CN109942544A - A kind of novel indazole analog derivative kinase inhibitor - Google Patents
A kind of novel indazole analog derivative kinase inhibitor Download PDFInfo
- Publication number
- CN109942544A CN109942544A CN201711394182.5A CN201711394182A CN109942544A CN 109942544 A CN109942544 A CN 109942544A CN 201711394182 A CN201711394182 A CN 201711394182A CN 109942544 A CN109942544 A CN 109942544A
- Authority
- CN
- China
- Prior art keywords
- base
- compound
- indazole
- alkyl
- synthesis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940043355 kinase inhibitor Drugs 0.000 title claims abstract description 23
- 239000003757 phosphotransferase inhibitor Substances 0.000 title claims abstract description 23
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 280
- 239000002253 acid Substances 0.000 claims abstract description 28
- 230000000694 effects Effects 0.000 claims abstract description 28
- 150000002148 esters Chemical class 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 claims abstract description 18
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims abstract description 17
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims abstract description 17
- 229940002612 prodrug Drugs 0.000 claims abstract description 15
- 239000000651 prodrug Substances 0.000 claims abstract description 15
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 claims abstract description 13
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 claims abstract description 13
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 claims abstract description 13
- 102000018967 Platelet-Derived Growth Factor beta Receptor Human genes 0.000 claims abstract description 13
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 claims abstract description 13
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 239000012453 solvate Substances 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 186
- -1 C2-6Acylamino- Chemical group 0.000 claims description 139
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 124
- 229920002554 vinyl polymer Polymers 0.000 claims description 95
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 88
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 62
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 206010028980 Neoplasm Diseases 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 33
- 210000004027 cell Anatomy 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 102220197900 rs121913516 Human genes 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 16
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 14
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 claims description 11
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 9
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 208000011580 syndromic disease Diseases 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 6
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 229930192474 thiophene Chemical group 0.000 claims description 6
- 201000002510 thyroid cancer Diseases 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 208000007033 Dysgerminoma Diseases 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 206010025135 lupus erythematosus Diseases 0.000 claims description 4
- 208000025113 myeloid leukemia Diseases 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 208000009137 Behcet syndrome Diseases 0.000 claims description 3
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 208000033464 Reiter syndrome Diseases 0.000 claims description 3
- 208000001106 Takayasu Arteritis Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 150000002240 furans Chemical class 0.000 claims description 3
- 208000024908 graft versus host disease Diseases 0.000 claims description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
- 210000003734 kidney Anatomy 0.000 claims description 3
- 230000004048 modification Effects 0.000 claims description 3
- 238000012986 modification Methods 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 3
- 208000002574 reactive arthritis Diseases 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 2
- 208000027496 Behcet 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
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 206010012735 Diarrhoea Diseases 0.000 claims description 2
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 208000001730 Familial dysautonomia Diseases 0.000 claims description 2
- 206010016935 Follicular thyroid cancer Diseases 0.000 claims description 2
- 208000007465 Giant cell arteritis Diseases 0.000 claims description 2
- 208000024869 Goodpasture syndrome Diseases 0.000 claims description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 2
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims description 2
- 208000001204 Hashimoto Disease Diseases 0.000 claims description 2
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 claims description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 2
- 208000005615 Interstitial Cystitis Diseases 0.000 claims description 2
- 208000000209 Isaacs syndrome Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims description 2
- 201000004404 Neurofibroma Diseases 0.000 claims description 2
- 206010072359 Neuromyotonia Diseases 0.000 claims description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
- 208000003435 Optic Neuritis Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm 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
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- 201000001638 Riley-Day syndrome Diseases 0.000 claims description 2
- 201000010208 Seminoma Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 201000003761 Vaginal carcinoma Diseases 0.000 claims description 2
- 208000003728 Vulvodynia Diseases 0.000 claims description 2
- 206010069055 Vulvovaginal pain Diseases 0.000 claims description 2
- 208000007502 anemia Diseases 0.000 claims description 2
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 2
- 208000019065 cervical carcinoma Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 201000002758 colorectal adenoma Diseases 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 201000011523 endocrine gland cancer Diseases 0.000 claims description 2
- 201000003914 endometrial carcinoma Diseases 0.000 claims description 2
- 210000004696 endometrium Anatomy 0.000 claims description 2
- 239000000835 fiber Substances 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 201000011066 hemangioma Diseases 0.000 claims description 2
- 208000020082 intraepithelial neoplasia Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000006178 malignant mesothelioma Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000005282 malignant pleural mesothelioma Diseases 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 206010028417 myasthenia gravis 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
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 claims description 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 201000003068 rheumatic fever Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 208000020408 systemic-onset juvenile idiopathic arthritis Diseases 0.000 claims description 2
- 206010043207 temporal arteritis Diseases 0.000 claims description 2
- 210000001550 testis Anatomy 0.000 claims description 2
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 claims description 2
- 206010043778 thyroiditis Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 208000035603 warm type autoimmune hemolytic anemia Diseases 0.000 claims description 2
- 206010001767 Alopecia universalis Diseases 0.000 claims 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 claims 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims 1
- 206010020880 Hypertrophy Diseases 0.000 claims 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims 1
- 208000032775 alopecia universalis congenita Diseases 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 claims 1
- 229910052804 chromium Inorganic materials 0.000 claims 1
- 239000011651 chromium Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 201000002491 encephalomyelitis Diseases 0.000 claims 1
- 210000004907 gland Anatomy 0.000 claims 1
- 201000002222 hemangioblastoma Diseases 0.000 claims 1
- 235000013372 meat Nutrition 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 210000003757 neuroblast Anatomy 0.000 claims 1
- 238000007614 solvation Methods 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 27
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 17
- 102000020233 phosphotransferase Human genes 0.000 abstract description 17
- 239000000203 mixture Substances 0.000 abstract description 3
- 239000002585 base Substances 0.000 description 377
- 238000003786 synthesis reaction Methods 0.000 description 182
- WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical compound NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 description 82
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 79
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 75
- 239000005864 Sulphur Substances 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 70
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 58
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 44
- 239000012074 organic phase Substances 0.000 description 42
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 41
- 239000012043 crude product Substances 0.000 description 38
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 38
- 229940080818 propionamide Drugs 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- 230000035772 mutation Effects 0.000 description 31
- 229910052786 argon Inorganic materials 0.000 description 29
- 239000007789 gas Substances 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 26
- GDWHWHNSNXLWPZ-UHFFFAOYSA-N 3-pyridin-3-yl-1h-indazole Chemical compound N=1NC2=CC=CC=C2C=1C1=CC=CN=C1 GDWHWHNSNXLWPZ-UHFFFAOYSA-N 0.000 description 23
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 23
- 238000005406 washing Methods 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- 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 21
- AZQJQRTZFPAGNV-UHFFFAOYSA-N 1-phenylindazole Chemical compound C12=CC=CC=C2C=NN1C1=CC=CC=C1 AZQJQRTZFPAGNV-UHFFFAOYSA-N 0.000 description 20
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 125000003118 aryl group Chemical group 0.000 description 18
- 235000002639 sodium chloride Nutrition 0.000 description 18
- 150000001470 diamides Chemical class 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 235000019260 propionic acid Nutrition 0.000 description 13
- 229940095574 propionic acid Drugs 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 11
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 102000015690 Proto-Oncogene Proteins c-bcr Human genes 0.000 description 9
- 108010024221 Proto-Oncogene Proteins c-bcr Proteins 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 229940017219 methyl propionate Drugs 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- JKNOZMLTXBPGNC-UHFFFAOYSA-N 3-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1H-indazole Chemical compound CN1CCN(CC1)CC2=CC=C(C=C2)C3=NNC4=CC=CC=C43 JKNOZMLTXBPGNC-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 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 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 150000003851 azoles Chemical class 0.000 description 7
- 229960000485 methotrexate Drugs 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 7
- ZPHGZFUMWZRHTL-UHFFFAOYSA-N 3-(3-fluorophenyl)-1h-indazole Chemical compound FC1=CC=CC(C=2C3=CC=CC=C3NN=2)=C1 ZPHGZFUMWZRHTL-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 6
- 239000005977 Ethylene Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 6
- 239000012964 benzotriazole Substances 0.000 description 6
- 229960004397 cyclophosphamide Drugs 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 229960002949 fluorouracil Drugs 0.000 description 6
- 238000010172 mouse model Methods 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- WGSXKYXKAARAKD-UHFFFAOYSA-N 1-fluoro-3-isocyanato-5-(trifluoromethyl)benzene Chemical group FC1=CC(N=C=O)=CC(C(F)(F)F)=C1 WGSXKYXKAARAKD-UHFFFAOYSA-N 0.000 description 5
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 description 5
- FWOPJXVQGMZKEP-UHFFFAOYSA-N 3-methyl-2h-indazole Chemical compound C1=CC=CC2=C(C)NN=C21 FWOPJXVQGMZKEP-UHFFFAOYSA-N 0.000 description 5
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 5
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 5
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 5
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 5
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 5
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 5
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 5
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 5
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 5
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 5
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 5
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- ZZLCFHIKESPLTH-UHFFFAOYSA-N 4-Methylbiphenyl Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1 ZZLCFHIKESPLTH-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 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
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000000386 microscopy Methods 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 3
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000001069 Raman spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229960002411 imatinib Drugs 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical compound OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 230000003647 oxidation Effects 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 3
- 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 3
- 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 3
- 229960002930 sirolimus Drugs 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- BGVGHYOIWIALFF-UHFFFAOYSA-N 1-fluoro-2-(trifluoromethyl)benzene Chemical compound FC1=CC=CC=C1C(F)(F)F BGVGHYOIWIALFF-UHFFFAOYSA-N 0.000 description 2
- DVVGIUUJYPYENY-UHFFFAOYSA-N 1-methylpyridin-2-one Chemical compound CN1C=CC=CC1=O DVVGIUUJYPYENY-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- WKGHUAZJNBXABN-UHFFFAOYSA-N 3-bromo-2-chloro-6-methyl-5-nitropyridine Chemical compound CC1=NC(Cl)=C(Br)C=C1[N+]([O-])=O WKGHUAZJNBXABN-UHFFFAOYSA-N 0.000 description 2
- DKIDEFUBRARXTE-UHFFFAOYSA-M 3-mercaptopropionate Chemical compound [O-]C(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-M 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 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
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 2
- GOYSWVUGDCGCPI-UHFFFAOYSA-N 5-tert-butyl-1,2-oxazole Chemical compound CC(C)(C)C1=CC=NO1 GOYSWVUGDCGCPI-UHFFFAOYSA-N 0.000 description 2
- 102100026008 Breakpoint cluster region protein Human genes 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
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 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
- 208000015023 Graves' disease Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 101710089165 Protein white Proteins 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 102000004357 Transferases Human genes 0.000 description 2
- 108090000992 Transferases Proteins 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000012298 atmosphere 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 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
- 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 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical group 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 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 2
- 229960004618 prednisone Drugs 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
- 125000006239 protecting group Chemical group 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 150000003235 pyrrolidines Chemical class 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 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 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 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
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 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
- 210000004885 white matter Anatomy 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-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
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-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
- 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
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-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
- YBWJVFMNWMLZEN-UHFFFAOYSA-N 1,2-difluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1F YBWJVFMNWMLZEN-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
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-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
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- IVJFXSLMUSQZMC-UHFFFAOYSA-N 1,3-dithiole Chemical compound C1SC=CS1 IVJFXSLMUSQZMC-UHFFFAOYSA-N 0.000 description 1
- QVFHFKPGBODJJB-UHFFFAOYSA-N 1,3-oxathiane Chemical compound C1COCSC1 QVFHFKPGBODJJB-UHFFFAOYSA-N 0.000 description 1
- WJJSZTJGFCFNKI-UHFFFAOYSA-N 1,3-oxathiolane Chemical compound C1CSCO1 WJJSZTJGFCFNKI-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 1
- 150000000094 1,4-dioxanes Chemical class 0.000 description 1
- CPRVXMQHLPTWLY-UHFFFAOYSA-N 1,4-oxathiine Chemical compound O1C=CSC=C1 CPRVXMQHLPTWLY-UHFFFAOYSA-N 0.000 description 1
- DGRVQOKCSKDWIH-UHFFFAOYSA-N 1-chloro-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1Cl DGRVQOKCSKDWIH-UHFFFAOYSA-N 0.000 description 1
- GBOWGKOVMBDPJF-UHFFFAOYSA-N 1-fluoro-3-(trifluoromethyl)benzene Chemical compound FC1=CC=CC(C(F)(F)F)=C1 GBOWGKOVMBDPJF-UHFFFAOYSA-N 0.000 description 1
- UNNNAIWPDLRVRN-UHFFFAOYSA-N 1-fluoro-4-(trifluoromethyl)benzene Chemical compound FC1=CC=C(C(F)(F)F)C=C1 UNNNAIWPDLRVRN-UHFFFAOYSA-N 0.000 description 1
- NFYCGFPFIVPLHI-UHFFFAOYSA-N 1-methylpiperazine;piperazine Chemical compound C1CNCCN1.CN1CCNCC1 NFYCGFPFIVPLHI-UHFFFAOYSA-N 0.000 description 1
- WHKWMTXTYKVFLK-UHFFFAOYSA-N 1-propan-2-ylpiperazine Chemical compound CC(C)N1CCNCC1 WHKWMTXTYKVFLK-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
- 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
- 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
- ILPBINAXDRFYPL-UHFFFAOYSA-N 2-octene Chemical compound CCCCCC=CC ILPBINAXDRFYPL-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
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical class N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-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
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical class CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 1
- UCZQXJKDCHCTAI-UHFFFAOYSA-N 4h-1,3-dioxine Chemical compound C1OCC=CO1 UCZQXJKDCHCTAI-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
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- 208000026872 Addison Disease Diseases 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
- 208000023328 Basedow disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-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
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229940126639 Compound 33 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
- 235000005956 Cosmos caudatus Nutrition 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241000219104 Cucurbitaceae Species 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
- 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
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- 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
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000003807 Graves Disease Diseases 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
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 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
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-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
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- ZNNHFUXTOVAUQF-UHFFFAOYSA-N N,N-dimethyl-1-[[2-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-amine Chemical compound C1C(N(C)C)CCN1CC1=CC=CC=C1C(F)(F)F ZNNHFUXTOVAUQF-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical class CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 1
- RQQDJYROSYLPPK-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 Chemical compound N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 RQQDJYROSYLPPK-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-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
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 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
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-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
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 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
- 201000008736 Systemic mastocytosis Diseases 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
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000000862 absorption spectrum Methods 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
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 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
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 208000030961 allergic reaction Diseases 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
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- REDXJYDRNCIFBQ-UHFFFAOYSA-N aluminium(3+) Chemical compound [Al+3] REDXJYDRNCIFBQ-UHFFFAOYSA-N 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
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000002590 anti-leukotriene effect Effects 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 238000003556 assay 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
- 229940125717 barbiturate Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 102000004441 bcr-abl Fusion Proteins Human genes 0.000 description 1
- 108010056708 bcr-abl Fusion Proteins Proteins 0.000 description 1
- 230000008901 benefit Effects 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
- 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229940124748 beta 2 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
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 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
- 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
- 230000005907 cancer growth Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 235000013339 cereals Nutrition 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
- 238000002512 chemotherapy Methods 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229960003290 cortisone acetate 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
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 229960000975 daunorubicin 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
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000035617 depilation Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000001514 detection method Methods 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
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 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
- 208000035475 disorder Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 208000037902 enteropathy Diseases 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960000556 fingolimod 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
- 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
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229960003336 fluorocortisol acetate Drugs 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000003694 hair properties Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000001469 hydantoins Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 229940073062 imuran Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000002473 indoazoles Chemical class 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 238000009616 inductively coupled plasma Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical class C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 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
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 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
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 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
- 206010025482 malaise Diseases 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
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 201000006512 mast cell neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 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
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 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
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 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
- QCCWVNLOJADEAV-UHFFFAOYSA-N n,n-dimethyl-1h-pyrrol-3-amine Chemical class CN(C)C=1C=CNC=1 QCCWVNLOJADEAV-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 150000005054 naphthyridines Chemical class 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
- 210000005036 nerve Anatomy 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 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
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 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
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QULYNCCPRWKEMF-UHFFFAOYSA-N parachlorobenzotrifluoride Chemical compound FC(F)(F)C1=CC=C(Cl)C=C1 QULYNCCPRWKEMF-UHFFFAOYSA-N 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000010452 phosphate 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
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate 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
- 230000002265 prevention Effects 0.000 description 1
- 210000001948 pro-b lymphocyte Anatomy 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 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
- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 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
- 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
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 125000006413 ring segment Chemical group 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
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 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
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 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
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 210000001519 tissue Anatomy 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
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 241001430294 unidentified retrovirus Species 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
- 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
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
-
- 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
- A61K31/435—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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/535—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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Neurology (AREA)
- Gynecology & Obstetrics (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Pregnancy & Childbirth (AREA)
- Gastroenterology & Hepatology (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Oncology (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of kinase inhibitors comprising the compound of formula (I) or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug.The invention further relates to the pharmaceutical compositions including the kinase inhibitor, and inhibit using these compounds and composition cell or subject selected from one of cKIT, BCR/ABL, PDGFR α, PDGFR β and VEGFR2 or a variety of tyrosine kinase activities and the purposes and method of preventing or treat kinase related disorder in subject.
