WO2020172906A1 - 一种新型pan-RAF激酶抑制剂及其用途 - Google Patents
一种新型pan-RAF激酶抑制剂及其用途 Download PDFInfo
- Publication number
- WO2020172906A1 WO2020172906A1 PCT/CN2019/077272 CN2019077272W WO2020172906A1 WO 2020172906 A1 WO2020172906 A1 WO 2020172906A1 CN 2019077272 W CN2019077272 W CN 2019077272W WO 2020172906 A1 WO2020172906 A1 WO 2020172906A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- alkoxy
- cancer
- alkyl
- synthesis
- Prior art date
Links
- 229940123690 Raf kinase inhibitor Drugs 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 183
- 230000000694 effects Effects 0.000 claims abstract description 26
- 239000002253 acid Substances 0.000 claims abstract description 24
- 239000002207 metabolite Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 102000016914 ras Proteins Human genes 0.000 claims abstract description 20
- 150000002148 esters Chemical class 0.000 claims abstract description 18
- 239000012453 solvate Substances 0.000 claims abstract description 18
- 229940002612 prodrug Drugs 0.000 claims abstract description 15
- 239000000651 prodrug Substances 0.000 claims abstract description 15
- -1 C 1-6 alkylsulfone Chemical group 0.000 claims description 117
- 125000003545 alkoxy group Chemical group 0.000 claims description 85
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 59
- 206010028980 Neoplasm Diseases 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 229940043355 kinase inhibitor Drugs 0.000 claims description 24
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000002252 acyl group Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 125000006642 (C1-C6) cyanoalkyl group Chemical group 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 13
- 206010009944 Colon cancer Diseases 0.000 claims description 12
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 12
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 12
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 201000001441 melanoma Diseases 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 8
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 4
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 230000002062 proliferating effect Effects 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 3
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 3
- 230000003211 malignant effect Effects 0.000 claims description 3
- 230000009826 neoplastic cell growth Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 230000005740 tumor formation Effects 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 208000007033 Dysgerminoma Diseases 0.000 claims description 2
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 2
- 206010014733 Endometrial cancer Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 206010014950 Eosinophilia Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 206010016935 Follicular thyroid cancer Diseases 0.000 claims description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 201000004404 Neurofibroma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010033701 Papillary thyroid cancer Diseases 0.000 claims description 2
- 208000000821 Parathyroid Neoplasms Diseases 0.000 claims description 2
- 206010033964 Parathyroid tumour benign Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 201000010208 Seminoma Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 201000008736 Systemic mastocytosis Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 201000005188 adrenal gland cancer Diseases 0.000 claims description 2
- 208000024447 adrenal gland neoplasm Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 201000002758 colorectal adenoma Diseases 0.000 claims description 2
- 201000011523 endocrine gland cancer Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 230000004761 fibrosis Effects 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 208000024908 graft versus host disease Diseases 0.000 claims description 2
- 201000002222 hemangioblastoma Diseases 0.000 claims description 2
- 201000011066 hemangioma Diseases 0.000 claims description 2
- 208000020082 intraepithelial neoplasia Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- 208000006178 malignant mesothelioma Diseases 0.000 claims description 2
- 201000005282 malignant pleural mesothelioma Diseases 0.000 claims description 2
- 201000006512 mast cell neoplasm Diseases 0.000 claims description 2
- 201000003686 parathyroid adenoma Diseases 0.000 claims description 2
- 208000014643 parathyroid gland adenoma Diseases 0.000 claims description 2
- 208000025061 parathyroid hyperplasia Diseases 0.000 claims description 2
- 208000028591 pheochromocytoma Diseases 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 230000002381 testicular Effects 0.000 claims description 2
- 208000013077 thyroid gland carcinoma Diseases 0.000 claims description 2
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 claims description 2
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 206010046885 vaginal cancer Diseases 0.000 claims description 2
- 208000013139 vaginal neoplasm Diseases 0.000 claims description 2
- 208000008720 Bone Marrow Neoplasms Diseases 0.000 claims 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims 1
- 201000006491 bone marrow cancer Diseases 0.000 claims 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims 1
- 210000004498 neuroglial cell Anatomy 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 213
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 12
- 102000020233 phosphotransferase Human genes 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 description 196
- 238000003786 synthesis reaction Methods 0.000 description 194
- 210000004027 cell Anatomy 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 230000035772 mutation Effects 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 20
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 20
- 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 19
- 125000003118 aryl group Chemical group 0.000 description 19
- 229940126142 compound 16 Drugs 0.000 description 19
- 229940079593 drug Drugs 0.000 description 19
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 229940125904 compound 1 Drugs 0.000 description 13
- 102200055464 rs113488022 Human genes 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 125000000753 cycloalkyl group Chemical group 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 0 CC=CC(C(C)=*C1)=CC1*(I(C)=C)=* Chemical compound CC=CC(C(C)=*C1)=CC1*(I(C)=C)=* 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 102000001253 Protein Kinase Human genes 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 229960004397 cyclophosphamide Drugs 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 108060006633 protein kinase Proteins 0.000 description 8
- 229960003862 vemurafenib Drugs 0.000 description 8
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229960002949 fluorouracil Drugs 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 238000010172 mouse model Methods 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000002054 transplantation Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 230000002100 tumorsuppressive effect Effects 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 102100031968 Ephrin type-B receptor 2 Human genes 0.000 description 4
- 101000967216 Homo sapiens Eosinophil cationic protein Proteins 0.000 description 4
- 101000712530 Homo sapiens RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 4
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 125000004404 heteroalkyl group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- LKYNGTHMKCTTQC-UHFFFAOYSA-N 1,2-oxazole-3-carboxamide Chemical compound NC(=O)C=1C=CON=1 LKYNGTHMKCTTQC-UHFFFAOYSA-N 0.000 description 3
- WJJSZTJGFCFNKI-UHFFFAOYSA-N 1,3-oxathiolane Chemical compound C1CSCO1 WJJSZTJGFCFNKI-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 3
- 238000000386 microscopy Methods 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- FYNMINFUAIDIFL-UHFFFAOYSA-N n-[6-methyl-5-[5-morpholin-4-yl-6-(oxan-4-yloxy)pyridin-3-yl]pyridin-3-yl]-3-(trifluoromethyl)benzamide Chemical compound C1=C(C=2C=C(C(OC3CCOCC3)=NC=2)N2CCOCC2)C(C)=NC=C1NC(=O)C1=CC=CC(C(F)(F)F)=C1 FYNMINFUAIDIFL-UHFFFAOYSA-N 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229910052717 sulfur Chemical group 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- YYACLQUDUDXAPA-MRXNPFEDSA-N (3r)-n-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1h-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide Chemical compound C1[C@H](F)CCN1S(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=NC(=NC=2)C2CC2)=C1F YYACLQUDUDXAPA-MRXNPFEDSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 2
- YABJJWZLRMPFSI-UHFFFAOYSA-N 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(C(F)(F)F)C=C1 YABJJWZLRMPFSI-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- WIQISTBTOQNVCE-UHFFFAOYSA-N 2-fluoro-1-methyl-4-nitrobenzene Chemical compound CC1=CC=C([N+]([O-])=O)C=C1F WIQISTBTOQNVCE-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- CWQPVVJGSOHOHK-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[4-methyl-3-[4-[5-(4-methylpiperazin-1-yl)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)N2CCN(CC2)C)C=CC1 CWQPVVJGSOHOHK-UHFFFAOYSA-N 0.000 description 2
- OILPCNLSLULGDW-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[3-[4-[4-(cyclopentylmethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCC2CCCC2)C=CC1 OILPCNLSLULGDW-UHFFFAOYSA-N 0.000 description 2
- LAVCQCXXKFSGQN-UHFFFAOYSA-N 3-chloro-N-[4-methyl-3-(4-pyridin-3-ylpyrazol-1-yl)phenyl]benzamide Chemical compound ClC=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC=2)C=CC=1 LAVCQCXXKFSGQN-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- WVGCPEDBFHEHEZ-UHFFFAOYSA-N 4-bromo-1h-pyrazole Chemical compound BrC=1C=NNC=1 WVGCPEDBFHEHEZ-UHFFFAOYSA-N 0.000 description 2
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 2
- FXUXETWMTWVGNQ-UHFFFAOYSA-N 5-tert-butyl-N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]-1,2-oxazole-3-carboxamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(=O)C2=NOC(=C2)C(C)(C)C FXUXETWMTWVGNQ-UHFFFAOYSA-N 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102100030708 GTPase KRas Human genes 0.000 description 2
- 102100039788 GTPase NRas Human genes 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 2
- 108010069236 Goserelin Proteins 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 2
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 2
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- HMXAPHUXQAGLOT-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[3-(trifluoromethyl)benzoyl]amino]phenyl]pyrazol-4-yl]pyridin-4-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(=O)C2=CC(=CC=C2)C(F)(F)F)N3C=C(C=N3)C4=C(C=CN=C4)NC(=O)C5C6C5COC6 HMXAPHUXQAGLOT-UHFFFAOYSA-N 0.000 description 2
- VDCDGCFJHHTNFT-UHFFFAOYSA-N N-[3-[1-[5-[(5-tert-butyl-1,2-oxazol-3-yl)carbamoylamino]-2-methylphenyl]pyrazol-4-yl]pyridin-4-yl]oxane-4-carboxamide Chemical compound C(C)(C)(C)C1=CC(=NO1)NC(NC=1C=CC(=C(C1)N1N=CC(=C1)C=1C=NC=CC1NC(=O)C1CCOCC1)C)=O VDCDGCFJHHTNFT-UHFFFAOYSA-N 0.000 description 2
- KRRPYALEOUDMLQ-UHFFFAOYSA-N N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2N=CN(C2)C=2C=C(C=CC2C)NC(C2=CC(=CC=C2)C(F)(F)F)=O KRRPYALEOUDMLQ-UHFFFAOYSA-N 0.000 description 2
- USJAYVCSRGTURN-UHFFFAOYSA-N N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]-3-phenylbenzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(=O)C=2C=C(C=CC2)C2=CC=CC=C2 USJAYVCSRGTURN-UHFFFAOYSA-N 0.000 description 2
- MJLSEBAMPKNXCH-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxan-4-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCC1CCOCC1 MJLSEBAMPKNXCH-UHFFFAOYSA-N 0.000 description 2
- WQSKREUCIWNRAD-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxetan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCC1COC1 WQSKREUCIWNRAD-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-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
- 229940100514 Syk tyrosine kinase inhibitor Drugs 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229930013356 epothilone Natural products 0.000 description 2
- 150000003883 epothilone derivatives Chemical class 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- NJYYWQHQUOODDL-UHFFFAOYSA-N oxetane-3-carboxamide Chemical compound NC(=O)C1COC1 NJYYWQHQUOODDL-UHFFFAOYSA-N 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 150000003527 tetrahydropyrans Chemical class 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- 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
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-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
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-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
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 1
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
- LKLLNYWECKEQIB-UHFFFAOYSA-N 1,3,5-triazinane Chemical compound C1NCNCN1 LKLLNYWECKEQIB-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- FZQXMGLQANXZRP-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-3-(3-imidazol-1-ylpropyl)thiourea Chemical compound C1=C(OC)C(OC)=CC=C1NC(=S)NCCCN1C=NC=C1 FZQXMGLQANXZRP-UHFFFAOYSA-N 0.000 description 1
- HJGCZEIXJXVXBK-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[3-[4-[4-(2-hydroxyethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]urea Chemical compound C(C)(C)(C)C1=CC(=NO1)NC(=O)NC1=CC(=C(C=C1)C)N1N=CC(=C1)C=1C=NC=CC1OCCO HJGCZEIXJXVXBK-UHFFFAOYSA-N 0.000 description 1
- JAZNWEFUOZKCEI-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]urea Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(=O)NC2=NOC(=C2)C(C)(C)C JAZNWEFUOZKCEI-UHFFFAOYSA-N 0.000 description 1
- QRRGHAZSLONGCO-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[4-methyl-3-[4-(5-morpholin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]urea Chemical compound C(C)(C)(C)C1=CC(=NO1)NC(=O)NC1=CC(=C(C=C1)C)N1N=CC(=C1)C=1C=NC=C(C1)N1CCOCC1 QRRGHAZSLONGCO-UHFFFAOYSA-N 0.000 description 1
