTYTM-UHFFFAOYSA-N 2-methyl-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-3-(prop-2-enoylamino)benzamide Chemical compound C(C=C)(=O)NC=1C(=C(C(=O)NC2=CC(=CC=C2)CNC2=NC(=NC=3N2N=CC=3C(C)C)NC2CCOCC2)C=CC=1)C XSUXGZNZLGTYTM-UHFFFAOYSA-N 0.000 claims 1
• BTCLIVZDAUUTIB-UHFFFAOYSA-N 2-methyl-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-5-(prop-2-enoylamino)benzamide Chemical compound C(C=C)(=O)NC=1C=CC(=C(C(=O)NC2=CC(=CC=C2)CNC2=NC(=NC=3N2N=CC=3C(C)C)NC2CCOCC2)C=1)C BTCLIVZDAUUTIB-UHFFFAOYSA-N 0.000 claims 1
• YDDYNUGTRZIDBE-UHFFFAOYSA-N 3-[[2-(1-methylpiperidin-4-yl)oxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]-N-(1-prop-2-enoylpiperidin-4-yl)benzamide Chemical compound CC(C)C1=C2N=C(OC3CCN(C)CC3)N=C(NC3=CC=CC(=C3)C(=O)NC3CCN(CC3)C(=O)C=C)N2N=C1 YDDYNUGTRZIDBE-UHFFFAOYSA-N 0.000 claims 1
• KEGHGZFHMWIENR-QHCPKHFHSA-N 3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]-N-[(3S)-1-prop-2-enoylpiperidin-3-yl]benzamide Chemical compound C(C=C)(=O)N1C[C@H](CCC1)NC(C1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1)=O KEGHGZFHMWIENR-QHCPKHFHSA-N 0.000 claims 1
• MFABFKUNLDYKGH-UHFFFAOYSA-N 3-cyclohexyl-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1H-pyrimidine-2,4-dione Chemical group FC(F)(F)C1=CC=CC(N2CCN(CC2)C=2NC(=O)N(C3CCCCC3)C(=O)C=2)=C1 MFABFKUNLDYKGH-UHFFFAOYSA-N 0.000 claims 1
• DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 claims 1
• BPLWBHASAAWOEU-UHFFFAOYSA-N 6-methyl-N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4CCCC(C)N4C(=O)C=C)=C3)N2N=C1 BPLWBHASAAWOEU-UHFFFAOYSA-N 0.000 claims 1
• 208000017897 Carcinoma of esophagus Diseases 0.000 claims 1
• 206010009944 Colon cancer Diseases 0.000 claims 1
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 1
• 206010023347 Keratoacanthoma Diseases 0.000 claims 1
• AGAAENRQSNCCAC-UHFFFAOYSA-N N-[2-fluoro-3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylazetidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4CCN4C(=O)C=C)=C3F)N2N=C1 AGAAENRQSNCCAC-UHFFFAOYSA-N 0.000 claims 1
• HDEQAJGPRMRXBF-UHFFFAOYSA-N N-[2-fluoro-3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4CCCCN4C(=O)C=C)=C3F)N2N=C1 HDEQAJGPRMRXBF-UHFFFAOYSA-N 0.000 claims 1
• UHLXABHWADOGJK-UHFFFAOYSA-N N-[2-fluoro-3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-(prop-2-enoylamino)cyclohexane-1-carboxamide Chemical compound CC(C)c1cnn2c(NCc3cccc(NC(=O)C4CCC(CC4)NC(=O)C=C)c3F)nc(NC3CCOCC3)nc12 UHLXABHWADOGJK-UHFFFAOYSA-N 0.000 claims 1
• JHUHPSALXXQVAT-UHFFFAOYSA-N N-[2-fluoro-5-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC(NC(=O)C4CCCCN4C(=O)C=C)=C(F)C=C3)N2N=C1 JHUHPSALXXQVAT-UHFFFAOYSA-N 0.000 claims 1
• OIHNLGJPJPMTFN-UHFFFAOYSA-N N-[2-methyl-5-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylazetidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC(NC(=O)C4CCN4C(=O)C=C)=C(C)C=C3)N2N=C1 OIHNLGJPJPMTFN-UHFFFAOYSA-N 0.000 claims 1
• ILXGDLOHOSSAFU-UHFFFAOYSA-N N-[3-[1-[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]ethyl]phenyl]-1-prop-2-enoylpiperidine-3-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NC(C)C3=CC=CC(NC(=O)C4CCCN(C4)C(=O)C=C)=C3)N2N=C1 ILXGDLOHOSSAFU-UHFFFAOYSA-N 0.000 claims 1
• UIEGCGWZWNFLPV-UHFFFAOYSA-N N-[3-[[(2-piperidin-4-yloxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino]methyl]phenyl]-1-prop-2-enoylpiperidine-4-carboxamide Chemical compound CC(C)C1=C2N=C(OC3CCNCC3)N=C(NCC3=CC=CC(NC(=O)C4CCN(CC4)C(=O)C=C)=C3)N2N=C1 UIEGCGWZWNFLPV-UHFFFAOYSA-N 0.000 claims 1
• SRTKYXXYKOVFFH-UHFFFAOYSA-N N-[3-[[[2-(1-methylpiperidin-4-yl)oxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylazetidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(OC3CCN(C)CC3)N=C(NCC3=CC=CC(NC(=O)C4CCN4C(=O)C=C)=C3)N2N=C1 SRTKYXXYKOVFFH-UHFFFAOYSA-N 0.000 claims 1
• QHIAVWIHYDEQOE-UHFFFAOYSA-N N-[3-[[[2-(1-methylpiperidin-4-yl)oxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-3-carboxamide Chemical compound CC(C)C1=C2N=C(OC3CCN(C)CC3)N=C(NCC3=CC=CC(NC(=O)C4CCCN(C4)C(=O)C=C)=C3)N2N=C1 QHIAVWIHYDEQOE-UHFFFAOYSA-N 0.000 claims 1
• RZLRMJBYKRNXCB-UHFFFAOYSA-N N-[3-[[[2-(1-methylpiperidin-4-yl)oxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-4-carboxamide Chemical compound CC(C)C1=C2N=C(OC3CCN(C)CC3)N=C(NCC3=CC=CC(NC(=O)C4CCN(CC4)C(=O)C=C)=C3)N2N=C1 RZLRMJBYKRNXCB-UHFFFAOYSA-N 0.000 claims 1
• LNIAIHWQEDDETK-UHFFFAOYSA-N N-[3-[[[2-(1-methylpiperidin-4-yl)oxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpyrrolidine-3-carboxamide Chemical compound CC(C)C1=C2N=C(OC3CCN(C)CC3)N=C(NCC3=CC=CC(NC(=O)C4CCN(C4)C(=O)C=C)=C3)N2N=C1 LNIAIHWQEDDETK-UHFFFAOYSA-N 0.000 claims 1
• UGFVHZWAOXCEDL-UHFFFAOYSA-N N-[3-[[[2-(1-methylpiperidin-4-yl)oxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-3-(prop-2-enoylamino)cyclohexane-1-carboxamide Chemical compound CC(C)C1=C2N=C(OC3CCN(C)CC3)N=C(NCC3=CC=CC(NC(=O)C4CCCC(C4)NC(=O)C=C)=C3)N2N=C1 UGFVHZWAOXCEDL-UHFFFAOYSA-N 0.000 claims 1
• VFICZOBNCSVFJY-UHFFFAOYSA-N N-[3-[[[2-(1-methylpiperidin-4-yl)oxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-prop-2-enoylmorpholine-2-carboxamide Chemical compound CC(C)C1=C2N=C(OC3CCN(C)CC3)N=C(NCC3=CC=CC(NC(=O)C4CN(CCO4)C(=O)C=C)=C3)N2N=C1 VFICZOBNCSVFJY-UHFFFAOYSA-N 0.000 claims 1
• AOOPXJCVKUIDDE-UHFFFAOYSA-N N-[3-[[[2-(1-methylpiperidin-4-yl)oxypyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-3-carboxamide Chemical compound CN1CCC(CC1)OC1=NC2=CC=NN2C(NCC2=CC=CC(NC(=O)C3CCCN(C3)C(=O)C=C)=C2)=N1 AOOPXJCVKUIDDE-UHFFFAOYSA-N 0.000 claims 1
• ZEZIQUAVXMWMHQ-UHFFFAOYSA-N N-[3-[[[2-(3-fluorooxan-4-yl)oxy-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-(prop-2-enoylamino)cyclohexane-1-carboxamide Chemical compound C(C=C)(=O)NC1CCC(CC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)OC1C(COCC1)F ZEZIQUAVXMWMHQ-UHFFFAOYSA-N 0.000 claims 1
• UJFOUMFEPVUHLH-UHFFFAOYSA-N N-[3-[[[2-(4-aminobutoxy)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-4-carboxamide Chemical compound CC(C)C1=C2N=C(OCCCCN)N=C(NCC3=CC=CC(NC(=O)C4CCN(CC4)C(=O)C=C)=C3)N2N=C1 UJFOUMFEPVUHLH-UHFFFAOYSA-N 0.000 claims 1
• JVAPFLBAEURREJ-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylazetidine-2-carboxamide Chemical compound C(C=C)(=O)N1C(CC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1 JVAPFLBAEURREJ-UHFFFAOYSA-N 0.000 claims 1
• ZVKYCZNUBZGERI-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4CCCCN4C(=O)C=C)=C3)N2N=C1 ZVKYCZNUBZGERI-UHFFFAOYSA-N 0.000 claims 1
• RCPRNUMVRKHPTG-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-3-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4CCCN(C4)C(=O)C=C)=C3)N2N=C1 RCPRNUMVRKHPTG-UHFFFAOYSA-N 0.000 claims 1
• CQGSKPPSPMWAPE-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpyrrolidine-2-carboxamide Chemical compound C(C=C)(=O)N1C(CCC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1 CQGSKPPSPMWAPE-UHFFFAOYSA-N 0.000 claims 1
• ROCSVCJJFDTHGZ-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-ynoylazetidine-2-carboxamide Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NCC=1C=C(C=CC=1)NC(=O)C1N(CC1)C(C#C)=O)NC1CCOCC1 ROCSVCJJFDTHGZ-UHFFFAOYSA-N 0.000 claims 1
• WXYJBUJBMFEFAX-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-2-(prop-2-enoylamino)benzamide Chemical compound C(C=C)(=O)NC1=C(C(=O)NC2=CC(=CC=C2)CNC2=NC(=NC=3N2N=CC=3C(C)C)NC2CCOCC2)C=CC=C1 WXYJBUJBMFEFAX-UHFFFAOYSA-N 0.000 claims 1
• VSYJBVCCOVYHPR-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-3-(prop-2-enoylamino)benzamide Chemical compound C(C=C)(=O)NC=1C=C(C(=O)NC2=CC(=CC=C2)CNC2=NC(=NC=3N2N=CC=3C(C)C)NC2CCOCC2)C=CC=1 VSYJBVCCOVYHPR-UHFFFAOYSA-N 0.000 claims 1
• ZIDAIHUEAWEVHL-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-prop-2-enoylmorpholine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4CN(CCO4)C(=O)C=C)=C3)N2N=C1 ZIDAIHUEAWEVHL-UHFFFAOYSA-N 0.000 claims 1
• KXKRFCPVCYJEIL-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-prop-2-enoylmorpholine-3-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4COCCN4C(=O)C=C)=C3)N2N=C1 KXKRFCPVCYJEIL-UHFFFAOYSA-N 0.000 claims 1
• UFBFKBXZFSIQKT-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-prop-2-ynoylmorpholine-3-carboxamide Chemical compound C(C)(C)C=1C=NN2C=1N=C(N=C2NCC=1C=C(C=CC=1)NC(=O)C1N(CCOC1)C(C#C)=O)NC1CCOCC1 UFBFKBXZFSIQKT-UHFFFAOYSA-N 0.000 claims 1
• BWHOKMJVCFLALP-UHFFFAOYSA-N N-[3-[[[2-(oxan-4-yloxy)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-3-carboxamide Chemical compound CC(C)C1=C2N=C(OC3CCOCC3)N=C(NCC3=CC=CC(NC(=O)C4CCCN(C4)C(=O)C=C)=C3)N2N=C1 BWHOKMJVCFLALP-UHFFFAOYSA-N 0.000 claims 1
• ADWXJDLAQHGNIE-UHFFFAOYSA-N N-[3-[[[2-[(3-aminocyclohexyl)amino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpyrrolidine-3-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCCC(N)C3)N=C(NCC3=CC=CC(NC(=O)C4CCN(C4)C(=O)C=C)=C3)N2N=C1 ADWXJDLAQHGNIE-UHFFFAOYSA-N 0.000 claims 1
• ONEXNQKMGKVENG-UHFFFAOYSA-N N-[3-[[[2-[(4-hydroxycyclohexyl)amino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-(prop-2-enoylamino)cyclohexane-1-carboxamide Chemical compound CC(C)c1cnn2c(NCc3cccc(NC(=O)C4CCC(CC4)NC(=O)C=C)c3)nc(NC3CCC(O)CC3)nc12 ONEXNQKMGKVENG-UHFFFAOYSA-N 0.000 claims 1