Description
Technical field
The present invention relates to a kind of novel kinase inhibitor compounds, the pharmaceutical composition including the compound, and make
Reduced or inhibited with these compound or compositions cell or subject cKIT (especially saltant type cKIT/T670I),
BCR/ABL (especially saltant type BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 activity, and in subject
The purposes and method of middle prevention or treatment kinase related disorder.
Background technique
Tyrosine kinase is that γ-phosphoric acid is transferred to the kinases on protein-tyrosine residue on a kind of catalysis ATP, can be catalyzed more
Kind substrate protein white matter tyrosine residue phosphorylation plays a significant role in cell growth, proliferation, differentiation.Kinase function is abnormal
It is of great significance in cancer, immune, nerve, metabolism and infectious diseases.About nearly 30 kinds different kinases conducts at present
The drug of target spot, the overwhelming majority are used to treating cancer.Majority is to belong to carcinogenic RNA disease in the protein tyrosine kinase found so far
The oncoprotein of poison, can also be generated by the proto-oncogene of vertebrate.
Tyrosine kinase inhibitor can be used as competitive inhibitor of the atriphos (ATP) in conjunction with tyrosine kinase,
Also the analog that can be used as tyrosine blocks the activity of tyrosine kinase, inhibits cell Proliferation, has developed several antitumor
Drug.
The kinases encoded in human genome has 518 kinds, and almost each signal transduction process is required to pass through phposphate
Cascade reaction (cascade) is got in touch with: prompt inhibition kinase activity can really eliminate the physiological reaction of cell.For example, cancer
Gene BCR (Breakpoint cluster region)-ABL fusion protein is the key that lead to chronic myelogenous leukemia
Factor, tyrosine activity have apparent therapeutic potential.Although ATP-binding site has the conservative of height, can open
Send out the small molecule on pharmacological characteristic with obvious selectivity.Normal cell can usually be resistant to the inhibition of kinases, therefore be
Selectivity kills tumour cell and provides the window of a treatment.Such as Dasatinib treats the drug resistant chronic marrow of Imatinib
Property leukaemia CML, can almost inhibit 9 kinases (and other multiple tyrosine kinase) of SRC family, but with it is traditional thin
Born of the same parents' chemotherapy is compared, and side effect is still easy tolerance.Therefore, the exploitation of new kinase inhibitor has important clinical meaning.
Summary of the invention
The present invention provides a kind of Azaindole kinase inhibitors, compound or its pharmaceutically acceptable salt, solvent including formula (I)
Compound, ester, acid, metabolin or prodrug:
Wherein, X is selected from
Y be selected from phenyl, thiophene -2- base, isoxazole -3- base, pyridin-3-yl, pyridin-4-yl, 2-Pyrrolidone -5- base,
N- methyl -2 (1H)-pyridone -5- base and furans -2- base;
R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3Group replace pyridin-3-yl, optionally
By R3Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces;
(R2)nIt indicates optionally by n independent R2Replaced substituent group, wherein n is the integer of 0-5, R2Independently selected from hydroxyl
Base, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Acylamino-, C1-6Alkyl amino, 4-
Methyl-imidazoles -1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl;
R5Selected from hydrogen and C1-6Alkyl amino.
In a preferred embodiment, kinase inhibitor of the invention includes the compound of formula (Ia) or its is pharmaceutically acceptable
Salt, solvate, ester, acid, metabolin or pro-drug:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3The pyridin-3-yl of group substitution,
Optionally by R3The phenyl that group replaces;
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Replaced substituent group, wherein n is
The integer of 0-5, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Alkyl amino, 4- methyl-
Imidazoles -1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl;
R5Selected from C1-6Alkyl amino.
In other preferred embodiment, kinase inhibitor of the invention includes the compound of formula (Ib) or its pharmacy can
Salt, solvate, ester, acid, metabolin or the pro-drug of receiving:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3The pyridin-3-yl of group substitution,
Optionally by R3Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces;
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Replaced substituent group,
Middle n is the integer of 0-5, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Alkyl halide
Oxygroup, C2-6Acylamino-, C1-6Alkyl amino, 4- methyl-imidazoles -1- base,
R3Selected from C1-6Alkyl and
R4Selected from C1-6Alkyl;
R5Selected from hydrogen and C1-6Alkyl amino.
The invention further relates to the pharmaceutical compositions for including the above compound and the compound or pharmaceutical composition to prevent
Or treat disease that is being adjusted by tyrosine kinase activity or being affected by it or being directed to tyrosine kinase activity, barrier
Hinder or the method and purposes of illness.
Detailed description of the invention
Fig. 1 a to 1c shows tumour of the compound 4 in TEL-cKIT/T670I-BaF3 cell tumour transplanting mouse model
Inhibitory effect.
Fig. 2 a to 2c shows tumour suppression of the compound 142 in P210/T315I-BaF3 cell tumour transplanting mouse model
Effect processed.
Specific embodiment
Term
Unless otherwise defined, all scientific and technical terminologies used herein all have the skill with claimed theme fields
Art personnel are commonly understood by identical meaning.
Unless otherwise indicated, the present invention is using mass spectrum, the NMR, HPLC, protein chemistry, life within the scope of art technology
The conventional methods such as object chemistry, recombinant DNA technology and pharmacology.Unless provide specific definition, otherwise with analysis described herein
The chemically relevant name of chemistry, synthetic organic chemistry and medicine and pharmaceutical chemistry etc. and laboratory operation and technology, are these
Known to the technical staff of field.In general, aforementioned techniques and step can be by well-known in the art and various one
As conventional method described in document and more specific document implement, these documents are cited in the present specification and discuss.
Term " alkyl " refers to aliphatic hydrocarbon groups, can be the alkyl of branch or straight chain.According to structure, alkyl be can be
Monoradical or bivalent radical (i.e. alkylidene).In the present invention, alkyl is preferably the alkyl with 1-8 carbon atom, more excellent
" low alkyl group " with 1-6 carbon atom is selected, even more preferably with the alkyl of 1-4 carbon atom.Typically alkyl includes
But be not limited to methyl, ethyl, propyl, butyl, amyl, hexyl etc..It should be understood that " alkyl " that is mentioned herein includes that may be present
The alkyl of all configurations and conformation, such as " propyl " that is mentioned herein includes n-propyl and isopropyl, " butyl " includes positive fourth
Base, isobutyl group and tert-butyl, " amyl " include n-pentyl, isopropyl, neopentyl, tertiary pentyl and amyl- 3- base etc..
Term " alkoxy " refers to-O- alkyl, and wherein alkyl is as defined herein.Typically alkoxy includes but is not limited to
Methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy etc..
Term " alkoxyalkyl " refers to that alkyl defined herein is replaced by alkoxy defined herein.
Term " aromatic radical " refers to that planar rings have the pi-electron system of delocalization and contain 4n+2 pi-electron, and wherein n is
Integer.Fragrant basic ring can be by five, six, seven, eight, nine or more than nine atomic buildings.Aromatic radical, which can be, optionally to be replaced.Art
Language " aromatic radical " includes isocyclic aryl (such as phenyl) and heterocyclic aryl (or " heteroaryl " or " heteroaryl perfume base ") group (such as pyrrole
Pyridine).The term includes monocycle or polycyclic (sharing the ring of the adjacent carbon atom pair) group of condensed ring.
The atom that terms used herein " aryl " refer to that each in fragrant basic ring constitutes ring is carbon atom.Aryl rings
By five, six, seven, eight, nine or nine atomic buildings can be more than.Aryl, which can be, optionally to be replaced.The example of aryl include but
It is not limited to phenyl, naphthalene, phenanthryl, anthryl, fluorenyl and indenyl.According to structure, aryl can be monoradical or bivalent radical (i.e.
Arlydene).
Term " aryloxy group " refers to-O- aryl, and wherein aryl is as defined herein.
Term " heteroaryl " refers to include one or more ring hetero atoms selected from nitrogen, oxygen and sulphur in aryl.Containing N " heteroaryl
Base " partially refers to that at least one skeletal atom is nitrogen-atoms in aromatic radical middle ring.According to structure, heteroaryl can be monovalent radical
Group or bivalent radical (i.e. inferior heteroaryl).The example of heteroaryl include but is not limited to pyridyl group, imidazole radicals, pyrimidine radicals, pyrazolyl,
Triazolyl, pyrazinyl, tetrazole radical, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrole radicals, quinoline
Quinoline base, isoquinolyl, indyl, benzimidazolyl, benzofuranyl, indazolyl, indolizine base, phthalazinyl, pyridazinyl, iso-indoles
Base, pteridyl, purine radicals, oxadiazoles base, thiadiazolyl group, furazanyl, benzofuraxan base, benzothienyl, benzothiazolyl, benzene
And oxazolyl, quinazolyl, naphthyridines base and furopyridyl etc..
Term " alkyl (aryl) " or " aralkyl " refer to that alkyl defined herein is replaced by aryl defined herein.Non- limit
The alkyl (aryl) of property processed includes benzyl, phenethyl etc..
Term " alkyl (heteroaryl) " or " heteroaryl alkyl " refer to alkyl defined herein by heteroaryl defined herein
Replace.
Terms used herein " miscellaneous alkyl " refer to that one or more skeletal chain atoms in alkyl defined herein are miscellaneous
Atom, such as oxygen, nitrogen, sulphur, silicon, phosphorus or their combination.The hetero atom (one or more) can be located inside miscellaneous alkyl
Any position or in the position that miscellaneous alkyl is connected with the rest part of molecule.
Terms used herein " Heterocyclylalkyl " or " heterocycle " refer to one or more composition rings in non-aromatic basic ring
Atom is the hetero atom selected from nitrogen, oxygen and sulphur.Heterocycloalkyl ring can be by three, four, five, six, seven, eight, nine or more than nine originals
Son is constituted.Heterocycloalkyl ring, which can be, optionally to be replaced.The example of Heterocyclylalkyl includes but is not limited to lactams, lactone, ring Asia
Amine, ring thioimines, cyclic carbramates, tetrahydric thiapyran, 4H- pyrans, oxinane, piperidines, 1,3- dioxin, 1,3- bis- are disliked
Alkane, 1,4- dioxin, 1,4- dioxanes, piperazine, 1,3- thioxane, 1,4- oxathiin, 1,4- oxygen thia
Hexamethylene, tetrahydro -1,4- thiazine, 2H-1,2- oxazines, maleimide, succinimide, barbiturates, thiobarbituricacidα-,
Dioxopiperazine, hydantoins, dihydrouracil, morpholine, trioxane, hexahydro -1,3,5- triazine, thiophane, tetrahydrofuran,
Pyrrolin, pyrrolidines, imidazolidine, pyrrolidones, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3- dioxole, 1,
3- dioxolane, 1,3- dithiole, 1,3- dithiolane, isoxazoline, isoxazole alkane, oxazoline, evil
Oxazolidine, oxazolidone, thiazoline, thiazolidine and 1,3- oxathiolane.According to structure, Heterocyclylalkyl can be monoradical
Or bivalent radical (i.e. sub- Heterocyclylalkyl).
Term " alkyl (Heterocyclylalkyl) " or " hetercycloalkylalkyl " refer to alkyl defined herein by defined herein miscellaneous
Naphthenic base replaces.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Term " halogenated alkyl ", " halogenated alkoxy " and " halogenated miscellaneous alkyl " include the knot of alkyl, alkoxy or miscellaneous alkyl
Structure, wherein at least one hydrogen are replaced by halogen atom.In some embodiments, if two or more hydrogen atoms are set by halogen atom
It changes, the halogen atom is same or different to each other.
Term " hydroxyl " refers to formula-OH group.
Term " cyano " refers to formula-CN group.
Term " ester group " refers to the chemical part with formula-COOR, and wherein R is selected from alkyl, naphthenic base, aryl, heteroaryl
(being connected by ring carbon) (is connected) with heterocycle by ring carbon.
Term " amino " refers to group-NH2。
Term " aminoacyl " refers to-CO-NH2。
Term " amide groups " or " acylamino- " refer to-NR-CO-R ', and wherein R and R ' are each independently hydrogen or alkyl.
Term " alkyl amino " refers to further by one or two alkyl-substituted amino-substituent, in particular to base
Group-NRR ', wherein R and R ' is each independently selected from hydrogen or low alkyl group, and condition is that-NRR ' is not-NH2." alkyl amino " packet
Include wherein-NH2Nitrogen connect at least one alkyl group compound group.The example of alkylamino group includes but unlimited
In methylamino, ethylamino etc.." dialkyl amido " includes wherein-NH2Nitrogen connect at least two other alkyl groups
Group.The example of dialkyl amino group includes but is not limited to dimethylamino, diethylamino etc..
Term " acyl group " refers to remaining monovalent radical after organic or inorganic oxyacid removes hydroxyl, general formula R-M
(O)-, wherein M is usually C.
Term " carbonyl " is the organo-functional group (C=O) being formed by connecting by two kinds of atoms of carbon and oxygen by double bond.
Term " alkanoyl " or " alkyl-carbonyl " refer to further by an alkyl-substituted carbonyl.Typical alkanoyl packet
Include but be not limited to acetyl group, propiono, bytyry, valeryl, caproyl etc..
Term " aryl carbonyl " refers to that carbonyl defined herein is replaced by aryl defined herein.