- ULQREENZEBCKQM-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[4-methyl-3-[4-(5-pyridin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]urea Chemical compound N1=CC(=CC(=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(=O)NC1=NOC(=C1)C(C)(C)C)C1=CC=NC=C1 ULQREENZEBCKQM-UHFFFAOYSA-N 0.000 description 1
- MHSLDASSAFCCDO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=NC=C1 MHSLDASSAFCCDO-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- PXTGBFLAUXRGKW-UHFFFAOYSA-N 1-[3-[4-[4-(2-hydroxyethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound OCCOC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(=O)NC1=CC(=CC=C1)C(F)(F)F PXTGBFLAUXRGKW-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- AMMPLVWPWSYRDR-UHFFFAOYSA-N 1-methylbicyclo[2.2.2]oct-2-ene-4-carboxylic acid Chemical compound C1CC2(C(O)=O)CCC1(C)C=C2 AMMPLVWPWSYRDR-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 1
- SIKYQDZZIQHNPN-UHFFFAOYSA-N 2-(4-methylimidazol-1-yl)-5-(trifluoromethyl)benzamide Chemical compound CC=1N=CN(C=1)C1=C(C(=O)N)C=C(C=C1)C(F)(F)F SIKYQDZZIQHNPN-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- QTMAZYGAVHCKKX-UHFFFAOYSA-N 2-[(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)methoxy]propane-1,3-diol Chemical compound NC1=NC=NC2=C1C(Br)=CN2COC(CO)CO QTMAZYGAVHCKKX-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- 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
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- XXUNIGZDNWWYED-UHFFFAOYSA-N 2-methylbenzamide Chemical compound CC1=CC=CC=C1C(N)=O XXUNIGZDNWWYED-UHFFFAOYSA-N 0.000 description 1
- OJZYVZNGKDTSFP-UHFFFAOYSA-N 2-morpholin-2-ylethanol Chemical compound OCCC1CNCCO1 OJZYVZNGKDTSFP-UHFFFAOYSA-N 0.000 description 1
- SCQZHPMTSDVGKB-UHFFFAOYSA-N 2-morpholin-4-ylethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN1CCOCC1 SCQZHPMTSDVGKB-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- MLMQPDHYNJCQAO-UHFFFAOYSA-N 3,3-dimethylbutyric acid Chemical compound CC(C)(C)CC(O)=O MLMQPDHYNJCQAO-UHFFFAOYSA-N 0.000 description 1
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 1
- KSJZBEKNYSCSGE-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[3-[4-[4-(cyclopentylmethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCC2CCCC2)C=CC1 KSJZBEKNYSCSGE-UHFFFAOYSA-N 0.000 description 1
- ZAULEDJSAQGHTJ-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(C2=CC(=CC=C2)C(C)C#N)=O ZAULEDJSAQGHTJ-UHFFFAOYSA-N 0.000 description 1
- NGXDSEQYPCLSTF-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[4-methyl-3-[4-(5-pyridin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]benzamide Chemical compound N1=CC(=CC(=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(C)C#N)=O)C1=CC=NC=C1 NGXDSEQYPCLSTF-UHFFFAOYSA-N 0.000 description 1
- AZPCGLQUXQLYPZ-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[4-methyl-3-[4-[4-(2-morpholin-4-ylethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCCN2CCOCC2)C=CC1 AZPCGLQUXQLYPZ-UHFFFAOYSA-N 0.000 description 1
- OTDJCRUVCRUOOY-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[4-methyl-3-[4-[4-(oxan-4-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCC2CCOCC2)C=CC1 OTDJCRUVCRUOOY-UHFFFAOYSA-N 0.000 description 1
- FENWQJWZBSJRJG-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[4-methyl-3-[4-[4-(oxetan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCC2COC2)C=CC1 FENWQJWZBSJRJG-UHFFFAOYSA-N 0.000 description 1
- JBWIECNFOSSEQS-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[4-methyl-3-[4-[4-(oxetan-3-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OC2COC2)C=CC1 JBWIECNFOSSEQS-UHFFFAOYSA-N 0.000 description 1
- RNEWNFSHZNTJRR-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[4-methyl-3-[4-[4-(oxolan-2-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCC2OCCC2)C=CC1 RNEWNFSHZNTJRR-UHFFFAOYSA-N 0.000 description 1
- DSFYUAJJZDSJGM-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[4-methyl-3-[4-[5-(4-methylpiperazine-1-carbonyl)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)C(=O)N2CCN(CC2)C)C=CC1 DSFYUAJJZDSJGM-UHFFFAOYSA-N 0.000 description 1
- UGBJDSMAIHMPLP-UHFFFAOYSA-N 3-(1-cyanoethyl)-N-[4-methyl-3-[4-[5-(oxetan-3-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)OC2COC2)C=CC1 UGBJDSMAIHMPLP-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- HAISBWQJTLBVGL-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[3-[4-[4-(2-hydroxyethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCCO)C=CC1 HAISBWQJTLBVGL-UHFFFAOYSA-N 0.000 description 1
- GRBHHWRRMNUHRH-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[3-[4-[4-(2-methoxyethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCCOC)C=CC1 GRBHHWRRMNUHRH-UHFFFAOYSA-N 0.000 description 1
- UOOJJJAYBKRQIP-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[3-[4-[4-(3-hydroxypropoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCCCO)C=CC1 UOOJJJAYBKRQIP-UHFFFAOYSA-N 0.000 description 1
- YOWJPXPWDIUBBC-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[3-[4-[4-(4-hydroxybutoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCCCCO)C=CC1 YOWJPXPWDIUBBC-UHFFFAOYSA-N 0.000 description 1
- JHIGDODULTWJSA-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[3-[4-[4-(furan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCC2=COC=C2)C=CC1 JHIGDODULTWJSA-UHFFFAOYSA-N 0.000 description 1
- HWEQERPHIWBPCF-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[3-[4-[4-[2-(dimethylamino)-2-oxoethoxy]pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCC(=O)N(C)C)C=CC1 HWEQERPHIWBPCF-UHFFFAOYSA-N 0.000 description 1
- CGCONLOTROUYSM-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[3-[4-[5-[2-(dimethylamino)-2-oxoethoxy]pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)OCC(=O)N(C)C)C=CC1 CGCONLOTROUYSM-UHFFFAOYSA-N 0.000 description 1
- JJEQYAOSMYMSBU-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[3-[4-[6-(cyclopropanecarbonylamino)-4-methylpyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC(=CC2C)NC(=O)C2CC2)C=CC1 JJEQYAOSMYMSBU-UHFFFAOYSA-N 0.000 description 1
- BMNQZRGMYCSERS-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[3-[4-[6-(cyclopropanecarbonylamino)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC(=CC2)NC(=O)C2CC2)C=CC1 BMNQZRGMYCSERS-UHFFFAOYSA-N 0.000 description 1
- CAWILZRDSKMVTL-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazol-1-yl]phenyl]benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2N=CN(C2)C=2C=C(C=CC2C)NC(C2=CC(=CC=C2)C(C)(C)C#N)=O CAWILZRDSKMVTL-UHFFFAOYSA-N 0.000 description 1
- PRLYEICXRPODGO-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(C2=CC(=CC=C2)C(C)(C)C#N)=O PRLYEICXRPODGO-UHFFFAOYSA-N 0.000 description 1
- URVZOOFQMRWLOK-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-(4-phenylmethoxypyridin-3-yl)pyrazol-1-yl]phenyl]benzamide Chemical compound C(C1=CC=CC=C1)OC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(C)(C)C#N)=O URVZOOFQMRWLOK-UHFFFAOYSA-N 0.000 description 1
- VAFWKCVSDBJHME-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-(5-morpholin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)N2CCOCC2)C=CC1 VAFWKCVSDBJHME-UHFFFAOYSA-N 0.000 description 1
- JJIMSHJGSJUPOP-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-(5-piperazin-1-ylpyridin-3-yl)pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)N2CCNCC2)C=CC1 JJIMSHJGSJUPOP-UHFFFAOYSA-N 0.000 description 1
- LVYDNTSORIOZOC-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-(5-pyridin-3-ylpyridin-3-yl)pyrazol-1-yl]phenyl]benzamide Chemical compound N1=CC(=CC(=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(C)(C)C#N)=O)C=1C=NC=CC1 LVYDNTSORIOZOC-UHFFFAOYSA-N 0.000 description 1
- VYODEQGHOQEYHS-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-(5-pyridin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]benzamide Chemical compound N1=CC(=CC(=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(C)(C)C#N)=O)C1=CC=NC=C1 VYODEQGHOQEYHS-UHFFFAOYSA-N 0.000 description 1
- RPCKUPGZOYUFRM-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[4-(oxan-4-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OC2CCOCC2)C=CC1 RPCKUPGZOYUFRM-UHFFFAOYSA-N 0.000 description 1
- QRLKDAWVHMMYML-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[4-(oxetan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCC2COC2)C=CC1 QRLKDAWVHMMYML-UHFFFAOYSA-N 0.000 description 1
- GSLRBKDGWBRBHS-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[4-(oxetan-3-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OC2COC2)C=CC1 GSLRBKDGWBRBHS-UHFFFAOYSA-N 0.000 description 1
- PAUVYPRTVZXDHX-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[4-(oxolan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCC2COCC2)C=CC1 PAUVYPRTVZXDHX-UHFFFAOYSA-N 0.000 description 1
- BUMCMTQYJUFGDS-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[4-(oxolan-3-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OC2COCC2)C=CC1 BUMCMTQYJUFGDS-UHFFFAOYSA-N 0.000 description 1
- BUMCMTQYJUFGDS-RUZDIDTESA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[4-[(3R)-oxolan-3-yl]oxypyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2O[C@H]2COCC2)C=CC1 BUMCMTQYJUFGDS-RUZDIDTESA-N 0.000 description 1
- BUMCMTQYJUFGDS-VWLOTQADSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[4-[(3S)-oxolan-3-yl]oxypyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2O[C@@H]2COCC2)C=CC1 BUMCMTQYJUFGDS-VWLOTQADSA-N 0.000 description 1
- RFKLQHGFIFJXJL-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[4-[[2-(oxan-4-yl)acetyl]amino]pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2NC(CC2CCOCC2)=O)C=CC1 RFKLQHGFIFJXJL-UHFFFAOYSA-N 0.000 description 1
- BBLKGSPYKMDWDC-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[4-[[2-(oxolan-3-yl)acetyl]amino]pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2NC(CC2COCC2)=O)C=CC1 BBLKGSPYKMDWDC-UHFFFAOYSA-N 0.000 description 1
- JUWRBTRPCUBTMG-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[5-(2-morpholin-4-ylethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)OCCN2CCOCC2)C=CC1 JUWRBTRPCUBTMG-UHFFFAOYSA-N 0.000 description 1
- IKWLEVJLGOITKH-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[5-(4-methylpiperazin-1-yl)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)N2CCN(CC2)C)C=CC1 IKWLEVJLGOITKH-UHFFFAOYSA-N 0.000 description 1
- GHIAAWOGRKLTEB-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[5-(4-methylpiperazine-1-carbonyl)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)C(=O)N2CCN(CC2)C)C=CC1 GHIAAWOGRKLTEB-UHFFFAOYSA-N 0.000 description 1
- MKIPKRRQJFLIGZ-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[5-(oxan-4-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)OC2CCOCC2)C=CC1 MKIPKRRQJFLIGZ-UHFFFAOYSA-N 0.000 description 1
- DMCMGWHSORVUOW-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[5-(oxetan-3-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)OC2COC2)C=CC1 DMCMGWHSORVUOW-UHFFFAOYSA-N 0.000 description 1
- APYDSBREMYKJHJ-UHFFFAOYSA-N 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[4-[5-[4-(4-methylpiperazin-1-yl)phenyl]pyridin-3-yl]pyrazol-1-yl]phenyl]benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(C)(C)C#N)=O)N1N=CC(=C1)C=1C=NC=C(C1)C1=CC=C(C=C1)N1CCN(CC1)C APYDSBREMYKJHJ-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- ZQOCDOFDUXPNGM-UHFFFAOYSA-N 3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)benzoic acid Chemical compound C1=NC(C)=CN1C1=CC(C(O)=O)=CC(C(F)(F)F)=C1 ZQOCDOFDUXPNGM-UHFFFAOYSA-N 0.000 description 1
- XGOXJJUNCPMFCP-UHFFFAOYSA-N 3-(4-methylimidazol-1-yl)-N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]-5-(trifluoromethyl)benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(C2=CC(=CC(=C2)C(F)(F)F)N2C=NC(=C2)C)=O XGOXJJUNCPMFCP-UHFFFAOYSA-N 0.000 description 1
- XBGXGCOLWCMVOI-UHFFFAOYSA-N 3-(trifluoromethyl)benzamide Chemical compound NC(=O)C1=CC=CC(C(F)(F)F)=C1 XBGXGCOLWCMVOI-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NNNYHNUZYYNHCS-UHFFFAOYSA-N 3-bromo-5-pyridin-3-ylpyridine Chemical compound BrC1=CN=CC(C=2C=NC=CC=2)=C1 NNNYHNUZYYNHCS-UHFFFAOYSA-N 0.000 description 1
- DDQYSZWFFXOXER-UHFFFAOYSA-N 3-bromopyridin-4-amine Chemical compound NC1=CC=NC=C1Br DDQYSZWFFXOXER-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-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
- YZSXDECACGXMHG-UHFFFAOYSA-N 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2N=CN(C2)C=2C=C(C=CC2C)NC(C2=CC(=C(C=C2)CN2CCN(CC2)C)C(F)(F)F)=O YZSXDECACGXMHG-UHFFFAOYSA-N 0.000 description 1
- VBEHBKABUGSUNX-UHFFFAOYSA-N 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(C2=CC(=C(C=C2)CN2CCN(CC2)C)C(F)(F)F)=O VBEHBKABUGSUNX-UHFFFAOYSA-N 0.000 description 1
- BBQFJPINLUKOQJ-UHFFFAOYSA-N 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[4-(5-pyridin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound N1=CC(=CC(=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=C(C=C1)CN1CCN(CC1)C)C(F)(F)F)=O)C1=CC=NC=C1 BBQFJPINLUKOQJ-UHFFFAOYSA-N 0.000 description 1
- UNQQVOMBCSCTDD-UHFFFAOYSA-N 4-[2-(5-bromopyridin-3-yl)oxyethyl]morpholine Chemical compound BrC1=CN=CC(OCCN2CCOCC2)=C1 UNQQVOMBCSCTDD-UHFFFAOYSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-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
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 1
- CAPKAYDTKWGFQB-UHFFFAOYSA-N 4-methyl-3-(trifluoromethyl)benzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(F)(F)F CAPKAYDTKWGFQB-UHFFFAOYSA-N 0.000 description 1
- ZNAAKOWGBPOGGI-UHFFFAOYSA-N 4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]aniline Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(N)C=CC2C ZNAAKOWGBPOGGI-UHFFFAOYSA-N 0.000 description 1
- QZBMCIZLECIDAB-UHFFFAOYSA-N 4-methyl-N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2N=CN(C2)C=2C=C(C=CC2C)NC(C2=CC(=C(C=C2)C)C(F)(F)F)=O QZBMCIZLECIDAB-UHFFFAOYSA-N 0.000 description 1
- WKTMECVNNLARNP-UHFFFAOYSA-N 4-methyl-N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(C2=CC(=C(C=C2)C)C(F)(F)F)=O WKTMECVNNLARNP-UHFFFAOYSA-N 0.000 description 1
- HSVJCVREJROAPF-UHFFFAOYSA-N 4-methyl-N-[4-methyl-3-[4-(5-morpholin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)N2CCOCC2)C=C1)C(F)(F)F HSVJCVREJROAPF-UHFFFAOYSA-N 0.000 description 1