• IAPOTAHTLZCKMS-UHFFFAOYSA-N N-[3-[[[2-[2-(2-methoxyethoxy)ethoxy]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpyrrolidine-3-carboxamide Chemical compound COCCOCCOC1=NC2=C(C=NN2C(NCC2=CC=CC(NC(=O)C3CCN(C3)C(=O)C=C)=C2)=N1)C(C)C IAPOTAHTLZCKMS-UHFFFAOYSA-N 0.000 claims 1
• JIVCYBOEYULWCW-LETIRJCYSA-N N-[3-[[[2-[[(3R)-oxan-3-yl]amino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(N[C@@H]3CCCOC3)N=C(NCC3=CC=CC(NC(=O)C4CCCCN4C(=O)C=C)=C3)N2N=C1 JIVCYBOEYULWCW-LETIRJCYSA-N 0.000 claims 1
• KGHZKXNQBOKOPW-QENMJEOYSA-N N-[3-[[[2-[[(3R,4R)-3-fluoropiperidin-4-yl]amino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpyrrolidine-3-carboxamide Chemical compound C(C=C)(=O)N1CC(CC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)N[C@H]1[C@@H](CNCC1)F KGHZKXNQBOKOPW-QENMJEOYSA-N 0.000 claims 1
• JIVCYBOEYULWCW-OWJIYDKWSA-N N-[3-[[[2-[[(3S)-oxan-3-yl]amino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-2-carboxamide Chemical compound C(C=C)(=O)N1C(CCCC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2C(C)C)N[C@@H]1COCCC1 JIVCYBOEYULWCW-OWJIYDKWSA-N 0.000 claims 1
• OPJYPQHGSWFBRW-UHFFFAOYSA-N N-[3-[[[5-(oxan-4-ylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-7-yl]amino]methyl]phenyl]-1-prop-2-enoylazetidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)C=C(NCC3=CC=CC(NC(=O)C4CCN4C(=O)C=C)=C3)N2N=C1 OPJYPQHGSWFBRW-UHFFFAOYSA-N 0.000 claims 1
• UAKAWJUFHDSOJH-UHFFFAOYSA-N N-[3-[[[8-ethyl-2-(1-methylpiperidin-4-yl)oxypyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-4-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)C(=O)NC1=CC(=CC=C1)CNC1=NC(=NC=2N1N=CC=2CC)OC1CCN(CC1)C UAKAWJUFHDSOJH-UHFFFAOYSA-N 0.000 claims 1
• ZGEMGZQHNPREAG-UHFFFAOYSA-N N-[3-fluoro-5-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylazetidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC(NC(=O)C4CCN4C(=O)C=C)=CC(F)=C3)N2N=C1 ZGEMGZQHNPREAG-UHFFFAOYSA-N 0.000 claims 1
• XOZFGRPMLWDGNR-UHFFFAOYSA-N N-[3-fluoro-5-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC(NC(=O)C4CCCCN4C(=O)C=C)=CC(F)=C3)N2N=C1 XOZFGRPMLWDGNR-UHFFFAOYSA-N 0.000 claims 1
• VOXFGWXRUYEQNE-UHFFFAOYSA-N N-[3-fluoro-5-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpyrrolidine-3-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=CC(NC(=O)C4CCN(C4)C(=O)C=C)=CC(F)=C3)N2N=C1 VOXFGWXRUYEQNE-UHFFFAOYSA-N 0.000 claims 1
• UWPGYPLYDBZYFN-UHFFFAOYSA-N N-[4-ethyl-3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-prop-2-enoylmorpholine-3-carboxamide Chemical compound C(C=C)(=O)N1C(COCC1)C(=O)NC1=CC(=C(C=C1)CC)CNC1=NC(=NC=2N1N=CC=2C(C)C)NC1CCOCC1 UWPGYPLYDBZYFN-UHFFFAOYSA-N 0.000 claims 1
• OKGGBEMQENGDSY-UHFFFAOYSA-N N-[4-fluoro-3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=C(F)C=CC(NC(=O)C4CCCCN4C(=O)C=C)=C3)N2N=C1 OKGGBEMQENGDSY-UHFFFAOYSA-N 0.000 claims 1
• KJXMHLGQPIRMAN-UHFFFAOYSA-N N-[4-fluoro-3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpyrrolidine-3-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=C(F)C=CC(NC(=O)C4CCN(C4)C(=O)C=C)=C3)N2N=C1 KJXMHLGQPIRMAN-UHFFFAOYSA-N 0.000 claims 1
• VZWWEOLFBTUSFX-UHFFFAOYSA-N N-[4-fluoro-3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-4-(prop-2-enoylamino)cyclohexane-1-carboxamide Chemical compound CC(C)c1cnn2c(NCc3cc(NC(=O)C4CCC(CC4)NC(=O)C=C)ccc3F)nc(NC3CCOCC3)nc12 VZWWEOLFBTUSFX-UHFFFAOYSA-N 0.000 claims 1
• RIFYCZACTIBQLA-UHFFFAOYSA-N N-[4-methyl-3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylazetidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=C(C)C=CC(NC(=O)C4CCN4C(=O)C=C)=C3)N2N=C1 RIFYCZACTIBQLA-UHFFFAOYSA-N 0.000 claims 1
• NLRKWNBKZSJEBF-UHFFFAOYSA-N N-[4-methyl-3-[[[2-(oxan-4-ylamino)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpiperidine-2-carboxamide Chemical compound CC(C)C1=C2N=C(NC3CCOCC3)N=C(NCC3=C(C)C=CC(NC(=O)C4CCCCN4C(=O)C=C)=C3)N2N=C1 NLRKWNBKZSJEBF-UHFFFAOYSA-N 0.000 claims 1
• 206010033128 Ovarian cancer Diseases 0.000 claims 1
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 1
• 201000006083 Xeroderma Pigmentosum Diseases 0.000 claims 1
• VALZSZJVEFACEZ-UHFFFAOYSA-N azetidine-3-carboxamide Chemical compound NC(=O)C1CNC1 VALZSZJVEFACEZ-UHFFFAOYSA-N 0.000 claims 1
• 201000008275 breast carcinoma Diseases 0.000 claims 1
• 208000019065 cervical carcinoma Diseases 0.000 claims 1
• 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims 1
• 201000007487 gallbladder carcinoma Diseases 0.000 claims 1
• 208000010749 gastric carcinoma Diseases 0.000 claims 1
• 201000003911 head and neck carcinoma Diseases 0.000 claims 1
• 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims 1
• 201000005296 lung carcinoma Diseases 0.000 claims 1
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
• RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 claims 1
• 201000001514 prostate carcinoma Diseases 0.000 claims 1
• 201000008261 skin carcinoma Diseases 0.000 claims 1
• 208000013077 thyroid gland carcinoma Diseases 0.000 claims 1
• 208000010570 urinary bladder carcinoma Diseases 0.000 claims 1
• 102100033144 Cyclin-dependent kinase 18 Human genes 0.000 abstract description 21
• 108010039798 PCTAIRE-3 protein kinase Proteins 0.000 abstract description 21
• 238000011282 treatment Methods 0.000 abstract description 17
• 239000003112 inhibitor Substances 0.000 abstract description 11
• 238000002360 preparation method Methods 0.000 abstract description 9
• 241000124008 Mammalia Species 0.000 abstract description 4
• 230000006806 disease prevention Effects 0.000 abstract description 3
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 283
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 264
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 258
• 230000015572 biosynthetic process Effects 0.000 description 170
• 238000003786 synthesis reaction Methods 0.000 description 168
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 159
• 239000011541 reaction mixture Substances 0.000 description 142
• 238000000034 method Methods 0.000 description 127
• 238000005160 1H NMR spectroscopy Methods 0.000 description 90
• 239000000243 solution Substances 0.000 description 84
• 238000006243 chemical reaction Methods 0.000 description 77
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 70
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 64
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 60
• 229910052938 sodium sulfate Inorganic materials 0.000 description 60
• 235000011152 sodium sulphate Nutrition 0.000 description 60
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 58
• 101710106276 Cyclin-dependent kinase 7 Proteins 0.000 description 58
• 239000012267 brine Substances 0.000 description 57
• 230000008569 process Effects 0.000 description 57
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 57
• 239000007832 Na2SO4 Substances 0.000 description 56
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 55
• 239000012074 organic phase Substances 0.000 description 52
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 45
• 239000010410 layer Substances 0.000 description 43
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 42
• 102000003903 Cyclin-dependent kinases Human genes 0.000 description 41
• 108090000266 Cyclin-dependent kinases Proteins 0.000 description 41
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
• 239000003153 chemical reaction reagent Substances 0.000 description 35
• 238000005481 NMR spectroscopy Methods 0.000 description 34
• 239000002904 solvent Substances 0.000 description 31
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
• 239000005457 ice water Substances 0.000 description 29
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
• 239000000376 reactant Substances 0.000 description 26
• 230000005764 inhibitory process Effects 0.000 description 22
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• 230000000694 effects Effects 0.000 description 20
• 239000000203 mixture Substances 0.000 description 20
• 238000003756 stirring Methods 0.000 description 20
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
• 239000007821 HATU Substances 0.000 description 19
• 108091000080 Phosphotransferase Proteins 0.000 description 19
• 102000020233 phosphotransferase Human genes 0.000 description 19
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
• 239000000543 intermediate Substances 0.000 description 18
• 238000002953 preparative HPLC Methods 0.000 description 17
• 238000010898 silica gel chromatography Methods 0.000 description 17
• YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 16
• DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 16
• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 16
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• 239000000047 product Substances 0.000 description 14
• QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 13
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 13