Term " optional " refers to that the one or more events described below may or may not occur, and the thing including generation
Both part and the event not occurred.Term " optionally replacing " or " substituted " refer to that mentioned group can be by one or more
A additional group replaces, and the additional group is respectively and independently selected from alkyl, naphthenic base, aryl, heteroaryl, heterocycle
Base, hydroxyl, alkoxy, cyano, halogen, amide groups, nitro, halogenated alkyl, amino, mesyl, alkyl-carbonyl, alkoxy carbonyl
Base, heteroaryl alkyl, hetercycloalkylalkyl, aminoacyl, amino protecting group etc..Wherein, amino protecting group is preferably selected from pivaloyl
Base, tertbutyloxycarbonyl, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, benzyl, to methoxybenzyl, allyloxycarbonyl and trifluoroacetyl group
Deng.
Terms used herein " tyrosine protein kinase (tyrosine protein kinase, TPK) " are a kind of catalysis
Upper γ-the phosphoric acid of ATP is transferred to the kinases on protein-tyrosine residue, can be catalyzed a variety of substrate protein white matter tyrosine residue phosphoric acid
Change, plays a significant role in cell growth, proliferation, differentiation.
" inhibition ", " inhibition " or " inhibitor " of terms used herein kinases, refers to that phosphate transferase activity is pressed down
System.
" metabolin " of compound disclosed herein is the derivative of the compound formed when the compound is metabolized.Art
Language " active metabolite " refers to the biologically active derivatives of the compound formed when the compound is metabolized.Art used herein
Language " is metabolized ", refers to the process of predetermined substance by organism transform summation (including but not limited to hydrolysis and by enzymatic
Reaction, such as oxidation reaction).Therefore, enzyme can produce specific structure and be changed into compound.For example, Cytochrome P450
It is catalyzed various oxidations and reduction reaction, while the glucuronic acid molecule of diphosphate glucose sweet acid based transferase catalytic activation is extremely
The conversion of aromatic alcohol, aliphatic alcohol, carboxylic acid, amine and free sulfydryl.The further information of metabolism can be from " The
Pharmacological Basis of Therapeutics ", the 9th edition, McGraw-Hill (1996) is obtained.It is disclosed herein
The metabolin of compound can be by giving compound to host and analyzing tissue sample from the host or by that will change
Object is closed to be incubated in vitro with liver cell and analyze gained compound to identify.Both methods is all known in the art.?
In some embodiments, the metabolin of compound be by oxidation process formed and it is corresponding with corresponding hydroxy-containing compounds.?
In some embodiments, compound is metabolized as pharmaceutical active metabolite.Terms used herein " adjusting ", refer to directly or
It connects and interacts with target, to change the activity of target, for example only, activity, suppression target including enhancing target
Activity, limit target target activity or the activity for extending target.
Terms used herein " target protein " refer to the protein molecule that can be combined by selective binding compounds or portion
Divide protein.In some embodiments, target protein is tyrosine kinase KIT (wild type or various mutation or combinations thereof), ABL
(wild type or various mutation or combinations thereof), EGFR (wild type or various mutation or combinations thereof), (wild type is various prominent by FLT3
Become or combinations thereof), VEGFR2 (wild type or various mutation or combinations thereof), RET (wild type or various mutation or combinations thereof),
PDGFR α (wild type or various mutation or combinations thereof), PDGFR β (wild type or various mutation or combinations thereof), BCR/ABL are (wild
Raw type or various mutation or combinations thereof), FGFR1 (wild type or various mutation or combinations thereof), (wild type is various prominent by FGFR2
Become or combinations thereof), FGFR3 (wild type or various mutation or combinations thereof), FGFR4 (wild type or various mutation or combinations thereof).
IC used herein50Refer to that the 50% of ceiling effect is obtained in the analysis for measuring such effect inhibits specific
Test amount, concentration or the dosage of compound.
EC used herein50Dosage, concentration or the amount for referring to measurement compound, particular assay compound is caused to induce,
The dose-dependant reaction of 50% maximum expression of stimulation or the specific reaction reinforced.
GI used herein50It is that the growth of 50% cell is instigated to be suppressed required drug concentration, i.e. drug makes 50% cell
The drug concentration when growth of (such as cancer cell) is inhibited or controls.
The novel kinase inhibitor of the present invention
The present invention provides a kind of Azaindole kinase inhibitors, compound or its pharmaceutically acceptable salt, solvent including formula (I)
Compound, ester, acid, metabolin or pro-drug:
Wherein, X is selected from
Y be selected from phenyl, thiophene -2- base, isoxazole -3- base, pyridin-3-yl, pyridin-4-yl, 2-Pyrrolidone -5- base,
N- methyl -2 (1H)-pyridone -5- base and furans -2- base;
R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3Group replace pyridin-3-yl, optionally
By R3Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces;
(R2)nIt indicates optionally by n independent R2Replaced substituent group, wherein n is the integer of 0-5, R2Independently selected from hydroxyl
Base, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Acylamino-, C1-6Alkyl amino, 4-
Methyl-imidazoles -1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl;
R5Selected from hydrogen and C1-6Alkyl amino.
In a preferred embodiment, kinase inhibitor of the invention includes the compound of formula (Ia) or its is pharmaceutically acceptable
Salt, solvate, ester, acid, metabolin or pro-drug:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3The pyridin-3-yl of group substitution,
Optionally by R3The phenyl that group replaces;
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Replaced substituent group, wherein n is
The integer of 0-5, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Alkyl amino, 4- methyl-
Imidazoles -1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl;
R5Selected from C1-6Alkyl amino.
In other preferred embodiment, kinase inhibitor of the invention includes the compound of formula (Ib) or its pharmacy can
Salt, solvate, ester, acid, metabolin or the pro-drug of receiving:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3The pyridin-3-yl of group substitution,
Optionally by R3Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces;
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Substituent group is taken
In generation, wherein n is the integer of 0-5, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6
Halogenated alkoxy, C2-6Acylamino-, C1-6Alkyl amino, 4- methyl-imidazoles -1- base,
R3Selected from C1-6Alkyl and
R4Selected from C1-6Alkyl;
R5Selected from hydrogen and C1-6Alkyl amino.
In the present invention, substituent group C1-6Alkyl is more preferably methyl, ethyl, isopropyl or tert-butyl, and halogen is more preferably
Fluorine or chlorine, C1-6Alkoxy is more preferably methoxyl group, C1-6Halogenated alkoxy is more preferably trifluoromethoxy, C1-6Halogenated alkyl is more
Preferably trifluoromethyl, C1-6Alkyl amino is more preferably dimethylamino, C2-6Acylamino- is more preferably acetyl group.
For each variable, any combination of above-mentioned group also among considering herein.It is to be understood that being mentioned herein
Substituent group and substitute mode on the compound of confession can be selected by those skilled in the art, in order to provide chemically stable
And can be used techniques known in the art and technology set forth herein synthesis compound.
Described herein is novel kinase inhibitor.The pharmaceutically acceptable salt, molten of this compound has been also described herein
Agent compound, ester, acid, pharmaceutical active metabolite and prodrug.
In other or further embodiment, by compound described herein give after organism in need
Its metabolism in vivo generates metabolin, and generated metabolin is subsequently used for generating desired effect, including desired therapeutic effect.
Compound described herein can be made into and/or be used as pharmaceutically acceptable salt.Pharmaceutically acceptable salt
Type includes but is not limited to: (1) acid-addition salts, by by the free alkali form of compound and pharmaceutically acceptable inorganic acid reaction
It is formed, described inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc.;Or formed with organic acid reaction, it is described
Organic acid for example acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, hydroxyacetic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid,
Succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3- (4- hydroxy benzoyl) benzoic acid, cortex cinnamomi
Acid, mandelic acid, Loprazolam, ethane sulfonic acid, 1,2- ethionic acid, 2- ethylenehydrinsulfonic acid, benzene sulfonic acid, toluenesulfonic acid, 4- methyl
Bicyclic-[2.2.2] oct-2-ene -1- formic acid, 2- naphthalene sulfonic acids, butylacetic acid, glucoheptonic acid, 4,4' methylene bis-(3- hydroxyl
Base -2- alkene -1- formic acid), 3- phenylpropionic acid, trimethylace tonitric, dodecyl sulphate, gluconic acid, glutamic acid, salicylic acid, hydroxyl
Naphthoic acid, stearic acid, muconic acid etc.;(2) base addition salts, the shape when acid proton in parent compound is replaced by metal ion
At, such as alkali metal ion (such as lithium, sodium, potassium), alkaline-earth metal ions (such as magnesium or calcium) or aluminium ion;Or match with organic base
Position.Acceptable organic base includes ethanol amine, diethanol amine, triethanolamine, trimethylamine, N- methyl glucose osamine, etc..It can connect
The inorganic base received includes aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide etc..
Various method analyses and identification can be used in the corresponding ion balance of pharmaceutically acceptable salt, the method includes
But be not limited to ion-exchange chromatography, ion chromatography, Capillary Electrophoresis, inductively coupled plasma body, atomic absorption spectrum, mass spectrum or
Any combination of them.
Recycle the salt using at least one of following technology: filtering is then filtered, solvent evaporation with non-solvent precipitation,
Or desivac is used in the case where aqueous solution.
Screening and characterize pharmaceutically acceptable salt, polymorphic and/or solvate can be used multiple technologies completion, described
Technology includes but is not limited to heat analysis, X-ray diffraction, spectrum, microscopy, elemental analysis.The various spectral techniques used
Including but not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).Various microscopies include but is not limited to IR
Microscopy and Raman (Raman) microscopy.
Pharmaceutical composition of the invention
The application also provides pharmaceutical composition, and it includes the compounds of at least one formula (I), (Ia) or (Ib) or described
Pharmaceutically acceptable salt, solvate, ester, acid, pharmaceutical active metabolite or the prodrug of compound and pharmaceutically acceptable load
The other therapeutic agents of body or excipient and person optionally.
Over the course for the treatment of, it according to circumstances can individually or with one or more other therapeutic agents be applied in combination.It can be with
By injecting, taking orally, suck, at least one of rectum and transdermal administration by the medicament administration comprising the compounds of this invention to suffering from
Person.Other therapeutic agents can be selected from following drug: immunosuppressor (such as tacrolimus, encircle rhzomorph, rapamycin, first
The ridge An Die, cyclophosphamide, imuran, mercaptopurine, mycophenolate or FTY720), glucocorticoids medicine (such as prednisone,
Cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydrogen hydroxyl prednisolone, times chlorine rice
Pine, fludrocortisone acetate, percorten, aldosterone), non-steroidal anti-inflammatory drugs (such as salicylate, aryl alkanoic acid,
2- arylpropionic acid, former times health class, examines former times class or sulphonanilid at N- aryl-anthranilic acid), allergic reaction bacterin, antihistamine
Medicine, anti-leukotriene medicine, beta-2-agonists, theophylline, anticholinergic agent or other selective kinase inhibitors (such as mTOR inhibitors, c-
Met inhibitor) or her2 antibody-drug.In addition, mentioned other therapeutic agents can also be rapamycin (Rapamycin),
Gram azoles replaces Buddhist nun (Crizotinib), tamoxifen, Raloxifene, Anastrozole, Exemestane, Letrozole, TrastuzumabTMIt is (bent appropriate
Pearl monoclonal antibody), GleevecTM(Imatinib), taxolTM(taxol), cyclophosphamide, Lovastatin, U.S. promise tetracycline
(Minosine), cytarabine, 5 FU 5 fluorouracil (5-FU), methotrexate (MTX) (MTX), taxotereTM(docetaxel), promise thunder
MoralTM(Goserelin), vincristine, vincaleukoblastinum, nocodazole, Teniposide, Etoposide, gemzarTM(gemcitabine), angstrom
Rich mycin (Epothilone), promise only sheet, camptothecine, daunorubicin (Daunonibicin), dactinomycin D, mitoxantrone, peace
Acridine, Doxorubicin (adriamycin), epirubicin or idarubicin.Alternatively, other therapeutic agents be also possible to cell because
Son such as G-CSF (granulocyte colony stimulating factor).Alternatively, other therapeutic agents are also possible to be such as, but not limited to, CMF (ring phosphorus
Amide, methotrexate (MTX) and 5 FU 5 fluorouracil), CAF (cyclophosphamide, adriamycin and 5 FU 5 fluorouracil), AC (sub- Baudrillard
Mycin and cyclophosphamide), FEC (5 FU 5 fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, ring phosphorus
Amide and taxol) or CMFP (cyclophosphamide, methotrexate (MTX), 5 FU 5 fluorouracil and prednisone).
In embodiments of the present invention, when treating according to the present invention to patient, the amount of given drug is depended on
Factors, such as specific dosage regimen, disease or implant treatment and its seriousness, subject in need for the treatment of or host
Unique (such as weight), still, according to specific ambient conditions, including for example used specific drug, administration route, control
The illness for the treatment of and the subject or host for the treatment of, administration dosage can routinely be determined by methods known in the art.In general,
For the dosage that adult treatment uses, administration dosage is typically at 0.02-5000mg/ days, for example, about 1-1500mg/ days models
It encloses.The required dosage is expressed as (or in a short time) one or be administered simultaneously or at interval appropriate in which can be convenient
Divided dose, such as daily two, three, four doses or more divided agent.It will be appreciated by persons skilled in the art that although giving
Dosage range is stated, but specific effective quantity can suitably be adjusted according to the case where patient and in conjunction with doctor diagnosed.
The purposes of drug of the invention
The compound or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or preceding of formula (I), (Ia) and (Ib)
The pharmaceutical composition of medicine or the compound including formula (I), (Ia) and (Ib) can be used for inhibiting tyrosine kinase KIT (wild type or
Various mutation or combinations thereof), ABL (wild type or various mutation or combinations thereof), EGFR (wild type or various mutation or its group
Close), FLT3 (wild type or various mutation or combinations thereof), VEGFR2 (wild type or various mutation or combinations thereof), RET it is (wild
Type or various mutation or combinations thereof), PDGFR α (wild type or various mutation or combinations thereof), (wild type is various prominent by PDGFR β
Become or combinations thereof), BCR/ABL (wild type or various mutation or combinations thereof), FGFR1 (wild type or various mutation or its group
Close), FGFR2 (wild type or various mutation or combinations thereof), FGFR3 (wild type or various mutation or combinations thereof), and/or
FGFR4 (wild type or various mutation or combinations thereof).
Preferably, the compound of the present invention and pharmaceutical composition are able to suppress tyrosine kinase KIT (especially saltant type
CKIT/T670I), BCR/ABL (especially saltant type BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 activity.
Therefore, the compound of the present invention and pharmaceutical composition can be used in treat or prevent KIT (especially saltant type cKIT/T670I),
BCR/ABL (especially saltant type BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 related disease.