- JAGUJFSFEOIBFA-UHFFFAOYSA-N 4-methyl-N-[4-methyl-3-[4-(5-pyridin-3-ylpyridin-3-yl)pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound N1=CC(=CC(=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=C(C=C1)C)C(F)(F)F)=O)C=1C=NC=CC1 JAGUJFSFEOIBFA-UHFFFAOYSA-N 0.000 description 1
- VIFGWQDHQSQEJB-UHFFFAOYSA-N 4-methyl-N-[4-methyl-3-[4-(5-pyridin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound N1=CC(=CC(=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=C(C=C1)C)C(F)(F)F)=O)C1=CC=NC=C1 VIFGWQDHQSQEJB-UHFFFAOYSA-N 0.000 description 1
- 150000000531 4H-pyrans Chemical class 0.000 description 1
- UCZQXJKDCHCTAI-UHFFFAOYSA-N 4h-1,3-dioxine Chemical compound C1OCC=CO1 UCZQXJKDCHCTAI-UHFFFAOYSA-N 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-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
- LPTVWZSQAIDCEB-UHFFFAOYSA-N 5-bromo-1h-pyrrolo[2,3-b]pyridine Chemical compound BrC1=CN=C2NC=CC2=C1 LPTVWZSQAIDCEB-UHFFFAOYSA-N 0.000 description 1
- VNYBIBSZZDAEOK-UHFFFAOYSA-N 5-bromopyridin-3-ol Chemical compound OC1=CN=CC(Br)=C1 VNYBIBSZZDAEOK-UHFFFAOYSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- IJRKLHTZAIFUTB-UHFFFAOYSA-N 5-nitro-2-(2-phenylethylamino)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1NCCC1=CC=CC=C1 IJRKLHTZAIFUTB-UHFFFAOYSA-N 0.000 description 1
- GGXGVZJHUKEJHO-UHFFFAOYSA-N 5-tert-butyl-1,2-oxazol-3-amine Chemical compound CC(C)(C)C1=CC(N)=NO1 GGXGVZJHUKEJHO-UHFFFAOYSA-N 0.000 description 1
- VJPQGAPUJCLKKF-UHFFFAOYSA-N 5-tert-butyl-N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazol-1-yl]phenyl]-1,2-oxazole-3-carboxamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2N=CN(C2)C=2C=C(C=CC2C)NC(=O)C2=NOC(=C2)C(C)(C)C VJPQGAPUJCLKKF-UHFFFAOYSA-N 0.000 description 1
- MZTXCGOPSTUICZ-UHFFFAOYSA-N 5-tert-butyl-N-[4-methyl-3-[4-[5-[4-(4-methylpiperazin-1-yl)phenyl]pyridin-3-yl]pyrazol-1-yl]phenyl]-1,2-oxazole-3-carboxamide Chemical compound C(C)(C)(C)C1=CC(=NO1)C(=O)NC1=CC(=C(C=C1)C)N1N=CC(=C1)C=1C=NC=C(C1)C1=CC=C(C=C1)N1CCN(CC1)C MZTXCGOPSTUICZ-UHFFFAOYSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-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
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 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
- 239000005711 Benzoic acid Substances 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
- GCKFKTIWNFSIAY-UHFFFAOYSA-N C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)OCCCN2CCOCC2)C=CC1 Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=C(C2)OCCCN2CCOCC2)C=CC1 GCKFKTIWNFSIAY-UHFFFAOYSA-N 0.000 description 1
- JGKLAQXOSLHMGY-UHFFFAOYSA-N C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCCN2CCOCC2)C=CC1 Chemical compound C(#N)C(C)(C)C=1C=C(C(=O)NC2=CC(=C(C=C2)C)N2N=CC(=C2)C=2C=NC=CC2OCCN2CCOCC2)C=CC1 JGKLAQXOSLHMGY-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
- BGGALFIXXQOTPY-NRFANRHFSA-N C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC Chemical compound C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC BGGALFIXXQOTPY-NRFANRHFSA-N 0.000 description 1
- JDUCJALNSAEANR-UHFFFAOYSA-N CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)OCCCN1CCOCC1 Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)OCCCN1CCOCC1 JDUCJALNSAEANR-UHFFFAOYSA-N 0.000 description 1
- BIKPLUZOZMETTI-UHFFFAOYSA-N CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)OCCN1CCOCC1 Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)OCCN1CCOCC1 BIKPLUZOZMETTI-UHFFFAOYSA-N 0.000 description 1
- SNGGKQBPGLWAOA-UHFFFAOYSA-N CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCCN1CCOCC1 Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCCN1CCOCC1 SNGGKQBPGLWAOA-UHFFFAOYSA-N 0.000 description 1
- SMDPIOMEJBGLBM-UHFFFAOYSA-N CC1=C(C=C(C=C1)[N+](=O)[O-])N1N=CC(=C1)C=1C=C(C=NC1)C=1C=NC=CC1 Chemical compound CC1=C(C=C(C=C1)[N+](=O)[O-])N1N=CC(=C1)C=1C=C(C=NC1)C=1C=NC=CC1 SMDPIOMEJBGLBM-UHFFFAOYSA-N 0.000 description 1
- QBEAQXLJMJWSPY-UHFFFAOYSA-N CC1=C(C=C(C=C1)[N+](=O)[O-])N1N=CC(=C1)C=1C=C2C(=NC1)NC=C2 Chemical compound CC1=C(C=C(C=C1)[N+](=O)[O-])N1N=CC(=C1)C=1C=C2C(=NC1)NC=C2 QBEAQXLJMJWSPY-UHFFFAOYSA-N 0.000 description 1
- UHNRLQRZRNKOKU-UHFFFAOYSA-N CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O Chemical compound CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O UHNRLQRZRNKOKU-UHFFFAOYSA-N 0.000 description 1
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- SDSLQMLIQQWCFU-UHFFFAOYSA-N Cc(ccc(NC(Cc1cc(C(F)(F)F)ccc1)=O)c1)c1-[n]1ncc(-c(c(C#N)c2)cnc2NC(C2CC2)=O)c1 Chemical compound Cc(ccc(NC(Cc1cc(C(F)(F)F)ccc1)=O)c1)c1-[n]1ncc(-c(c(C#N)c2)cnc2NC(C2CC2)=O)c1 SDSLQMLIQQWCFU-UHFFFAOYSA-N 0.000 description 1
- ITIGLNYGJBSPSS-UHFFFAOYSA-N Cc(ccc(NC(Cc1cc(C(F)(F)F)ccc1)=O)c1)c1-[n]1ncc(-c2ccccc2OCC2COC2)c1 Chemical compound Cc(ccc(NC(Cc1cc(C(F)(F)F)ccc1)=O)c1)c1-[n]1ncc(-c2ccccc2OCC2COC2)c1 ITIGLNYGJBSPSS-UHFFFAOYSA-N 0.000 description 1
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000248349 Citrus limon Species 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102000000340 Glucosyltransferases Human genes 0.000 description 1
- 108010055629 Glucosyltransferases Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 101000771237 Homo sapiens Serine/threonine-protein kinase A-Raf Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 206010069755 K-ras gene mutation Diseases 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- HCPWRTXQGNHVDV-UHFFFAOYSA-N N-(3-bromopyridin-4-yl)oxane-4-carboxamide Chemical compound BrC1=CN=CC=C1NC(=O)C1CCOCC1 HCPWRTXQGNHVDV-UHFFFAOYSA-N 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- LIMFPAAAIVQRRD-BCGVJQADSA-N N-[2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl]-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]-5-propan-2-ylisoquinolin-3-amine Chemical compound F[C@H]1CN(CC[C@H]1OC)C1=NC=CC(=N1)NC=1N=CC2=C(C=CC(=C2C=1)C(C)C)N1[C@@H]([C@H](C1)CS(=O)(=O)C)C LIMFPAAAIVQRRD-BCGVJQADSA-N 0.000 description 1
- KHMRABRQMBAESE-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenyl]pyrazol-4-yl]pyridin-4-yl]-2-(oxan-4-yl)acetamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1NC(CC1CCOCC1)=O KHMRABRQMBAESE-UHFFFAOYSA-N 0.000 description 1
- BETKFWOLMNPGAT-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenyl]pyrazol-4-yl]pyridin-4-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(=O)CC2=CC(=CC=C2)C(F)(F)F)N3C=C(C=N3)C4=C(C=CN=C4)NC(=O)C5C6C5COC6 BETKFWOLMNPGAT-UHFFFAOYSA-N 0.000 description 1
- WGSKYNPMLDSCLS-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenyl]pyrazol-4-yl]pyridin-4-yl]oxane-4-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1NC(=O)C1CCOCC1 WGSKYNPMLDSCLS-UHFFFAOYSA-N 0.000 description 1
- OCRQWHNMIBSYBU-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenyl]pyrazol-4-yl]pyridin-4-yl]oxolane-3-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1NC(=O)C1COCC1 OCRQWHNMIBSYBU-UHFFFAOYSA-N 0.000 description 1
- ZLSNJMBWBPSTDW-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[3-(trifluoromethyl)benzoyl]amino]phenyl]pyrazol-4-yl]pyridin-4-yl]oxane-4-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1NC(=O)C1CCOCC1 ZLSNJMBWBPSTDW-UHFFFAOYSA-N 0.000 description 1
- PONYYJVNQICCFD-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[3-(trifluoromethyl)benzoyl]amino]phenyl]pyrazol-4-yl]pyridin-4-yl]oxolane-3-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1NC(=O)C1COCC1 PONYYJVNQICCFD-UHFFFAOYSA-N 0.000 description 1
- LRJITDYJNUZQMZ-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[3-(trifluoromethyl)phenyl]carbamoylamino]phenyl]pyrazol-4-yl]pyridin-4-yl]-2-(oxan-4-yl)acetamide Chemical compound CC1=C(C=C(C=C1)NC(=O)NC1=CC(=CC=C1)C(F)(F)F)N1N=CC(=C1)C=1C=NC=CC1NC(CC1CCOCC1)=O LRJITDYJNUZQMZ-UHFFFAOYSA-N 0.000 description 1
- MOJJOVRHVHBWAR-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[3-(trifluoromethyl)phenyl]carbamoylamino]phenyl]pyrazol-4-yl]pyridin-4-yl]-2-(oxolan-3-yl)acetamide Chemical compound CC1=C(C=C(C=C1)NC(=O)NC1=CC(=CC=C1)C(F)(F)F)N1N=CC(=C1)C=1C=NC=CC1NC(CC1COCC1)=O MOJJOVRHVHBWAR-UHFFFAOYSA-N 0.000 description 1
- BRKCWCHFLSNKKP-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[3-(trifluoromethyl)phenyl]carbamoylamino]phenyl]pyrazol-4-yl]pyridin-4-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(=O)NC2=CC=CC(=C2)C(F)(F)F)N3C=C(C=N3)C4=C(C=CN=C4)NC(=O)C5C6C5COC6 BRKCWCHFLSNKKP-UHFFFAOYSA-N 0.000 description 1
- BRCMFVWPXZSBFG-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[3-(trifluoromethyl)phenyl]carbamoylamino]phenyl]pyrazol-4-yl]pyridin-4-yl]oxane-4-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(=O)NC1=CC(=CC=C1)C(F)(F)F)N1N=CC(=C1)C=1C=NC=CC1NC(=O)C1CCOCC1 BRCMFVWPXZSBFG-UHFFFAOYSA-N 0.000 description 1
- SBBYZYNISAQKTE-UHFFFAOYSA-N N-[3-[1-[2-methyl-5-[[3-(trifluoromethyl)phenyl]carbamoylamino]phenyl]pyrazol-4-yl]pyridin-4-yl]oxolane-3-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(=O)NC1=CC(=CC=C1)C(F)(F)F)N1N=CC(=C1)C=1C=NC=CC1NC(=O)C1COCC1 SBBYZYNISAQKTE-UHFFFAOYSA-N 0.000 description 1
- JWKRFNTVRWOCTP-UHFFFAOYSA-N N-[3-[1-[5-[(5-tert-butyl-1,2-oxazol-3-yl)carbamoylamino]-2-methylphenyl]pyrazol-4-yl]pyridin-4-yl]-2-(oxan-4-yl)acetamide Chemical compound C(C)(C)(C)C1=CC(=NO1)NC(NC=1C=CC(=C(C1)N1N=CC(=C1)C=1C=NC=CC1NC(CC1CCOCC1)=O)C)=O JWKRFNTVRWOCTP-UHFFFAOYSA-N 0.000 description 1
- DXECRQKNTCGOHI-UHFFFAOYSA-N N-[3-[1-[5-[(5-tert-butyl-1,2-oxazol-3-yl)carbamoylamino]-2-methylphenyl]pyrazol-4-yl]pyridin-4-yl]-2-(oxolan-3-yl)acetamide Chemical compound C(C)(C)(C)C1=CC(=NO1)NC(NC=1C=CC(=C(C1)N1N=CC(=C1)C=1C=NC=CC1NC(CC1COCC1)=O)C)=O DXECRQKNTCGOHI-UHFFFAOYSA-N 0.000 description 1
- PHWOJZSNLKJAQW-UHFFFAOYSA-N N-[3-[1-[5-[(5-tert-butyl-1,2-oxazol-3-yl)carbamoylamino]-2-methylphenyl]pyrazol-4-yl]pyridin-4-yl]-3-methyloxetane-3-carboxamide Chemical compound C(C)(C)(C)C1=CC(=NO1)NC(NC=1C=CC(=C(C1)N1N=CC(=C1)C=1C=NC=CC1NC(=O)C1(COC1)C)C)=O PHWOJZSNLKJAQW-UHFFFAOYSA-N 0.000 description 1
- SQSKCJUCCSZKLG-UHFFFAOYSA-N N-[3-[1-[5-[(5-tert-butyl-1,2-oxazol-3-yl)carbamoylamino]-2-methylphenyl]pyrazol-4-yl]pyridin-4-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide Chemical compound CC1=C(C=C(C=C1)NC(=O)NC2=NOC(=C2)C(C)(C)C)N3C=C(C=N3)C4=C(C=CN=C4)NC(=O)C5C6C5COC6 SQSKCJUCCSZKLG-UHFFFAOYSA-N 0.000 description 1
- LKBMLOTZZLPDFL-UHFFFAOYSA-N N-[3-[1-[5-[(5-tert-butyl-1,2-oxazol-3-yl)carbamoylamino]-2-methylphenyl]pyrazol-4-yl]pyridin-4-yl]oxolane-3-carboxamide Chemical compound C(C)(C)(C)C1=CC(=NO1)NC(NC=1C=CC(=C(C1)N1N=CC(=C1)C=1C=NC=CC1NC(=O)C1COCC1)C)=O LKBMLOTZZLPDFL-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- OEKVTUGEZZVRJD-UHFFFAOYSA-N N-[3-[4-[4-(2-hydroxyethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound OCCOC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O OEKVTUGEZZVRJD-UHFFFAOYSA-N 0.000 description 1
- VLGZASHXRNBKMA-UHFFFAOYSA-N N-[3-[4-[4-(2-methoxyethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound COCCOC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O VLGZASHXRNBKMA-UHFFFAOYSA-N 0.000 description 1
- ZQCVROCARQWOMG-UHFFFAOYSA-N N-[3-[4-[4-(3-hydroxypropoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound OCCCOC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O ZQCVROCARQWOMG-UHFFFAOYSA-N 0.000 description 1
- DFWHUOXLDLMJHX-UHFFFAOYSA-N N-[3-[4-[4-(4-hydroxybutoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound OCCCCOC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O DFWHUOXLDLMJHX-UHFFFAOYSA-N 0.000 description 1
- XNMRXFAFIILNTL-UHFFFAOYSA-N N-[3-[4-[4-(cyclopentylmethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound C1(CCCC1)COC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(CC1=CC(=CC=C1)C(F)(F)F)=O XNMRXFAFIILNTL-UHFFFAOYSA-N 0.000 description 1
- VMFCKWJUBXSZJK-UHFFFAOYSA-N N-[3-[4-[4-(cyclopentylmethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound C1(CCCC1)COC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O VMFCKWJUBXSZJK-UHFFFAOYSA-N 0.000 description 1
- GCLCFYKHHKCALZ-UHFFFAOYSA-N N-[3-[4-[4-(furan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound O1C=C(C=C1)COC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(CC1=CC(=CC=C1)C(F)(F)F)=O GCLCFYKHHKCALZ-UHFFFAOYSA-N 0.000 description 1
- ZDSKVCQALVITHI-UHFFFAOYSA-N N-[3-[4-[4-(furan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound O1C=C(C=C1)COC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O ZDSKVCQALVITHI-UHFFFAOYSA-N 0.000 description 1
- LJBQNPDBFRTTCG-UHFFFAOYSA-N N-[3-[4-[4-[(1-acetylpyrrolidin-3-yl)methoxy]pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(2-cyanopropan-2-yl)benzamide Chemical compound C(C)(=O)N1CC(CC1)COC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(C)(C)C#N)=O LJBQNPDBFRTTCG-UHFFFAOYSA-N 0.000 description 1
- PRFMMNFJMAFRAV-UHFFFAOYSA-N N-[3-[4-[4-[(1-acetylpyrrolidin-3-yl)methoxy]pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound C(C)(=O)N1CC(CC1)COC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O PRFMMNFJMAFRAV-UHFFFAOYSA-N 0.000 description 1
- LCRGVMVUFDRKRZ-UHFFFAOYSA-N N-[3-[4-[4-[2-(dimethylamino)-2-oxoethoxy]pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CN(C(COC1=C(C=NC=C1)C=1C=NN(C1)C1=C(C=CC(=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)C)=O)C LCRGVMVUFDRKRZ-UHFFFAOYSA-N 0.000 description 1
- DDYZMYUDWLMAKN-UHFFFAOYSA-N N-[3-[4-[4-[2-(dimethylamino)-2-oxoethoxy]pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound CN(C(COC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)=O)C DDYZMYUDWLMAKN-UHFFFAOYSA-N 0.000 description 1
- RKKTVHSIGYTMNT-UHFFFAOYSA-N N-[3-[4-[4-[[1-[2-(dimethylamino)acetyl]pyrrolidin-3-yl]methoxy]pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound CN(CC(=O)N1CC(CC1)COC1=C(C=NC=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C RKKTVHSIGYTMNT-UHFFFAOYSA-N 0.000 description 1
- BNBYGUBRXFZQFZ-UHFFFAOYSA-N N-[3-[4-[4-cyano-6-(cyclopropanecarbonylamino)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(2-cyanopropan-2-yl)benzamide Chemical compound C(#N)C1=C(C=NC(=C1)NC(=O)C1CC1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(C)(C)C#N)=O BNBYGUBRXFZQFZ-UHFFFAOYSA-N 0.000 description 1