• 230000022131 cell cycle Effects 0.000 description 13
• ONPGOSVDVDPBCY-CQSZACIVSA-N 6-amino-5-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-n-[4-(4-methylpiperazine-1-carbonyl)phenyl]pyridazine-3-carboxamide Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NN=1)N)=CC=1C(=O)NC(C=C1)=CC=C1C(=O)N1CCN(C)CC1 ONPGOSVDVDPBCY-CQSZACIVSA-N 0.000 description 12
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
• ODUIXUGXPFKQLG-QWRGUYRKSA-N [2-(4-chloro-2-fluoroanilino)-5-methyl-1,3-thiazol-4-yl]-[(2s,3s)-2,3-dimethylpiperidin-1-yl]methanone Chemical compound C[C@H]1[C@@H](C)CCCN1C(=O)C1=C(C)SC(NC=2C(=CC(Cl)=CC=2)F)=N1 ODUIXUGXPFKQLG-QWRGUYRKSA-N 0.000 description 12
• 229940086542 triethylamine Drugs 0.000 description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
• 238000004128 high performance liquid chromatography Methods 0.000 description 11
• 150000001408 amides Chemical class 0.000 description 10
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 10
• 238000012512 characterization method Methods 0.000 description 9
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
• AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 8
• 239000000460 chlorine Substances 0.000 description 8
• 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 8
• 239000006196 drop Substances 0.000 description 8
• 229910000027 potassium carbonate Inorganic materials 0.000 description 8
• XSCVJHCFMXPRNY-UHFFFAOYSA-N pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine Chemical compound N1=C(N)N=C(N)N2N=CC=C21 XSCVJHCFMXPRNY-UHFFFAOYSA-N 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
• 239000007787 solid Substances 0.000 description 8
• 238000013518 transcription Methods 0.000 description 8
• 230000035897 transcription Effects 0.000 description 8
• 239000011701 zinc Substances 0.000 description 8
• 229910021529 ammonia Inorganic materials 0.000 description 7
• 239000002585 base Substances 0.000 description 7
• 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 7
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
• 239000003814 drug Substances 0.000 description 7
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 7
• 230000002401 inhibitory effect Effects 0.000 description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
• 230000026731 phosphorylation Effects 0.000 description 7
• 238000006366 phosphorylation reaction Methods 0.000 description 7
• 235000015320 potassium carbonate Nutrition 0.000 description 7
• SZUXYYIDZMHWDD-UHFFFAOYSA-N pyrazolo[1,5-a][1,3,5]triazin-4-amine Chemical compound NC1=NC=NC2=CC=NN12 SZUXYYIDZMHWDD-UHFFFAOYSA-N 0.000 description 7
• 229910000104 sodium hydride Inorganic materials 0.000 description 7
• 239000000758 substrate Substances 0.000 description 7
• 229910052725 zinc Inorganic materials 0.000 description 7
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
• 241001465754 Metazoa Species 0.000 description 6
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 230000006369 cell cycle progression Effects 0.000 description 6
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
• 125000002950 monocyclic group Chemical group 0.000 description 6
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
• 230000002062 proliferating effect Effects 0.000 description 6
• ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 6
• 239000000377 silicon dioxide Substances 0.000 description 6
• 239000007858 starting material Substances 0.000 description 6
• QQOWHRYOXYEMTL-UHFFFAOYSA-N triazin-4-amine Chemical compound N=C1C=CN=NN1 QQOWHRYOXYEMTL-UHFFFAOYSA-N 0.000 description 6
• 102100036883 Cyclin-H Human genes 0.000 description 5
• 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 5
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
• HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 5
• BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 5
• 229950010817 alvocidib Drugs 0.000 description 5
• 235000019270 ammonium chloride Nutrition 0.000 description 5
• 125000004429 atom Chemical group 0.000 description 5
• 229910052799 carbon Inorganic materials 0.000 description 5
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
• 239000003085 diluting agent Substances 0.000 description 5
• 239000012044 organic layer Substances 0.000 description 5
• 108090000623 proteins and genes Proteins 0.000 description 5
• 230000001105 regulatory effect Effects 0.000 description 5
• 239000011593 sulfur Chemical group 0.000 description 5
• 208000024891 symptom Diseases 0.000 description 5
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
• DILISPNYIVRDBP-UHFFFAOYSA-N 2-[3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]-2-naphthalen-2-ylimidazol-4-yl]acetonitrile Chemical compound OC(CNC1=NC=CC(=N1)N1C(=NC=C1CC#N)C1=CC2=CC=CC=C2C=C1)C DILISPNYIVRDBP-UHFFFAOYSA-N 0.000 description 4
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
• 101100533230 Caenorhabditis elegans ser-2 gene Proteins 0.000 description 4
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
• 102000016736 Cyclin Human genes 0.000 description 4
• 108050006400 Cyclin Proteins 0.000 description 4
• 108010068237 Cyclin H Proteins 0.000 description 4
• 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 4
• 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 4
• 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 4
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
• 102000009572 RNA Polymerase II Human genes 0.000 description 4
• 108010009460 RNA Polymerase II Proteins 0.000 description 4
• 235000011114 ammonium hydroxide Nutrition 0.000 description 4
• 238000003556 assay Methods 0.000 description 4
• 239000012298 atmosphere Substances 0.000 description 4
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
• 229910000024 caesium carbonate Inorganic materials 0.000 description 4
• 235000014113 dietary fatty acids Nutrition 0.000 description 4
• 239000000194 fatty acid Substances 0.000 description 4
• 229930195729 fatty acid Natural products 0.000 description 4
• 239000000706 filtrate Substances 0.000 description 4
• 239000012458 free base Substances 0.000 description 4
• 230000006870 function Effects 0.000 description 4
• UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 4
• 238000004519 manufacturing process Methods 0.000 description 4
• 230000004048 modification Effects 0.000 description 4
• 238000012986 modification Methods 0.000 description 4
• YBXBWBBVLXZQBJ-UHFFFAOYSA-N n-[2-(5-hydroxy-2-methyl-1h-indol-3-yl)ethyl]-2-methoxyacetamide Chemical compound C1=C(O)C=C2C(CCNC(=O)COC)=C(C)NC2=C1 YBXBWBBVLXZQBJ-UHFFFAOYSA-N 0.000 description 4
• PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
• AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 4
• 239000001301 oxygen Chemical group 0.000 description 4
• 125000006413 ring segment Chemical group 0.000 description 4
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
• 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 4
• OFBHRFQOAARPHM-ONEGZZNKSA-N (E)-4-bromo-N,N-dimethylbut-2-enamide Chemical compound CN(C)C(=O)\C=C\CBr OFBHRFQOAARPHM-ONEGZZNKSA-N 0.000 description 3
• DOTGZROJTAUYFQ-OWOJBTEDSA-N (e)-4-bromobut-2-enoic acid Chemical compound OC(=O)\C=C\CBr DOTGZROJTAUYFQ-OWOJBTEDSA-N 0.000 description 3
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
• DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 3
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
• 239000005695 Ammonium acetate Substances 0.000 description 3
• 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
• 229940125888 CDK7 inhibitor Drugs 0.000 description 3
• 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 3
• 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 3
• 230000033616 DNA repair Effects 0.000 description 3
• BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
• 108010010803 Gelatin Proteins 0.000 description 3
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
• 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 3
• 150000001204 N-oxides Chemical class 0.000 description 3
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
• 239000002253 acid Substances 0.000 description 3
• 150000001412 amines Chemical class 0.000 description 3
• 235000019257 ammonium acetate Nutrition 0.000 description 3
• 229940043376 ammonium acetate Drugs 0.000 description 3
• MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound 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 3
• 239000000872 buffer Substances 0.000 description 3
• 239000002775 capsule Substances 0.000 description 3
• 230000004663 cell proliferation Effects 0.000 description 3
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
• 238000004440 column chromatography Methods 0.000 description 3
• 238000010511 deprotection reaction Methods 0.000 description 3
• 239000008273 gelatin Substances 0.000 description 3
• 229920000159 gelatin Polymers 0.000 description 3
• 235000019322 gelatine Nutrition 0.000 description 3