Specifically, the compound of the present invention or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug,
And pharmaceutical composition can be used for treating or preventing one or more diseases selected from the following: solid tumor (including it is benign and dislike
Property type), especially sarcoma, gastrointestinal stromal tumor (Gastrointestinal Stromal Tumors, GIST), acute grain it is thin
Born of the same parents' leukaemia (Acute Myeloblastic Leukemia, AML), chronic myelogenous leukemia (Chronic Myelogenous
Leukemia, CML), celiothelioma, thyroid cancer (thyroid carcinoma), systemic mast cell disease, acidophic cell
Increase syndrome (HES), fibre modification, rheumatoid arthritis, panarthritis, chorionitis, lupus erythematosus, graft-versus-host
Sick (graft-versus-host disease, GVHD), neurofibroma, pulmonary hypertension, Alzheimer disease, seminoma,
Psoriasis, dysgerminoma, mast cell tumor, lung cancer, bronchiolar carcinoma, dysgerminoma, the formation of testis intraepithelial neoplasia, black
Plain tumor, breast cancer, neuroblastoma, mamillary/follicular thyroid cancer, malignant lymphoma, non-Hodgkin lymphoma, 2 types are more
The formation of hair property endocrine tumor, pheochromocytoma, thyroid cancer, parathyroid hyperplasia/adenoma, colon cancer, colorectal adenomas, ovum
Nest cancer, prostate cancer, spongioblastoma, brain tumor, glioblastoma, cancer of pancreas, malignant pleural mesothelioma, at blood vessel
Cytoma, hemangioma, kidney, liver cancer, adrenal, bladder cancer, gastric cancer, the carcinoma of the rectum, carcinoma of vagina, cervical carcinoma, carcinoma of endometrium,
Huppert's disease, neck and head tumor, arthritis, rheumatic arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammation
Property enteropathy, psoriasis arthropathica, osteoarthritis, Still disease (Still's disease), adolescent arthritis, diabetes,
Myasthenia gravis, Hashimoto thyroiditis (Hashimoto's thyroiditis), Order thyroiditis (Ord's
Hyroiditis), Graves disease (Graves'disease), rheumatoid arthritis syndrome (
Syndrome), multiple sclerosis, Guillain-Barre syndrome (Guillain-Barr é syndrome), acute disseminated brain ridge
Marrow inflammation, Addision's disease (Addison's disease), view property eye battle array it is twin-the twin syndrome of flesh battle array, ankylosing spondylitis, anti-phosphatide
Antibody Syndrome, alpastic anemia, oneself immunity hepatitis, chylous diarrhea (coeliac disease), Gourde(G) Paasche are thorough comprehensive
Simulator sickness (Goodpasture's syndrome), Idiopathic Thrombocytopenic Purpura, optic neuritis, chorionitis, primary gallbladder
Juice cirrhosis, Reiter syndrome (Reiter's syndrome), takayasu's arteritis (Takayasu's arteritis),
It is temporal arteritis, warm type autoimmune hemolytic anemia, Wegner's granulomatosis (Wegener's granulomatosis), complete
Body depilation, behcet disease (Behcet's disease), confirmed fatigue, familial dysautonomia, endometrium
Dystopy, interstitial cystitis, neuromyotonia, chorionitis, Vulvodynia, or combinations thereof.Particularly preferred treatment gastrointestinal stromal tumor,
Acute myeloblastic leukemia, chronic myelogenous leukemia, thyroid cancer, or combinations thereof.
The preparation of compound
Using Standard synthetic techniques well known by persons skilled in the art or using methods known in the art be described herein
Method combination, the compound of formula (I), (Ia) and (Ib) can be synthesized.In addition, solvent given herein, temperature and other anti-
Answer condition that can be changed according to art technology.As further guidance, synthetic method below also can use.
The reaction can use in order, to provide compound described herein;Or they can be used for synthesizing segment,
The segment is then added by method described herein and/or methods known in the art.
In some embodiments, it provided herein is the preparation sides of tyrosine kinase inhibitor compound described herein
Method and its application method.In some embodiments, the scheme synthesis of following synthesis can be used in compound described herein.It can
Compound is synthesized by using selectable starting material appropriate with following similar methods to use.
Starting material for synthesizing compound described herein can be synthesized or can obtain from commercial source.Herein
Technology well known by persons skilled in the art can be used to other related compounds with different substituents in the compound of description
And Material synthesis.The conventional method for preparing compound disclosed herein can come from reaction known in the art, and the reaction
It can be modified by the reagent and condition being deemed appropriate by those skilled in the art, it is each in the molecule of offer to be incorporated herein
Kind part.
If desired, routine techniques separation and purifying can be used in reaction product, including but not limited to filters, distills, knot
The methods of brilliant, chromatography.Conventional method characterization, including physical constant and spectrum data can be used in these products.
Using synthetic method described herein, compound disclosed herein is obtained with good yield and purity.According to herein
The compound of disclosed method preparation is purified by conventional method known in the art, such as filtering, recrystallization, chromatography, distillation
And combinations thereof.
Site on the aromatic moiety of the compound of formula (I), (Ia) and (Ib) may be easy to that various metabolism occur instead
It answers, therefore substituent group appropriate is introduced on aromatic ring structure, for example, only for example, halogen can restore, reduces or disappear
Except this metabolic pathway.
Embodiment
Non-limiting embodiment in detail below is to be interpreted as being merely illustrative, not limit in any way originally
It is open.Although without being described in further detail, it is believed that those skilled in the art can be based on description herein, completely benefit
Use the disclosure.
Embodiment 1:(E)-N1- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base)-N3- (3- tolyl) third
The synthesis of diamides
(E) -3- oxo -3- (3- (2- (2- pyridyl group) vinyl) -1- (and tetrahydro -2H- pyrans -2- base] -1H- indazole -6-
Base) amino)-methyl propionate (1b): (E) -3- (2- (pyridine -2- base) vinyl) -1- (tetrahydro -2H- is added in round-bottomed flask
Pyrans -2- base) anhydrous methylene chloride (100 milliliters), triethylamine (6.8 milliliters) is added in -1H- indazole -6- amine (10.0 grams) afterwards, so
System is set to be cooled to 0 degree with ice-water bath afterwards.Then methylmalonate list acyl chlorides (3.9 milliliters) are slowly added to.Reaction system is in room
Under temperature, argon gas protection reaction 14 hours.After reaction, system solvent evaporated under reduced pressure, gains be diluted with water after with two
Chloromethanes extraction.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, decompression
Crude Compound 1b is obtained after being evaporated.LC/MS:M+H 421.18.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.62
(s, 1H), 8.22 (s, 1H), 8.15 (d, J=8.5Hz, 1H), 7.86 (dd, J=24.7,13.4Hz, 2H), 7.69 (d, J=
7.3Hz, 1H), 7.58 (d, J=16.4Hz, 1H), 7.31 (d, J=8.5Hz, 2H), 5.76 (s, 1H), 3.92 (d, J=
10.0Hz, 1H), 3.69 (s, 4H), 3.56 (s, 2H), 2.43 (d, J=11.1Hz, 1H), 2.03 (s, 2H), 1.80 (s, 1H),
1.61(s,2H)。
(E) -3- oxo -3- (3- (2- (2- pyridyl group) vinyl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6-
Base) amino) propionic acid (1c): (E) -3- oxo -3- (3- (2- (2- pyridyl group) vinyl) -1- (four is added in round-bottomed flask
Hydrogen -2H- pyrans -2- base] -1H- indazole -6- base) amino) tetrahydrofuran (40 milliliters), water (40 is added in-methyl propionate (8 grams) afterwards
Milliliter), lithium hydroxide (2.5 grams).Reaction system at room temperature, argon gas protection reaction 4 hours.After reaction, system is subtracting
Solvent evaporated is depressed, it is 3-5 that gains, which are neutralized to pH with the dilute hydrochloric acid of 1 mol/L, there is solid precipitation.Water phase is filtered to obtain analysis
Solid out obtains crude Compound 1c after solid is dry.LC/MS:M+H407.17.1H NMR(400MHz,DMSO-d6)δ10.46
(s, 1H), 8.62 (s, 1H), 8.24 (s, 1H), 8.14 (d, J=8.5Hz, 1H), 8.00-7.79 (m, 2H), 7.71 (d, J=
7.2Hz, 1H), 7.59 (d, J=16.3Hz, 1H), 7.33 (d, J=9.3Hz, 2H), 5.77 (d, J=8.6Hz, 1H), 3.92
(d, J=9.7Hz, 1H), 3.73 (s, 1H), 3.63 (s, 2H), 2.44 (d, J=10.5Hz, 1H), 2.03 (s, 2H), 1.79 (s,
1H),1.60(s,2H)。
(E)-N1- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base)-N3- (3- tolyl) malonamide
(1): (E) -3- oxo -3- (3- (2- (2- pyridyl group) vinyl) -1- (tetrahydro -2H- pyrans -2- being added in round-bottomed flask
Base) -1H- indazole -6- base) amino) N,N-dimethylformamide (5 milliliters), meta-aminotoluene (27 is added in propionic acid (100 milligrams) afterwards
Milligram), 2- (7- aoxidize benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (120 milligrams) and triethylamine (0.05
Milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, gained
Object is extracted with ethyl acetate after being diluted with water.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Have
Machine obtains crude product mutually through filtering, after evaporated under reduced pressure and is dissolved in anhydrous methylene chloride (5 milliliters), is added trifluoroacetic acid (1 milliliter).Reactant
System is stirred at room temperature 14 hours under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, after gains are diluted with water
PH > 10 are neutralized to saturated sodium bicarbonate solution.Water phase is extracted with ethyl acetate, and organic phase uses water, saturated common salt washing respectively
It is dry with anhydrous sodium sulfate after washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.After the pressurized silica gel column chromatography purification of crude product
Obtain embodiment compound 1.LC/MS:M+H 412.16.1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),10.43(s,
1H), 10.16 (s, 1H), 8.62 (s, 1H), 8.18 (d, J=24.7Hz, 2H), 7.86 (d, J=33.3Hz, 2H), 7.68 (s,
1H),7.48(s,3H),7.23(s,3H),6.92(s,1H),3.54(s,2H),2.30(s,3H)。
Embodiment 2:(E)-N1- (4- fluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third
Diamides
The synthesis of 2 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M
+1)+:416.14。
Embodiment 3:(E)-N1- phenyl-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) malonamide
The synthesis of 3 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M
+1)+:398.15。
Embodiment 4:(E)-N1- (3- fluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third
Diamides
The synthesis of 4 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M
+1)+:416.14。
Embodiment 5:(E)-N1- (4- ((4- methyl piperazine base -1- base) methyl) phenyl)-N3- (3- (2- (2- pyridyl group)
Vinyl) -1H- indazole -6- base) malonamide
The synthesis of 5 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M
+1)+:510.25。
Embodiment 6:(E)-N1- (4- chlorphenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third
Diamides
The synthesis of 6 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M
+1)+:432.11。
Embodiment 7:(E)-N1- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base)-N3- (thiophene -2- Ji Jia
Base) malonamide
The synthesis of 7 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M
+1)+:418.12。
Embodiment 8:(E)-N1- (3- bromophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third
Diamides
The synthesis of 8 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M
+1)+:476.06。
Embodiment 9:(E)-N1- (3- chlorphenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third
Diamides
The synthesis of 9 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z(M
+1)+:432.11。
Embodiment 10:(E)-N1- (3 (4- methylpiperazine-1-yl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)-
1H- indazole -6- base) malonamide
The synthesis of 10 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:496.23。
Embodiment 11:(E)-N1- (the chloro- 4- fluorophenyl of 3-)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6-
Base) malonamide
The synthesis of 11 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:450.10。
Embodiment 12:(E)-N1- (3- (dimethylamino) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- Yin
Azoles -6- base) malonamide
The synthesis of 12 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:441.19。
Embodiment 13:(E)-N1- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base)-N3- (3,4,5- front three
Phenyl) malonamide
The synthesis of 13 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:488.18。
Embodiment 14:(E)-N1- (3- methoxyphenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6-
Base) malonamide
The synthesis of 14 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:428.16。
Embodiment 15:(E)-N1- (4- ((4- ethyl piperazidine -1- base) methyl) -3- (trifluoromethyl) phenyl)-N3- (3-
(2- (2- pyridyl group) vinyl) -1H- indazole -6- base) malonamide
The synthesis of 15 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:592.25。
Embodiment 16:(E)-N1- (4- ((4- isopropyl piperazine -1- base) methyl) -3- (trifluoromethyl) phenyl)-N3- (3-
(2- (2- pyridyl group) vinyl) -1H- indazole -6- base) malonamide
The synthesis of 16 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:606.27。
Embodiment 17:(R, E)-N1- (4- ((3- (dimethylamino) pyrrolidin-1-yl) methyl) -3- (trifluoromethyl) benzene
Base)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) malonamide
The synthesis of 17 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:692.26。
Embodiment 18:(E)-N1- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base)-N3- (3- trifluoromethyl
Phenyl) malonamide
The synthesis of 18 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:466.14。
Embodiment 19:(E)-N1- (2- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)-
1H- indazole -6- base) malonamide
The synthesis of 19 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:484.13。
Embodiment 20:(E)-N1- (2- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)-
1H- indazole -6- base) malonamide
The synthesis of 20 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:484.13。
Embodiment 21:(E)-N1- (2- chloro- 5- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)-
1H- indazole -6- base) malonamide
The synthesis of 21 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:500.10。
Embodiment 22:(E)-N1- (3- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)-
1H- indazole -6- base) malonamide
The synthesis of 22 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:484.13。
Embodiment 23:(E)-N1- (2,3- difluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6-
Base) malonamide
The synthesis of 23 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:434.13。
Embodiment 24:(E)-N1- (2- chlorphenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6- base) third
Diamides
The synthesis of 24 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:432.11。
Embodiment 25:(E)-N1- (2,3,4- trifluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -
6- yl) malonamide
The synthesis of 25 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:452.12。
Embodiment 26:(E)-N1- (3,5- difluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6-
Base) malonamide
The synthesis of 26 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:434.13。
Embodiment 27:(E)-N1- (3,4- difluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6-
Base) malonamide
The synthesis of 27 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:434.13。
Embodiment 28:(E)-N1- (2,3,4,5,6- pentafluorophenyl group)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- Yin
Azoles -6- base) malonamide
The synthesis of 28 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:488.10。
Embodiment 29:(E)-N1- (2- fluoro- 4- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)-
1H- indazole -6- base) malonamide
The synthesis of 29 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:484.13。
Embodiment 30:(E)-N1- (2,4 difluorobenzene base)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6-
Base) malonamide
The synthesis of 30 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:434.13。
Embodiment 31:(E)-N1- (2- chloro- 3- (trifluoromethyl) phenyl)-N3- (3- (2- (2- pyridyl group) vinyl)-
1H- indazole -6- base) malonamide
The synthesis of 31 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:500.10。
Embodiment 32:(E)-N1- (2,5- difluorophenyl)-N3- (3- (2- (2- pyridyl group) vinyl) -1H- indazole -6-
Base) malonamide
The synthesis of 32 compound of embodiment is completed by using the step of being similar to described in embodiment 1.MS(ESI)m/z
(M+1)+:434.13。
The synthesis of embodiment 33:N1- (3- chlorphenyl)-N3- (1H- indazole -6- base) malonamide
6- nitro -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (2b): 6- nitro -1H- Yin is added in round-bottomed flask
Tetrahydrofuran (40 milliliters), 3,4- dihydro -2H- pyrans (80 grams) and methanesulfonic acid (89 microlitres) is added in azoles (1.5 grams) afterwards.Reactant
System is heated to back flow reaction 14 hours under protection of argon gas.After reaction, system solvent evaporated under reduced pressure, gains water
It is extracted with ethyl acetate after dilution.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase warp
It filters, crude product 2b is obtained after evaporated under reduced pressure.LC/MS:M+H 248.09.
6- amino -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (2c): compound 6- nitro -1- is added in methyl alcohol
(tetrahydro -2H- pyrans -2- base) -1H- indazole (1.5 grams), adds palladium/carbon (64 milligrams), is stirred at room temperature 4 hours under atmosphere of hydrogen.Silicon
Diatomaceous earth filtering, filtrate decompression obtain crude product 2c after being evaporated.LC/MS:M+H 218.12.