- SVERDLADFIPNNU-UHFFFAOYSA-N N-[3-[4-[4-cyano-6-(cyclopropanecarbonylamino)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound C(#N)C1=C(C=NC(=C1)NC(=O)C1CC1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O SVERDLADFIPNNU-UHFFFAOYSA-N 0.000 description 1
- MCPFMVUHANISSG-UHFFFAOYSA-N N-[3-[4-[5-[2-(dimethylamino)-2-oxoethoxy]pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CN(C(COC=1C=NC=C(C1)C=1C=NN(C1)C1=C(C=CC(=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)C)=O)C MCPFMVUHANISSG-UHFFFAOYSA-N 0.000 description 1
- XSBJCLAKPOOUAD-UHFFFAOYSA-N N-[3-[4-[5-[2-(dimethylamino)-2-oxoethoxy]pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound CN(C(COC=1C=C(C=NC1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)=O)C XSBJCLAKPOOUAD-UHFFFAOYSA-N 0.000 description 1
- RHXYQZVUEOUWMT-UHFFFAOYSA-N N-[3-[4-[6-(cyclopropanecarbonylamino)-4-methylpyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound C1(CC1)C(=O)NC1=CC(=C(C=N1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O)C RHXYQZVUEOUWMT-UHFFFAOYSA-N 0.000 description 1
- TZSUWSSRKPYVQB-UHFFFAOYSA-N N-[3-[4-[6-(cyclopropanecarbonylamino)pyridin-3-yl]pyrazol-1-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound C1(CC1)C(=O)NC1=CC=C(C=N1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(C1=CC(=CC=C1)C(F)(F)F)=O TZSUWSSRKPYVQB-UHFFFAOYSA-N 0.000 description 1
- IHYVCWMRZWUYDY-UHFFFAOYSA-N N-[4-methyl-3-(4-pyridin-3-ylpyrazol-1-yl)phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC=1 IHYVCWMRZWUYDY-UHFFFAOYSA-N 0.000 description 1
- DHFGLBXSFWMIOC-UHFFFAOYSA-N N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(C2=CC(=CC=C2)C(F)(F)F)=O DHFGLBXSFWMIOC-UHFFFAOYSA-N 0.000 description 1
- DEESSXKPNDIRQB-UHFFFAOYSA-N N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]-3-[4-(trifluoromethyl)phenyl]benzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(C2=CC(=CC=C2)C2=CC=C(C=C2)C(F)(F)F)=O DEESSXKPNDIRQB-UHFFFAOYSA-N 0.000 description 1
- QPOMDNWGBXYYRR-UHFFFAOYSA-N N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]-3-pyridin-2-ylbenzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(C2=CC(=CC=C2)C2=NC=CC=C2)=O QPOMDNWGBXYYRR-UHFFFAOYSA-N 0.000 description 1
- OINCLUBGCICKNG-UHFFFAOYSA-N N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]-3-sulfamoylbenzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(C2=CC(=CC=C2)S(N)(=O)=O)=O OINCLUBGCICKNG-UHFFFAOYSA-N 0.000 description 1
- KTMKDTUSKOQWAG-UHFFFAOYSA-N N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]-3-thiophen-3-ylbenzamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(C2=CC(=CC=C2)C2=CSC=C2)=O KTMKDTUSKOQWAG-UHFFFAOYSA-N 0.000 description 1
- WUJWURAKXXLWFE-UHFFFAOYSA-N N-[4-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]phenyl]quinoline-7-carboxamide Chemical compound N1C=CC=2C1=NC=C(C2)C=2C=NN(C2)C=2C=C(C=CC2C)NC(=O)C2=CC=C1C=CC=NC1=C2 WUJWURAKXXLWFE-UHFFFAOYSA-N 0.000 description 1
- OOJZLOWHTHZMBO-UHFFFAOYSA-N N-[4-methyl-3-[4-(5-morpholin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)N1CCOCC1 OOJZLOWHTHZMBO-UHFFFAOYSA-N 0.000 description 1
- BAEYEEVMPJLYOO-UHFFFAOYSA-N N-[4-methyl-3-[4-(5-morpholin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=C(C=C1)CN1CCN(CC1)C)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)N1CCOCC1 BAEYEEVMPJLYOO-UHFFFAOYSA-N 0.000 description 1
- WDPFWDSFZXLYDC-UHFFFAOYSA-N N-[4-methyl-3-[4-(5-piperazin-1-ylpyridin-3-yl)pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)N1CCNCC1 WDPFWDSFZXLYDC-UHFFFAOYSA-N 0.000 description 1
- ZYHZKVHYRXZZEU-UHFFFAOYSA-N N-[4-methyl-3-[4-(5-pyridin-4-ylpyridin-3-yl)pyrazol-1-yl]phenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound N1=CC(=CC(=C1)C=1C=NN(C1)C=1C=C(C=CC1C)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)C1=CC=NC=C1 ZYHZKVHYRXZZEU-UHFFFAOYSA-N 0.000 description 1
- ONUPGBNBZOFUKK-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(1-methylsulfonylazetidin-3-yl)oxypyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OC1CN(C1)S(=O)(=O)C ONUPGBNBZOFUKK-UHFFFAOYSA-N 0.000 description 1
- LBAWXLUAUDKTEO-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(2-morpholin-4-ylethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCCN1CCOCC1 LBAWXLUAUDKTEO-UHFFFAOYSA-N 0.000 description 1
- LYMUMVZABAJEPC-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxan-4-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCC1CCOCC1 LYMUMVZABAJEPC-UHFFFAOYSA-N 0.000 description 1
- KUHVDTCMLGOCRA-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxan-4-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OC1CCOCC1 KUHVDTCMLGOCRA-UHFFFAOYSA-N 0.000 description 1
- OAJVWKSOSKQNOV-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxan-4-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OC1CCOCC1 OAJVWKSOSKQNOV-UHFFFAOYSA-N 0.000 description 1
- URNJWUAXVPJHLX-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxetan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCC1COC1 URNJWUAXVPJHLX-UHFFFAOYSA-N 0.000 description 1
- UZQMSZPQFNEEOP-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxolan-2-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCC1OCCC1 UZQMSZPQFNEEOP-UHFFFAOYSA-N 0.000 description 1
- DQUYQUWNLQKMJV-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxolan-2-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCC1OCCC1 DQUYQUWNLQKMJV-UHFFFAOYSA-N 0.000 description 1
- WFSZYZYOPUNYBZ-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxolan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCC1COCC1 WFSZYZYOPUNYBZ-UHFFFAOYSA-N 0.000 description 1
- LWMSOVHQRLKWFA-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxolan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCC1COCC1 LWMSOVHQRLKWFA-UHFFFAOYSA-N 0.000 description 1
- BWOSQZYKSHJYKW-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxolan-3-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OC1COCC1 BWOSQZYKSHJYKW-UHFFFAOYSA-N 0.000 description 1
- NNRCBMFKADGHEA-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-(oxolan-3-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OC1COCC1 NNRCBMFKADGHEA-UHFFFAOYSA-N 0.000 description 1
- IOOOOUBXIBYORN-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-[(1-methylsulfonylpyrrolidin-3-yl)methoxy]pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1OCC1CN(CC1)S(=O)(=O)C IOOOOUBXIBYORN-UHFFFAOYSA-N 0.000 description 1
- NNRCBMFKADGHEA-JOCHJYFZSA-N N-[4-methyl-3-[4-[4-[(3R)-oxolan-3-yl]oxypyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1O[C@H]1COCC1 NNRCBMFKADGHEA-JOCHJYFZSA-N 0.000 description 1
- NNRCBMFKADGHEA-QFIPXVFZSA-N N-[4-methyl-3-[4-[4-[(3S)-oxolan-3-yl]oxypyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1O[C@@H]1COCC1 NNRCBMFKADGHEA-QFIPXVFZSA-N 0.000 description 1
- RSWLIXUJEAMMAE-UHFFFAOYSA-N N-[4-methyl-3-[4-[4-[[2-(oxan-4-yl)acetyl]amino]pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=CC1NC(CC1CCOCC1)=O RSWLIXUJEAMMAE-UHFFFAOYSA-N 0.000 description 1
- QZNGMRDDVHQERR-UHFFFAOYSA-N N-[4-methyl-3-[4-[5-(2-morpholin-4-ylethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)OCCN1CCOCC1 QZNGMRDDVHQERR-UHFFFAOYSA-N 0.000 description 1
- IHFVJLYRVKTPKK-UHFFFAOYSA-N N-[4-methyl-3-[4-[5-(3-morpholin-4-ylpropoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)OCCCN1CCOCC1 IHFVJLYRVKTPKK-UHFFFAOYSA-N 0.000 description 1
- YMPZJKORDOWWEA-UHFFFAOYSA-N N-[4-methyl-3-[4-[5-(4-methylpiperazin-1-yl)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)N1CCN(CC1)C YMPZJKORDOWWEA-UHFFFAOYSA-N 0.000 description 1
- VGGBNTWQVALXDH-UHFFFAOYSA-N N-[4-methyl-3-[4-[5-(4-methylpiperazine-1-carbonyl)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)C(=O)N1CCN(CC1)C VGGBNTWQVALXDH-UHFFFAOYSA-N 0.000 description 1
- NJMAHWOVHCNBGD-UHFFFAOYSA-N N-[4-methyl-3-[4-[5-(oxan-4-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)OC1CCOCC1 NJMAHWOVHCNBGD-UHFFFAOYSA-N 0.000 description 1
- RLYYHOMSEIRJTH-UHFFFAOYSA-N N-[4-methyl-3-[4-[5-(oxan-4-yloxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)OC1CCOCC1 RLYYHOMSEIRJTH-UHFFFAOYSA-N 0.000 description 1
- QMKNCTCDJZBPOO-UHFFFAOYSA-N N-[4-methyl-3-[4-[5-(oxolan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)OCC1COCC1 QMKNCTCDJZBPOO-UHFFFAOYSA-N 0.000 description 1
- PTTMIDWHVCAKHX-UHFFFAOYSA-N N-[4-methyl-3-[4-[5-(oxolan-3-ylmethoxy)pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)OCC1COCC1 PTTMIDWHVCAKHX-UHFFFAOYSA-N 0.000 description 1
- PHGGFVXWPFCBHL-UHFFFAOYSA-N N-[4-methyl-3-[4-[5-[4-(4-methylpiperazin-1-yl)phenyl]pyridin-3-yl]pyrazol-1-yl]phenyl]-2-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)C1=CC=C(C=C1)N1CCN(CC1)C PHGGFVXWPFCBHL-UHFFFAOYSA-N 0.000 description 1
- MDWNWDBQBZLSAT-UHFFFAOYSA-N N-[4-methyl-3-[4-[5-[4-(4-methylpiperazin-1-yl)phenyl]pyridin-3-yl]pyrazol-1-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=C(C=C(C=C1)NC(C1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=NC=C(C1)C1=CC=C(C=C1)N1CCN(CC1)C MDWNWDBQBZLSAT-UHFFFAOYSA-N 0.000 description 1
- JIJZIDMODQVXFG-UHFFFAOYSA-N N-[5-[1-[2-methyl-5-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenyl]pyrazol-4-yl]pyridin-2-yl]cyclopropanecarboxamide Chemical compound CC1=C(C=C(C=C1)NC(CC1=CC(=CC=C1)C(F)(F)F)=O)N1N=CC(=C1)C=1C=CC(=NC1)NC(=O)C1CC1 JIJZIDMODQVXFG-UHFFFAOYSA-N 0.000 description 1
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 description 1
- 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
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 description 1
- 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 101150062264 Raf gene Proteins 0.000 description 1
- 238000001530 Raman microscopy Methods 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102100029437 Serine/threonine-protein kinase A-Raf Human genes 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 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
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical class O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000002431 aminoalkoxy group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002590 anti-leukotriene effect Effects 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940111133 antiinflammatory and antirheumatic drug oxicams Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 1
- 125000003710 aryl 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
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 1
- 238000001593 atomic mass spectrometry Methods 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- OZKIMYLEHNQVTI-UHFFFAOYSA-N benzene;carbonochloridic acid Chemical compound OC(Cl)=O.C1=CC=CC=C1 OZKIMYLEHNQVTI-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229940125388 beta agonist Drugs 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037396 body weight Effects 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
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004966 cyanoalkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 1
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 description 1
- 125000002993 cycloalkylene 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
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 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
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 229960002465 dabrafenib Drugs 0.000 description 1
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 229960004486 desoxycorticosterone acetate Drugs 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 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
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- SYWHXTATXSMDSB-GSLJADNHSA-N fludrocortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O SYWHXTATXSMDSB-GSLJADNHSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960003336 fluorocortisol acetate Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000006588 heterocycloalkylene group Chemical group 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000009616 inductively coupled plasma Methods 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000003951 lactams Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- CMJCXYNUCSMDBY-ZDUSSCGKSA-N lgx818 Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 CMJCXYNUCSMDBY-ZDUSSCGKSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000005229 liver cell Anatomy 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
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229940014456 mycophenolate Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- MFIGJRRHGZYPDD-UHFFFAOYSA-N n,n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)NCCNC(C)C MFIGJRRHGZYPDD-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- VMFMUJZRXZXYAH-UHFFFAOYSA-N n-[5-[[5-chloro-4-[2-[2-(dimethylamino)-2-oxoacetyl]anilino]pyrimidin-2-yl]amino]-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl]prop-2-enamide Chemical compound C=CC(=O)NC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)C(=O)C(=O)N(C)C)C(Cl)=CN=2)C(OC)=CC=1N1CCN(C)CC1 VMFMUJZRXZXYAH-UHFFFAOYSA-N 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- LPOIGVZLNWEGJG-UHFFFAOYSA-N n-benzyl-5-(4-methylpiperazin-1-yl)-2-nitroaniline Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(NCC=2C=CC=CC=2)=C1 LPOIGVZLNWEGJG-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 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
- 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
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 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
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- AVPKHOTUOHDTLW-UHFFFAOYSA-N oxane-4-carboxylic acid Chemical compound OC(=O)C1CCOCC1 AVPKHOTUOHDTLW-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 108010014186 ras Proteins Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 102220197775 rs1057519695 Human genes 0.000 description 1
- 102200006532 rs112445441 Human genes 0.000 description 1
- 102220053950 rs121913238 Human genes 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 238000012447 xenograft mouse model Methods 0.000 description 1
- 229940033942 zoladex Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- kinase inhibitor compounds are provided herein, pharmaceutical compositions comprising the compounds, and the use of the compounds in therapy.