• 235000011852 gelatine desserts Nutrition 0.000 description 3
• 238000001727 in vivo Methods 0.000 description 3
• 238000011534 incubation Methods 0.000 description 3
• 239000004615 ingredient Substances 0.000 description 3
• OBJNFLYHUXWUPF-IZZDOVSWSA-N n-[3-[[5-chloro-4-(1h-indol-3-yl)pyrimidin-2-yl]amino]phenyl]-4-[[(e)-4-(dimethylamino)but-2-enoyl]amino]benzamide Chemical compound C1=CC(NC(=O)/C=C/CN(C)C)=CC=C1C(=O)NC1=CC=CC(NC=2N=C(C(Cl)=CN=2)C=2C3=CC=CC=C3NC=2)=C1 OBJNFLYHUXWUPF-IZZDOVSWSA-N 0.000 description 3
• LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 3
• CXWQAPHDSYDHBR-UHFFFAOYSA-N piperidine-4-carboxamide Chemical compound NC(=O)C1CCNCC1.NC(=O)C1CCNCC1 CXWQAPHDSYDHBR-UHFFFAOYSA-N 0.000 description 3
• 125000003386 piperidinyl group Chemical group 0.000 description 3
• 239000003755 preservative agent Substances 0.000 description 3
• 230000002265 prevention Effects 0.000 description 3
• 235000018102 proteins Nutrition 0.000 description 3
• 102000004169 proteins and genes Human genes 0.000 description 3
• 239000011347 resin Substances 0.000 description 3
• 229920005989 resin Polymers 0.000 description 3
• 229920006395 saturated elastomer Polymers 0.000 description 3
• 238000000926 separation method Methods 0.000 description 3
• 239000000741 silica gel Substances 0.000 description 3
• 229910002027 silica gel Inorganic materials 0.000 description 3
• 239000011734 sodium Substances 0.000 description 3
• 235000017557 sodium bicarbonate Nutrition 0.000 description 3
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
• 239000012279 sodium borohydride Substances 0.000 description 3
• 229910000033 sodium borohydride Inorganic materials 0.000 description 3
• 239000000725 suspension Substances 0.000 description 3
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
• 230000001225 therapeutic effect Effects 0.000 description 3
• 239000011534 wash buffer Substances 0.000 description 3
• CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
• KEEKMOIRJUWKNK-CABZTGNLSA-N (2S)-2-[[2-[(4R)-4-(difluoromethyl)-2-oxo-1,3-thiazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide Chemical compound FC([C@H]1N(C(SC1)=O)C=1N=C2N(CCOC3=C2C=CC(=C3)N[C@H](C(=O)N)C)C=1)F KEEKMOIRJUWKNK-CABZTGNLSA-N 0.000 description 2
• UUHNQHFOIVLAQX-BJILWQEISA-N (e)-4-(dimethylamino)but-2-enoic acid;hydrochloride Chemical compound Cl.CN(C)C\C=C\C(O)=O UUHNQHFOIVLAQX-BJILWQEISA-N 0.000 description 2
• ITGIYLMMAABTHC-ONEGZZNKSA-N (e)-4-(dimethylazaniumyl)but-2-enoate Chemical compound CN(C)C\C=C\C(O)=O ITGIYLMMAABTHC-ONEGZZNKSA-N 0.000 description 2
• BAUWRHPMUVYFOD-UHFFFAOYSA-N 1-methylpiperidin-4-ol Chemical compound CN1CCC(O)CC1 BAUWRHPMUVYFOD-UHFFFAOYSA-N 0.000 description 2
• 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 description 2
• PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
• XBUIBIHOIQNJQG-UHFFFAOYSA-N 1-prop-2-enoylpiperidine-4-carboxylic acid Chemical compound OC(=O)C1CCN(C(=O)C=C)CC1 XBUIBIHOIQNJQG-UHFFFAOYSA-N 0.000 description 2
• BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 2
• SSORSZACHCNXSJ-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)-3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound ClC=1C=C(C=CC=1Cl)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NCC(C)O SSORSZACHCNXSJ-UHFFFAOYSA-N 0.000 description 2
• CWNRYVQFAMHXLM-UHFFFAOYSA-N 2-formylbutanenitrile Chemical compound CCC(C=O)C#N CWNRYVQFAMHXLM-UHFFFAOYSA-N 0.000 description 2
• HYJMPMKNCACNOC-UHFFFAOYSA-N 3-fluoro-1-methylpiperidin-4-ol Chemical compound CN1CCC(O)C(F)C1 HYJMPMKNCACNOC-UHFFFAOYSA-N 0.000 description 2
• AVXCVBXAVNDIGV-UHFFFAOYSA-N 3-fluoro-4-phenylmethoxypiperidine Chemical compound C(C1=CC=CC=C1)OC1C(CNCC1)F AVXCVBXAVNDIGV-UHFFFAOYSA-N 0.000 description 2
• RDCODVKTTJWFAR-UHFFFAOYSA-N 4-ethyl-1h-pyrazol-5-amine Chemical compound CCC=1C=NNC=1N RDCODVKTTJWFAR-UHFFFAOYSA-N 0.000 description 2
• RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 2
• 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 2
• BWJHJLINOYAPEG-HOTGVXAUSA-N 8-chloro-6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclopentyl]-7-methyl-2H-1,3-benzoxazin-4-one Chemical compound ClC1=C(C(=CC=2C(N(COC=21)[C@@H]1[C@H](CCC1)O)=O)CC=1C=NC(=CC=1)Cl)C BWJHJLINOYAPEG-HOTGVXAUSA-N 0.000 description 2
• CSSPFDIICWOTSY-HNNXBMFYSA-N C(#N)C=1C=C(C(=O)N[C@@H]2CN(CCC2)C(=O)OC(C)(C)C)C=CC=1 Chemical compound C(#N)C=1C=C(C(=O)N[C@@H]2CN(CCC2)C(=O)OC(C)(C)C)C=CC=1 CSSPFDIICWOTSY-HNNXBMFYSA-N 0.000 description 2
• 229940126074 CDK kinase inhibitor Drugs 0.000 description 2
• 102100030933 CDK-activating kinase assembly factor MAT1 Human genes 0.000 description 2
• 102100040428 Chitobiosyldiphosphodolichol beta-mannosyltransferase Human genes 0.000 description 2
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
• 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 2
• 102100036876 Cyclin-K Human genes 0.000 description 2
• 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 2
• 102100034770 Cyclin-dependent kinase inhibitor 3 Human genes 0.000 description 2
• RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 2
• BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
• 102000004190 Enzymes Human genes 0.000 description 2
• 108090000790 Enzymes Proteins 0.000 description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
• LRULVYSBRWUVGR-FCHUYYIVSA-N GSK2879552 Chemical compound C1=CC(C(=O)O)=CC=C1CN1CCC(CN[C@H]2[C@@H](C2)C=2C=CC=CC=2)CC1 LRULVYSBRWUVGR-FCHUYYIVSA-N 0.000 description 2
• 241000282412 Homo Species 0.000 description 2
• 101000583935 Homo sapiens CDK-activating kinase assembly factor MAT1 Proteins 0.000 description 2
• 101000891557 Homo sapiens Chitobiosyldiphosphodolichol beta-mannosyltransferase Proteins 0.000 description 2
• 101000713127 Homo sapiens Cyclin-K Proteins 0.000 description 2
• 101000945639 Homo sapiens Cyclin-dependent kinase inhibitor 3 Proteins 0.000 description 2
• 239000012448 Lithium borohydride Substances 0.000 description 2
• 241000699670 Mus sp. Species 0.000 description 2
• ZTCLCSCHTACERP-AWEZNQCLSA-N N-[(1S)-1-[3-chloro-5-fluoro-2-[[2-methyl-4-(2-methyl-1,2,4-triazol-3-yl)quinolin-8-yl]oxymethyl]phenyl]ethyl]-2-(difluoromethoxy)acetamide Chemical compound C1=C(C=C(C(=C1Cl)COC1=CC=CC2=C(C=3N(N=CN=3)C)C=C(C)N=C12)[C@@H](NC(=O)COC(F)F)C)F ZTCLCSCHTACERP-AWEZNQCLSA-N 0.000 description 2
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
• MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 2
• 159000000021 acetate salts Chemical class 0.000 description 2
• 230000004913 activation Effects 0.000 description 2
• 230000006907 apoptotic process Effects 0.000 description 2
• 125000002619 bicyclic group Chemical group 0.000 description 2
• 230000000903 blocking effect Effects 0.000 description 2
• 239000000969 carrier Substances 0.000 description 2
• 230000001413 cellular effect Effects 0.000 description 2
• 229910052801 chlorine Inorganic materials 0.000 description 2
• IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
• 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
• GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
• 230000003828 downregulation Effects 0.000 description 2
• 229940079593 drug Drugs 0.000 description 2
• 239000003480 eluent Substances 0.000 description 2
• 239000011737 fluorine Substances 0.000 description 2
• 229910052731 fluorine Inorganic materials 0.000 description 2
• 235000019253 formic acid Nutrition 0.000 description 2
• 238000009472 formulation Methods 0.000 description 2
• 108091006104 gene-regulatory proteins Proteins 0.000 description 2
• 102000034356 gene-regulatory proteins Human genes 0.000 description 2
• 230000012010 growth Effects 0.000 description 2
• 201000005787 hematologic cancer Diseases 0.000 description 2
• 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
• 230000007246 mechanism Effects 0.000 description 2
• LSNOAQQZECGQNS-UHFFFAOYSA-N morpholine-2-carboxamide Chemical compound NC(=O)C1CNCCO1 LSNOAQQZECGQNS-UHFFFAOYSA-N 0.000 description 2
• 125000002757 morpholinyl group Chemical group 0.000 description 2
• VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 2
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 2
• 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
• 239000002953 phosphate buffered saline Substances 0.000 description 2
• 125000004193 piperazinyl group Chemical group 0.000 description 2
• 239000000843 powder Substances 0.000 description 2
• VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
• 238000000746 purification Methods 0.000 description 2
• 125000004076 pyridyl group Chemical group 0.000 description 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
• 235000004400 serine Nutrition 0.000 description 2
• 150000003355 serines Chemical class 0.000 description 2
• UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
• 239000003826 tablet Substances 0.000 description 2