3- oxo -3- ((1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) methyl propionate (2d): in circle
6- amino -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (1 gram) is added in the flask of bottom, anhydrous methylene chloride (30 millis are added afterwards
Rise), triethylamine (1 milliliter), then so that system is cooled to 0 degree with ice-water bath.Then it is slowly added to methylmalonate list acyl chlorides
(0.6 milliliter).Reaction system at room temperature, argon gas protection reaction 14 hours.After reaction, system is evaporated molten under reduced pressure
Agent, gains are extracted with dichloromethane after being diluted with water.Organic phase is respectively with using anhydrous sodium sulfate after water, saturated common salt water washing
It is dry.Organic phase obtains crude product 2d through filtering after evaporated under reduced pressure.LC/MS:M+H 318.13.
3- oxo -3- ((1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) propionic acid (2e): by 3- oxo -
3- ((1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) (1 gram) addition tetrahydrofuran (10 milliliters) of methyl propionate
With water (10 milliliters), lithium hydroxide (0.7 gram) then is added.Reaction system at room temperature, argon gas protection reaction 4 hours.Reaction
After, system solvent evaporated under reduced pressure, gains, which are neutralized to pH 3-5 with the dilute hydrochloric acid of 1 mol/L, solid precipitation.Water
It is mutually filtered to be precipitated solid, obtains crude product 2e after solid is dry.LC/MS:M+H 304.12.
N1- (3- chlorphenyl)-N3- (1H- indazole -6- base) malonamide (33): 3- oxo -3- is added in round-bottomed flask
N,N-dimethylformamide is added in ((1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) propionic acid (50 milligrams) afterwards
(5 milliliters), m-chloroaniline (25 milligrams), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (94
Milligram) and triethylamine (0.05 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, system exists
Lower solvent evaporated is depressurized, gains are extracted with ethyl acetate after being diluted with water.After organic phase uses water, saturated common salt water washing respectively
It is dry with anhydrous sodium sulfate.Organic phase obtains crude product through filtering, after evaporated under reduced pressure and is dissolved in anhydrous methylene chloride (5 milliliters), is added three
Fluoroacetic acid (1 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, system is evaporated under reduced pressure
Solvent, gains with saturated sodium bicarbonate solution are neutralized to pH > 10 after being diluted with water.Water phase is extracted with ethyl acetate, organic phase
Respectively with dry with anhydrous sodium sulfate after water, saturated common salt water washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Crude product
Sterling compound 33 is obtained after pressurized silica gel column chromatography purification.LC/MS:329.07.
Embodiment 34:N1- (4- ((4- ethyl piperazidine -1- base) methyl) -3- (trifluoromethyl) phenyl)-N3- (1H- indazole -
6- yl) malonamide
The synthesis of 34 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:489.21。
Embodiment 35:N1- (1H- indazole -6- base)-N3- malonamide
The synthesis of 35 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:294.11。
Embodiment 36:N1- (3- fluorophenyl)-N3- (1H- indazole -6- base) malonamide
The synthesis of 36 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:313.10。
Embodiment 37:N1- (1H- indazole -6- base)-N3- (3- (4- methylpiperazine-1-yl) phenyl) malonamide
The synthesis of 37 compound of embodiment is completed by using the step of being similar to described in embodiment 33.
MS(ESI)m/z(M+1)+:393.19。
Embodiment 38:N1- (1H- indazole -6- base)-N3- (3,4,5- trimethoxyphenyl) malonamide
The synthesis of 38 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:385.14。
Embodiment 39:N1- (the chloro- 4- fluorophenyl of 3-)-N3- (1H- indazole -6- base) malonamide
The synthesis of 39 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:347.06。
Embodiment 40:N1- (3- (dimethylamino) phenyl)-N3- (1H- indazole -6- base) malonamide
The synthesis of 40 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:338.15。
Embodiment 41:N1- (1H- indazole -6- base)-N3- (3- methoxyphenyl) malonamide
The synthesis of 41 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:325.12。
Embodiment 42:N1- (4- chlorphenyl)-N3- (3- methyl-1 H- indazole -6- base) malonamide
The synthesis of 42 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:343.08。
Embodiment 43:N1- (3- fluorophenyl)-N3- (3- methyl-1 H- indazole -6- base) malonamide
The synthesis of 43 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:327.11。
Embodiment 44:N1- (3- methyl-1 H- indazole -6- base)-N3- (3- (trifluoromethyl) phenyl) malonamide
The synthesis of 44 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:377.11。
Embodiment 45:N1- (4- chloro- 3- (trifluoromethyl) phenyl)-N3- (3- methyl-1 H- indazole -6- base) malonamide
The synthesis of 45 compound of embodiment is completed by using the step of being similar to described in embodiment 33.MS(ESI)m/z
(M+1)+:411.07。
The synthesis of embodiment 46:N1- phenyl-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
6- nitro -3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (3b): add in round-bottomed flask
Enter the iodo- 6- nitro -1- of 3- (tetrahydro -2H- pyrans -2- base) -1H- indazole (5 grams) be added afterwards 1,4- dioxane (100 milliliters),
Water (20 milliliters), 3- pyridine boronic acid (2.7 grams), Pd (Ph3P)4(0.7 gram) and potassium carbonate (5.5 grams).Reaction system is protected in argon gas
80 DEG C are heated under shield to react 14 hours.After reaction, solvent evaporated, gains use second after being diluted with water to system under reduced pressure
Acetoacetic ester extraction.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, decompression
Crude product is obtained after being evaporated.Sterling 3b is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H 325.12.
6- amino -3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (3c): additionization in methyl alcohol
Close object 6- nitro -3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (3 grams), palladium/carbon (97 milligrams), hydrogen
Atmosphere is stirred at room temperature 4 hours under enclosing.Diatomite filtering, filtrate decompression obtain crude product 3c after being evaporated.LC/MS:M+H 295.15.
3- oxo -3- ((pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) propionic acid first
Ester (3d): 6- amino -3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (1 is added in round-bottomed flask
Gram) anhydrous methylene chloride (30 milliliters), triethylamine (0.7 milliliter) are added afterwards, then so that system is cooled to 0 degree with ice-water bath.It connects
Be slowly added to methylmalonate list acyl chlorides (0.4 milliliter).Reaction system at room temperature, argon gas protection reaction 14 hours.Reaction
After, solvent evaporated, gains are extracted with dichloromethane system after being diluted with water under reduced pressure.Organic phase with respectively with water,
It is dry with anhydrous sodium sulfate after saturated common salt water washing.Organic phase obtains crude product 3d through filtering after evaporated under reduced pressure.LC/MS:M+H
395.16。
3- oxo -3- ((pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) propionic acid
(3e): by 3- oxo -3- ((pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) methyl propionate
Then lithium hydroxide (0.6 gram) is added in (1 gram) addition tetrahydrofuran (10 milliliters) and water (10 milliliters).Reaction system is in room temperature
Under, argon gas protection reaction 4 hours.After reaction, system solvent evaporated under reduced pressure, the dilute hydrochloric acid of 1 mol/L of gains
Being neutralized to pH 3-5 has solid precipitation.Water phase is filtered to be precipitated solid, obtains crude product 3e after solid is dry.LC/MS:M+H
381.14。
N1- phenyl-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide (46): it is added in round-bottomed flask
3- oxo -3- ((pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) amino) after propionic acid (50 milligrams)
N,N-dimethylformamide (5 milliliters), aniline (16 milligrams), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethyl is added
Base urea hexafluorophosphoric acid ester (75 milligrams) and triethylamine (0.05 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.
After reaction, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase is used respectively
It is dry with anhydrous sodium sulfate after water, saturated common salt water washing.Organic phase obtains crude product through filtering, after evaporated under reduced pressure and is dissolved in anhydrous dichloro
Methane (5 milliliters) is added trifluoroacetic acid (1 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.Reaction terminates
Afterwards, system solvent evaporated under reduced pressure, gains with saturated sodium bicarbonate solution are neutralized to pH > 10 after being diluted with water.Water phase is used
Ethyl acetate extraction, organic phase are dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, and is subtracted
Pressure obtains crude product after being evaporated.Sterling compound 46 is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:372.13.
Embodiment 47:N1- (3- fluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 47 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:390.39。
Embodiment 48:N1- (4- chloro- 3- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third
Diamides
The synthesis of 48 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:474.84。
Embodiment 49:N1- (5- (tert-butyl) isoxazole -3- base)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third
Diamides
The synthesis of 49 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:419.45。
Embodiment 50:N1- (3- (4- methyl-1 H-imidazole-1-group) -5- (trifluoromethyl) phenyl)-N3- (3- (pyridine -3-
Base) -1H- indazole -6- base) malonamide
The synthesis of 50 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:520.48。
Embodiment 51:N1- (3- (pyridin-3-yl) -1H- indazole -6- base)-N3- (3- (trifluoromethyl) phenyl) malonyl
Amine
The synthesis of 51 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:540.39。
Embodiment 52:N1- (2- fluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide.
The synthesis of 52 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:390.39。
Embodiment 53:N1- (the chloro- 4- fluorophenyl of 3-)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 53 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:424.83。
Embodiment 54:N1- (4- methoxyl group -3- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6-
Base) malonamide
The synthesis of 54 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:470.42。
Embodiment 55:N1- (2,6- difluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 55 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:408.38。
Embodiment 56:N1- (2- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third
Diamides
The synthesis of 56 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:458.11。
Embodiment 57:N1- (3- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third
Diamides
The synthesis of 57 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:458.11。
Embodiment 58:N1- (2,3,4- trifluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 58 compound of compound is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:426.11。
Embodiment 59:N1- (2,3- difluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 59 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:408.12。
Embodiment 60:N1- (3,5- difluorophenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 60 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:408.12。
Embodiment 61:N1- (3- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third
Diamides
The synthesis of 61 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:458.11。
Embodiment 62:N1- (2- chloro- 5- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third
Diamides
The synthesis of 62 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:474.09。
Embodiment 63:N1- (4- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third
Diamides
The synthesis of 63 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:458.11。
Embodiment 64:N1- (4- chlorphenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) malonamide
The synthesis of 64 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:406.10。
Embodiment 65:N1- (2- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (pyridin-3-yl) -1H- indazole -6- base) third
Diamides
The synthesis of 65 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:458.12。
Embodiment 66:N1- (the chloro- 4- fluorophenyl of 3-)-N3- (3- (3- fluorophenyl) -1H- indazole -6- base) malonamide
The synthesis of 66 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:441.06。
Embodiment 67:N1- (4- chloro- 3- (trifluoromethyl) phenyl)-N3- (3- (3- fluorophenyl) -1H- indazole -6- base) third
Diamides
The synthesis of 67 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:491.08。
Embodiment 68:N1- (4- chlorphenyl)-N3- (3- (3- fluorophenyl) -1H- indazole -6- base) malonamide
The synthesis of 68 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:423.09。
Embodiment 69:N1- (3- fluorophenyl)-N3- (3- (3- fluorophenyl) -1H- indazole -6- base) malonamide
The synthesis of 69 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:407.12。
Embodiment 70:N1- (3- (3- fluorophenyl) -1H- indazole -6- base)-N3- (3- (4- methyl-1 H-imidazole-1-group) -
5- (trifluoromethyl) phenyl) malonamide
The synthesis of 70 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:537.15。
Embodiment 71:N1- (3- (3- fluorophenyl) -1H- indazole -6- base)-N3- (m- tolyl) malonamide
The synthesis of 71 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:403.14。
Embodiment 72:N1- (3- (4- methyl-1 H-imidazole-1-group) -5- (trifluoromethyl) phenyl)-N3- (3- (4- (4- first
Base piperazine -1- base) phenyl) -1H- indazole -6- base) malonamide
The synthesis of 72 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:617.61。
Embodiment 73:N1- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- base)-N3- (3- (fluoroform
Base) phenyl) malonamide
The synthesis of 73 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:537.55。
Embodiment 74:N1- (2- fluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- base)
Malonamide
The synthesis of 74 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:487.55。
Embodiment 75:N1- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- base)-N3- (m- tolyl)
Malonamide
The synthesis of 75 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:483.58。
Embodiment 76:N1- (3- fluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6- base)
Malonamide
The synthesis of 76 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:487.55。
Embodiment 77:N1- (2- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)-
1H- indazole -6- base) malonamide
The synthesis of 77 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:555.54。
Embodiment 78:N1- (2- chloro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)-
1H- indazole -6- base) malonamide
The synthesis of 78 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:572.00。
Embodiment 79:N1- (4- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)-
1H- indazole -6- base) malonamide
The synthesis of 79 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:555.55。
Embodiment 80:N1- (2,6- difluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6-
Base) malonamide
The synthesis of 80 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:505.54。
Embodiment 81:N1- (2- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)-
1H- indazole -6- base) malonamide
The synthesis of 81 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:555.55。
Embodiment 82:N1- (the chloro- 4- fluorophenyl of 3-)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -
6- yl) malonamide
The synthesis of 82 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:521.99。
Embodiment 83:N1- (3- chloro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)-
1H- indazole -6- base) malonamide
The synthesis of 83 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:571.17。
Embodiment 84:N1- (2,3,4- trifluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -
6- yl) malonamide
The synthesis of 84 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:523.20。
Embodiment 85:N1- (2,3- difluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6-
Base) malonamide
The synthesis of 85 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:505.54。
Embodiment 86:N1- (3,5- difluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6-
Base) malonamide
The synthesis of 86 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:505.54。
Embodiment 87:N1- (3,4- difluorophenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl) -1H- indazole -6-
Base) malonamide
The synthesis of 87 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:505.54。