- pyrazole or imidazole derivatives suitable for inhibiting RAF and/or RAS kinase and for treating conditions mediated by RAF and/or RAS kinase.
- the RAF gene family includes BRAF, ARAF and CRAF.
- BRAF is an oncogene located on the long arm of chromosome 7, encoding a protein of 766 amino acid residues. It is a serine/threonine-specific kinase and an important part of the RAS/RAF/MEK/ERK signaling pathway. Transduction factor. After BRAF protein is phosphorylated by RAS kinase, BRAF protein has kinase activity to activate downstream MEK protein. MEK protein then activates ERK protein. ERK protein enters the cell nucleus, and then activates various downstream proteins to start downstream. The transcription of this gene realizes cell proliferation and division.
- the 600th amino acid residue of BRAF changes from valine to glutamate, and the BRAF protein is always activated.
- the continuous activation of the RAS protein leads to the formation of downstream BRAF-BRAF homodimers or BRAF-CRAF heterodimers, which transmit activation signals downward and promote the malignant proliferation of tumor cells. Therefore, the development of small molecule targeted drugs targeting pan-RAF can simultaneously inhibit cancers caused by BRAF V600E mutations and RAS mutations.
- BRAF inhibitors Vemurafenib, Dabrafenib and LGX818 have been approved for the treatment of melanoma with BRAF mutations.
- these two drugs do not work in tumors with RAS mutations.
- the main reason is that RAS mutation can lead to the formation of dimers of BRAF and CRAF, and inhibiting BRAF can activate CRAF;
- the listed BRAF inhibitors have weak inhibitory effect on CRAF, the BRAF inhibitors lose their anti-cancer effect. Therefore, the development of Pan-RAF inhibitors that can simultaneously act on BRAF and CRAF proteins and can effectively inhibit the downstream MEK and ERK activities has become a hot spot in the research and development of RAF inhibitors.
- the present invention provides a selective kinase inhibitor, including a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
- X is selected from
- One of Y and Z is carbon and the other is nitrogen, preferably Y is nitrogen and Z is carbon;
- a ring is selected from Preferably And the substituents of R 4 and R 5 are respectively located in the meta and para positions of the benzene ring;
- R 1 , R 2 and R 3 are each independently selected from H, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, phenyl, pyridyl, phenyl C 1-6 alkoxy, furyl C 1 -6 alkoxy, R 6 is optionally substituted heterocycloalkyl, optionally substituted heterocyclic alkyl substituted with R 6 group, R 6 is optionally substituted heterocyclyl alkylcarbonyl, optionally R 6 being unsubstituted heterocycloalkyl group, R 6 is optionally substituted heterocycloalkyl C 1-6 alkoxy group, R 6 is optionally substituted heterocycloalkyl C 1-6 alkoxy Amido, C 3-6 cycloalkyl C 1-6 alkanoylamino, and C 1-6 alkylamin
- R 4 and R 5 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, heterocycloalkyl optionally substituted by R 6 C 1- 6 alkyl, R 6 is optionally substituted phenyl, optionally substituted with R 6 substituted heteroaryl, amino and sulfonyl, or R 4 and R 5 together form a And R 4 and R 5 are not H at the same time;
- R 6 is independently selected from oxo, C 1-6 alkyl, C 2-6 alkanoyl, C 1-6 alkylsulfone, C 1-6 alkylamino C 2-6 alkanoyl, and C 1- 6 haloalkyl.
- R 1 , R 2 and R 3 are each independently selected from H, cyano, C 1-6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n- Butyl, tert-butyl, etc.), C 1-6 hydroxyalkoxy (e.g. hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, etc.), C 3- 6 cycloalkyl C 1-6 alkoxy (e.g. cyclopentyl methoxy, etc.), C 1-6 alkoxy C 1-6 alkoxy (e.g.
- benzene Group pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), phenyl C 1-6 alkoxy (e.g. phenylmethoxy etc.), furyl C 1-6 alkoxy (E.g. furan-3-ylmethoxy, etc.), heterocycloalkyl optionally substituted by R 6 (e.g. N-morpholinyl, piperazin-1-yl, 4-methyl-piperazine-1- Group, etc.), heterocycloalkylphenyl optionally substituted by R 6 (e.g.
- heterocycloalkylcarbonyl optionally substituted by R 6
- R 6 4-methyl-piperazin-1-ylcarbonyl, etc.
- heterocycloalkyloxy optionally substituted by R 6
- tetrahydropyran-4-yloxy tetrahydrofuran-3-yloxy
- Oxetan-3-yloxy azetidine-3-yloxy, etc.
- heterocycloalkyl C 1-6 alkoxy optionally substituted by R 6
- a selective pan-RAF kinase inhibitor including a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or pro- medicine:
- R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
- R 1 is selected from H, pyridyl, heterocycloalkyl, heterocycloalkylphenyl optionally substituted by C 1-6 alkyl, heterocycloalkyloxy, heterocycloalkyl C 1-6 alkoxy Group, and C 1-6 alkylaminocarbonyl C 1-6 alkoxy;
- R 2 is selected from H, C 1-6 alkyl, C 1-6 hydroxyalkoxy, C 1-6 alkoxy C 1-6 alkoxy group, a heterocyclic oxy group, and heterocycloalkyl C 1-6 alkoxy;
- R 3 is selected from H, and C 3-6 cycloalkyl C 1-6 alkanoylamino;
- R 1 , R 2 and R 3 are not H at the same time;
- R 4 is selected from C 1-6 haloalkyl and C 1-6 cyanoalkyl
- R 5 is selected from H, C 1-6 alkyl, and optionally substituted heterocyclyl C 1-6 alkyl C 1-6 alkyl.
- R 1 is selected from 3-pyridyl, 4-pyridyl, N-morpholinyl, heterocycloalkyloxy, heterocycloalkyl C 1-6 alkoxy, and C 1 -6 alkylaminocarbonyl C 1-6 alkoxy;
- R 4 is selected from C 1-6 haloalkyl and C 1-6 cyanoalkyl;
- R 2 , R 3 and R 5 are all H.
- R 2 is selected from C 1-6 hydroxyalkoxy, C 1-6 alkoxy C 1-6 alkoxy, heterocycloalkyloxy, and heterocycloalkyl C 1-6 alkoxy;
- R 4 is selected from C 1-6 haloalkyl and C 1-6 cyanoalkyl;
- R 1 , R 3 and R 5 are all H.
- a selective pan-RAF kinase inhibitor including a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
- X is selected from Preferably
- One of Y and Z is carbon and the other is nitrogen;
- a ring is selected from Preferably
- R 4 and R 5 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, piperazinyl C 1-6 optionally substituted by R 6 alkyl, R 6 is optionally substituted phenyl, optionally substituted imidazolyl substituted with R 6, R 6 is optionally substituted thienyl group, R 6 is optionally substituted pyridyl group, an amino group, and a sulfo Acyl group, or R 4 and R 5 together form And R 4 and R 5 are not H at the same time;
- R 6 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the kinase inhibitor of the present invention, a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.
- the present invention also relates to the use of the kinase inhibitor of the present invention in the preparation of drugs for inhibiting the activity of tyrosine kinase RAF and/or RAS, and the preparation for the treatment, prevention or improvement of tyrosine kinase RAF And/or use in medicines for diseases, disorders or conditions that modulate or are affected by RAS activity or involve tyrosine kinase RAF and/or RAS activity.
- Figures 1a to 1b show the tumor suppressive effects of test compounds in A375 cell tumor transplantation mouse models.
- Figures 2a to 2c show the tumor suppressive effect of the test compound in the Calu-6 cell tumor transplantation mouse model.
- Figures 3a to 3b show the tumor suppressive effects of test compounds in a mouse model of HCT116 cell tumor transplantation.
- Figures 4a to 4b show the tumor suppressive effects of test compounds in a mouse model of COLO205 cell tumor transplantation.
- Figures 5a to 5b show the tumor suppressive effects of test compounds in a BxPC3 cell tumor transplantation mouse model.
- the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the technical scope of the art.
- mass spectrometry NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology
- nomenclature and laboratory operations and techniques related to the analytical chemistry, synthetic organic chemistry, and medicine and medicinal chemistry described herein are known to those skilled in the art.
- the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general documents and more specific documents, which are cited and discussed in this specification.
- alkyl refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl group. According to the structure, the alkyl group may be a monovalent group or a divalent group (ie, an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include but are not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl and the like.
- alkyl includes all possible configurations and conformations of the alkyl group.
- the "propyl” mentioned herein includes n-propyl and isopropyl
- butyl includes n-butyl.
- Pentyl includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and pent-3-yl.
- alkoxy refers to -O-alkyl, where alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like.
- alkoxyalkyl means that an alkyl group as defined herein is substituted with an alkoxy group as defined herein.
- cycloalkyl refers to a monocyclic or polycyclic group, which contains only carbon and hydrogen. Cycloalkyl groups include groups having 3-12 ring atoms. Depending on the structure, the cycloalkyl group may be a monovalent group or a divalent group (e.g., cycloalkylene). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3-8 carbon atoms, more preferably a "lower cycloalkyl group" having 3-6 carbon atoms.
- cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
- alkyl(cycloalkyl) or "cycloalkylalkyl” means that an alkyl group as defined herein is substituted with a cycloalkyl group as defined herein.
- Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
- aromatic group refers to a planar ring having a delocalized ⁇ electron system and containing 4n+2 ⁇ electrons, where n is an integer.
- the aromatic ring can be composed of five, six, seven, eight, nine, or more than nine atoms.
- Aromatic groups may be optionally substituted.
- aryl includes carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaryl”) groups (e.g., pyridine).
- the term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
- aryl means that each atom of the aromatic ring is a carbon atom.
- the aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms.
- Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl, and indenyl.
- the aryl group may be a monovalent group or a divalent group (ie, an arylene group).
- aryloxy refers to -O-aryl, where aryl is as defined herein.
- heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
- the N-containing “heteroaryl” moiety means that at least one skeleton atom in the ring of the aromatic group is a nitrogen atom.
- the heteroaryl group may be a monovalent group or a divalent group (ie, heteroarylene).
- heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole Group, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, isoindyl Dolyl, pterridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , Naphthyridiny
- alkyl(aryl) or “aralkyl” means that an alkyl group as defined herein is substituted with an aryl group as defined herein.
- Non-limiting alkyl (aryl) groups include benzyl, phenethyl and the like.
- alkyl(heteroaryl) or “heteroarylalkyl” means that an alkyl group as defined herein is substituted by a heteroaryl group as defined herein.
- heteroalkyl as used herein means that one or more of the backbone chain atoms in the alkyl group defined herein is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof.
- the heteroatom(s) can be located at any position within the heteroalkyl group or at the position where the heteroalkyl group is connected to the rest of the molecule.
- heterocycloalkyl or “heterocyclyl” as used herein means that one or more of the atoms constituting the ring in the non-aromatic ring are heteroatoms selected from nitrogen, oxygen and sulfur.
- the heterocycloalkyl ring may be a monocyclic or polycyclic ring composed of three, four, five, six, seven, eight, nine, or more than nine atoms.
- the heterocycloalkyl ring may be optionally substituted.
- heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiolan, 1,4- Oxythiolane, 1,4-oxathiolane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, Pakistan Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene,
- alkyl(heterocycloalkyl) or “heterocycloalkylalkyl” means that an alkyl group as defined herein is substituted by a heterocycloalkyl group as defined herein.
- alkoxy(heterocycloalkyl) or “heterocycloalkylalkoxy” means that an alkoxy group as defined herein is substituted by a heterocycloalkyl group as defined herein.
- halo or halogen refers to fluorine, chlorine, bromine and iodine.
- haloalkyl examples include structures of alkyl, alkoxy, or heteroalkyl, in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are the same or different from each other.
- hydroxyl refers to the -OH group.
- cyano refers to the -CN group.
- ester group refers to a chemical moiety having the formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (connected through a ring carbon) and heterocyclyl (connected through a ring carbon).
- amino refers to the -NH 2 group.
- aminoacyl refers to the -CO-NH 2 group.
- alkylaminoacyl refers to the group -CO-NH-R, where R is an alkyl group as defined herein.
- amido or “amido” refers to -NR-CO-R', where R and R'are each independently hydrogen or alkyl.
- alkylamino refers to an amino substituent further substituted by one or two alkyl groups, specifically referring to the group -NRR', wherein R and R'are each independently selected from hydrogen or lower alkyl, with the condition of- NRR' is not -NH 2 .
- Alkylamino includes groups of compounds in which the nitrogen of -NH 2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like.
- Dialkyl amino includes groups wherein the nitrogen -NH 2 group is connected to at least two additional alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
- alkylaminoalkyl means that an alkyl group as defined herein is substituted with an alkylamino group as defined herein.
- aminoalkyl refers to an alkyl substituent further substituted with one or more amino groups.
- aminoalkoxy refers to an alkoxy substituent further substituted with one or more amino groups.
- hydroxyalkyl or "hydroxyalkyl” refers to an alkyl substituent further substituted with one or more hydroxy groups.
- cyanoalkyl refers to an alkyl substituent further substituted with one or more cyano groups.
- acyl refers to the monovalent atomic group remaining after the hydroxyl group is removed from an organic or inorganic oxyacid.
- the general formula is R-M(O)-, where M is usually C.
- alkanoyl or “alkylcarbonyl” refers to a carbonyl group further substituted with an alkyl group.
- Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like.
- arylcarbonyl means that the carbonyl group defined herein is substituted with an aryl group defined herein.
- alkoxycarbonyl refers to a carbonyl group further substituted with an alkoxy group.
- heterocycloalkylcarbonyl refers to a carbonyl group further substituted with a heterocycloalkyl group.
- alkylaminocarbonyl cycloalkylaminocarbonyl
- arylaminocarbonyl arylaminocarbonyl
- aralkylaminocarbonyl heteroarylaminocarbonyl
- alkylcarbonylalkyl or “alkanoylalkyl” refers to an alkyl group further substituted with an alkylcarbonyl group.
- alkylcarbonylalkoxy or “alkanoylalkoxy” refers to an alkoxy group further substituted with an alkylcarbonyl group.
- optional means that one or more events described later may or may not occur, and include both events that occur and events that do not occur.
- the term “optionally substituted” or “substituted” means that the mentioned group may be substituted by one or more additional groups, which are each and independently selected from alkyl, cycloalkyl , Aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amido, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl Alkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc.
- the amino protecting group is preferably selected from the group consisting of pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl.
- tyrosine protein kinase is a type of kinase that catalyzes the transfer of ⁇ -phosphate from ATP to protein tyrosine residues, and can catalyze a variety of substrate protein tyrosine residues. Base phosphorylation plays an important role in cell growth, proliferation and differentiation.
- inhibitor of a kinase as used herein refers to the inhibition of phosphotransferase activity.
- a “metabolite” of a compound disclosed herein is a derivative of a compound formed when the compound is metabolized.
- active metabolite refers to a biologically active derivative of a compound formed when the compound is metabolized.
- metabolized refers to the total number of processes in which a specific substance is changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structures and convert them into compounds.
- cytochrome P450 catalyzes various oxidation and reduction reactions
- diphosphate glucosyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.
- Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing a tissue sample from the host, or by incubating the compound with liver cells in vitro and analyzing the resulting compound. Both of these methods are known in the art.