• ABPXAMVUXVELLR-UHFFFAOYSA-N tert-butyl 3-fluoro-4-phenylmethoxypiperidine-1-carboxylate Chemical compound C(C1=CC=CC=C1)OC1C(CN(CC1)C(=O)OC(C)(C)C)F ABPXAMVUXVELLR-UHFFFAOYSA-N 0.000 description 2
• XVUGYASNBHHQBN-UHFFFAOYSA-N tert-butyl 4-[(3-nitrobenzoyl)amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1NC(=O)C1=CC=CC([N+]([O-])=O)=C1 XVUGYASNBHHQBN-UHFFFAOYSA-N 0.000 description 2
• NCIQNWYJLAAFAH-UHFFFAOYSA-N tert-butyl 4-carbonochloridoylpiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(Cl)=O)CC1 NCIQNWYJLAAFAH-UHFFFAOYSA-N 0.000 description 2
• CGMHBBYFYZTHDD-UHFFFAOYSA-N tert-butyl N-(3-cyano-4-ethylphenyl)carbamate Chemical compound C(#N)C=1C=C(C=CC=1CC)NC(OC(C)(C)C)=O CGMHBBYFYZTHDD-UHFFFAOYSA-N 0.000 description 2
• RJLNRCVWZZYPFC-UHFFFAOYSA-N tert-butyl N-(4-bromo-3-cyanophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(C#N)=C(Br)C=C1 RJLNRCVWZZYPFC-UHFFFAOYSA-N 0.000 description 2
• 238000012360 testing method Methods 0.000 description 2
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
• 238000002560 therapeutic procedure Methods 0.000 description 2
• 238000004809 thin layer chromatography Methods 0.000 description 2
• 235000008521 threonine Nutrition 0.000 description 2
• 150000003588 threonines Chemical class 0.000 description 2
• 230000000699 topical effect Effects 0.000 description 2
• 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
• 239000003039 volatile agent Substances 0.000 description 2
• KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 2
• SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
• BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
• NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
• CIUYJYRQKYGNQP-UHFFFAOYSA-N (3-nitrophenyl)methanamine Chemical compound NCC1=CC=CC([N+]([O-])=O)=C1 CIUYJYRQKYGNQP-UHFFFAOYSA-N 0.000 description 1
• MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
• NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 1
• YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
• OIIOPWHTJZYKIL-PMACEKPBSA-N (5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one Chemical compound C1(=C(N=C(C2=C(C(C3=CC=CC(=C3Cl)C3=NC(OC)=C(N=C3)CNC[C@H]3NC(=O)CC3)=CC=C2)Cl)C=N1)OC)CNC[C@H]1NC(=O)CC1 OIIOPWHTJZYKIL-PMACEKPBSA-N 0.000 description 1
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
• XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 description 1
• LCFFREMLXLZNHE-GBOLQPHISA-N (e)-2-[(3r)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile Chemical compound C12=C(N)N=CN=C2N([C@@H]2CCCN(C2)C(=O)C(/C#N)=C/C(C)(C)N2CCN(CC2)C2COC2)N=C1C(C(=C1)F)=CC=C1OC1=CC=CC=C1 LCFFREMLXLZNHE-GBOLQPHISA-N 0.000 description 1
• ACFFAMJSFZINGL-OWOJBTEDSA-N (e)-4-bromobut-2-enoyl chloride Chemical compound ClC(=O)\C=C\CBr ACFFAMJSFZINGL-OWOJBTEDSA-N 0.000 description 1
• YKIKDQYYTAOTPL-IHWYPQMZSA-N (z)-2-bromobut-2-enoic acid Chemical compound C\C=C(/Br)C(O)=O YKIKDQYYTAOTPL-IHWYPQMZSA-N 0.000 description 1
• VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
• WZCQRUWWHSTZEM-UHFFFAOYSA-N 1,3-phenylenediamine Chemical compound NC1=CC=CC(N)=C1 WZCQRUWWHSTZEM-UHFFFAOYSA-N 0.000 description 1
• JQAOHGMPAAWWQO-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCCC1C(O)=O JQAOHGMPAAWWQO-UHFFFAOYSA-N 0.000 description 1
• HRMRQBJUFWFQLX-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)C1 HRMRQBJUFWFQLX-UHFFFAOYSA-N 0.000 description 1
• ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
• OMMBYRSUPXNTEK-UHFFFAOYSA-N 1-methyl-4-nitro-1h-pyrazole-3-carboxylic acid Chemical compound CN1C=C([N+]([O-])=O)C(C(O)=O)=N1 OMMBYRSUPXNTEK-UHFFFAOYSA-N 0.000 description 1
• VBROFLVSVXVQEG-UHFFFAOYSA-N 1-prop-2-enoylpiperidine-3-carboxylic acid Chemical compound OC(=O)C1CCCN(C(=O)C=C)C1 VBROFLVSVXVQEG-UHFFFAOYSA-N 0.000 description 1
• WAQCGNDULBMNQJ-UHFFFAOYSA-N 1-prop-2-enoylpyrrolidine-3-carboxylic acid Chemical compound OC(=O)C1CCN(C(=O)C=C)C1 WAQCGNDULBMNQJ-UHFFFAOYSA-N 0.000 description 1
• VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
• VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
• KDDPNNXAZURUGP-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)-3-[2-(piperidin-3-ylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound ClC=1C=C(C=CC=1Cl)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NC1CNCCC1 KDDPNNXAZURUGP-UHFFFAOYSA-N 0.000 description 1
• BWSQKOKULIALEW-UHFFFAOYSA-N 2-[2-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-(piperidin-3-ylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound FC1=C(C=C(C=C1)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NC1CNCCC1)C(F)(F)F BWSQKOKULIALEW-UHFFFAOYSA-N 0.000 description 1
• TXIPVVLKTCCGPA-UHFFFAOYSA-N 2-[3-[2-[[1-(cyclopropanecarbonyl)piperidin-3-yl]amino]pyrimidin-4-yl]-2-quinolin-2-ylimidazol-4-yl]acetonitrile Chemical compound C1(CC1)C(=O)N1CC(CCC1)NC1=NC=CC(=N1)N1C(=NC=C1CC#N)C1=NC2=CC=CC=C2C=C1 TXIPVVLKTCCGPA-UHFFFAOYSA-N 0.000 description 1
• DWKNOLCXIFYNFV-HSZRJFAPSA-N 2-[[(2r)-1-[1-[(4-chloro-3-methylphenyl)methyl]piperidin-4-yl]-5-oxopyrrolidine-2-carbonyl]amino]-n,n,6-trimethylpyridine-4-carboxamide Chemical compound CN(C)C(=O)C1=CC(C)=NC(NC(=O)[C@@H]2N(C(=O)CC2)C2CCN(CC=3C=C(C)C(Cl)=CC=3)CC2)=C1 DWKNOLCXIFYNFV-HSZRJFAPSA-N 0.000 description 1
• PAYROHWFGZADBR-UHFFFAOYSA-N 2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propane-1,3-diol Chemical compound C1=C(I)C(OC)=CC(C(C)C)=C1OC1=CN=C(NC(CO)CO)N=C1N PAYROHWFGZADBR-UHFFFAOYSA-N 0.000 description 1
• LHASZEBEQGPCFM-CJFMBICVSA-N 2-amino-4-[(1r)-1-[[(6r)-6-[(5-chloro-2-methoxyphenyl)methyl]-7-oxo-3-(phenoxyamino)-5,6-dihydro-2h-1,4-diazepine-1-carbonyl]amino]propyl]benzoic acid Chemical compound C([C@@H]1CNC(CN(C1=O)C(=O)N[C@H](CC)C=1C=C(N)C(C(O)=O)=CC=1)=NOC=1C=CC=CC=1)C1=CC(Cl)=CC=C1OC LHASZEBEQGPCFM-CJFMBICVSA-N 0.000 description 1
• KPRPFTOLWQQUAV-OCVAFRRMSA-N 2-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-5-[4-[(1R,5S)-3-(oxan-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl]phenyl]pyridine-3-carboxamide Chemical compound NC1=C(C(=O)NC23CCC(CC2)(CC3)O)C=C(C=N1)C1=CC=C(C=C1)[C@@]12CN(C[C@H]2C1)C1CCOCC1 KPRPFTOLWQQUAV-OCVAFRRMSA-N 0.000 description 1
• VHCSBTPOPKFYIU-UHFFFAOYSA-N 2-chloroethanesulfonyl chloride Chemical compound ClCCS(Cl)(=O)=O VHCSBTPOPKFYIU-UHFFFAOYSA-N 0.000 description 1
• DOBWRWWGRZTEHG-UHFFFAOYSA-N 2-methylsulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one Chemical compound O=C1NC(SC)=NC2=CC=NN21 DOBWRWWGRZTEHG-UHFFFAOYSA-N 0.000 description 1
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
• BVGDAZBTIVRTGO-UONOGXRCSA-N 3-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[4-methoxy-6-[(2s)-2-methylpiperazin-1-yl]pyridin-3-yl]pyridin-2-amine Chemical compound C1([C@@H](C)OC=2C(N)=NC=C(C=2)C2=CN=C(C=C2OC)N2[C@H](CNCC2)C)=C(Cl)C=CC(F)=C1Cl BVGDAZBTIVRTGO-UONOGXRCSA-N 0.000 description 1
• BHMZMZOMQYFFQL-UHFFFAOYSA-N 3-amino-4-fluorobenzonitrile Chemical compound NC1=CC(C#N)=CC=C1F BHMZMZOMQYFFQL-UHFFFAOYSA-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
• GYLKKXHEIIFTJH-UHFFFAOYSA-N 3-cyanobenzoic acid Chemical compound OC(=O)C1=CC=CC(C#N)=C1 GYLKKXHEIIFTJH-UHFFFAOYSA-N 0.000 description 1
• BTIDYJKZPLRVTG-UHFFFAOYSA-N 3-fluoro-1-methyl-4-phenylmethoxypiperidine Chemical compound C(C1=CC=CC=C1)OC1C(CN(CC1)C)F BTIDYJKZPLRVTG-UHFFFAOYSA-N 0.000 description 1
• 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 1
• UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
• GSDQYSSLIKJJOG-UHFFFAOYSA-N 4-chloro-2-(3-chloroanilino)benzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1NC1=CC=CC(Cl)=C1 GSDQYSSLIKJJOG-UHFFFAOYSA-N 0.000 description 1
• RRBPEHJNXHJYQN-UHFFFAOYSA-N 4-chloro-2-methylsulfanyl-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazine Chemical compound N1=C(SC)N=C(Cl)N2N=CC(C(C)C)=C21 RRBPEHJNXHJYQN-UHFFFAOYSA-N 0.000 description 1
• PDFYLKPBYWPEDQ-UHFFFAOYSA-N 4-chloro-2-methylsulfanylpyrazolo[1,5-a][1,3,5]triazine Chemical compound N1=C(SC)N=C(Cl)N2N=CC=C21 PDFYLKPBYWPEDQ-UHFFFAOYSA-N 0.000 description 1
• WYYZMOWBDJCGSN-UHFFFAOYSA-N 4-chloro-8-ethyl-2-methylsulfanylpyrazolo[1,5-a][1,3,5]triazine Chemical compound ClC1=NC(SC)=NC2=C(CC)C=NN21 WYYZMOWBDJCGSN-UHFFFAOYSA-N 0.000 description 1
• OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
• VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
• VAWTVSTXVGCVJW-UHFFFAOYSA-N 5-amino-2-bromobenzonitrile Chemical compound NC1=CC=C(Br)C(C#N)=C1 VAWTVSTXVGCVJW-UHFFFAOYSA-N 0.000 description 1
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
• XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 1
• IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 1
• 229920001817 Agar Polymers 0.000 description 1
• 201000004384 Alopecia Diseases 0.000 description 1
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
• 229920000856 Amylose Polymers 0.000 description 1
• 201000001320 Atherosclerosis Diseases 0.000 description 1
• IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 description 1
• 102000051485 Bcl-2 family Human genes 0.000 description 1
• 108700038897 Bcl-2 family Proteins 0.000 description 1
• LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
• JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
• 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
• 101150059217 CDK12 gene Proteins 0.000 description 1
• 101150035324 CDK9 gene Proteins 0.000 description 1
• 101100327354 Caenorhabditis elegans cdk-12 gene Proteins 0.000 description 1
• 208000024172 Cardiovascular disease Diseases 0.000 description 1
• 108091035707 Consensus sequence Proteins 0.000 description 1
• 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 1
• 102100023263 Cyclin-dependent kinase 10 Human genes 0.000 description 1
• 102100038113 Cyclin-dependent kinase 14 Human genes 0.000 description 1
• 102100033245 Cyclin-dependent kinase 16 Human genes 0.000 description 1
• 102100033145 Cyclin-dependent kinase 19 Human genes 0.000 description 1
• 102100034741 Cyclin-dependent kinase 20 Human genes 0.000 description 1
• 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 1
• 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 description 1
• 101710177611 DNA polymerase II large subunit Proteins 0.000 description 1
• 101710184669 DNA polymerase II small subunit Proteins 0.000 description 1
• 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
• 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
• 239000004375 Dextrin Substances 0.000 description 1
• 229920001353 Dextrin Polymers 0.000 description 1
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
• 102000001301 EGF receptor Human genes 0.000 description 1
• 108060006698 EGF receptor Proteins 0.000 description 1
• 229910052693 Europium Inorganic materials 0.000 description 1
• MWHHJYUHCZWSLS-UHFFFAOYSA-N FC=1C=C(C=CC1C1=C2CNC(C2=C(C=C1)C=1NC(=CN1)C)=O)NC(=O)NC1=C(C=C(C=C1F)F)F Chemical compound FC=1C=C(C=CC1C1=C2CNC(C2=C(C=C1)C=1NC(=CN1)C)=O)NC(=O)NC1=C(C=C(C=C1F)F)F MWHHJYUHCZWSLS-UHFFFAOYSA-N 0.000 description 1
• 102100035237 GA-binding protein alpha chain Human genes 0.000 description 1
• 239000012981 Hank's balanced salt solution Substances 0.000 description 1
• 101000713120 Homo sapiens Cyclin-H Proteins 0.000 description 1
• 101000868333 Homo sapiens Cyclin-dependent kinase 1 Proteins 0.000 description 1
• 101000908138 Homo sapiens Cyclin-dependent kinase 10 Proteins 0.000 description 1
• 101000884374 Homo sapiens Cyclin-dependent kinase 14 Proteins 0.000 description 1
• 101000944357 Homo sapiens Cyclin-dependent kinase 16 Proteins 0.000 description 1
• 101000944345 Homo sapiens Cyclin-dependent kinase 19 Proteins 0.000 description 1
• 101000945708 Homo sapiens Cyclin-dependent kinase 20 Proteins 0.000 description 1
• 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 1
• 101000909198 Homo sapiens DNA polymerase delta catalytic subunit Proteins 0.000 description 1
• 101001022105 Homo sapiens GA-binding protein alpha chain Proteins 0.000 description 1
• 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 description 1
• 101000713879 Homo sapiens T-complex protein 1 subunit eta Proteins 0.000 description 1
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
• 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 description 1
• 206010061218 Inflammation Diseases 0.000 description 1
• 239000007760 Iscove's Modified Dulbecco's Medium Substances 0.000 description 1
• 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
• 240000007472 Leucaena leucocephala Species 0.000 description 1
• 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
• 208000034578 Multiple myelomas Diseases 0.000 description 1
• 241000699660 Mus musculus Species 0.000 description 1
• 208000031888 Mycoses Diseases 0.000 description 1
• WXPUVOYPDRURKR-UHFFFAOYSA-N N-[3-[[[2-(2-methylpropoxy)-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]-1-prop-2-enoylpyrrolidine-3-carboxamide Chemical compound CC(C)COC1=NC2=C(C=NN2C(NCC2=CC=CC(NC(=O)C3CCN(C3)C(=O)C=C)=C2)=N1)C(C)C WXPUVOYPDRURKR-UHFFFAOYSA-N 0.000 description 1
• POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 1
• UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
• QIUAOSGKSFGSKL-HNNXBMFYSA-N NCC=1C=C(C(=O)N[C@@H]2CN(CCC2)C(=O)OC(C)(C)C)C=CC=1 Chemical compound NCC=1C=C(C(=O)N[C@@H]2CN(CCC2)C(=O)OC(C)(C)C)C=CC=1 QIUAOSGKSFGSKL-HNNXBMFYSA-N 0.000 description 1
• 229910017912 NH2OH Inorganic materials 0.000 description 1
• 208000012902 Nervous system disease Diseases 0.000 description 1
• 208000025966 Neurological disease Diseases 0.000 description 1
• UQONAEXHTGDOIH-AWEZNQCLSA-N O=C(N1CC[C@@H](C1)N1CCCC1=O)C1=CC2=C(NC3(CC3)CCO2)N=C1 Chemical compound O=C(N1CC[C@@H](C1)N1CCCC1=O)C1=CC2=C(NC3(CC3)CCO2)N=C1 UQONAEXHTGDOIH-AWEZNQCLSA-N 0.000 description 1
• 241000283973 Oryctolagus cuniculus Species 0.000 description 1
• NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [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 1
• 235000019483 Peanut oil Nutrition 0.000 description 1
• 229930182555 Penicillin Natural products 0.000 description 1
• JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
• 102000002508 Peptide Elongation Factors Human genes 0.000 description 1
• 108010068204 Peptide Elongation Factors Proteins 0.000 description 1
• ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
• 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
• 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
• 108010012271 Positive Transcriptional Elongation Factor B Proteins 0.000 description 1
• 102000019014 Positive Transcriptional Elongation Factor B Human genes 0.000 description 1
• 102000001253 Protein Kinase Human genes 0.000 description 1
• 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
• 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
• 208000017442 Retinal disease Diseases 0.000 description 1
• 206010038923 Retinopathy Diseases 0.000 description 1
• 101100273253 Rhizopus niveus RNAP gene Proteins 0.000 description 1
• 229940124639 Selective inhibitor Drugs 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
• 101100174378 Sphingobium sp. (strain NBRC 103272 / SYK-6) fhs gene Proteins 0.000 description 1
• 235000021355 Stearic acid Nutrition 0.000 description 1
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
• 229930006000 Sucrose Natural products 0.000 description 1
• 102100036476 T-complex protein 1 subunit eta Human genes 0.000 description 1
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
• ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
• 108091023040 Transcription factor Proteins 0.000 description 1
• 102000040945 Transcription factor Human genes 0.000 description 1
• 229920004890 Triton X-100 Polymers 0.000 description 1
• 239000013504 Triton X-100 Substances 0.000 description 1
• SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
• 230000002159 abnormal effect Effects 0.000 description 1
• PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
• 230000009471 action Effects 0.000 description 1
• 239000004480 active ingredient Substances 0.000 description 1
• 125000002252 acyl group Chemical group 0.000 description 1
• 239000000654 additive Substances 0.000 description 1
• 239000008272 agar Substances 0.000 description 1
• 235000010419 agar Nutrition 0.000 description 1
• 150000001298 alcohols Chemical class 0.000 description 1
• 150000001338 aliphatic hydrocarbons Chemical group 0.000 description 1
• 125000003342 alkenyl group Chemical group 0.000 description 1
• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
• 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
• 150000005215 alkyl ethers Chemical class 0.000 description 1
• 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 description 1
• 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
• 125000006350 alkyl thio alkyl group Chemical group 0.000 description 1
• 125000004414 alkyl thio group Chemical group 0.000 description 1
• 125000000304 alkynyl group Chemical group 0.000 description 1
• 231100000360 alopecia Toxicity 0.000 description 1
• 125000005122 aminoalkylamino group Chemical group 0.000 description 1
• 125000005097 aminocarbonylalkyl group Chemical group 0.000 description 1
• IMHBYKMAHXWHRP-UHFFFAOYSA-N anilazine Chemical compound ClC1=CC=CC=C1NC1=NC(Cl)=NC(Cl)=N1 IMHBYKMAHXWHRP-UHFFFAOYSA-N 0.000 description 1
• 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
• 230000002424 anti-apoptotic effect Effects 0.000 description 1
• 230000005735 apoptotic response Effects 0.000 description 1
• 238000013459 approach Methods 0.000 description 1
• 206010003246 arthritis Diseases 0.000 description 1
• 125000005128 aryl amino alkyl group Chemical group 0.000 description 1
• 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
• 125000001769 aryl amino group Chemical group 0.000 description 1
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
• 125000005110 aryl thio group Chemical group 0.000 description 1
• 125000005164 aryl thioalkyl group Chemical group 0.000 description 1
• 125000004104 aryloxy group Chemical group 0.000 description 1
• 239000012131 assay buffer Substances 0.000 description 1
• 238000011717 athymic nude mouse Methods 0.000 description 1
• 230000001363 autoimmune Effects 0.000 description 1
• 239000012752 auxiliary agent Substances 0.000 description 1
• 125000003725 azepanyl group Chemical group 0.000 description 1
• 125000002393 azetidinyl group Chemical group 0.000 description 1
• 230000008901 benefit Effects 0.000 description 1
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
• AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 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
• 238000010256 biochemical assay Methods 0.000 description 1
• 230000008827 biological function Effects 0.000 description 1
• 230000033228 biological regulation Effects 0.000 description 1
• 239000012472 biological sample Substances 0.000 description 1
• 239000004305 biphenyl Substances 0.000 description 1
• 235000010290 biphenyl Nutrition 0.000 description 1
• 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
• 210000004369 blood Anatomy 0.000 description 1
• 239000008280 blood Substances 0.000 description 1
• 230000037396 body weight Effects 0.000 description 1
• 210000000481 breast Anatomy 0.000 description 1
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
• 229910052794 bromium Inorganic materials 0.000 description 1
• 239000006172 buffering agent Substances 0.000 description 1
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
• OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
• 125000004452 carbocyclyl group Chemical group 0.000 description 1
• 150000001718 carbodiimides Chemical class 0.000 description 1
• 150000001721 carbon Chemical group 0.000 description 1
• 125000004432 carbon atom Chemical group C* 0.000 description 1
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
• 108010089576 carboxy-terminal domain kinase Proteins 0.000 description 1
• 125000004181 carboxyalkyl group Chemical group 0.000 description 1
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
• 230000003197 catalytic effect Effects 0.000 description 1
• 230000024245 cell differentiation Effects 0.000 description 1
• 230000032823 cell division Effects 0.000 description 1
• 230000003915 cell function Effects 0.000 description 1
• 230000033077 cellular process Effects 0.000 description 1
• 230000005754 cellular signaling Effects 0.000 description 1
• 239000001913 cellulose Substances 0.000 description 1
• 229920002678 cellulose Polymers 0.000 description 1
• 235000010980 cellulose Nutrition 0.000 description 1
• 210000003169 central nervous system Anatomy 0.000 description 1
• 210000003679 cervix uteri Anatomy 0.000 description 1
• 239000002738 chelating agent Substances 0.000 description 1
• 238000001311 chemical methods and process Methods 0.000 description 1
• 238000004587 chromatography analysis Methods 0.000 description 1
• 238000003776 cleavage reaction Methods 0.000 description 1
• AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
• 210000001072 colon Anatomy 0.000 description 1
• 239000003086 colorant Substances 0.000 description 1
• 229940125904 compound 1 Drugs 0.000 description 1
• 229940126543 compound 14 Drugs 0.000 description 1
• 229940126142 compound 16 Drugs 0.000 description 1
• 229940126540 compound 41 Drugs 0.000 description 1
• 229940125844 compound 46 Drugs 0.000 description 1
• 229940127271 compound 49 Drugs 0.000 description 1
• 238000007796 conventional method Methods 0.000 description 1
• 239000006071 cream Substances 0.000 description 1
• 125000004122 cyclic group Chemical group 0.000 description 1
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 210000000172 cytosol Anatomy 0.000 description 1
• 230000002939 deleterious effect Effects 0.000 description 1
• 230000001419 dependent effect Effects 0.000 description 1
• 238000011161 development Methods 0.000 description 1
• 230000018109 developmental process Effects 0.000 description 1
• 235000019425 dextrin Nutrition 0.000 description 1
• UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 1
• 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 1
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
• 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
• 238000010790 dilution Methods 0.000 description 1
• 239000012895 dilution Substances 0.000 description 1
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
• VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
• 230000003292 diminished effect Effects 0.000 description 1
• 229910001873 dinitrogen Inorganic materials 0.000 description 1
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
• 239000002552 dosage form Substances 0.000 description 1
• 231100000673 dose–response relationship Toxicity 0.000 description 1
• 239000008298 dragée Substances 0.000 description 1
• 239000003221 ear drop Substances 0.000 description 1
• 229940047652 ear drops Drugs 0.000 description 1
• 230000002500 effect on skin Effects 0.000 description 1
• 239000000839 emulsion Substances 0.000 description 1
• 210000003238 esophagus Anatomy 0.000 description 1
• GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 1
• PAVZHTXVORCEHP-UHFFFAOYSA-N ethylboronic acid Chemical compound CCB(O)O PAVZHTXVORCEHP-UHFFFAOYSA-N 0.000 description 1
• OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
• 230000005284 excitation Effects 0.000 description 1
• 239000003889 eye drop Substances 0.000 description 1
• 229940012356 eye drops Drugs 0.000 description 1
• 150000004665 fatty acids Chemical class 0.000 description 1
• 239000000796 flavoring agent Substances 0.000 description 1
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
• 125000001153 fluoro group Chemical group F* 0.000 description 1
• 235000013355 food flavoring agent Nutrition 0.000 description 1
• 235000003599 food sweetener Nutrition 0.000 description 1
• 210000000232 gallbladder Anatomy 0.000 description 1
• 239000007789 gas Substances 0.000 description 1
• XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
• 229960002584 gefitinib Drugs 0.000 description 1
• 239000000499 gel Substances 0.000 description 1
• 239000003349 gelling agent Substances 0.000 description 1
• 238000003209 gene knockout Methods 0.000 description 1
• 230000002068 genetic effect Effects 0.000 description 1
• 229910052736 halogen Inorganic materials 0.000 description 1
• 150000002367 halogens Chemical class 0.000 description 1
• 210000003128 head Anatomy 0.000 description 1
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
• BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
• 125000002632 imidazolidinyl group Chemical group 0.000 description 1
• 238000000338 in vitro Methods 0.000 description 1
• 230000005917 in vivo anti-tumor Effects 0.000 description 1
• 238000003121 in-cell western assay Methods 0.000 description 1
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
• 229910052738 indium Inorganic materials 0.000 description 1
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
• 125000001041 indolyl group Chemical group 0.000 description 1
• 230000004054 inflammatory process Effects 0.000 description 1
• 230000000977 initiatory effect Effects 0.000 description 1
• 239000007924 injection Substances 0.000 description 1
• 238000002347 injection Methods 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
• 230000016507 interphase Effects 0.000 description 1
• 238000007918 intramuscular administration Methods 0.000 description 1
• 238000007915 intraurethral administration Methods 0.000 description 1
• 238000001990 intravenous administration Methods 0.000 description 1
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• 229910052740 iodine Inorganic materials 0.000 description 1
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
• 230000002427 irreversible effect Effects 0.000 description 1
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
• SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
• 229940043355 kinase inhibitor Drugs 0.000 description 1
• 239000008101 lactose Substances 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 239000007788 liquid Substances 0.000 description 1
• 238000004811 liquid chromatography Methods 0.000 description 1
• 239000012669 liquid formulation Substances 0.000 description 1
• RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
• 239000006210 lotion Substances 0.000 description 1
• 239000007937 lozenge Substances 0.000 description 1
• 239000000314 lubricant Substances 0.000 description 1
• 210000004072 lung Anatomy 0.000 description 1
• ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
• 239000001095 magnesium carbonate Substances 0.000 description 1
• 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
• 235000019359 magnesium stearate Nutrition 0.000 description 1
• 230000014759 maintenance of location Effects 0.000 description 1
• 238000004949 mass spectrometry Methods 0.000 description 1
• 238000001819 mass spectrum Methods 0.000 description 1
• 239000000463 material Substances 0.000 description 1