Embodiment 88:N1- (3- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- (4- methylpiperazine-1-yl) phenyl)-
1H- indazole -6- base) malonamide
The synthesis of 88 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:555.55。
Embodiment 89:N1- (3- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl)
Phenyl) -1H- indazole -6- base) malonamide
The synthesis of 89 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:567.22。
Embodiment 90:N1- (4- chloro- 3- (trifluoromethyl) phenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl)
Phenyl) -1H- indazole -6- base) malonamide
The synthesis of 90 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:585.19。
Embodiment 91:N1- (2,3- difluorophenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -1H-
Indazole -6- base) malonamide
The synthesis of 91 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:519.22。
Embodiment 92:N1- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -1H- indazole -6- base)-N3- is (m-
Tolyl) malonamide
The synthesis of 92 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:497.25。
Embodiment 93:N1- (2- fluorophenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -1H- indazole -
6- yl) malonamide
The synthesis of 93 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:501.23。
Embodiment 94:N1- (3- fluorophenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -1H- indazole -
6- yl) malonamide
The synthesis of 94 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:501.23。
Embodiment 95:N1- (4- fluoro- 3- (trifluoromethyl) phenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl)
Phenyl) -1H- indazole -6- base) malonamide
The synthesis of 95 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:569.22。
Embodiment 96:N1- (2- fluoro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl)
Phenyl) -1H- indazole -6- base) malonamide
The synthesis of 96 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:569.22。
Embodiment 97:N1- (3- chloro- 5- (trifluoromethyl) phenyl)-N3- (3- (4- ((4- methylpiperazine-1-yl) methyl)
Phenyl) -1H- indazole -6- base) malonamide
The synthesis of 97 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:585.19。
Embodiment 98:N1- (3- (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -1H- indazole -6- base)-N3- phenyl
Malonamide
The synthesis of 98 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:483.24。
Embodiment 99:N1- (3- (3- carbamoyl) phenyl -1H- indazole -6- base)-N3- (chloro- 5- of 3- (trifluoromethyl)
Phenyl) malonamide
The synthesis of 99 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/z
(M+1)+:516.09。
Embodiment 100:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (4- chloro- 3- (trifluoromethyl) benzene
Base) malonamide
The synthesis of 100 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:516.09。
Embodiment 101:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (m- tolyl) malonamide
The synthesis of 101 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:428.16。
Embodiment 102:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2- fluorophenyl) malonamide
The synthesis of 102 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:432.13。
Embodiment 103:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (4- fluoro- 3- (trifluoromethyl) benzene
Base) malonamide
The synthesis of 103 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:500.12。
Embodiment 104:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (3- fluoro- 5- (trifluoromethyl) benzene
Base) malonamide
The synthesis of 104 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:500.12。
Embodiment 105:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2,3- difluorophenyl) malonyl
Amine
The synthesis of 105 compound of compound is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:450.13。
Embodiment 106:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2- fluoro- 5- (trifluoromethyl) benzene
Base) malonamide
The synthesis of 106 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:500.13。
Embodiment 107:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2,3,4- trifluorophenyl) the third two
Amide
The synthesis of 107 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:468.12。
Embodiment 108:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (3,5- difluorophenyl) malonyl
Amine
The synthesis of 108 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:450.13。
Embodiment 109:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (3- fluorophenyl) malonamide
The synthesis of 109 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:432.14。
Embodiment 110:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (3- (trifluoromethyl) phenyl) third
Diamides
The synthesis of 110 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:482.13。
Embodiment 111:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2- chloro- 5- (trifluoromethyl) benzene
Base) malonamide
The synthesis of 111 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:516.10。
Embodiment 112:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (the chloro- 4- fluorophenyl of 3-) malonyl
Amine
The synthesis of 112 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:466.10。
Embodiment 113:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (4- methoxyl group -3- (fluoroform
Base) phenyl) malonamide
The synthesis of 113 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:512.14。
Embodiment 114:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (3- (4- methyl-1 H- imidazoles -1-
Base) -5- (trifluoromethyl) phenyl) malonamide
The synthesis of 114 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:562.17。
Embodiment 115:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2,6- difluorophenyl) malonyl
Amine
The synthesis of 115 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:550.13。
Embodiment 116:N1- (5- (tert-butyl) isoxazole -3- base)-N3- (3- (3- aminoacyl) phenyl -1H- indazole -6-
Base) malonamide
The synthesis of 116 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:461.18。
Embodiment 117:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (4- chlorphenyl) malonamide
The synthesis of 117 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:448.10。
Embodiment 118:N1- (3- (3- aminoacyl) phenyl -1H- indazole -6- base)-N3- (2- fluoro- 3- (trifluoromethyl) benzene
Base) malonamide
The synthesis of 118 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:500.13。
Embodiment 119:N1- (3- fluorophenyl)-N3- (3- (6- picoline -3- base) -1H- indazole -6- base) malonamide
The synthesis of 119 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:404.14。
Embodiment 120:N1- (4- methoxyl group -3- (trifluoromethyl) phenyl)-N3- (3- (6- picoline -3- base) -1H-
Indazole -6- base) malonamide
The synthesis of 120 compound of embodiment is completed by using the step of being similar to described in embodiment 46.MS(ESI)m/
z(M+1)+:484.15。
Embodiment 121:(E)-N- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) ethyl) cigarette
The synthesis of amide
(E) -2- ((3- (2- (pyridine -2- base) vinyl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base)
Sulphur) ethyl -1- amine (4c): the iodo- 3- of (E) -6- [2- (pyridine -2- base) vinyl] -1- (tetrahydro -2H- is added in round-bottomed flask
Pyrans -2- base) DMAC N,N' dimethyl acetamide (20 milliliters), 2- aminoothyl mercaptan (1.1 grams), Pd is added in -1H- indazole (5 grams) afterwards
(OAc)2(0.3 gram) and 9,9- dimethyl -4,5- double diphenylphosphine xanthenes (0.8 gram), N, N- diisopropylethylamine (6.5 millis
It rises).Reaction system is heated to 150 DEG C under protection of argon gas and reacts 2 hours.After reaction, system solvent evaporated under reduced pressure,
Gains are extracted with ethyl acetate after being diluted with water.Organic phase is done after using water, saturated common salt water washing respectively with anhydrous sodium sulfate
It is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Sterling 4c is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H
381.16。
(E)-N- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) ethyl) niacinamide (121):
(E) -2- ((3- (2- (pyridine -2- base) vinyl) -1- (tetrahydro -2H pyrans -2- base) -1H- indazole-is added in round-bottomed flask
6- yl) sulphur) ethyl -1- amine (50 milligrams) be added afterwards N,N-dimethylformamide (5 milliliters), niacin (19 milligrams), 2- (7- oxidation
Benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (75 milligrams) and triethylamine (0.04 milliliter).Reaction system exists
It is stirred at room temperature 14 hours under argon gas protection.After reaction, solvent evaporated, gains use second after being diluted with water to system under reduced pressure
Acetoacetic ester extraction.Organic phase is dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, decompression
Crude product is obtained after being evaporated to be dissolved in anhydrous methylene chloride (5 milliliters), is added trifluoroacetic acid (1 milliliter).Reaction system is under protection of argon gas
It is stirred at room temperature 14 hours.After reaction, solvent evaporated, gains use saturated sodium bicarbonate after being diluted with water to system under reduced pressure
Solution is neutralized to pH > 10.Water phase is extracted with ethyl acetate, and organic phase is respectively with using anhydrous slufuric acid after water, saturated common salt water washing
Sodium is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Sterling compound is obtained after the pressurized silica gel column chromatography purification of crude product
121.LC/MS:M+H 402.13.
Embodiment 122:(E) -5- oxo-N- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)
Ethyl) pyrrolidines -2- formamide
The synthesis of 122 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI)
m/z(M+1)+:408.14。
Embodiment 123:(E) -1- methyl -2- oxo-N- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6-
Base) sulphur) ethyl) -1,2- dihydropyridine -3- formamide
The synthesis of 123 compound of compound is completed by using the step of being similar to described in embodiment 121.MS(ESI)
m/z(M+1)+:432.14。
Embodiment 124:(E) -1- (3,4- difluorophenyl) -3- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- Yin
Azoles -6- base) sulphur) ethyl) and urea synthesis
(E) -2- ((3- (2- (pyridine -2- base) vinyl) -1- (tetrahydro -2H- pyrans -2- is added in round-bottomed flask
Base) -1H- indazole -6- base) sulphur) methylene chloride (5 milliliters), 3,4- difluorophenyl isocyanic acid is added in ethyl -1- amine (50 milligrams) afterwards
Ester (23 milligrams).Trifluoroacetic acid (1 milliliter) is added after being stirred at room temperature under protection of argon gas 14 hours in reaction system.Reaction system after
It is continuous to be stirred at room temperature under protection of argon gas 14 hours.After reaction, system solvent evaporated under reduced pressure, after gains are diluted with water
PH > 10 are neutralized to saturated sodium bicarbonate solution.Water phase is extracted with ethyl acetate, and organic phase uses water, saturated common salt washing respectively
It is dry with anhydrous sodium sulfate after washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.After the pressurized silica gel column chromatography purification of crude product
Obtain sterling compound 124.LC/MS:M+H 452.12.
Embodiment 125:(E) -1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- ((3- (2- (pyridine -2- base) ethylene
Base) -1H- indazole -6- base) sulphur) ethyl) urea
The synthesis of 125 compound of embodiment is completed by using the step of being similar to described in embodiment 124.MS(ESI)
m/z(M+1)+:518.09。
Embodiment 126:(E) -1- (2- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) ethyl) -3-
(3- (trifluoromethyl) phenyl) urea
The synthesis of 126 compound of embodiment is completed by using the step of being similar to described in embodiment 124.MS(ESI)
m/z(M+1)+:484.13。
Embodiment 127:(E) -4- ((4- methylpiperazine-1-yl) methyl)-N- (3- ((3- (2- (pyridine -2- base) ethylene
Base) -1H- indazole -6- base) sulphur) propyl) -3- (trifluoromethyl) benzamide
The synthesis of 127 compound of compound is completed by using the step of being similar to described in embodiment 121.MS(ESI)
m/z(M+1)+:595.23。
Embodiment 128:(E)-N- (3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propyl) furan
It mutters -2- formamide
The synthesis of 128 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI)
m/z(M+1)+:405.48。
Embodiment 129:(E)-N- (3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propyl) benzene
Amide
The synthesis of 129 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI)
m/z(M+1)+:401.13。
Embodiment 130:(E) -2- hydroxy-n-(3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)
Propyl) Pyrazinamide
The synthesis of 130 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI)
m/z(M+1)+:432.51。
Embodiment 131:(E) the chloro- N- of -4- (3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) third
Base) -3- (trifluoromethyl) benzamide
The synthesis of 131 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI)
m/z(M+1)+:517.96。
Embodiment 132:(E) -4- ((4- methylpiperazine-1-yl) methyl)-N- (3- ((3- (2- (pyridine -2- base) ethylene
Base) -1H- indazole -6- base) sulphur) propyl) benzamide
The synthesis of 132 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI)
m/z(M+1)+:527.25。
Embodiment 133:(E)-N- (3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propyl) thiophene
Pheno -2- formamide
The synthesis of 133 compound of embodiment is completed by using the step of being similar to described in embodiment 121.MS(ESI)
m/z(M+1)+:421.11。
Embodiment 134:(E)-N (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -3- ((3- (2- (pyridine -2- base) second
Alkenyl) -1H- indazole -6- base) sulphur) and propionamide synthesis
(E)-(3- (3- (2- (2- pyridyl group) vinyl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) sulphur)
Methyl propionate (5b): the iodo- 3- of (E) -6- [2- (pyridine -2- base) vinyl] -1- (tetrahydro -2H- pyrrole is added in round-bottomed flask
Mutter -2- base) DMAC N,N' dimethyl acetamide (20 milliliters), 3- mercapto-propionate (1.7 grams), Pd is added in -1H- indazole (5 grams) afterwards
(OAc)2(0.3 gram) and 9,9- dimethyl -4,5- double diphenylphosphine xanthenes (0.8 gram), N, N- diisopropylethylamine (6.5 millis
It rises).Reaction system is heated to 150 DEG C under protection of argon gas and reacts 2 hours.After reaction, system solvent evaporated under reduced pressure,
Gains are extracted with ethyl acetate after being diluted with water.Organic phase is done after using water, saturated common salt water washing respectively with anhydrous sodium sulfate
It is dry.Organic phase obtains crude product through filtering after evaporated under reduced pressure.Sterling 5b is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H
424.16。
(E)-(3- (3- (2- (2- pyridyl group) vinyl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) sulphur)
Propionic acid (5c): by (E)-(3- (3- (2- (2- pyridyl group) vinyl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base)
Sulphur) (1 gram) addition tetrahydrofuran (20 milliliters) of methyl propionate and water (20 milliliters), lithium hydroxide (1.7 grams) then are added.Reaction
System at room temperature, argon gas protection reaction 4 hours.After reaction, system solvent evaporated under reduced pressure, gains with 1 mole/
The dilute hydrochloric acid risen, which is neutralized to pH 3-5, solid precipitation.Water phase obtains crude product 5c after solid is dry through the solid was filtered.LC/MS:M+
H 410.14。
(E)-N (4- ((4- methylpiperazine-1-yl) methyl) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H-
Indazole -6- base) sulphur) propionamide (134): (E)-(3- (3- (2- (2- pyridyl group) vinyl) -1- (four is added in round-bottomed flask
Hydrogen -2H- pyrans -2- base) -1H- indazole -6- base) sulphur) N,N-dimethylformamide (5 milliliters), 4- is added in propionic acid (50 milligrams) afterwards
((4- methylpiperazine-1-yl) methyl) aniline (28 milligrams), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea six
Fluorophosphoric acid ester (70 milligrams) and triethylamine (0.05 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.Reaction knot
Shu Hou, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase uses water, saturation respectively
It is dry with anhydrous sodium sulfate after brine It.Organic phase obtains crude product through filtering, after evaporated under reduced pressure and is dissolved in anhydrous methylene chloride (5
Milliliter), it is added trifluoroacetic acid (1 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction, system
Solvent evaporated under reduced pressure, gains with saturated sodium bicarbonate solution are neutralized to pH > 10 after being diluted with water.Water phase ethyl acetate
Extraction, organic phase are dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is through filtering, after evaporated under reduced pressure
Obtain crude product.Sterling compound 134 is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H 513.23.