- the metabolite of the compound is formed by an oxidation process and corresponds to the corresponding hydroxyl-containing compound.
- the compound is metabolized into a pharmaceutically active metabolite.
- modulation refers to directly or indirectly interacting with a target to change the activity of the target. For example, it includes enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.
- target protein refers to a protein molecule or part of a protein that can be bound by a selective binding compound.
- the target protein is tyrosine kinase RAF (wild type or various mutations or combinations thereof), tyrosine kinase RAS (wild type or various mutations or combinations thereof), BCR/ABL (wild type Or various mutations or combinations thereof), ABL (wild-type or various mutations or combinations thereof), KIT (wild-type or various mutations or combinations thereof), EGFR (wild-type or various mutations or combinations thereof), FLT3 ( Wild type or various mutations or combinations thereof), VEGFR2 (wild type or various mutations or combinations thereof), RET (wild type or various mutations or combinations thereof), PDGFR ⁇ (wild type or various mutations or combinations thereof), PDGFR ⁇ (wild type or various mutations or combinations thereof), FGFR1 (wild type or various mutations or combinations thereof), FGFR2 (wild type or various mutations or combinations thereof), FGFR3
- IC 50 refers to a 50% of the maximum effect is obtained in the analysis of the inhibition effect of such measurement, concentration or dosage.
- EC 50 refers to a measured dose, concentration or amount of a compound, at a dose of 50% of maximal expression of the compound to induce, stimulate or enhance a particular reaction assays rely on specific reaction caused.
- the GI 50 used herein refers to the concentration of the drug required to inhibit 50% of the cell growth, that is, the drug concentration when the drug inhibits or controls the growth of 50% of the cells (such as cancer cells).
- Novel kinase inhibitor of the present invention Novel kinase inhibitor of the present invention
- the present invention provides a selective pan-RAF kinase inhibitor, including a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
- X is selected from
- One of Y and Z is carbon and the other is nitrogen;
- a ring is selected from
- R 1 , R 2 and R 3 are each independently selected from H, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, C 3-6 cycloalkyl C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, phenyl, pyridyl, phenyl C 1-6 alkoxy, furyl C 1 -6 alkoxy, R 6 is optionally substituted heterocycloalkyl, optionally substituted heterocyclic alkyl substituted with R 6 group, R 6 is optionally substituted heterocyclyl alkylcarbonyl, optionally R 6 being unsubstituted heterocycloalkyl group, R 6 is optionally substituted heterocycloalkyl C 1-6 alkoxy group, R 6 is optionally substituted heterocycloalkyl C 1-6 alkoxy Amido, C 3-6 cycloalkyl C 1-6 alkanoylamino, and C 1-6 alkylamin
- R 4 and R 5 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, heterocycloalkyl optionally substituted by R 6 C 1- 6 alkyl, R 6 is optionally substituted phenyl, optionally substituted with R 6 substituted heteroaryl, amino and sulfonyl, or R 4 and R 5 together form a And R 4 and R 5 are not H at the same time;
- Y is nitrogen and Z is carbon.
- ring A in formula (I) is And the substituents of R 4 and R 5 are respectively located at the meta and para positions of the benzene ring; more preferably, R 4 is not H and R 5 is H.
- R 2 and R 3 are H; and R 1 is selected from phenyl, pyridyl, heterocycloalkyl optionally substituted with C 1-6 alkyl, optionally C 1- 6 alkyl substituted heterocycloalkylphenyl, heterocycloalkylcarbonyl optionally substituted by C 1-6 alkyl, heterocycloalkyloxy, heterocycloalkyl C 1-6 alkoxy, and C 1-6 alkylaminocarbonyl C 1-6 alkoxy.
- R 1 is H;
- R 1 , R 2 and R 3 are each independently selected from H, cyano, C 1-6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n- Butyl, tert-butyl, etc.), C 1-6 hydroxyalkoxy (e.g. hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, etc.), C 3- 6 cycloalkyl C 1-6 alkoxy (e.g. cyclopentyl methoxy, etc.), C 1-6 alkoxy C 1-6 alkoxy (e.g.
- benzene Group pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), phenyl C 1-6 alkoxy (e.g. phenylmethoxy etc.), furyl C 1-6 alkoxy (E.g. furan-3-ylmethoxy, etc.), heterocycloalkyl optionally substituted by R 6 (e.g. N-morpholinyl, piperazin-1-yl, 4-methyl-piperazine-1- Group, etc.), heterocycloalkylphenyl optionally substituted by R 6 (e.g.
- heterocycloalkylcarbonyl optionally substituted by R 6
- R 6 4-methyl-piperazin-1-ylcarbonyl, etc.
- heterocycloalkyloxy optionally substituted by R 6
- tetrahydropyran-4-yloxy tetrahydrofuran-3-yloxy
- Oxetan-3-yloxy azetidine-3-yloxy, etc.
- heterocycloalkyl C 1-6 alkoxy optionally substituted by R 6
- tetrahydropyran-4-yl Formylamino, tetrahydrofuran-3-ylcarboxamido, tetrahydropyran-4-ylacetamido, tetrahydrofuran-3-ylacetamido, 3-methyl-oxetan-3-ylcarboxamido, 3-oxabicyclo[3.1.0]hexane-6-ylcarboxamido, etc.), C 3-6 cycloalkyl C 1-6 alkanoylamino (for example, cyclopropylcarboxamido, etc.), and C 1-6 alkylaminocarbonyl C 1-6 alkoxy (such as dimethylaminocarbonylmethoxy, etc.), wherein R 1 , R 2 and R 3 are not H at the same time.
- a selective pan-RAF kinase inhibitor including a compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or pro- medicine:
- R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
- R 1 is selected from H, pyridyl (e.g. 3-pyridyl, 4-pyridyl), heterocycloalkyl (e.g. N-morpholinyl, piperazin-1-yl), optionally C 1-6 alkyl Group substituted heterocycloalkylphenyl (e.g. 4-methyl-piperazin-1-ylphenyl), heterocycloalkyloxy (e.g. tetrahydropyran-4-yloxy, oxetane -3-yloxy), heterocycloalkyl C 1-6 alkoxy (e.g.
- R 2 is selected from H, C 1-6 alkyl (e.g. methyl), C 1-6 hydroxyalkoxy (e.g. 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy), C 1-6 alkoxy C 1-6 alkoxy (e.g. 2-methoxyethoxy), heterocycloalkyloxy (e.g. tetrahydropyran-4-yloxy, tetrahydrofuran-3-yl Oxy, oxetan-3-yloxy, azetidine-3-yloxy), and heterocycloalkyl C 1-6 alkoxy (e.g.
- R 3 is selected from H, and C 3-6 cycloalkyl C 1-6 alkanoylamino (for example, cyclopropylcarboxamido);
- R 1 , R 2 and R 3 are not H at the same time;
- R 4 is selected from C 1-6 haloalkyl (for example, trifluoromethyl), and C 1-6 cyanoalkyl (for example, 2-cyanoethyl-2-yl, 2-cyanoprop-2-yl);
- R 5 is selected from H, C 1-6 alkyl (e.g. methyl), and heterocycloalkyl C 1-6 alkyl optionally substituted by C 1-6 alkyl (e.g. 4-methyl-piperazine -1-ylmethyl).
- R 1 is selected from 3-pyridyl, 4-pyridyl, N-morpholinyl, heterocycloalkyloxy (preferably oxetan-3-yloxy), hetero Cycloalkyl C 1-6 alkoxy (preferably 3-morpholinopropoxy, tetrahydrofuran-3-ylmethoxy), and C 1-6 alkylaminocarbonyl C 1-6 alkoxy (preferably two Methylaminocarbonylmethoxy);
- R 4 is selected from C 1-6 haloalkyl (preferably trifluoromethyl), and C 1-6 cyanoalkyl (preferably 2-cyanoethyl-2-yl, 2-cyano Propyl-2-yl);
- R 2 , R 3 and R 5 are all H.
- R 2 is selected from C 1-6 hydroxyalkoxy (preferably 3-hydroxypropoxy, 4-hydroxybutoxy), C 1-6 alkoxy C 1-6 alkane Oxy group (preferably 2-methoxyethoxy), heterocycloalkyloxy (preferably tetrahydropyran-4-yloxy, tetrahydrofuran-3-yloxy, oxetan-3-yl Oxy), and heterocycloalkyl C 1-6 alkoxy (preferably tetrahydropyran-4-ylmethoxy, oxetan-3-ylmethoxy); R 4 is selected from C 1 -6 haloalkyl (preferably trifluoromethyl), and C 1-6 cyanoalkyl (preferably 2-cyanoethyl-2-yl, 2-cyanoprop-2-yl); R 1 , R 3 and R 5 is all H.
- C 1-6 hydroxyalkoxy preferably 3-hydroxypropoxy, 4-hydroxybutoxy
- C 1-6 alkoxy C 1-6 alkane Oxy group preferably
- a selective pan-RAF kinase inhibitor including a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
- X is selected from Preferably
- One of Y and Z is carbon and the other is nitrogen;
- a ring is selected from Preferably
- R 4 and R 5 are each independently selected from H, C 1-6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.), C 1-6 haloalkyl (E.g. trifluoromethyl), C 1-6 cyanoalkyl (e.g. 2-cyanoethyl-2-yl, 2-cyanoprop-2-yl), piperazinyl optionally substituted with R 6 C 1-6 alkyl (e.g.
- R 6 is optionally substituted phenyl, optionally substituted imidazolyl substituted with R 6, R 6 is optionally substituted thienyl , Pyridyl optionally substituted by R 6 and aminosulfonyl, or R 4 and R 5 together form And R 4 and R 5 are not H at the same time;
- R 6 is independently selected from C 1-6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.) and C 1-6 haloalkyl (e.g. trifluoromethyl ).
- C 1-6 alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.
- C 1-6 haloalkyl e.g. trifluoromethyl
- the present invention provides the following compounds or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof:
- novel kinase inhibitors Described herein are novel kinase inhibitors.
- the pharmaceutically acceptable salts, solvates, esters, acids, pharmaceutically active metabolites and prodrugs of this compound are also described herein.
- the compounds described herein are administered to an organism in need and metabolized in its body to produce metabolites, and the produced metabolites are then used to produce a desired effect, including a desired therapeutic effect.
- the compounds described herein can be formulated and/or used as pharmaceutically acceptable salts.
- the types of pharmaceutically acceptable salts include, but are not limited to: (1) Acid addition salts, formed by reacting the free base form of a compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids such as acetic acid, propionic acid, caproic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid Acid, 1,2-ethanedisulfonic acid, 2-
- Acceptable organic bases include ethanolamine, diethanolamine, Triethanolamine, trimethylamine, N-methylglucamine, etc.
- Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like.
- the corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using various methods, including but not limited to ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any of them. combination.
- the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or lyophilization in the case of an aqueous solution.
- the screening and characterization of pharmaceutically acceptable salts, polymorphs, and/or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, microscopy methods, and elemental analysis.
- the various spectroscopy techniques used include but are not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).
- Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.
- the application also provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate, ester, acid, pharmaceutically active metabolite or prodrug of the compound, and A pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.
- the drug containing the compound of the present invention can be administered to the patient by at least one of injection, oral, inhalation, rectal and transdermal administration.
- Other therapeutic agents can be selected from the following drugs: immunosuppressive agents (e.g. tacrolimus, cyclosporin, rapamycin, methotrine, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate FTY720), glucocorticoid drugs (e.g.
- prednisone cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydroxyprednisolone, beclomethasone , Fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (e.g.
- salicylate arylalkanoic acid, 2-arylpropionic acid, N-arylanthranilic acid, Oxicams, coxibs, or sulfanilides
- allergy vaccines antihistamines, antileukotrienes, ⁇ -agonists, theophylline, anticholinergics, or other selective kinase inhibitors (e.g., mTOR inhibitors) , C-Met inhibitor) or her2 antibody-drug.
- the other therapeutic agents mentioned can also be rapamycin, crizotinib, tamoxifen, raloxifene, anastrozole, exemestane, letrozole , Herceptin TM (trastuzumab), Gleevec TM (imatinib), taxol TM (paclitaxel), cyclophosphamide, lovastatin, Miele tetracycline (Minosine), cytarabine, 5-fluorouracil (5-FU), methotrexate (MTX), taxotere TM (docetaxel), Zoladex TM (goserelin), vincristine, vinblastine, nocodazole oxazole, teniposide, etoposide, GEMZAR (TM) (gemcitabine), epothilone (epothilone), the promise of this CD, camptothecin, daunorubicin (Daunonibic, Her
- other therapeutic agents may also be cytokines such as G-CSF (granulocyte colony stimulating factor).
- other therapeutic agents can also be, for example, but not limited to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (sub- Driamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide and paclitaxel) or CMFP (cyclophosphamide, A Methotrexate, 5-fluorouracil and prednisone).
- CMF cyclophosphamide, methotrexate and 5-fluorouracil
- CAF cyclophosphamide, doxorubicin and 5-fluorouracil
- AC sub- Driamycin
- the amount of a given drug depends on many factors, such as the specific dosing regimen, the type of disease or condition and its severity, and the subject in need of treatment Or the uniqueness of the host (such as body weight), but, depending on the specific surrounding conditions, including, for example, the specific drug that has been used, the route of administration, the condition to be treated, and the subject or host to be treated, the dosage may be known in the art
- the method is routinely decided.
- the administered dose is typically in the range of 0.02-5000 mg/day, for example, about 1-1500 mg/day.
- the required dose can conveniently be expressed as one dose, or simultaneous (or within a short period of time) or divided doses at appropriate intervals, such as two, three, four or more divided doses per day.
- the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the doctor's diagnosis.
- the compounds of the present invention can include their pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs, or pharmaceutical compositions that inhibit a tyrosine kinase RAF (wild type or various mutations or its Combination) and/or RAS (wild type or various mutations or combinations thereof) activity.
- the compound of the present invention or its pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug, or its pharmaceutical composition can be used to treat, prevent or ameliorate one or more diseases selected from the following group: entity Tumors (including benign or particularly malignant types), especially sarcomas, gastrointestinal stromal tumors (Gastrointestinal Stromal Tumors, GIST), colorectal cancer (colon cancer), acute myeloid leukemia (Acute Myeloblastic Leukemia, AML), chronic myeloid Leukemia (Chronic Myelogenous Leukemia, CML), neoplasia, systemic mastocytosis, eosinophilia syndrome, fibrosis, lupus erythematosus, graft versus host disease, neurofibroma, pulmonary hypertension, Alzheimer's disease , Seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchial cancer, testicular intraepithelial n
- Particularly preferred treatment head and neck cancer, thyroid cancer, melanoma, colorectal cancer, lung cancer, breast cancer, pancreatic cancer, esophageal cancer, liver cancer, leukemia, neoplasia or similar diseases, or Its combination.
- the compounds of the present invention can be synthesized using standard synthesis techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein.
- the solvent, temperature and other reaction conditions given herein can be changed according to the skill in the art.
- the following synthesis methods can also be used.
- the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments that are subsequently added by the methods described herein and/or methods known in the art.
- provided herein are methods of preparing the tyrosine kinase inhibitor compounds described herein and methods of using them.
- the compounds described herein can be synthesized using the following synthetic scheme. A method similar to that described below can be used to synthesize the compound by using appropriate optional starting materials.