• 238000005259 measurement Methods 0.000 description 1
• 239000002609 medium Substances 0.000 description 1
• MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
• 238000011201 multiple comparisons test Methods 0.000 description 1
• VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 1
• 125000001624 naphthyl group Chemical group 0.000 description 1
• IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
• 210000003739 neck Anatomy 0.000 description 1
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 230000001537 neural effect Effects 0.000 description 1
• 208000015122 neurodegenerative disease Diseases 0.000 description 1
• 230000000926 neurological effect Effects 0.000 description 1
• 231100000252 nontoxic Toxicity 0.000 description 1
• 230000003000 nontoxic effect Effects 0.000 description 1
• 238000010606 normalization Methods 0.000 description 1
• 238000011580 nude mouse model Methods 0.000 description 1
• QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
• OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
• XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
• 239000002674 ointment Substances 0.000 description 1
• 239000004006 olive oil Substances 0.000 description 1
• 235000008390 olive oil Nutrition 0.000 description 1
• 238000001543 one-way ANOVA Methods 0.000 description 1
• 229950006098 orthocaine Drugs 0.000 description 1
• 210000001672 ovary Anatomy 0.000 description 1
• 125000000160 oxazolidinyl group Chemical group 0.000 description 1
• 125000003566 oxetanyl group Chemical group 0.000 description 1
• 125000004430 oxygen atom Chemical group O* 0.000 description 1
• 210000000496 pancreas Anatomy 0.000 description 1
• 238000007911 parenteral administration Methods 0.000 description 1
• 239000002245 particle Substances 0.000 description 1
• 239000006072 paste Substances 0.000 description 1
• 239000000312 peanut oil Substances 0.000 description 1
• 239000001814 pectin Substances 0.000 description 1
• 235000010987 pectin Nutrition 0.000 description 1
• 229920001277 pectin Polymers 0.000 description 1
• 239000008188 pellet Substances 0.000 description 1
• 230000035515 penetration Effects 0.000 description 1
• 229940049954 penicillin Drugs 0.000 description 1
• 210000001428 peripheral nervous system Anatomy 0.000 description 1
• 229940124531 pharmaceutical excipient Drugs 0.000 description 1
• 239000012071 phase Substances 0.000 description 1
• 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
• RIXVESSVKLKKFV-UHFFFAOYSA-N piperazine-1,4-dicarboxylic acid Chemical compound OC(=O)N1CCN(C(O)=O)CC1 RIXVESSVKLKKFV-UHFFFAOYSA-N 0.000 description 1
• RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
• 239000002798 polar solvent Substances 0.000 description 1
• 125000003367 polycyclic group Chemical group 0.000 description 1
• 229920001223 polyethylene glycol Polymers 0.000 description 1
• 229920000642 polymer Polymers 0.000 description 1
• 235000011181 potassium carbonates Nutrition 0.000 description 1
• 230000003389 potentiating effect Effects 0.000 description 1
• 238000012746 preparative thin layer chromatography Methods 0.000 description 1
• 230000000861 pro-apoptotic effect Effects 0.000 description 1
• 230000035755 proliferation Effects 0.000 description 1
• 230000001737 promoting effect Effects 0.000 description 1
• 238000011321 prophylaxis Methods 0.000 description 1
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 210000002307 prostate Anatomy 0.000 description 1
• 108060006633 protein kinase Proteins 0.000 description 1
• 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
• WPFZGADUIUVTCF-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidin-7-amine Chemical compound NC1=CC=NC2=CC=NN12 WPFZGADUIUVTCF-UHFFFAOYSA-N 0.000 description 1
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
• VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 description 1
• 150000003254 radicals Chemical class 0.000 description 1
• 102000005962 receptors Human genes 0.000 description 1
• 108020003175 receptors Proteins 0.000 description 1
• 238000001953 recrystallisation Methods 0.000 description 1
• 230000009467 reduction Effects 0.000 description 1
• 230000022983 regulation of cell cycle Effects 0.000 description 1
• 230000004044 response Effects 0.000 description 1
• 208000037803 restenosis Diseases 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 238000012552 review Methods 0.000 description 1
• 239000012266 salt solution Substances 0.000 description 1
• 230000007017 scission Effects 0.000 description 1
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• OEBIHOVSAMBXIB-SJKOYZFVSA-N selitrectinib Chemical compound C[C@@H]1CCC2=NC=C(F)C=C2[C@H]2CCCN2C2=NC3=C(C=NN3C=C2)C(=O)N1 OEBIHOVSAMBXIB-SJKOYZFVSA-N 0.000 description 1
• 238000013207 serial dilution Methods 0.000 description 1
• RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
• 235000012239 silicon dioxide Nutrition 0.000 description 1
• 210000003491 skin Anatomy 0.000 description 1
• 208000000587 small cell lung carcinoma Diseases 0.000 description 1
• 229910000029 sodium carbonate Inorganic materials 0.000 description 1
• 235000017550 sodium carbonate Nutrition 0.000 description 1
• 239000012312 sodium hydride Substances 0.000 description 1
• 206010041823 squamous cell carcinoma Diseases 0.000 description 1
• 239000008117 stearic acid Substances 0.000 description 1
• 239000011550 stock solution Substances 0.000 description 1
• 210000002784 stomach Anatomy 0.000 description 1
• 229960005322 streptomycin Drugs 0.000 description 1
• 238000000547 structure data Methods 0.000 description 1
• 238000007920 subcutaneous administration Methods 0.000 description 1
• 239000005720 sucrose Substances 0.000 description 1
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
• 230000004083 survival effect Effects 0.000 description 1
• 239000000375 suspending agent Substances 0.000 description 1
• 239000003765 sweetening agent Substances 0.000 description 1
• 239000006188 syrup Substances 0.000 description 1
• 235000020357 syrup Nutrition 0.000 description 1
• 239000000454 talc Substances 0.000 description 1
• 229910052623 talc Inorganic materials 0.000 description 1
• 235000012222 talc Nutrition 0.000 description 1
• 229910052715 tantalum Inorganic materials 0.000 description 1
• AKQXKEBCONUWCL-QMMMGPOBSA-N tert-butyl (3s)-3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](N)C1 AKQXKEBCONUWCL-QMMMGPOBSA-N 0.000 description 1
• KOXPDOIQJWADCD-UHFFFAOYSA-N tert-butyl 3-[(3-acetylphenyl)carbamoyl]piperidine-1-carboxylate Chemical compound CC(=O)C1=CC=CC(NC(=O)C2CN(CCC2)C(=O)OC(C)(C)C)=C1 KOXPDOIQJWADCD-UHFFFAOYSA-N 0.000 description 1
• GKTFJMUSQMYVMI-UHFFFAOYSA-N tert-butyl 3-[[3-(1-aminoethyl)phenyl]carbamoyl]piperidine-1-carboxylate Chemical compound NC(C)C=1C=C(C=CC=1)NC(=O)C1CN(CCC1)C(=O)OC(C)(C)C GKTFJMUSQMYVMI-UHFFFAOYSA-N 0.000 description 1
• KIXNRLAQJLFCPJ-UHFFFAOYSA-N tert-butyl 3-[[3-(aminomethyl)phenyl]carbamoyl]piperidine-1-carboxylate Chemical compound NCC=1C=C(C=CC=1)NC(=O)C1CN(CCC1)C(=O)OC(C)(C)C KIXNRLAQJLFCPJ-UHFFFAOYSA-N 0.000 description 1
• XRNLYXKYODGLMI-UHFFFAOYSA-N tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)C(F)C1 XRNLYXKYODGLMI-UHFFFAOYSA-N 0.000 description 1
• JZNWQLLPLOQGOI-UHFFFAOYSA-N tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)C(F)C1 JZNWQLLPLOQGOI-UHFFFAOYSA-N 0.000 description 1
• MKJAGWYNZFHBGV-UHFFFAOYSA-N tert-butyl 4-[(3-aminobenzoyl)amino]piperidine-1-carboxylate Chemical compound NC=1C=C(C(=O)NC2CCN(CC2)C(=O)OC(C)(C)C)C=CC=1 MKJAGWYNZFHBGV-UHFFFAOYSA-N 0.000 description 1
• BGANJLQRTXSLMU-UHFFFAOYSA-N tert-butyl N-[3-(aminomethyl)-4-ethylphenyl]carbamate Chemical compound NCC=1C=C(C=CC=1CC)NC(OC(C)(C)C)=O BGANJLQRTXSLMU-UHFFFAOYSA-N 0.000 description 1
• LIYMTLVBAVHPBU-UHFFFAOYSA-N tert-butyl n-(4-hydroxybutyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCO LIYMTLVBAVHPBU-UHFFFAOYSA-N 0.000 description 1
• 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
• 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
• 229940124597 therapeutic agent Drugs 0.000 description 1
• 238000011287 therapeutic dose Methods 0.000 description 1
• 125000001984 thiazolidinyl group Chemical group 0.000 description 1
• 150000003573 thiols Chemical class 0.000 description 1
• 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
• 239000006208 topical dosage form Substances 0.000 description 1
• 231100000440 toxicity profile Toxicity 0.000 description 1
• 230000005029 transcription elongation Effects 0.000 description 1
• 230000037426 transcriptional repression Effects 0.000 description 1
• 230000009261 transgenic effect Effects 0.000 description 1
• 230000032258 transport Effects 0.000 description 1
• 210000003932 urinary bladder Anatomy 0.000 description 1
• 229910052720 vanadium Inorganic materials 0.000 description 1
• 230000003612 virological effect Effects 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1