Embodiment 135:(E)-N- (3- fluorophenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base)
Sulphur) propionamide
The synthesis of 135 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:419.26。
Embodiment 136:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (3,4,5-
Trimethoxyphenyl) propionamide
The synthesis of 136 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:491.16。
Embodiment 137:(E)-N- (3- chlorphenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base)
Sulphur) propionamide
The synthesis of 137 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:435.09。
Embodiment 138:(E)-N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -
1H- indazole -6- base) sulphur) propionamide
The synthesis of 138 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:503.08。
Embodiment 139:(E)-N- (3- methoxyphenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6-
Base) sulphur) propionamide
The synthesis of 139 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:431.01。
Embodiment 140:(E)-N- (3- (dimethylamino) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H-
Indazole -6- base) sulphur) propionamide
The synthesis of 140 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:444.17。
Embodiment 141:(E)-N- (3- (4- methylpiperazine-1-yl) phenyl) -3- ((3- (2- (pyridine -2- base) ethylene
Base) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 141 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:499.22。
Embodiment 142:(E)-N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl)-phenyl) -3- ((3-
(2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 142 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:581.22。
Embodiment 143:(E)-N- (the fluoro- 4- aminomethyl phenyl of 3-) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- Yin
Azoles -6- base) sulphur) propionamide
The synthesis of 143 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:433.14。
Embodiment 144:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (4- (trifluoro
Methoxyl group) phenyl) propionamide
The synthesis of 144 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:485.11。
Embodiment 145:(E)-N- benzyl -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionyl
Amine
The synthesis of 145 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:415.15。
Embodiment 146:(E)-N- (4- acetyl phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6-
Base) sulphur) propionamide
The synthesis of 146 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:443.14。
Embodiment 147:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (m- toluene
Base) propionamide
The synthesis of 147 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:415.15。
Embodiment 148:(E)-N- (3,4- 3,5-dimethylphenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -
6- yl) sulphur) propionamide
The synthesis of 148 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:429.16。
Embodiment 149:(E)-N- (4- methoxy-benzyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6-
Base) sulphur) propionamide
The synthesis of 149 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:445.16。
Embodiment 150:(E)-N- (4- (tert-butyl) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -
6- yl) sulphur) propionamide
The synthesis of 150 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:457.18。
Embodiment 151:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (p- toluene
Base) propionamide
The synthesis of 151 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:415.15。
Embodiment 152:(E)-N- (4- methoxyl group -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) ethylene
Base) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 152 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:499.13。
Embodiment 153:(E)-N- (the fluoro- 4- aminomethyl phenyl of 3-) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- Yin
Azoles -6- base) sulphur) propionamide
The synthesis of 153 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:433.14。
Embodiment 154:(E)-N- (4- methyl -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) ethylene
Base) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 154 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:483.14。
Embodiment 155:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (3- (trifluoro
Methyl) benzyl) propionamide
The synthesis of 155 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:483.14。
Embodiment 156:(E)-N- phenyl -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionyl
Amine
The synthesis of 156 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:401.14。
Embodiment 157:(E)-N- (4- fluoro- 3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -
1H- indazole -6- base) sulphur) propionamide
The synthesis of 157 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:487.11。
Embodiment 158:(E)-N- (4- ((4- ethyl piperazidine -1- base) methyl) -3- (trifluoromethyl) phenyl) -3- ((3-
(2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 158 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:595.24。
Embodiment 159:(E)-N- ((4- (((2- dimethylamino) ethyl) (methyl) amino) methyl) -3- (fluoroform
Base) phenyl) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 159 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:583.24。
Embodiment 160:(E)-N- (4- ((3- (dimethylamino) pyrroles -1- base) methyl) -3- (trifluoromethyl) phenyl) -
3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 160 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:595.24。
Embodiment 161:(E)-N- (3- (4- methyl-1 H-imidazole-1-group) -5- (trifluoromethyl) phenyl) -3- ((3- (2-
(pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 161 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:549.16。
Embodiment 162:(E)-N- (4- ((4- methyl piperidine -1- base) methyl) -3- (trifluoromethyl)-phenyl) -3- ((3-
(2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 162 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:580.23。
Embodiment 163:(E)-N- (4- (morpholine methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (2- (pyridine -2- base)
Vinyl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 163 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:568.19。
Embodiment 164:(E) -3- ((3- (2- (pyridine -2- base) vinyl) -1H- indazole -6- base) sulphur)-N- (4- (pyrrole
Cough up -1- ylmethyl) -3- (trifluoromethyl) phenyl) propionamide
The synthesis of 164 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:552.20。
Embodiment 165:3- ((1H- indazole -6- base) sulphur)-N- (4- methyl -3- (trifluoromethyl) phenyl) propionamide
The synthesis of 165 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:380.10。
Embodiment 166:3- ((1H- indazole -6- base) sulphur)-N- (4- ((4- ethyl piperazidine -1- base) methyl) -3- (fluoroform
Base) phenyl) propionamide
The synthesis of 166 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:492.20。
Embodiment 167:3- ((1H- indazole -6- base) sulphur)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide
The synthesis of 167 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:400.04。
Embodiment 168:3- ((1H- indazole -6- base) sulphur)-N- (4- fluorophenyl) propionamide
The synthesis of 168 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:316.08。
Embodiment 169:3- ((1H- indazole -6- base) sulphur)-N- (thiophene -2- methyl) propionamide
The synthesis of 169 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:318.07。
Embodiment 170:3- ((1H- indazole -6- base) sulphur)-N- (3- (trifluoromethyl) phenyl) propionamide
The synthesis of 170 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:366.08。
Embodiment 171:3- ((1H- indazole -6- base) sulphur)-N- (3- fluorophenyl) propionamide
The synthesis of 171 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:316.08。
Embodiment 172:3- ((1H- indazole -6- base) sulphur)-N- (2,3- difluorophenyl) propionamide
The synthesis of 172 compound of embodiment is completed by using the step of being similar to described in embodiment 134.MS(ESI)
m/z(M+1)+:334.07。
Embodiment 173:N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (pyridine -
3- yl) -1H- indazole -6- base) sulphur) and propionamide synthesis
6- iodo- 3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (6a): it is added in round-bottomed flask
6- amino -3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (5 grams), after acetic acid (20ml) then is added
System is set to be cooled to 0 degree with ice-water bath.The sulfuric acid (11 milliliters) of 3 mol/Ls is continuously added, is added sodium nitrite (1.8 grams), instead
Answer system under protection of argon gas 0 degree stirring 4 hours after, be added 3 mol/Ls potassium iodide (17 milliliters).Reaction system is in argon gas
Lower 0 degree of protection is stirred 3 hours.After reaction, filtering reacting solution obtained solid is dissolved with ethyl acetate, and organic phase is used respectively
It is dry with anhydrous sodium sulfate after saturated sodium bicarbonate, saturated common salt water washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure
6a.LC/MS:M+H 406.03.
3- ((3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) sulphur) methyl propionate (6b):
The iodo- 3- of 6- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole (2 grams) is added in round-bottomed flask, N is added afterwards,
N- dimethyl acetamide (10 milliliters), 3- mercapto-propionate (0.7 gram), palladium acetate (0.1 gram) and 9,9- dimethyl -4,5- are double
Diphenylphosphine xanthene (0.3 gram), N, N- diisopropylethylamine (2.7 milliliters).Reaction system is heated to 150 under protection of argon gas
DEG C reaction 2 hours.After reaction, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Have
Machine is mutually respectively with dry with anhydrous sodium sulfate after water, saturated common salt water washing.Organic phase obtains crude product through filtering after evaporated under reduced pressure.
Sterling 6b is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H 398.14.
3- ((3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) sulphur) propionic acid (6c): in circle
3- ((3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- base) sulphur) methyl propionate is added in the flask of bottom
Tetrahydrofuran (20 milliliters) and water (20 milliliters) is added in (1 gram) afterwards, and lithium hydroxide (0.6 gram) then is added.Reaction system is in room
Under temperature, argon gas protection reaction 4 hours.After reaction, system solvent evaporated under reduced pressure, dilute salt of 1 mol/L of gains
Acid, which is neutralized to pH 3-5, solid precipitation.Water phase obtains crude product 6c after solid is dry through the solid was filtered.LC/MS:M+H
384.13。
N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (pyridin-3-yl) -1H-
Indazole -6- base) sulphur) propionamide (173): (3- ((3- (pyridin-3-yl) -1- (tetrahydro -2H- pyrans-is added in round-bottomed flask
2- yl) -1H- indazole -6- base) sulphur) N,N-dimethylformamide (5 milliliters), 4- ((4- methyl piperazine is added in propionic acid (50 milligrams) afterwards
Piperazine -1- base) methyl) -3- (trifluoromethyl) aniline (42 milligrams), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethyl
Urea hexafluorophosphoric acid ester (74 milligrams) and triethylamine (0.05 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.Instead
After answering, solvent evaporated, gains are extracted with ethyl acetate system after being diluted with water under reduced pressure.Organic phase use respectively water,
It is dry with anhydrous sodium sulfate after saturated common salt water washing.Organic phase obtains crude product through filtering, after evaporated under reduced pressure and is dissolved in anhydrous dichloromethane
Alkane (5 milliliters) is added trifluoroacetic acid (1 milliliter).Reaction system is stirred at room temperature 14 hours under protection of argon gas.After reaction,
System solvent evaporated under reduced pressure, gains with saturated sodium bicarbonate solution are neutralized to pH > 10 after being diluted with water.Water phase acetic acid
Ethyl ester extraction, organic phase are dried after using water, saturated common salt water washing respectively with anhydrous sodium sulfate.Organic phase is filtered, and decompression is steamed
Crude product is obtained after dry.Sterling compound 173 is obtained after the pressurized silica gel column chromatography purification of crude product.LC/MS:M+H 555.20.
Embodiment 174:N- (3- fluorophenyl) -3- ((3- (pyridin-3-yl) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 174 compound of embodiment is completed by using the step of being similar to described in embodiment 173.MS(ESI)
m/z(M+1)+:393.11。
Embodiment 175:N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (6- first
Yl pyridines -3- base) -1H- indazole -6- base) sulphur) propionamide
The synthesis of 175 compound of embodiment is completed by using the step of being similar to described in embodiment 173.MS(ESI)
m/z(M+1)+:568.22。
Embodiment 176:3- ((3- methyl-1 H- indazole -6- base) sulphur)-N- (4- ((4- methylpiperazine-1-yl) methyl) -3-
(trifluoromethyl) phenyl) propionamide
The synthesis of 176 compound of embodiment is completed by using the step of being similar to described in embodiment 173.MS(ESI)
m/z(M+1)+:492.20。
Embodiment 177:3- ((3- (1- methyl-1 H pyrazoles -4- base) -1H- indazole -6- base) sulphur)-N- (4- ((4- methyl piperazine
Piperazine -1- base) methyl) -3- (trifluoromethyl) phenyl) propionamide
The synthesis of 177 compound of embodiment is completed by using the step of being similar to described in embodiment 173.MS(ESI)
m/z(M+1)+:558.22。
Embodiment 178:N- (4- ((4- methylpiperazine-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- ((3- (phenyl -
1H- indazole -6- base) sulphur) propionamide
The synthesis of 178 compound of embodiment is completed by using the step of being similar to described in embodiment 173.MS(ESI)
m/z(M+1)+:554.21。
Embodiment 179: the influence to cancer cell multiplication
By testing influence (table 2) of the compound of the present invention to growth of cancer cells, compound pair in text is further assessed
The inhibiting effect of cancer cell multiplication and its to inhibit cancer cell multiplication selectivity.It has been selected in the present embodiment, between human gastrointestinal tract
Matter oncocyte system cell GIST-T1 (expression wild type C-KIT gene) (being purchased from Cosmo Bio Co., Ltd. (Japan)), mouse
Pro B lymphocyte BaF3 (is purchased from ATCC).In addition, the present embodiment has also selected mouse P210/BaF3 (to stablize expression P210Bcr-Abl
Mutated genes), mouse P210/T315I-BaF3 (stablize expression saltant type P210Bcr-Abl/T315I kinases), mouse Tel-
CKit-BaF3 (stablizing expression C-KIT wild type kinase), mouse Tel-cKit/V559D-BaF3 (stablize expression C-KIT
V559D be mutated type kinase), mouse Tel-cKit/V559D/T670I-BaF3 (stablize expression C-KIT V559D/T670I mutation
Type kinase), mouse Tel-cKit/T670I-BaF3 (stablize expression C-KIT T670I be mutated type kinase), mouse Tel-PDGFR
α-BaF3 (stablizing PDGF-B expression R alpha kinase), mouse Tel-PDGFR β-BaF3 (stablizing PDGF-B expression R beta kinase), mouse Tel-
VEGFR2-BaF3 (stablizing VEGF expression R2 kinases), mouse Tel-RET-BaF3 (stablizing expression RET kinases), mouse Tel-
FLT3-BaF3 (stablizing expression FLT3 kinases), mouse Tel-FGFR1-BaF3 (stablizing expression FGFR1 kinases), mouse Tel-
FGFR2-BaF3 (stablizing expression FGFR2 kinases), mouse Tel-FGFR3-BaF3 (stablizing expression FGFR3 kinases), mouse Tel-
FGFR4-BaF3 (stablizes expression FGFR4 kinases).Above-mentioned cell line is constructed by this laboratory, construction method are as follows: distinguish through PCR
Expand mankind P210Bcr-Abl, P210Bcr-Abl/T315I, C-KIT, C-KIT V559D, C-KIT V559D/T670I, C-
KIT T670I, PDGFR α, PDGFR β, VEGFR2, RET, FLT3, FGFR1, FGFR2, FGFR3, FGFR4 kinases region sequence, and
The MSCV-Puro carrier with N-terminal TEL segment and/or NPM segment and/or TPR segment is inserted respectively into (to be purchased from
Clontech), by retrovirus method, stabilization is transferred to mouse BaF3 cell, and removes IL-3 growth factor, final
To dependence P210Bcr-Abl, P210Bcr-Abl/T315I, C-KIT, C-KIT/V559D, C-KIT/V559D/T670I, C-
KIT/T670I, PDGFR α, PDGFR β, VEGFR2, RET, FLT3, FGFR1, FGFR2, FGFR3, FGFR4 are transferred to the cell of albumen
System.
In embodiment by various concentration (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μ
M, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM in DMSO) test compound be added separately to above-mentioned cell
In, and it is incubated for 72 hours, with CCK8 (Bei Bo, China) cell viability detection kit, by the reduction dehydrogenation in living cells
Enzyme is quantitative determined to detect number of viable cells.Determine that the compound of the present invention is directed to the GI of each test cell50It is worth (unit),
Experimental result is shown in Table 2.
Table 2
2 (Continued) of table
2 (Continued) of table
By test discovery the compound of the present invention major target class be CKIT, CKIT/T670I, BCR-ABL/T315I,
PDGFR α, PDGFR β and VEGFR2.The compound of the present invention is to TEL-CKIT/T670I-BaF3, gastrointestinal stromal tumor GIST-
T1 has apparent inhibiting effect, this can prove that these compounds can be used in treating gastrointestinal stromal tumor, and for T670I
It is especially effective that point mutation generates drug resistant gastrointestinal stromal tumor.In addition, some preferred compounds of the invention are also further right
P210/T315I-BaF3 cell has effect.P210/T315I-BaF3 is a kind of cell line of BCR-ABL/T315I mutation, and
BCR-ABL/T315I is medicament-resistant mutation common in chronic myelogenous leukemia clinic, currently without particularly preferred little molecules in inhibiting
Agent can treat the chronic myelogenous leukemia of the mutation.
Based on the above discovery, present inventor further selects preferred compounds of the invention 142 to test, really
It is thin to human chronic myeloblastic leukemia cell K562 (expression P210Bcr-Abl mutated genes), human chronic myeloblastic leukemia to determine it
Born of the same parents MEG-01 (expression P210Bcr-Abl mutated genes), human chronic myeloblastic leukemia cell Ku812 (expression P210Bcr-Abl
Mutated genes) (above-mentioned cell is purchased from ATCC (U.S.)) GI50It is worth (unit), experimental result is shown in Table 3.
Table 3
GI50/μM | Compound 142 |
K562 | 0.0012 |
KU812 | 0.005 |
MEG01 | 0.0014 |
As shown above, some preferred compounds of the invention have very strong inhibition to make in P210/T315I-BaF3 cell
With, and these compounds also express three kinds chronic myeloid leukemia cel l line K562, MEG- of BCR-ABL fusion
01, the proliferation of KU812 has significant inhibition, GI50Respectively less than 0.01 μM.This proves preferred compounds of the invention to chronic Myelogenous
Leukaemia has preferable therapeutic effect, and also has to drug resistant chronic myelogenous leukemia caused by point mutation T315I certain
Therapeutic effect.
Embodiment 180: zoopery
In the present embodiment, compound 4 and compound 142 are tested respectively in TEL-cKIT/T670I-BaF3 and P210/
Experimental result in the mouse model of T315I-BaF3.