- the starting materials used to synthesize the compounds described herein can be synthesized or can be obtained from commercial sources.
- the compounds described herein and other related compounds with different substituents can be synthesized using techniques and raw materials known to those skilled in the art.
- the general methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties in the molecules provided herein.
- reaction product can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and other methods. These products can be characterized using conventional methods, including physical constants and spectral data.
- Example 15 1-(3-(4-([3,4'-Bipyridin]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(5 -(Tert-butyl)isoxazol-3-yl)urea 15
- Example 18 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-methyl-3-(4-(5-morpholinopyridin-3-yl)-1H -Pyrazol-1-yl)phenyl)urea 18
- the product was mixed with 5-bromopyridin-3-ol (2.8g, 0.9eq) and potassium carbonate (3.7g, 2eq) and stirred in DMF (30ml) at 70°C for 5 hours. After concentration, diluted with ethyl acetate (150ml), washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product 4-(2-((5-bromopyridin-3-yl)oxy)ethyl Yl)morpholine g (3.2g).
- Step 2 The synthesis of compound 41 was accomplished by using a procedure similar to that described in Example 1. Exact Mass (calculated value): 550.26; MS (ESI) m/z (M+1)+: 551.26.
- Example 50 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4-(5-((tetrahydro-2H-pyran-4-yl)oxy )Pyridin-3-yl)-1H-pyrazol-1-yl)phenyl)benzamide 50
- Example 62 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)methoxy)pyridine-3- Yl)-1H-pyrazol-1-yl)phenyl)benzamide 62
- Example 65 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4-(5-((tetrahydrofuran-3-yl)methoxy)pyridine-3- (Yl)-1H-pyrazol-1-yl)phenyl)benzamide 65
- Example 68 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl )-1H-pyrazol-1-yl)phenyl)benzamide 68
- Example 70 N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)phenyl) -2-(3-(Trifluoromethyl)phenyl)acetamide 70
- Example 72 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydro-2H-pyran-4-yl)methoxy (Yl)pyridin-3-yl)-1H-pyrazol-1-yl)phenyl)benzamide 72
- Example 73 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine -3-yl)-1H-pyrazol-1-yl)phenyl)benzamide 73
- Example 80 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(4-(oxetan-3-yloxy)pyridin-3-yl) -1H-Pyrazol-1-yl)phenyl)benzamide 80
- Example 84 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4-(5-(oxetan-3-yloxy)pyridine-3 -Yl)-1H-pyrazol-1-yl)phenyl)benzamide 84
- Example 88 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(4-(oxetan-3-ylmethoxy)pyridin-3-yl )-1H-pyrazol-1-yl)phenyl)benzamide 88
- Example 96 N-(4-methyl-3-(4-(4-((tetrahydrofuran-2-yl)methoxy)pyridin-3-yl)-1H-pyrazol-1-yl)phenyl )-2-(3-(Trifluoromethyl)phenyl)acetamide 96
- Example 102 3-(1-cyanoethyl)-N-(3-(4-(4-(furan-3-ylmethoxy)pyridin-3-yl)-1H-pyrazole-1- (Yl)-4-methylphenyl)benzamide 102
- Example 104 N-(3-(4-(4-(furan-3-ylmethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- 2-(3-(Trifluoromethyl)phenyl)acetamide 104
- Example 105 (S)-3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyridine -3-yl)-1H-pyrazol-1-yl)phenyl)benzamide 105
- Example 106 (R)-3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyridine -3-yl)-1H-pyrazol-1-yl)phenyl)benzamide 106
- Example 118 3-(2-cyanopropan-2-yl)-N-(3-(4-(4-((1-(2-(dimethylamino)acetyl)pyrrolidine-3- (Yl)methoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)benzamide 118
- Example 120 N-(4-methyl-3-(4-(4-((1-(methylsulfonyl)pyrrolidin-3-yl)methoxy)pyridin-3-yl)-1H- Pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 120
- Example 121 N-(3-(4-(4-((1-(2-(dimethylamino)acetyl)pyrrolidin-3-yl)methoxy)pyridin-3-yl)-1H -Pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 121
- Example 123 N-(3-(4-(4-((1-Acetylaza-3-yl)oxy)pyridin-3-yl)-1H-pyrazol-1-yl)-4- (Methylphenyl))-3-(trifluoromethyl)benzamide 123
- Example 124 N-(4-methyl-3-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)oxy)pyridin-3-yl)- 1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 124
- Step 2 The synthesis of final compound 125 was accomplished by using a procedure similar to that described in Example 1. Exact Mass (calculated value): 548.25; MS (ESI) m/z (M+1)+: 549.25.
- Example 127 N-(3-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-1H-pyrazol-4-yl )Pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide 127
- Example 128 N-(3-(1-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazol-4-yl )Pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide 128
- Example 129 N-(3-(1-(5-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-methylphenyl)-1H-pyrazole -4-yl)pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide 129
- Example 130 3-(2-cyanopropane-2-yl)-N-(4-methyl-3-(4-(4-(2-(tetrahydro-2H-pyran-4-yl) Acetylamino)pyridin-3-yl)-1H-pyrazol-1-yl)phenyl)benzamide 130
- Example 132 N-(4-methyl-3-(4-(4-(2-(tetrahydro-2H-pyran-4-yl)acetylamino)pyridin-3-yl)-1H-pyrazole -1-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide 132
- Example 133 N-(3-(1-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazol-4-yl )Pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide 133
- Example 134 N-(3-(1-(5-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-methylphenyl)-1H-pyrazole -4-yl)pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide 134
- Example 135 3-(2-cyanopropane-2-yl)-N-(4-methyl-3-(4-(4-(2-(tetrahydrofuran-3-yl)acetamido)pyridine-3 -Yl)-1H-pyrazol-1-yl)phenyl)benzamide 135
- Example 136 N-(4-methyl-3-(4-(4-(2-(tetrahydrofuran-3-yl)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)benzene Yl)-3-(trifluoromethyl)benzamide 136
- Example 137 N-(4-methyl-3-(4-(4-(2-(tetrahydrofuran-3-yl)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)benzene Yl)-2-(3-(trifluoromethyl)phenyl)acetamide 137
- Example 138 N-(3-(1-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazol-4-yl )Pyridin-4-yl)-2-(tetrahydrofuran-3-yl)acetamide 138
- Example 139 N-(3-(1-(5-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-methylphenyl)-1H-pyrazole -4-yl)pyridin-4-yl)-2-(tetrahydrofuran-3-yl)acetamide 139
- Example 140 N-(3-(1-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-1H-pyrazole-4- (Yl)pyridin-4-yl)tetrahydrofuran-3-carboxamide 140
- Example 142 N-(3-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-1H-pyrazol-4-yl )Pyridin-4-yl)tetrahydrofuran-3-carboxamide 142
- Example 150 N-(3-(1-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-1H-pyrazole-4- (Pyridin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 150
- Example 151 N-(3-(1-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-1H-pyrazol-4-yl)pyridine-4 -Yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 151
- Example 152 N-(3-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)-1H-pyrazol-4-yl )Pyridin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 152
- Example 154 N-(3-(1-(5-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)2-methylphenyl)-1H-pyrazole- 4-yl)pyridin-4-yl)-3-oxabicyclo[3.1.0]hexane-6-carboxamide 154
- Example 155 3-(2-cyanopropane-2-yl)-N-(3-(4-(4-(2-hydroxyethoxy)pyridin-3-yl)-1H-pyrazole-1 -Yl)-4-methylphenyl)benzamide 155
- Example 157 1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-(4-(4-(2-hydroxyethoxy)pyridin-3-yl)-1H -Pyrazol-1-yl)-4-methylphenyl)urea 157
- Example 158 1-(3-(4-(4-(2-hydroxyethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3- (3-(Trifluoromethyl)phenyl)urea 158
- Example 159 3-(2-cyanopropan-2-yl)-N-(3-(4-(4-(2-methoxyethoxy)pyridin-3-yl)-1H-pyrazole -1-yl)-4-methylphenyl)benzamide 159
- Example 165 3-(2-cyanopropane-2-yl)-N-(3-(4-(4-(4-hydroxybutoxy)pyridin-3-yl)-1H-pyrazole-1 -Yl)-4-methylphenyl)benzamide 165
- Example 167 N-(3-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3 -(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide 167
- Example 168 N-(3-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-4 -((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide 168
- Example 170 N-(3-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3 -(Trifluoromethyl)benzamide 170
- Example 172 N-(3-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-5 -(Tert-butyl)isoxazole-3-carboxamide 172
- Example 173 1-(3-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3 -(5-(tert-butyl)isoxazol-3-yl)urea 173
- Comparative Compound 1 was accomplished by using procedures similar to those described in Example 1. Exact Mass (calculated value): 422.14; MS(ESI) m/z(M+1)+: 423.14.
- Comparative Compound 2 was accomplished by using a procedure similar to that described in Example 1. Exact Mass (calculated value): 388.11; MS(ESI) m/z(M+1)+: 389.12.
- Example 186 Effect on the proliferation of cancer cells
- mouse primary B cell BaF3 purchased from ATCC
- mouse BaF3-FL-BRAF-V600E stably expressing full-length BRAF-V600E mutant kinase
- melanoma cell A375 expressing BRAF-V600E mutation
- Type kinase purchased from Nanjing Kebai Biotechnology Co., Ltd.
- colorectal cancer cell COLO205 expressing BRAF-V600E mutant kinase, purchased from ATCC, USA
- human acute leukemia cell OCI-AML-3 expressing NRAS-Q61L mutant Kinase, purchased from Nanjing Kebai Biotechnology Co., Ltd.
- human acute leukemia cell NB4 expressing KRAS-A18D mutant kinase, purchased from ATCC, USA).
- the method for constructing the above-mentioned BaF3-FL-BRAF-V600E mutant cell line is: amplify the sequence of the human full-length BRAF-V600E mutant kinase region by PCR, and insert it into the MSCV-Puro vector (purchased from Clontech), by retroviral method, Stable transfer into mouse BaF3 cells, and withdraw IL-3 growth factor, and finally get a cell line that depends on the full-length BRAF-V600E mutation transfer protein.
- test compounds of different concentrations (0.000508 ⁇ M, 0.00152 ⁇ M, 0.00457 ⁇ M, 0.0137 ⁇ M, 0.0411 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.11 ⁇ M, 3.33 ⁇ M, 10 ⁇ M in DMSO) were added to the above cells respectively. After incubating for 72 hours, the Cell Titer-Glo (Promega, USA) cell viability detection kit was used to detect the number of living cells by quantitatively determining the ATP in living cells. The GI 50 value (unit) of the compound of the present invention against each test cell was determined, and the experimental results are shown in Table 2.
- the compound of the present invention can achieve comparable or even better inhibitory activity to the cell lines BaF3-FL-BRAF-V600E, A375, and COLO205 expressing BRAF-V600E than that of the comparative compound 1, and achieve more than that of the comparative compound 2. Good inhibitory activity.
- the compound of the present invention also showed inhibitory activity comparable to or better than that of Comparative Compound 1 and Comparative Compound 2.
- the data shows that the compound 16 of the present invention has a strong inhibitory effect on BRAF protein, BRAF-V600E protein and RAF1 (CRAF) Y340D protein in vitro, which is better than the control compound PLX4032.
- the feeding conditions are as follows: temperature is 20 ⁇ 26°C, humidity is 35-75%, light is 12 hours of lighting, 12 hours of darkness, corncob bedding is changed once a week, free eating, free drinking, and the tail number is marked.
- temperature is 20 ⁇ 26°C
- humidity 35-75%
- light 12 hours of lighting
- 12 hours of darkness corncob bedding is changed once a week
- free eating, free drinking and the tail number is marked.
- the raising and use of animals will strictly follow the regulations of the International Laboratory Animal Evaluation and Certification Management Committee.
- the preparation methods of compound 16 and comparative compound 1 are as follows. Accurately weigh 10 mg of the compound to be tested and place it in a sterile vial, then dissolve it with a small amount of DMSO, and then add 5% glucose solution to make the volume to 5 ml to obtain a gavage solution with a concentration of 2 mg/mL; precise measurement 0.5ml of 2mg/mL of the above-mentioned intragastric test solution, add 4.5ml of 5% glucose solution to make the volume to 5ml, to obtain an intravenous injection test solution with a concentration of 0.2mg/mL. In the experiment, it is currently equipped and used.
- 6 SD rats were randomly divided into two groups, and the synthetic compounds were given by intragastric administration and tail vein injection respectively.
- the intragastric group 0h before administration and 5min, 15min, 30min, 1h, 1.5h, 2h, 4h, 6h, 9h, 12h, 24h after administration;
- the tail vein group 0h before administration and 2min, 5min after administration , 15min, 30min, 1h, 2h, 4h, 6h, 9h, 12h about 0.3mL blood sample collected from the retro-orbital venous plexus, placed in a 1.5mL centrifuge tube with heparin (Sigma, USA), centrifuged at 6000rpm for 3min to separate plasma, Then take the upper layer of 100 ⁇ L of plasma in a new 1.5mL centrifuge tube and store it at -80°C for determination.
- the peak area ratio of the sample and the internal standard As/Ais is used as the ordinate, the concentration C ( ⁇ g/mL) is the abscissa, and the weighting coefficient is 1/C 2 for linear regression to obtain the standard curve of the compound in rat plasma.
- the LC-MS/MS measurement method is as follows.
- Experimental instrument API 4000 triple quadrupole detector (AB SCIEX, USA), operating software is Analyst 1.5.1 (American Applied Biosystems Co., Ltd.); Shimadzu LC-30AD liquid pump, Shimadzu DGU-20A Gas unit, Shimadzu CTO-30A column thermostat, SIL-30AC autosampler (Shimadzu Corporation, Japan).
- Chromatographic conditions Chromatographic column is Hanbang Hedera ODS-2 (Jiangsu Hanbang Technology Co., Ltd., China), Dim. (mm): 150 ⁇ 2.1, Pro. No: H18100205.15; Ser.
- test compound 16 comparative compound 1, and control compound LY30019120 (purchased from MedChemExpress, China), PLX4032 (purchased from MedChemExpress, China), RAF709 (purchased from MedChemExpress, China), RAF265 (purchased from MedChemExpress, China), respectively, were tested.
- mice (A375/COLO205) and nude mice (HCT116/Calu-6/BxPC3) female mice from Beijing Weitong Lihua Experimental Animal Co., Ltd., and raise them at SPF level
- SCID mice A375/COLO205
- nude mice HCT116/Calu-6/BxPC3
- mice Male Weitong Lihua Experimental Animal Co., Ltd., and raise them at SPF level
- drinking water and litter were sterilized by autoclaving, and all operations on mice were performed under sterile conditions.
- mice were orally administered castor oil: ethanol: water (1:1:6) vehicle (5 mice) every day; the dose for A375 transplanted tumors was 50 mg/kg, 100 mg/ kg of compound 16, 100mg/kg of PLX4032; for Calu-6 xenograft doses of 50mg/kg, 100mg/kg, 200mg/kg of compound 16, 100mg/kg of RAF709, 60mg/kg LY30019120, and 100mg/kg Comparative compound 1; for HCT116 transplanted tumor doses of 50mg/kg, 100mg/kg compound 16, 100mg/kg of RAF709 and 60mg/kg LY30019120; for COLO205 transplanted tumor doses of 25mg/kg, 50mg/kg, 100mg/kg Compound 16, 100 mg/kg PLX4032; for BxPC3 xenograft tumors, the doses are 50 mg/kg, 100 mg/kg, 200 mg/
- mice were sacrificed on the 36th, 42, 26, 35 or 42 days;
- the compound 16 of the present invention has a better inhibitory effect than the control compound in a mouse xenograft model of different cancer cells expressing KRAS, BRAF or NRAS mutations.
- the comparison compound 1 has a strong toxicity. All mice died on the eighth day, while the compound 16 did not have any toxicity. This also proves that the compound of the present invention is effective in pyridine.
- the introduction of morpholine substituents on the base produced unexpected drug effects in mice, and did not produce significant toxicity.
- the present invention provides a novel pan-RAF kinase inhibitor, which includes a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof.
- the present invention also provides formula ( The use and method of the compound of I) for preventing or treating diseases related to RAF and/or RAS kinase activity. Therefore, the above inhibitors can be made into corresponding drugs, which are suitable for industrial applications.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Transplantation (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
IC 50(nM) | 化合物16 | PLX4032 |
BRAF | 5.9 | 17.5 |
BRAF-V600E | 5.89 | 41.7 |
RAF1(CRAF)Y340D | 3.55 | 23.5 |
Claims (17)
- 一种激酶抑制剂,包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:其中,Y和Z中一个为碳,另一个为氮;R 1、R 2和R 3各自独立地选自H、氰基、C 1-6烷基、C 1-6烷氧基、C 1-6羟基烷基、C 1-6羟基烷氧基、C 3-6环烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、苯基、吡啶基、苯基C 1-6烷氧基、呋喃基C 1-6烷氧基、任选地被R 6取代的杂环烷基、任选地被R 6取代的杂环烷基苯基、任选地被R 6取代的杂环烷基羰基、任选地被R 6取代的杂环烷基氧基、任选地被R 6取代的杂环烷基C 1-6烷氧基、任选地被R 6取代的杂环烷基C 1-6烷酰氨基、C 3-6环烷基C 1-6烷酰氨基、和C 1-6烷基氨基羰基C 1-6烷氧基,或R 1与R 3一起形成 其中R 1、R 2和R 3不同时为H;R 4和R 5各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基烷基、任选地被R 6取代的杂环烷基C 1-6烷基、任选地被R 6取代的苯基、任选地被R 6取代的杂芳基、和氨基磺酰基,或R 4与R 5一起形成 且R 4和R 5不同时为H;R 6独立地选自氧代、C 1-6烷基、C 2-6烷酰基、C 1-6烷基砜基、C 1-6 烷基氨基C 2-6烷酰基、和C 1-6卤代烷基。
- 根据权利要求1所述的激酶抑制剂,其中Y为氮,Z为碳。
- 根据权利要求1所述的激酶抑制剂,其中R 2和R 3为H;且R 1选自苯基、吡啶基、任选地被C 1-6烷基取代的杂环烷基、任选地被C 1-6烷基取代的杂环烷基苯基、任选地被C 1-6烷基取代的杂环烷基羰基、杂环烷基氧基、杂环烷基C 1-6烷氧基、和C 1-6烷基氨基羰基C 1-6烷氧基。
- 根据权利要求1所述的激酶抑制剂,其中R 1为H;R 2选自H、氰基、C 1-6烷基、C 1-6羟基烷氧基、C 3-6环烷基C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、苯基C 1-6烷氧基、呋喃基C 1-6烷氧基、任选地被R 6基团取代的杂环烷基氧基、任选地被R 6基团取代的杂环烷基C 1-6烷氧基、任选地被C 1-6烷基取代的杂环烷基C 1-6烷酰氨基、和C 1-6烷基氨基羰基C 1-6烷氧基,其中R 6独立地选自氧代、C 2-6烷酰基、C 1-6烷基砜基、C 1-6烷基氨基C 2-6烷酰基;R 3选自H和C 3-6环烷基C 1-6烷酰氨基;且R 2和R 3不同时为H。
- 根据权利要求6所述的激酶抑制剂,其中R 1选自H、吡啶基、杂环烷基、任选地被C 1-6烷基取代的杂环烷基苯基、杂环烷基氧基、杂环烷基C 1-6烷氧基、和C 1-6烷基氨基羰基C 1-6烷氧基;R 2选自H、C 1-6烷基、C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷氧基、杂环烷基氧基、和杂环烷基C 1-6烷氧基;R 3选自H、和C 3-6环烷基C 1-6烷酰氨基;其中R 1、R 2和R 3不同时为H;R 4选自C 1-6卤代烷基、和C 1-6氰基烷基;R 5选自H、C 1-6烷基、和任选地被C 1-6烷基取代的杂环烷基C 1-6烷基。
- 根据权利要求6所述的激酶抑制剂,其中R 1选自H、3-吡啶基、4-吡啶基、N-吗啉基、哌嗪-1-基、4-甲基-哌嗪-1-基苯基、四氢吡喃-4-基氧基、氧杂环丁烷-3-基氧基、2-吗啉代乙氧基、3-吗啉代丙氧基、四氢呋喃-3-基甲氧基、和二甲氨基羰基甲氧基;R 2选自H、甲基、2-羟基乙氧基、3-羟基丙氧基、4-羟基丁氧基、2-甲氧基乙氧基、四氢吡喃-4-基氧基、四氢呋喃-3-基氧基、氧杂环丁烷-3-基氧基、氮杂环丁烷-3-基氧基、2-吗啉代乙氧基、四氢呋喃-2-基甲氧基、四氢呋喃-3-基甲氧基、四氢吡喃-4-基甲氧基、氧杂环丁烷-3-基甲氧基、和吡咯烷-3-基甲氧基;R 3选自H、和环丙基甲酰氨基;其中R 1、R 2和R 3不同时为H;R 4选自三氟甲基、2-氰基乙-2-基、和2-氰基丙-2-基;R 5选自H、甲基、和4-甲基-哌嗪-1-基甲基。
- 根据权利要求6所述的激酶抑制剂,其中R 1选自3-吡啶基、4-吡啶基、N-吗啉基、杂环烷基氧基、杂环烷基C 1-6烷氧基、和C 1-6烷基氨基羰基C 1-6烷氧基;R 4选自C 1-6卤代烷基、和C 1-6氰基烷基;R 2、 R 3和R 5均为H。
- 根据权利要求6所述的激酶抑制剂,其中R 2选自C 1-6羟基烷氧基、C 1-6烷氧基C 1-6烷氧基、杂环烷基氧基、和杂环烷基C 1-6烷氧基;R 4选自C 1-6卤代烷基、和C 1-6氰基烷基;R 1、R 3和R 5均为H。
- 一种药物组合物,其包括如权利要求1-12中任一项所述的激酶抑制剂、和药学上可接受的载体或赋形剂、以及任选的其它治疗剂。
- 如权利要求1-12中任一项所述的激酶抑制剂,用于抑制酪氨酸激酶RAF和/或RAS活性的用途。
- 如权利要求1-12中任一项所述的激酶抑制剂,用于治疗、预防或改善由酪氨酸激酶RAF和/或RAS活性调节的或者受其影响的或者其中涉及酪氨酸激酶RAF和/或RAS活性的疾病、障碍或病症的用途。
- 如权利要求15所述的激酶抑制剂的用途,其中所述疾病、障碍或病症选自以下增殖性疾病:实体瘤、肉瘤、胃肠道间质瘤、结直肠癌、急性粒细胞白血病、慢性髓性白血病、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合征、纤维变性、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠 癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成或其组合。
- 如权利要求15所述的激酶抑制剂的用途,其中所述疾病、障碍或病症选自以下增殖性疾病:头颈癌、甲状腺癌、黑色素瘤、结直肠癌、肺癌、乳腺癌、胰腺癌、食管癌、肝癌、白血病、瘤形成或其组合。
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/433,395 US20220143001A1 (en) | 2019-02-26 | 2019-03-07 | Novel pan-raf kinase inhibitor and use thereof |
CA3130471A CA3130471C (en) | 2019-02-26 | 2019-03-07 | Pan-raf kinase inhibitor and use thereof |
JP2021549734A JP7311918B2 (ja) | 2019-02-26 | 2019-03-07 | 新型汎rafキナーゼ阻害剤及びその使用 |
MX2021010295A MX2021010295A (es) | 2019-02-26 | 2019-03-07 | Nuevo inhibidor de cinasa pan-proteina de fibrosarcoma rapidamente acelerado (raf) y su uso. |
KR1020217030711A KR102668390B1 (ko) | 2019-02-26 | 2019-03-07 | 신규한 pan-RAF 키나아제 저해제 및 이의 용도 |
AU2019431153A AU2019431153B2 (en) | 2019-02-26 | 2019-03-07 | New-type pan-RAF kinase inhibitor and use thereof |
EP19916848.5A EP3932913A4 (en) | 2019-02-26 | 2019-03-07 | NEW-TYPE PAN-RAF KINASE INHIBITOR AND USES THEREOF |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910139510.XA CN111606887B (zh) | 2019-02-26 | 2019-02-26 | 一种新型激酶抑制剂 |
CN201910139510.X | 2019-02-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020172906A1 true WO2020172906A1 (zh) | 2020-09-03 |
Family
ID=72197832
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2019/077272 WO2020172906A1 (zh) | 2019-02-26 | 2019-03-07 | 一种新型pan-RAF激酶抑制剂及其用途 |
Country Status (8)
Country | Link |
---|---|
US (1) | US20220143001A1 (zh) |
EP (1) | EP3932913A4 (zh) |
JP (1) | JP7311918B2 (zh) |
CN (1) | CN111606887B (zh) |
AU (1) | AU2019431153B2 (zh) |
CA (1) | CA3130471C (zh) |
MX (1) | MX2021010295A (zh) |
WO (1) | WO2020172906A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022188792A1 (zh) * | 2021-03-12 | 2022-09-15 | 四川科伦博泰生物医药股份有限公司 | 具有蛋白激酶抑制活性的杂环化合物、包含其的药物组合物及其制备方法和用途 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115925632A (zh) * | 2022-11-02 | 2023-04-07 | 江苏海洋大学 | 具有抗肿瘤活性的咪唑苯基氨基苯甲酰胺类化合物 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101501023A (zh) * | 2006-07-07 | 2009-08-05 | 贝林格尔.英格海姆国际有限公司 | 苯基取代的杂芳基衍生物及其作为抗肿瘤剂的用途 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7531560B2 (en) * | 2004-11-10 | 2009-05-12 | Boehringer Ingelheim Pharmaceuticals, Inc. | Anti-cytokine heterocyclic compounds |
US9290507B2 (en) * | 2010-03-26 | 2016-03-22 | Boehringer Ingelheim International Gmbh | B-RAF kinase inhibitors |
-
2019
- 2019-02-26 CN CN201910139510.XA patent/CN111606887B/zh active Active
- 2019-03-07 US US17/433,395 patent/US20220143001A1/en active Pending
- 2019-03-07 WO PCT/CN2019/077272 patent/WO2020172906A1/zh active Search and Examination
- 2019-03-07 JP JP2021549734A patent/JP7311918B2/ja active Active
- 2019-03-07 EP EP19916848.5A patent/EP3932913A4/en active Pending
- 2019-03-07 CA CA3130471A patent/CA3130471C/en active Active
- 2019-03-07 MX MX2021010295A patent/MX2021010295A/es unknown
- 2019-03-07 AU AU2019431153A patent/AU2019431153B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101501023A (zh) * | 2006-07-07 | 2009-08-05 | 贝林格尔.英格海姆国际有限公司 | 苯基取代的杂芳基衍生物及其作为抗肿瘤剂的用途 |
Non-Patent Citations (3)
Title |
---|
"The Pharmacological Basis of Therapeutics", 1996, MCGRAW-HILL |
HU, LIMING ET AL.: "Design, synthesis, and biological activity of phenyl-pyrazole derivatives as BCR-ABL kinase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 23, no. 13, 12 May 2015 (2015-05-12), XP029170490, DOI: 20190731133154X * |
See also references of EP3932913A4 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022188792A1 (zh) * | 2021-03-12 | 2022-09-15 | 四川科伦博泰生物医药股份有限公司 | 具有蛋白激酶抑制活性的杂环化合物、包含其的药物组合物及其制备方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
AU2019431153A1 (en) | 2021-09-09 |
CN111606887B (zh) | 2023-03-17 |
EP3932913A1 (en) | 2022-01-05 |
JP7311918B2 (ja) | 2023-07-20 |
CA3130471C (en) | 2023-06-20 |
AU2019431153B2 (en) | 2022-05-19 |
MX2021010295A (es) | 2021-10-22 |
US20220143001A1 (en) | 2022-05-12 |
JP2022521964A (ja) | 2022-04-13 |
KR20210132143A (ko) | 2021-11-03 |
CN111606887A (zh) | 2020-09-01 |
EP3932913A4 (en) | 2022-09-07 |
CA3130471A1 (en) | 2020-09-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10793543B2 (en) | Selective C-KIT kinase inhibitor | |
BR112017003312B1 (pt) | Compostos de indazol como inibidores de fgfr quinase, preparação e uso dos mesmos | |
WO2017152707A1 (zh) | 吡啶胺基嘧啶衍生物甲磺酸盐的结晶形式及其制备和应用 | |
WO2019011228A1 (zh) | 咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮类化合物及其应用 | |
JP2022547294A (ja) | キナーゼ阻害剤としての3,5-ジ置換ピラゾール化合物およびその応用 | |
WO2020172906A1 (zh) | 一种新型pan-RAF激酶抑制剂及其用途 | |
KR20170043546A (ko) | 퀴나졸린 유도체 | |
JP2010111702A (ja) | 複素環化合物、その製造法および用途 | |
WO2021174581A1 (zh) | 吲唑类化合物的新用途 | |
WO2021036814A1 (zh) | 吡唑衍生物及其用途 | |
RU2792626C1 (ru) | Новый ингибитор киназы pan-raf и его применение | |
WO2020118753A1 (zh) | 一种喹啉结构的pan-KIT激酶抑制剂及其用途 | |
KR102668390B1 (ko) | 신규한 pan-RAF 키나아제 저해제 및 이의 용도 | |
CN110283160B (zh) | 一种pdgfr激酶抑制剂 | |
CN109942544B (zh) | 一类新型吲唑类衍生物激酶抑制剂 | |
CN111138426B (zh) | 吲唑类激酶抑制剂及其用途 | |
WO2020043078A1 (zh) | 新型氮杂三环类化合物的盐型、晶型及其用途 | |
WO2021004482A1 (zh) | 取代的吡唑并喹唑啉酮化合物及其应用 | |
JP2010018601A (ja) | 複素環化合物、その製造法および用途 | |
WO2020187291A1 (zh) | 吡唑并嘧啶化合物和药物组合物及其应用 | |
JP2022548055A (ja) | 置換イミダゾキノキサリン化合物およびその応用 | |
JP2010031001A (ja) | 複素環化合物、その製造法および用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19916848 Country of ref document: EP Kind code of ref document: A1 |
|
DPE1 | Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101) | ||
ENP | Entry into the national phase |
Ref document number: 3130471 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2021549734 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2019431153 Country of ref document: AU Date of ref document: 20190307 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20217030711 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2019916848 Country of ref document: EP Effective date: 20210927 |