Experimental procedure is as follows:
(1) small from the Bal b/c female of Beijing dimension experimental animal Co., Ltd, tonneau China purchase raising 4-6 week old
Mouse is raised in SPF grades of laboratories, and through autoclave sterilization aseptic process, all operations in relation to mouse exist for drinking-water and padding
It is carried out under aseptic condition;
Dorsal sc is injected separately into about 5 × 10 on the left of all mouse respectively within (2) the 0th days6A TEL-cKIT/T670I-
BaF3 or 5 × 106A P210/T315I-BaF3 cell;
(3) for the mouse model of TEL-cKIT/T670I-BaF3 since the 6th day, every angel correspond to Mouse oral to
Medicine methylcellulose (HKI) solvent (5 mouse);Dosage is the compound 4 (5 mouse) of 25mg/kg mouse weight;Dosage is
The Imatinib (being purchased from MedChem Express, China) (5 mouse) of 100mg/kg mouse weight.For P210/T315I-BaF3
Mouse model since the 6th day, every angel correspond to Mouse oral administration methylcellulose (HKI) solvent (5 mouse);Dosage
For the compound 142 (5 mouse) of 25mg/kg mouse weight;Dosage is the compound 142 (5 mouse) of 50mg/kg mouse weight;Dosage
For the compound 142 (5 mouse) of 100mg/kg mouse weight;
(4) since the 6th day, the length/width of vernier caliper measurement subcutaneous tumor is used daily, and records mouse weight daily,
The influence of compound 4 and compound 142 to mouse weight is determined respectively;
(5) the 18th days execution mouse take out subcutaneous tumor, and tumour weighing is compared;
(6) subendothelial tumour growth trend, gross tumor volume calculation method: length × wide × wide/2mm are counted3。
Experimental result is as shown in Fig. 1 a-c and 2a-c.Mouse tumor model of the compound 4 in TEL-cKIT/T670I-BaF3
In, dosage has shown the effect of certain inhibition mouse tumor when being 25mg/kg, and with the increasing of medication number of days
Add, compound 4 is more significant to the inhibiting effect of mouse tumor, and tumour inhibiting rate is up to 49.6%.Compound 4 not only effectively inhibits
The growth of mouse tumor, and the weight of mouse is not influenced substantially, show that compound 4 is applicable to animal administration.This
Demonstrating CKIT/T670I inhibitor compound 4 of the invention can be used in treating the gastrointestinal stromal tumor of T670I mutation.For
For compound 142 in P210/T315I-BaF3 mouse model, dosage has shown certain inhibition when being 25mg/kg
The effect of mouse tumor, and with the increase of dosage and medication number of days, compound 142 is cured the inhibiting effect of mouse tumor
Hair is significant, and tumour inhibiting rate is up to 69% when medication 100mg/kg.Compound 142 not only effectively inhibits the growth of mouse tumor, and
And the weight of mouse is not influenced substantially, show that compound 142 is applicable to animal administration.This also demonstrates of the invention
BCR-ABL/T315I inhibitor compound 142 can be used in treating the chronic myelogenous leukemia of T315I mutation.
Industrial applicability
The present invention provides a kind of Azaindole kinase inhibitors compound, can be used for reducing or inhibiting cell or subject
CKIT (especially saltant type cKIT/T670I), BCR/ABL (especially saltant type BCR-ABL/T315I), PDGFR α, PDGFR
β, and/or VEGFR2 kinase activity, and/or prevent or treat cKIT (especially saltant type cKIT/ in subject
T670I), BCR/ABL (especially saltant type BCR-ABL/T315I), PDGFR α, PDGFR β, and/or VEGFR2 activity related diseases
Disease.Thus, it can be made into corresponding drug, be suitable for industrial application.
Although being explained in detail herein to the present invention, however, the present invention is not limited thereto, those skilled in the art can
It is modified with principle according to the present invention, therefore, the various modifications that all principles according to the invention carry out all should be understood as
Fall into protection scope of the present invention.
Claims (11)
1. a kind of kinase inhibitor comprising the compound of formula (I) or its pharmaceutically acceptable salt, solvate, ester, acid, generation
Thank object or pro-drug:
Wherein, X is selected from
Y is selected from phenyl, thiophene -2- base, isoxazole -3- base, pyridin-3-yl, pyridin-4-yl, 2-Pyrrolidone -5- base, N- first
Base -2 (1H)-pyridone -5- base and furans -2- base;
R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3Group replace pyridin-3-yl, optionally by R3
Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces;
(R2)nIt indicates optionally by n independent R2Replaced substituent group, wherein n is the integer of 0-5, R2Independently selected from hydroxyl, halogen
Element, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Acylamino-, C1-6Alkyl amino, 4- methyl-
Imidazoles -1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl;
R5Selected from hydrogen and C1-6Alkyl amino.
2. kinase inhibitor according to claim 1 comprising the compound of (Ia) or its pharmaceutically acceptable salt, solvent
Compound, ester, acid, metabolin or pro-drug:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3The pyridin-3-yl and appoint that group replaces
Choosing is by R3The phenyl that group replaces;
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Replaced substituent group, wherein n is 0-5's
Integer, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6Alkyl amino, 4- methyl-imidazoles-
1- base,
R3Selected from halogen, aminoacyl, C1-6Alkyl,
R4Selected from C1-6Alkyl;
R5Selected from C1-6Alkyl amino.
3. kinase inhibitor according to claim 1 comprising the compound of (Ib) or its pharmaceutically acceptable salt, solvent
Compound, ester, acid, metabolin or pro-drug:
Wherein R1Selected from hydrogen, C1-6Alkyl, 2- (pyridine -2- base) vinyl, optionally by R3Group replace pyridin-3-yl, optionally
By R3Group replace phenyl and optionally by R3Pyrazoles -4- the base that group replaces;
(R2)nIt indicates in the ortho position of phenyl ring, meta position and contraposition optionally by n independent R2Replaced substituent group,
Middle n is the integer of 0-5, R2Independently selected from halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Halogenated alkyl, C1-6It is halogenated
Alkoxy, C2-6Acylamino-, C1-6Alkyl amino, 4- methyl-imidazoles -1- base,
R3Selected from C1-6Alkyl and
R4Selected from C1-6Alkyl;
R5Selected from hydrogen and C1-6Alkyl amino.
4. kinase inhibitor according to claim 1 comprising following compound or its pharmaceutically acceptable salt, solvation
Object, ester, acid, metabolin or prodrug:
5. a kind of pharmaceutical composition comprising such as compound of any of claims 1-4 or its is pharmaceutically acceptable
Salt, solvate, ester, acid, metabolin or pro-drug and pharmaceutically acceptable carrier or excipient, and optional
Other therapeutic agents.
6. according to claim 1 kinase inhibitor described in any one of -4 preparation for inhibit selected from cKIT, BCR/ABL,
Purposes in the drug of one of PDGFR α, PDGFR β and VEGFR2 or a variety of tyrosine kinase activities.
7. purposes according to claim 6, wherein the kinase inhibitor is selected from saltant type cKIT/T670I for inhibiting
With one of saltant type BCR-ABL/T315I or a variety of tyrosine kinase activities.
8. according to claim 1 kinase inhibitor described in any one of -4 preparation for treat or prevent by selected from cKIT,
It is that one of BCR/ABL, PDGFR α, PDGFR β and VEGFR2 or a variety of tyrosine kinase activities are adjusted or by its shadow
Purposes in the drug of loud disease, obstruction and illness.
9. purposes according to claim 8, wherein the disease, obstruction and illness by selected from saltant type cKIT/T670I and
One of saltant type BCR-ABL/T315I or a variety of tyrosine kinase activities are adjusted or are affected by it.
10. purposes according to claim 8 or claim 9, wherein the disease, obstruction and illness are selected from: solid tumor, especially meat
Tumor, gastrointestinal stromal tumor, acute myeloblastic leukemia, chronic myelogenous leukemia, celiothelioma, thyroid cancer, systemic mast are thin
Born of the same parents' disease, hypereosinophilic syndrome, fibre modification, rheumatoid arthritis, panarthritis, chorionitis, lupus erythematosus, shifting
Graft versus host disease, neurofibroma, pulmonary hypertension, Alzheimer disease, seminoma, psoriasis, dysgerminoma, hypertrophy
Cell tumour, lung cancer, bronchiolar carcinoma, dysgerminoma, the formation of testis intraepithelial neoplasia, melanoma, breast cancer, neuroblast
Tumor, mamillary/follicular thyroid cancer, malignant lymphoma, non-Hodgkin lymphoma, the formation of 2 type Multiple Endocrine tumors, thermophilic chromium
Cytoma, parathyroid hyperplasia/adenoma, colon cancer, colorectal adenomas, oophoroma, prostate cancer, spongioblastoma, brain
Tumour, glioblastoma, cancer of pancreas, malignant pleural mesothelioma, hemangioblastoma, hemangioma, kidney, liver cancer, on kidney
Gland cancer, bladder cancer, gastric cancer, the carcinoma of the rectum, carcinoma of vagina, cervical carcinoma, carcinoma of endometrium, Huppert's disease, neck and head tumor, pass
Save inflammation, rheumatic arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory bowel disease, psoriasis arthropathica, Bones and joints
Inflammation, Still disease, adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis, Order thyroiditis, Greif
This disease, rheumatoid arthritis syndrome, multiple sclerosis, Guillain-Barre syndrome, acute diseminated encephalomyelitis, A Di
It is gloomy disease, view property eye battle array it is twin-the twin syndrome of flesh battle array, ankylosing spondylitis, antiphospholipid antibody syndrome, alpastic anemia, from
Body autoallergic, chylous diarrhea, goodpasture's syndrome, Idiopathic Thrombocytopenic Purpura, optic neuritis, chorionitis,
Primary biliary cirrhosis, Reiter syndrome, takayasu's arteritis, temporal arteritis, warm type autoimmune hemolytic anemia,
Wegner's granulomatosis, alopecia universalis, behcet disease, confirmed fatigue, familial dysautonomia, endometrium are different
Position, interstitial cystitis, neuromyotonia, chorionitis, Vulvodynia, or combinations thereof.
11. purposes according to claim 8 or claim 9, wherein the disease, obstruction and illness are selected from: gastrointestinal stromal tumor, urgency
Property granulocytic leukemia, chronic myelogenous leukemia, thyroid cancer, or combinations thereof.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711394182.5A CN109942544B (en) | 2017-12-21 | 2017-12-21 | Novel indazole derivative kinase inhibitor |
PCT/CN2017/118602 WO2019119481A1 (en) | 2017-12-21 | 2017-12-26 | Carbazole derivative kinase inhibitor |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711394182.5A CN109942544B (en) | 2017-12-21 | 2017-12-21 | Novel indazole derivative kinase inhibitor |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109942544A true CN109942544A (en) | 2019-06-28 |
CN109942544B CN109942544B (en) | 2021-06-11 |
Family
ID=66993021
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711394182.5A Active CN109942544B (en) | 2017-12-21 | 2017-12-21 | Novel indazole derivative kinase inhibitor |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN109942544B (en) |
WO (1) | WO2019119481A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111138426B (en) * | 2018-11-02 | 2023-03-10 | 安徽中科拓苒药物科学研究有限公司 | Indazole kinase inhibitor and application thereof |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1747950A (en) * | 2002-12-19 | 2006-03-15 | 美国辉瑞有限公司 | 2-(1h-indazole-6-ylamino)-benzamide compounds as protein kinases inhibitors useful for the treatment of ophthalmic diseases |
CN101005843A (en) * | 2004-06-28 | 2007-07-25 | 布里斯托尔-迈尔斯·斯奎布公司 | Pyrrolotriazine kinase inhibitors |
CN101052634A (en) * | 2004-11-03 | 2007-10-10 | 拜耳先灵医药股份有限公司 | Anthranilamide pyridinureas as vegf receptor kinase inhibitors |
CN101056870A (en) * | 2004-11-03 | 2007-10-17 | 拜耳先灵医药股份有限公司 | Nicotinamide pyridinureas as vascular endothelial growth factor (vegf) receptor kinase inhibitors |
CN102239150A (en) * | 2008-12-05 | 2011-11-09 | 韩国科学技术研究院 | Novel indazole derivatives or pharmaceutically acceptable salts thereof as protein kinase inhibitors for proliferative diseases treatment, and a pharmaceutical composition containing the same as an active ingredient |
WO2012003418A2 (en) * | 2010-07-02 | 2012-01-05 | The University Of North Carolina At Chapel Hill | Functionally selective ligands of dopamine d2 receptors |
CN105906568A (en) * | 2016-04-28 | 2016-08-31 | 西安交通大学 | Cyclopropane diamide compound with antitumor activity and preparation method and application thereof |
-
2017
- 2017-12-21 CN CN201711394182.5A patent/CN109942544B/en active Active
- 2017-12-26 WO PCT/CN2017/118602 patent/WO2019119481A1/en active Application Filing
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1747950A (en) * | 2002-12-19 | 2006-03-15 | 美国辉瑞有限公司 | 2-(1h-indazole-6-ylamino)-benzamide compounds as protein kinases inhibitors useful for the treatment of ophthalmic diseases |
CN101005843A (en) * | 2004-06-28 | 2007-07-25 | 布里斯托尔-迈尔斯·斯奎布公司 | Pyrrolotriazine kinase inhibitors |
CN101052634A (en) * | 2004-11-03 | 2007-10-10 | 拜耳先灵医药股份有限公司 | Anthranilamide pyridinureas as vegf receptor kinase inhibitors |
CN101056870A (en) * | 2004-11-03 | 2007-10-17 | 拜耳先灵医药股份有限公司 | Nicotinamide pyridinureas as vascular endothelial growth factor (vegf) receptor kinase inhibitors |
CN102239150A (en) * | 2008-12-05 | 2011-11-09 | 韩国科学技术研究院 | Novel indazole derivatives or pharmaceutically acceptable salts thereof as protein kinase inhibitors for proliferative diseases treatment, and a pharmaceutical composition containing the same as an active ingredient |
WO2012003418A2 (en) * | 2010-07-02 | 2012-01-05 | The University Of North Carolina At Chapel Hill | Functionally selective ligands of dopamine d2 receptors |
CN105906568A (en) * | 2016-04-28 | 2016-08-31 | 西安交通大学 | Cyclopropane diamide compound with antitumor activity and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN109942544B (en) | 2021-06-11 |
WO2019119481A1 (en) | 2019-06-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104844566B (en) | A kind of kinase inhibitor of new structure | |
CN110582483B (en) | Compound containing o-amino heteroaromatic alkynyl and preparation method and application thereof | |
CN104829610B (en) | A kind of novel cloth Shandong tyrosine kinase inhibitor | |
CN106883213B (en) | Dual inhibitor of EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) | |
CN106008511B (en) | Pteridine ketone derivatives and its application as EGFR, BLK, FLT3 inhibitor | |
HUE031955T2 (en) | Novel pyrrolopyrimidine compounds as inhibitors of protein kinases | |
CN104341425B (en) | Deuterated acetylene-derivative, its pharmaceutical composition and application | |
CN104854103B (en) | There is the acyl amino compound cycloalkyl of the illness of reaction suitable for the regulation treated to dopamine D 3 receptor | |
BRPI0712816B1 (en) | pyrrolpyrimidine compounds and their use | |
TW200829558A (en) | Quinazolines for PDK1 inhibition | |
BR112021018704B1 (en) | HETEROARYL DERIVATIVE, METHOD FOR PRODUCING THE SAME, AND PHARMACEUTICAL COMPOSITION INCLUDING THE SAME AS AN EFFECTIVE COMPONENT | |
JP2013523658A (en) | Pyrazolyl-pyrimidines as kinase inhibitors | |
CN106928231A (en) | The kinase inhibitor of the new EGFR wild types of one class and saltant type | |
CN108368060A (en) | A kind of novel pyridine derivatives kinase inhibitor | |
CN107922350A (en) | New benzimidazole compound and its medical usage | |
CN110256436B (en) | Purines as Trk kinase inhibitors | |
CN107383019B (en) | Pyrazolo [4,3-h] quinazoline compounds and application thereof | |
CN109942544A (en) | A kind of novel indazole analog derivative kinase inhibitor | |
JP2023508376A (en) | Cyano-substituted pyridines and cyano-substituted pyrimidine-based compounds, methods of preparation and uses thereof | |
JP7311918B2 (en) | Novel pan-RAF kinase inhibitor and use thereof | |
CN113350347B (en) | Use of indazoles | |
CN111303024B (en) | Quinoline-structured pan-KIT kinase inhibitor and application thereof | |
CN111138426B (en) | Indazole kinase inhibitor and application thereof | |
CN107805240A (en) | A kind of new PDGFR kinase inhibitors and application thereof | |
JP2015124211A (en) | Quinazolinone derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |