CN114805359A - 炔代杂环化合物fgfr抑制剂的制备方法和用途 - Google Patents
炔代杂环化合物fgfr抑制剂的制备方法和用途 Download PDFInfo
- Publication number
- CN114805359A CN114805359A CN202110118468.0A CN202110118468A CN114805359A CN 114805359 A CN114805359 A CN 114805359A CN 202110118468 A CN202110118468 A CN 202110118468A CN 114805359 A CN114805359 A CN 114805359A
- Authority
- CN
- China
- Prior art keywords
- compound
- membered
- cycloalkyl
- cancer
- alkyl
- 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
- -1 alkynyl heterocyclic compound Chemical class 0.000 title claims description 85
- 238000002360 preparation method Methods 0.000 title abstract description 41
- 229940125829 fibroblast growth factor receptor inhibitor Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 108091008794 FGF receptors Proteins 0.000 claims abstract description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 8
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 claims abstract 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 16
- 229940002612 prodrug Drugs 0.000 claims description 16
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000003003 spiro group Chemical group 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 206010005003 Bladder cancer Diseases 0.000 claims description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 7
- 206010017758 gastric cancer Diseases 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 201000011549 stomach cancer Diseases 0.000 claims description 7
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 206010014733 Endometrial cancer Diseases 0.000 claims description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 5
- 208000034578 Multiple myelomas Diseases 0.000 claims description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 201000004101 esophageal cancer Diseases 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 18
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 abstract description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract 1
- 229940124639 Selective inhibitor Drugs 0.000 abstract 1
- 238000000034 method Methods 0.000 description 46
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 125000004429 atom Chemical group 0.000 description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 239000001301 oxygen Chemical group 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 229910052717 sulfur Chemical group 0.000 description 9
- 239000011593 sulfur Chemical group 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- AKQXKEBCONUWCL-QMMMGPOBSA-N tert-butyl (3s)-3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](N)C1 AKQXKEBCONUWCL-QMMMGPOBSA-N 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 6
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 6
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 6
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 6
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 6
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 150000002391 heterocyclic compounds Chemical class 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-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
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 4
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- CMIBWIAICVBURI-SSDOTTSWSA-N tert-butyl (3r)-3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](N)C1 CMIBWIAICVBURI-SSDOTTSWSA-N 0.000 description 4
- DQQJBEAXSOOCPG-SSDOTTSWSA-N tert-butyl n-[(3r)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCNC1 DQQJBEAXSOOCPG-SSDOTTSWSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 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 3
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- 229940126639 Compound 33 Drugs 0.000 description 3
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 3
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 3
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 3
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 238000006751 Mitsunobu reaction Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 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 3
- 230000002378 acidificating effect Effects 0.000 description 3
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000000460 chlorine Substances 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
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 3
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- CMIBWIAICVBURI-ZETCQYMHSA-N tert-butyl (3s)-3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](N)C1 CMIBWIAICVBURI-ZETCQYMHSA-N 0.000 description 3
- DQQJBEAXSOOCPG-ZETCQYMHSA-N tert-butyl n-[(3s)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCNC1 DQQJBEAXSOOCPG-ZETCQYMHSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- KEIPNCCJPRMIAX-HNNXBMFYSA-N 1-[(3s)-3-[4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]pyrazolo[3,4-d]pyrimidin-1-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound COC1=CC(OC)=CC(C#CC=2C3=C(N)N=CN=C3N([C@@H]3CN(CC3)C(=O)C=C)N=2)=C1 KEIPNCCJPRMIAX-HNNXBMFYSA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- HUSBBWQIJMRKLI-UHFFFAOYSA-N 1-ethynyl-3,5-dimethoxybenzene Chemical group COC1=CC(OC)=CC(C#C)=C1 HUSBBWQIJMRKLI-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 2
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 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
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 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
- 241000282412 Homo Species 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 101100334745 Mus musculus Fgfr4 gene Proteins 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125878 compound 36 Drugs 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- MGZKYOAQVGSSGC-DLBZAZTESA-N fisogatinib Chemical compound COc1cc(OC)c(Cl)c(c1Cl)-c1ccc2nc(N[C@@H]3COCC[C@@H]3NC(=O)C=C)ncc2c1 MGZKYOAQVGSSGC-DLBZAZTESA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- OLAHOMJCDNXHFI-UHFFFAOYSA-N n'-(3,5-dimethoxyphenyl)-n'-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-n-propan-2-ylethane-1,2-diamine Chemical compound COC1=CC(OC)=CC(N(CCNC(C)C)C=2C=C3N=C(C=NC3=CC=2)C2=CN(C)N=C2)=C1 OLAHOMJCDNXHFI-UHFFFAOYSA-N 0.000 description 2
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 2
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 2
- 238000007481 next generation sequencing Methods 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research 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
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- WPGLRFGDZJSQGI-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(N)C1 WPGLRFGDZJSQGI-UHFFFAOYSA-N 0.000 description 2
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 2
- NEMXVXVJGXZDRR-UHFFFAOYSA-N tert-butyl n-(azetidin-3-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CNC1 NEMXVXVJGXZDRR-UHFFFAOYSA-N 0.000 description 2
- WUOQXNWMYLFAHT-QMMMGPOBSA-N tert-butyl n-[(3s)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCCNC1 WUOQXNWMYLFAHT-QMMMGPOBSA-N 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-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
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000000196 1,4-pentadienyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 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
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VRQMAABPASPXMW-HDICACEKSA-N AZD4547 Chemical compound COC1=CC(OC)=CC(CCC=2NN=C(NC(=O)C=3C=CC(=CC=3)N3C[C@@H](C)N[C@@H](C)C3)C=2)=C1 VRQMAABPASPXMW-HDICACEKSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- QADPYRIHXKWUSV-UHFFFAOYSA-N BGJ-398 Chemical compound C1CN(CC)CCN1C(C=C1)=CC=C1NC1=CC(N(C)C(=O)NC=2C(=C(OC)C=C(OC)C=2Cl)Cl)=NC=N1 QADPYRIHXKWUSV-UHFFFAOYSA-N 0.000 description 1
- 229940124649 Balversa Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QFUIJOBJAQBGDH-HNNXBMFYSA-N C(C=C)(=O)N1C[C@H](CC1)N1N=C(C(=C1NC)C(=O)N)C#CC1=CC(=CC(=C1)OC)OC Chemical compound C(C=C)(=O)N1C[C@H](CC1)N1N=C(C(=C1NC)C(=O)N)C#CC1=CC(=CC(=C1)OC)OC QFUIJOBJAQBGDH-HNNXBMFYSA-N 0.000 description 1
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 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
- 230000004544 DNA amplification Effects 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- CUDVHEFYRIWYQD-UHFFFAOYSA-N E-3810 free base Chemical compound C=1C=C2C(C(=O)NC)=CC=CC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCC1(N)CC1 CUDVHEFYRIWYQD-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229940125407 FGF401 Drugs 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MBWRLLRCTIYXDW-UHFFFAOYSA-N N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide Chemical compound ClC1=C(C(=C(C=C1OC)OC)Cl)NC(N(C)C1=CC(=NC=N1)NC1=C(C=C(C=C1)N1CCN(CC1)CC)NC(C=C)=O)=O MBWRLLRCTIYXDW-UHFFFAOYSA-N 0.000 description 1
- BHKDKKZMPODMIQ-UHFFFAOYSA-N N-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-7-formyl-6-[(4-methyl-2-oxopiperazin-1-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide Chemical compound COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C=O)nc23)ncc1C#N BHKDKKZMPODMIQ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229940126233 Pemazyre Drugs 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 229940125828 TAS-120 Drugs 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
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 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
- 125000003368 amide group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005870 benzindolyl group Chemical group 0.000 description 1
- 125000000928 benzodioxinyl group Chemical group O1C(=COC2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=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
- 125000005878 benzonaphthofuranyl group Chemical group 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 125000004652 decahydroisoquinolinyl group Chemical group C1(NCCC2CCCCC12)* 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229950004444 erdafitinib Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940121561 fisogatinib Drugs 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940121446 futibatinib Drugs 0.000 description 1
- 239000002223 garnet Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000009650 gentamicin protection assay Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical class C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000013038 irreversible inhibitor Substances 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
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000006654 negative regulation of apoptotic process Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 1
- 229960004378 nintedanib Drugs 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
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 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
- 229940121317 pemigatinib Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 230000003234 polygenic effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000003410 quininyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000003699 striated muscle Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- XSJPKMUFBHSIRA-UHFFFAOYSA-N tert-butyl 3-(aminomethyl)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(CN)C1 XSJPKMUFBHSIRA-UHFFFAOYSA-N 0.000 description 1
- WPWXYQIMXTUMJB-UHFFFAOYSA-N tert-butyl 3-(aminomethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(CN)C1 WPWXYQIMXTUMJB-UHFFFAOYSA-N 0.000 description 1
- OGCCBDIYOAFOGK-UHFFFAOYSA-N tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CN)C1 OGCCBDIYOAFOGK-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DQQJBEAXSOOCPG-UHFFFAOYSA-N tert-butyl n-pyrrolidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNC1 DQQJBEAXSOOCPG-UHFFFAOYSA-N 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
本发明公开一种FGFR蛋白酪氨酸激酶的临床突变体的选择性抑制剂,及具有通式(I)所示的化合物及其可药用的盐,含有所述化合物和/或其药用的盐的药物组合物、应用所述化合物或可药用的盐治疗或者预防FGFR激酶相关性病症、特别是肿瘤的药物中的用途,这是一类含有炔类杂环模板化合物,同时公开了该类化合物的或其可药用的盐的药物组合物的制备方法。
Description
技术领域:
本发明涉及一种作为FGFR抑制剂的炔类杂环化合物或其可药用的盐;含有所述炔代杂环化合物或其可药用的盐的药物组合物;所述炔代杂环化合物或其可药用的盐的制备方法;所述炔代杂环化合物或其可药用的盐、或含有所述炔代杂环化合物或其可药用的盐的药物组合物在制备用于治疗和/或预防FGFR相关性病症、特别是肿瘤的药物中的用途。
背景技术:
成纤维细胞生长因子受体(Fibroblast Growth Factor Receptor,FGFR)是一类受体酪胺酸激酶(RTK),FGFR家族主要包括FGFR1-、FGFR2、FGFR3和FGFR4四种亚型。FGFR1是一种跨膜蛋白质,属于受体酪氨酸激酶,由三个主要部分组成:即细胞外段、跨膜区和细胞段,细胞外段是配体成纤维细胞生长因子(Fibroblast growth factor,FGFs)的结合区。FGFs也是一个多基因家族,现已有19个成员,即FGF1又称为酸性成纤维细胞生长因子(acidic FGF,aFGF),FGF2也称为碱性成纤维细胞生长相关文档因子(basic FGF,bFGF),它们具有刺激成纤维细胞、血管内皮细胞、平滑肌细胞和神经细胞生长的生物学活性。
然而,当FGFR发生突变或者过表达时,会引起FGFR信号通路的过度激活,并进一步诱发正常细胞癌变。其中,RAS-RAF-MAPK的过度激活可刺激细胞增殖与分化;PI3K-AKT过度激活会使得细胞凋亡受抑制;SATA与促进肿瘤侵袭和转移,增强肿瘤免疫逃逸能力密切相关;PLCγ信号通路则是肿瘤细胞转移调控的重要途径。根据2015年发表在ClinicalCancer Research的一项研究,针对4853个各类实体瘤的下一代测序(NGS)显示,大约有7.1%的癌症中发现FGFR畸变(aberrations)并异常激活,其中大部分是基因扩增(66%),其次是突变(26%)和重排(8%)。几乎所有检测的恶性肿瘤中均存在FGFR畸变,发生率较高的癌症有尿非小细胞肺癌、食管癌、黑色素瘤、胃癌、多发性骨髓瘤、肝癌、胆管癌、***癌、皮肤癌、卵巢癌、子宫内膜癌、***、膀胱癌、乳腺癌、结肠癌、胶质瘤、以及横纹肌肉瘤等肿瘤中也发现了FGFR的异常激活。
目前市场上已有一些非FGFR特异性药物,比如pfizer的Sunitinib、Eisai的lenvatini和Boehringer Ingelheimr的nintedanib。而FDA批准上市的FGFR抑制剂只有Balversa(Erdafitinib)和Pemazyre(pemigatinib)。进入临床的FGFR1/2/3的小分子抑制剂有:Infigratinib(BGJ398)和AZD4547,fisogatinib(BLU-554)、Roblitinib(FGF401)、H3B6527,lucitanib(E-3810)、Futibatinib(TAS-120)、RPN1371、ICP-192、derazantinib、3D185、BPI-17509、HMPL-453。
尽管FGFR抑制剂的开发吸引了国内外众多公司布局,虽然已经有2个FGFR抑制剂上市,但由于其在治疗多种恶性肿瘤所展示的前景,仍需要开发新的化合物。经过不断努力,本发明设计一类拥有自主知识产权的对FGFR-1-4蛋白激酶表现出优异活性的不可逆抑制剂。
发明内容
为解决上述问题,本发明提供了式(I)所示的一种新型FGFR酪氨酸激酶抑制剂的化合物或其立体异构体、稳定同位素衍生物、水合物、溶剂化物、药学上可接受的盐:
其中:
X1,X2,X3,X4可以独立地选自N、CR1;
环B为苯环或者5-6元杂芳环,其中上述的苯环和杂芳环任选被一个或多个G1所取代;
R1独立地选自H、氰基、卤素、C1-6烷基、COOH、CONH2、NHCOH、CONHR2、OR2或-NHR2;;
R2独立地选自H、氰基、卤素、C1-6烷基、C3-6环烷基、3-6元杂环烷基、-OR3、-NR3R4、-C(O)NR3R4,其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR5、-NR5R6、C1-6烷基、C3-6环烷基或3-6元杂环烷基;
U独立地选自-C0-4烷基-、-CR7R8-、-C1-2烷基(R7)(OH)-、-C(O)-、-CR7R8O-、-OCR7R8-、-SCR7R8-、-CR7R8S-、-NR7-、-NR7C(O)-、-C(O)NR7-、-NR7C(O)NR8-、-CF2-、-O-、-S-、-S(O)m-、-NR7S(O)2-、-S(O)2NR7-;
Y不存在或选C3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基,其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G2所取代;
当a为双键时,Ra、Rb和Rc各自独立地选自H、氰基,卤素、C1-6烷基、C3-6环烷基或3-6元杂环基。其中所述烷基,环烷基和杂环基任选被1个或多个G3所取代;
Ra和Rb或Rb和Rc任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环;
当键a为三键时,Ra和Rc不存在,Rb独立选自H、氰基,卤素、C1-6烷基、C3-6环烷基或3-6元杂环基被一个或多个G4所取代;
R9独立地选自H、C1-6烷基、C3-6环烷基或3-6元杂环基,其中所述烷基,环烷基和杂环基任选被1个或多个G5所取代;
G1、G2、G3、G4和G5各自独立选自氰基,卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR10、-OC(O)NR10R11、-C(O)OR10、-C(O)NR10R11、-C(O)R10、-NR10R11、-NR10C(O)R11、-NR10C(O)NR11R12、-S(O)mR10或-NR10S(O)mR11,其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基,卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR13、-OC(O)NR13R14、-C(O)OR13、-C(O)NR13R14、-C(O)R13、-NR13R14、-NR13C(O)R14、-NR13C(O)NR14R15、-S(O)mR13或-NR13S(O)mR14的取代基所取代;
R3、R4、R5、R6、R7、R8、R10、R11、R12、R13、R14和R15各自独立选自氢、氰基、卤素、C1-6烷基、C3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基;且
m为1或2。
本发明根据所述结构通式(I)的化合物包括编号1-36的一种,但不限于以下化合物:
本发明提供了上述新型FGFR抑制剂或其异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐的方法。
本发明化合物可用于治疗或者预防FGFR相关性肿瘤、例如非小细胞肺癌、食管癌、黑色素瘤横纹肌肉瘤、细胞癌、多发性骨髓瘤、乳腺癌、卵巢癌、子宫内膜癌、***、胃癌、结肠癌、膀胱癌、胰腺癌、肺癌、***癌和肝癌(例如肝细胞癌)、更具体为肝癌、胃癌和膀胱癌。因此、再一方面,本发明提供一种治疗或者预防FGFR介导的疾病(例如所肿瘤的)方法、其包括给予有需要的患者治疗有效量的本发明所化合物或其前药、稳定同位素衍生物、多晶型物、溶剂化物、可药用的盐、异构体及其混合物、或包含所化合物的药物组合物。
本发明的另一方面涉及作为药物或者医药用途的通式(I)所示的化合物或其前药、稳定同位素衍生物、多晶型物、溶剂化物、可药用的盐、异构体及其混合物、其用于治或者预防FGFR介的疾病、例如肿瘤或炎症性疾病、包括但不限于非小细胞肺癌、食管癌、黑色素、横纹肌肉瘤、野细胞癌、多发性骨髓瘤、乳腺癌、卵巢癌、子宫内膜癌、宫癌、胃癌、结膈癌、膀胱癌、胰腺癌、肺癌、***癌。
本发明进一步涉及一种药物组合物,所述药物组合物包含本发明所述化合物或其前药、稳定同位素衍生物、可药用的盐异构体及其混合物及药学上可接受的载体、稀释剂、赋形剂。
本发明的另一方面涉及通式(I)所示的化合物或其前药稳定同位素衍生物、可药用的盐、异构体及其混合物、或所药物组合物在制备药物中的用途、其中所越药物用于治疗或者预防FGFR介的疾病例如肿瘤和炎症性疾病。
根据本发明,所药物可以是任何药物剂型包括但不限于片剂、囊剂、溶液剂、冻干制剂、注射剂。
某些化学术语
除非有相反陈述,否则下列用在说明书和权利要求书中的术语。
具有下述含义在本文中使用的表示方式“Cx-y”表示碳原子数的范围、其中x和y均为整数,例如C3-8环烷基表示具有3-8个碳原子的环烷基,即具有3、4、5、6、7或8个碳原子的环烷基。还应理解,“C3-8”还包含其中的任意亚范围、例如C3-7、C3-6、C4-7、C4-6、C5-6等。
“烷基”指含有1至20个碳原子,例如1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链或支链的烃基基团。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基和2-乙基丁基。所述烷基可以是取代的或未取代的。
“烯基”指含有至少一个碳碳双键和通常2至20个碳原子例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。烯基的非限制性实例包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基-2-丙烯基、1,4-戊二烯基和1,4-丁二烯基。所述烯基可以是取代的或未取代的。
“炔基”指含有至少一个碳碳三键和通常2至20个碳原子,例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。炔基的非限制性实例包括乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基和3-丁炔基。所述炔基可以是取代的或未取代的。
“环烷基”指含有3至14个碳环原子的饱和环形烃基取代基。环烷基可以是单碳环,通常含有3至7个碳环原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基和环庚基。环烷基可选择地可以是稠合到一起的双或三环、如十氢萘基、所述环烷基可以是取代的或未取代的。
“杂环基”、“杂环烷基”、“杂环”是指稳定的3-18元单价非芳香环,包括2-12个碳原子,1-6个选自氮、氧和硫的杂原子。除非另作说明,杂环基基团可以是单环、双环、三环或四环***,其可能包含稠环、螺环或桥环***,杂环基上的氮、碳或硫可选择性的被氧化,氮原子可选择性的被季铵化,杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环,只要与分子的其余部分连接的是非芳香环上的原子。为了本申请,杂环基优选的是一个稳定的4-11元单价非芳香单环或二环,其包含1-3个选自氮、氧和硫的杂原子,更优选的是一个稳定的4-8元单价非芳香单环,其包含1-3个选自氮、氧和硫的杂原子。杂环基的非限制性实例包括氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、1,1-二氧-硫代吗啉基、咪唑烷基、咪唑啉基、异噻唑烷基、异恶唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、恶嗪基、哌嗪基、哌啶基、4-哌啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎宁环基、四氢呋喃基、四氢吡喃基等。
“螺杂环基”指5至20元,单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子选自氮、氧或S(0)(其m是整数0至2)的杂原子,其余环原子为碳。这些可以含有一个或多个双键,但没有一个环具有完全共扼的电子***优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环基。螺环烷基的非限制性实施例包含:
“稠杂环基”指5至20元,***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***,其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实施例包含:
“芳基”或“芳香基”指含有6至14个碳原子的芳香族环或稠合多环基团,较佳为6至10元,例如苯基和萘基,最佳苯基所芳基环可以稠合于杂芳基、杂环基或环烷基环上、其中与母体结构连接在一起的环为芳基环、非限制性实例包括:
“杂芳基”或“杂芳香基”是指5-16元环状***,其包含1-15个碳原子,优选的1-10个碳原子,1-4个选自氮,氧和硫的杂原子,至少一个芳香环。除非另作说明,杂芳基可以是单环、双环、三环或四环***,其可能包含稠环或桥环***,只要与分子其它部分的连接点为芳环原子,杂芳环上的氮原子、碳原子和硫原子可以透择性的被氧化,氮原子可选择性的被季铵化。为了本发明,杂芳基优选的为稳定的4-11元单芳香环,其包含1-3个选自氮、氧和硫的杂原子,更优选的为稳定的5-8元单芳香环,其包含1-3个选自选自氮、氧和硫的杂原子。杂芳基的非限定性实例包括吖啶基、氮杂卓基、苯并咪唑基、苯并吲哚基、苯并二氧芑基、苯并二恶茂基、苯并呋喃酮基、苯并呋喃基、苯并萘并呋喃基、苯并吡喃酮基、苯并吡喃基、苯并吡唑基、苯并噻二唑基、苯并噻唑基、苯并***基、呋喃基、咪唑基、吲唑基、吲哚基、恶唑基、嘌呤基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、奎宁基、四唑基,噻二唑基、噻唑基、噻吩基、三嗪基,***基等。本申请中,杂芳基优选为5-8元杂芳基,其包含1-3选自选自氮、氧和硫的杂原子,更优选为吡啶基、嘧啶基、噻唑基。所述杂芳基可以是取代的或未取代的。
“卤素”指氟、氯、溴或碘。
“羟基”指-OH,“氨基”指-NH2,“酰胺基”指-NHCO-,“氰基”指-CN,“硝基”指-NO2,“异氰基”指-NC,“三氟甲基”指-CF3。
本文单独或作为其它成分的一部分使用的术语“杂原子”或“杂”是指除碳和氢之外的原子,杂原子独立地选自氧、氮、硫、磷、硅、硒和锡,但不限于这些原子,在出现两个或更多杂原子的实施方案中,所述两个或更多杂原子可彼此相同,或者所述两个或更多杂原子中的一些或全部此不同。
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个原子,较佳为5个、更佳为1~3个原子彼此独立地被相应数目的取代基取代。不言而喻,取代基处在它们的可能的化学位置本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离的胺基或羟基与具有不饱和(如烯烃)键的碳原子结合时可能是不稳定的。所述取代基包括但不限于羟基、胺基、卤素、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基等。
“药物组合物”指含有一种或多种本文所述的化合物或其可药用的盐或前药以及其他分例如可药用的载体和赋形剂的组合物。药物组合物的目的是促对生物体的给药、利于活性成分的吸收进而发挥生物活性。
“异构体”指具有相同分子式但其原子结合的性质或顺序或其原子的空间排列不同的化合物称为“异构体”、其原子空间排列不同的异构体称为“立体异构体”。立体异构体包括光学异构体、几何异构体和构象异构体。本发明的化合物可以以光学异构体形式存在。根据手性碳原子周围取代基的构型,这些光学异构体是“R”或“S”构型。光学异构体包括对映异构体和非对映异构体、制备和分离光学异构体的方法是本领域中已知的。
本发明的化合物也可以存在几何异构体。本发明考虑由碳-碳双键、碳-氮双键、环烷基或杂环基团周的取代基的分布所产生的各种几何异构体和其混合物。碳-碳双键或碳-氮键周围的取代基指定为Z或E构型、环烷基或杂环周围的取代基指定为顺式或反式构型。
本发明的化合物还可能显示互变异构现象,例如酮-烯醇互变异构。
应该理解,本发明包括任何互变异构或立体异构形式和其混合物、并且不仅限于化合物的命名或化学结式中所使用的任何一个互变异构或立体异构形式。
“同位素”是在本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。适合并入本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、氟和氯,分别例如但不限于2H、3H、13C、14C、15N、18O、31P、32P、35S、18F和36Cl。本发明的同位素标记化合物通常可通过本域技术人员已知的传统技术或通过与所附实施例中描的那些类似的方法使用适当的同位素标记的试剂代替非同位素标记的剂制。这样的化合物具有各种潜在用途、例如作为测定生物活性中的标样和试剂。在稳定同位素的情况下,这样的化合物具有有利地改变生物、药理学或药代动力学性质的潜力。
“前药”是指本发明的化合物可以以前药的形式给予。前药是指在活体内的生理条件下例如通过氧化、还原、水解等(它们各自利用酶或在没有酶参与下进行)转化成本发明的生物活性化合物的衍生物。前药的实例是下述化合物:其中本发明的化合物中的胺基被酰化、烷基化或磷酸化,例如二十烷酰基胺基、丙胺酰胺基、新戊酰氧基甲基胺基、或其中羟基被酰化、烷基化、磷酸化或转化成硼酸盐,例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙胺酰氧基、或其中羧基被酯化或酰胺化,或其中巯基与选择性地向靶和/或向细胞的胞质溶胶递送药物的载体分子,例如肽形成二硫桥键、这些化合物可以由本发明的化合物根据公知方法制备。
“可药用的盐”或者“药学上可接受的”是指由可药用的碱或酸,包括无机碱或酸和有机碱或酸制成的。在本发明的化合物含有一个或多个酸性或碱性基团的情况下,本发明还包含它们相应的可药用盐。因此,含有酸性基团的本发明的化合物可以以盐形式存在并可根据本发明使用,例如作为碱金属盐、碱土金属盐或作为铵盐。这样的盐的更确切实例包括钠盐、钾盐、钙盐、镁盐或与胺或有机胺,例如伯胺、仲胺、叔胺、环胺等,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、乙醇胺、二环己胺、乙二胺、嘌呤、哌嗪、哌啶、胆碱和咖啡因等特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因的盐。含有碱性基团的本发明的化合物可以盐形式存在并可根据本发明以它们与无机或有机酸的加成的形式使用。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、磷酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、胺基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其它酸。如果本发明的化合物在分子中同时含有酸性和碱性基团,本发明除所提到的盐形式外还包括内盐或内铵盐。各盐通过本领域技术人员已知的常规方法获得,例如通过在溶剂或分散剂中使这些与有机或无机酸或碱接触或通过与其它盐阴离子交换或阳离子交换。
因此,在本申请中当提及“化合物”、“本发明化合物”或“本发明所化合物”时,包括所有所述化合物形式、例如其前药、稳定同位素衍生物、可药用的盐、异构体、内消旋体、外消旋体、对映异构体、非对映异体及其混合物。
在本文中、术语“肿瘤”包括良性肿瘤和恶性肿瘤(例如癌症)。
在本文中,术语“癌症”包括FGFR激酶参与其发生的各种恶性肿瘤、包括但不限于非小细胞肺癌、食管癌、黑色素瘤、横纹肌肉榴、细胞癌、多发性骨髓瘤、乳腺癌卵巢癌、子宫膜癌、***、胃癌、结癌、膀胱癌、胰腺癌、肺癌、乳腺癌、***癌和肝癌(例如肝细胞癌),更具体为肝癌、胃癌和膀胱癌。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解或生物***的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本发明使用的术语“多晶型物”或“多晶型(现象)”是指本发明的化合物具有多种晶型格形态,本发明的一些化合物可能有一个以上的晶体形式,本发明涵盖所有的多品型态或其混合物。
本发明化合物的中间体化合物及其多品形物也在本发明的范围内。
结晶经常产生本发明化合物的溶剂化物,本文所用术语“溶剂化物”是指由一个或多个本发明化合物分子和一个或多个溶剂分子组合成的合体。
溶剂可以是水,这种情况下,溶剂化物是水合物。另外还可以是有机溶剂。因此,本发明化合物可作为水合物存在,包括一水合物、二水合物、半水合物、三水合物、四水合物等,以及相应的溶剂化形态。本发明化合物可以是真溶剂化物,但在其它一些情况下,本发明化合物也可能只是偶然保留了水或水跟一些其它溶剂的混合物本发明化合物可在一种溶剂中反应或在一种溶剂中沉淀或结晶。本发明化合物的溶剂化物也包括在本发明的范围内。
本文所用的跟制剂,组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂等渗剂、溶剂、或乳化剂。
文所用术语“主体”、“患者”、“对象”或“个体”是指患有疾病、紊乱或病症等的个体,包括哺乳动物和非哺乳动物,哺乳动物的实例包括但不限于哺乳动物纲的任何成员:人,非人的灵长类动物(例如黑猩猩和其它猿类和猴);家畜,例如牛,马、绵羊,山羊,猪;家养动物,例如兔,狗和猫;实验室动物,包括啮齿类动物,如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中,所述哺乳动物为人。
本文所用术语“治疗”是指对哺乳动物特别是人类的相关疾病病症的治疗,包括
(i)预防哺乳动物,特别是之前已经暴露在某个疾病或病症下但尚未被诊断患有该疾病或病症的哺乳动物,产生相应的疾病或病症;
(ii)抑制疾病或病症,即,控制其发展;
(iii)缓解疾病或病症,即,使疾病或病症消退缓;
(iv)缓解疾病或病症引起的症状。
本文所用术语“疾病”和“病症”可以互相替代,也可以是不同意思,因为某些特定疾病或病症还没有已知的致病因子(所以发病原因尚不清楚),所以还不能被认作疾病而只能被看做不想要的状况或综合症,所述综合症或多或少有一些具体症状已经被临床研究人员证实。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法这些方法。包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
合成方法
本发明还提供制备所述化合物的方法。本发明通式(I)所述化合物的制备,可通过以下示例性方法和实施例完成,但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可通过本领域技术人员所知的合成技术合成本发明所述的化合物,或者综合使用本领域已知方法和本发明所述的方法。每步应所得的产物用本领域已知的分离技术得到,包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需要的起始原料和化学试剂可以根据文献(reaxys)常规合成或购买。
本发明通式(I)所述炔代杂环类化合物可按照方法A所述路线合成:1、起始物A1与前体L-U-Y-P(其中L为离去基团,U-Y-P为含有带保护胺基的官能团,P为胺基的保护基)在碱作用下发生取代反应生成A2,可与一带有羟基的前体(HO-U-Y-P)通过光延反应(mitsunobu反应)得到A2;2、A2与芳香炔通过sonogashira偶联得到A3;3、A3中胺基去保护得到A4;4、A4中的胺基被含有和激酶配体结合域内半胱胺酸残基志反应的功能团的化学试剂(例如,烯丙酰氯等)衍生得到通式(I)所述化合物。
方法A:
也可以按照方法B所述路线合成,起始物A1与芳香炔通过sonogashira偶联得到B1;B1再与前体L-U-Y-P在碱作用下发生取代反应生成A3,或与一带有羟基的前体(HO-U-Y-P)通过光延反应(mitsunobu反应)得到A3;再用方法A的方法,得到通式(I)所述化合物。
方法B
也可以按照方法C所述路线合成,起始物A1与SEMCl在碱作用下上SEM保护基生成C1;C1与芳香炔通过sonogashira偶联得到C2;C2与前体L-U-Y-P在碱作用下发生取代反应生成B2,或与一带有羟基的前体(HO-U-Y-P)通过光延反应(mitsunobu反应)得到C3,除去保护基得到A4,再用方法A的方法,得到通式(I)所述化合物。
方法C
除非另有说明,温度是摄氏温度。试剂购自Chem blocks Inc、Astatech Inc或麦克林等商业供应商,并且这些试剂可直接使用无需进一步纯化,除非另有说明。
除非另有说明,下列反应在室温、无水溶剂中、氮气或气的正压下或使用干燥管进行;玻璃器皿烘干和/或加热干燥。
除非另有说明,柱色谱纯化使用青岛海洋化工厂的200-300目硅胶;制备薄层色谱使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254);MS的测定用ThernoLCD Fleet型(ESI)液相色谱-质谱联用仪。
核磁数据(1H NMR)使用Bruker Avance-400MHz或Varian Oxford-400Hz核磁仪,核磁数据使用的溶剂有CDCl3、CD3OD、D2O、DMS-d6等,以四甲基硅烷(0.000ppm)为基准或以残留溶剂为基准(CDCl3:7.26ppm;CD3OD:3.31ppm;D2O:4.79ppm;d6-DMSO:2.50ppm)当标明峰形多样性时,以下简写表示不同峰形:s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数,则以Hertz(Hz)为单位。
具体实施方式
以下通过具体的实施例进一步说明本发明。
实施例1:3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基氮杂环丁烷-3-胺基)-1H-吡唑[3,4-d]嘧啶(化合物1)的制备
步骤1:化合物1b的合成
于反应瓶中加入化合物4-氯-3-碘H-吡唑[3,4-d]嘧啶1a(2.81g,10.0mmol),3,5-二甲氧基苯乙炔(2.42g,15.0mmol),双三苯基磷二氯化钯(702mg,1.0mmol),碘化亚铜(190mg,1.0mmol),三乙胺(5.06g,50.0mmol)和N,N-二甲基甲酰胺50ml。氮气置换3次,搅拌下90℃反应过夜。冷却至室温,反应液用乙酸乙酯和水稀释,乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到化合物1b(2.04g,产率65%),LC/MS(ESI):m/z=313[M+H]+。
步骤2:化合物1c的合成
于反应瓶中加入化合物1b(0.94g,3.0mmol),1-叔丁氧羰基-3-氨基氮杂环丁烷(0.62g,3.6mmol),碳酸钾(0.83g,6.0mmol)和N,N-二甲基甲酰胺10ml。搅拌下100℃反应4小时。冷却至室温,反应液用乙酸乙酯和水稀释,乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到化合物1c(1.00g,产率74%),LC/MS(ESI):m/z=451[M+H]+。
步骤3:化合物1d的合成
于反应瓶中加入中间体1c(0.90g,2.0mmol),4ml乙酸乙酯,4N HCl的1,4-二氧六环溶液4ml。室温下搅拌2小时,反应液用1N氢氧化钠溶液中和,乙酸乙酯萃取。所得有机相再用饱和碳酸氢钠和饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。得到化合物1d(0.67g,产率96%),直接用于下一步,LC/MS(ESI):m/z=351[M+H]+。
步骤4:化合物1的合成
于反应瓶中加入化合物1d(350mg,1.0mmol),三乙胺(152mg,1.5mmol),4ml四氢呋喃,冰水浴冷却后缓慢滴加丙烯酰氯(136mg,1.5mmol)的0.5ml四氢呋喃溶液。加完后继续搅拌4小时。反应液用甲醇淬灭反应并减压蒸干。残余物通过柱层析纯化,得到化合物1(186mg,产率46%)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.82(s,1H),8.22(s,1H),6.94-6.65(m,5H),6.38(dd,1H),6.16(dd,1H),5.80-5.70(dd,1H),4.95-4.82(m,1H),4.58-4.52(t,1H),4.26-4.22(m,2H),3.99-3.90(m,1H),3.78(s,6H);LC/MS(ESI):m/z=405.1[M+H]+.
实施例2:3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基氮杂环丁烷-3-胺基)-1H-吡咯[3,4-d]嘧啶(化合物2)的制备
用与实施例1相似的方法步骤1:化合物2b的合成
于反应瓶中加入化合物4-氯-3-碘H-吡唑[3,4-d]嘧啶1a(2.80g,10.0mmol),3,5-二甲氧基苯乙炔(2.42g,15.0mmol),双三苯基磷二氯化钯(702mg,1.0mmol),碘化亚铜(190mg,1.0mmol),三乙胺(5.06g,50.0mmol)和N,N-二甲基甲酰胺50ml。氮气置换3次,搅拌下90℃反应过夜。冷却至室温,反应液用乙酸乙酯和水稀释,乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到化合物2b(2.22g,产率71%),LC/MS(ESI):m/z=314[M+H]+。
步骤2:化合物2c的合成
于反应瓶中加入化合物2b(0.94g,3.0mmol),1-叔丁氧羰基-3-氨基氮杂环丁烷(0.62g,3.6mmol),碳酸钾(0.83g,6.0mmol)和N,N-二甲基甲酰胺10ml。搅拌下100℃反应4小时。冷却至室温,反应液用乙酸乙酯和水稀释,乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到化合物1c(0.96g,产率71%),LC/MS(ESI):m/z=450[M+H]+。
步骤3:化合物1d的合成
于反应瓶中加入中间体2c(0.90g,2.0mmol),4ml乙酸乙酯,4N HCl的1,4-二氧六环溶液4ml。室温下搅拌2小时,反应液用1N氢氧化钠溶液中和,乙酸乙酯萃取。所得有机相再用饱和碳酸氢钠和饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。得到化合物2d(0.67g,产率93%),直接用于下一步,LC/MS(ESI):m/z=351[M+H]+。
步骤4:化合物1的合成
于反应瓶中加入化合物2d(350mg,1.0mmol),三乙胺(152mg,1.5mmol),4ml四氢呋喃,冰水浴冷却后缓慢滴加丙烯酰氯(136mg,1.5mmol)的0.5ml四氢呋喃溶液。加完后继续搅拌4小时。反应液用甲醇淬灭反应并减压蒸干。残余物通过柱层析纯化,得到化合物1(142mg,产率38%)为黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.04(s,1H),8.17(s,1H),6.94-6.77(m,5H),6.36-5.64(m,3H),4.83-4.76(m,1H),4.59(t,1H),4.31(t,1H),4.07-4.04(m,1H),3.74-3.78(m,7H);LC/MS(ESI):m/z=404.2[M+H]+.
实施例3:3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基氮杂环丁烷-3-甲胺基)-1H-吡唑[3,4-d]嘧啶(化合物3)的制备
用与实施例1相似的方法(中间体换为1-叔丁氧羰基-3-(氨甲基)吖丁啶)得到化合物3(147mg,产率35%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.81(s,1H),8.21(s,1H),6.94-6.65(m,4H),6.38(dd,1H),6.16(dd,1H),5.80-5.70(dd,1H),4.40(dd,1H),4.30(dd,1H),3.78(s,6H),3.70-3.60(m,2H),3.02-2.92(m,2H),2.75-2.65(m,1H);LC/MS(ESI):m/z=419.2[M+H]+.
实施例4:3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基吡咯烷-3-甲胺基)-1H-吡唑[3,4-d]嘧啶(化合物4)的制备
用与实施例1相似的方法(中间体换为1-叔丁氧羰基-3-(氨基甲基)吡咯烷)得到化合物4(164mg,产率38%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.82(s,1H),8.22(s,1H),6.95-6.54(m,5H),6.20-6.10(m,1H),5.72-5.62(m,1H),3.78(s,6H),3.60(m,2H),3.34(m,2H),3.17-3.00(m,2H),2.77-2.12(m,2H),1.77(m,1H);LC/MS(ESI):m/z=433.2[M+H]+.
实施例5:3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基哌啶-3-甲胺基)-1H-吡唑[3,4-d]嘧啶(化合物5)的制备
用与实施例1相似的方法(中间体换为1-叔丁氧羰基-3-(氨基甲基)哌啶)得到化合物5(138mg,产率31%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.81(s,1H),8.25(s,1H),6.95-6.55(m,5H),6.06(m,1H),5.64(m,1H),4.36(m,2H),4.01(m,2H),3.78(s,6H),3.06(m,2H),1.79(m,1H),1.59(m,2H),0.98(m,2H);LC/MS(ESI):m/z=447.2[M+H]+.
实施例6:3-(3,5-二甲氧基苯乙炔基)-4-(6-丙烯酰基-2,6-二氮螺[3,4]辛烷-2-基)-1H-吡唑[3,4-d]嘧啶(化合物6)的制备
用与实施例3相似的方法(中间体换为6-叔丁氧羰基-2,6-二氮螺[3,4]辛烷)得到化合物6(120mg,产率27%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.83(s,1H),8.23(s,1H),6.95-6.54(m,3H),6.46-6.38(m,2H),5.79-5.72(m,1H),4.50-4.43(m,4H),3.88-3.78(m,8H),3.75-3.62(m,2H),2.35-2.31(m,1H),2.29-2.22(m,1H);LC/MS(ESI):m/z=445.1[M+H]+.
实施例7:3-(3,5-二甲氧基苯乙炔基)-4-(6-丙烯酰基-2,6-二氮螺[3,4]庚烷-2-基)-1H-吡唑[3,4-d]嘧啶(化合物7)的制备
用与实施例1相似的方法(中间体换为6-叔丁氧羰基-2,6-二氮螺[3,4]庚烷)得到化合物7(108mg,产率25%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.83(s,1H),8.23(s,1H),6.95-6.29(m,5H),5.64(m,1H),4.60(s,4H),4.11(s,4H),3.78(s,6H);LC/MS(ESI):m/z=431.2[M+H]+.
实施例8:3-(3,5-二甲氧基苯乙炔基)-4-(6-丙烯酰基-2,6-二氮螺[3,5]壬烷-2-基)-1H-吡唑[3,4-d]嘧啶(化合物8)的制备
用与实施例3相似的方法(中间体换为6-叔丁氧羰基-2,6-二氮螺[3,5]壬烷)得到化合物8(124mg,产率27%,此为最后一步产率,下同)为淡黄色固体。LC/MS(ESI):m/z=459.2[M+H]+.
实施例9:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(3-丙烯酰胺基吡咯烷-1-基)-1H-吡唑[3,4-d]嘧啶(化合物9)的制备
用与实施例1相似的方法(中间体换为(S)-3-叔丁氧羰基氨基吡咯烷)得到化合物9(175mg,产率42%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.82(s,1H),8.39(d,1H),8.21(s,1H),6.94(d,2H),6.65(d,1H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.58(dd,1H),4.45-4.30(m,1H),3.78(s,6H),3.30-3.23(m,2H),3.14-2.97(m,2H),2.38-2.22(m,2H);LC/MS(ESI):m/z=419.2[M+H]+.
实施例10:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(3-丙烯酰胺基哌啶-1-基)-1H-吡唑[3,4-d]嘧啶(化合物10)的制备
用与实施例3相似的方法(中间体换为(S)-3-叔丁氧羰基氨基哌啶)得到化合物10(168mg,产率41%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.81(s,1H),8.23(s,1H),8.12(d,1H),6.94(d,2H),6.64(d,1H),6.22-6.16(m,1H),6.10-6.04(m,1H),5.59(dd,1H),4.02(s,1H),3.78(s,6H),3.57(m,2H),2.80(m,2H),1.88-1.69(m,1H),1.54(s,1H),1.44-1.14(m,2H);LC/MS(ESI):m/z=433.1[M+H]+.
实施例11:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基吡咯烷-3-胺基)-1H-吡唑[3,4-d]嘧啶(化合物11)的制备
用与实施例3相似的方法(中间体换为(S)-1-叔丁氧羰基-3-氨基吡咯烷)得到化合物11(150mg,产率36%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.82(s,1H),8.21(s,1H),6.94-6.64(m,4H),6.27(dd,1H),6.14(dd,1H),5.64(dd,1H),5.16(d,1H),4.34-4.10(m,1H)3.99-3.40(m,9H),2.34-2.18(m,1H),2.15-1.94(m,1H);LC/MS(ESI):m/z=419.2[M+H]+.
实施例12(S)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基哌啶-3-胺基)-1H-吡唑[3,4-d]嘧啶(化合物12)的制备
用与实施例3相似的方法(中间体换为(S)-1-叔丁氧羰基-3-氨基哌啶)得到化合物12(198mg,产率46%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.81(s,1H),8.22(s,1H),6.94-6.64(m,4H),6.84-6.36(m,1H),6.04(dd,1H),5.64(dd,1H),3.97(s,1H)3.81-3.77(m,8H),3.31-3,00(m,2H),1.77(m,1H),1.48(m,3H);LC/MS(ESI):m/z=433.2[M+H]+.
实施例13:(R)-3-(3,5-二甲氧基苯乙炔基)-4-(3-丙烯酰胺基吡咯烷-1-基)-1H-吡咯[3,4-d]嘧啶(化合物13)的制备
用与实施例2相似的方法(中间体换为(R)-3-叔丁氧羰基氨基吡咯烷)得到化合物13(141mg,产率34%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.06(s,1H),8.38(d,1H),8.16(s,1H),6.94-6.77(m,4H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.59(dd,1H),4.45-4.29(m,1H),3.77(s,6H),3.30-3.22(m,2H),3.14-2.96(m,2H),2.38-2.23(m,2H);LC/MS(ESI):m/z=418.2[M+H]+.
实施例14:3(S)-3-(3,5-二甲氧基苯乙炔基)-4-(3-丙烯酰胺基哌啶-1-基)-1H-吡咯[3,4-d]嘧啶(化合物14)的制备
用与实施例2相似的方法(中间体换为(S)-1-叔丁氧羰基-3-氨基哌啶)得到化合物5(151mg,产率35%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.08(s,1H),8.09(br s,1H),8.16(s,1H),6.95-6.76(m,4H),6.22-6.16(m,1H),6.10-6.04(m,1H),5.59(dd,1H),4.02(s,1H),3.77(s,6H),3.57(m,2H),2.80(m,2H),1.88-1.69(m,1H),1.54(s,1H),1.45-1.14(m,2H);LC/MS(ESI):m/z=432.1[M+H]+.
实施例15:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基吡咯烷-3-胺基)-1H-吡咯[3,4-d]嘧啶(化合物15)的制备
用与实施例2相似的方法(中间体换为(S)-1-叔丁氧羰基-3-氨基哌啶)得到化合物5(164mg,产率38%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.07(s,1H),8.17(s,1H),6.94-6.64(m,4H),6.27(dd,1H),6.14(dd,1H),5.64(dd,1H),5.16(d,1H),4.34-4.10(m,1H)3.99-3.40(m,9H),2.34-2.18(m,1H),2.15-1.93(m,1H);LC/MS(ESI):m/z=432.1[M+H]+.
实施例16:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基哌啶-3-胺基)-1H-吡咯[3,4-d]嘧啶(化合物16)的制备
用与实施例2相似的方法(中间体换为(S)-1-叔丁氧羰基-3-氨基哌啶)得到化合物16(125mg,产率29%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.07(s,1H),8.16(s,1H),6.94-6.64(m,5H),6.54-6.36(m,1H),6.04(dd,1H),5.64(dd,1H),3.97(s,1H)3.81-3.77(m,8H),3.31-3,00(m,2H),1.77(m,1H),1.48(m,3H);LC/MS(ESI):m/z=432.1[M+H]+.
实施例17:(R)-3-(3,5-二甲氧基苯乙炔基)-4-(3-丁-2-炔酰胺基吡咯烷-1-基)-1H-吡唑[3,4-d]嘧啶(化合物17)的制备
用与实施例3相似的方法(中间体换为(R)-3-叔丁氧羰基氨基吡咯烷)得到化合物17(125mg,产率29%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.81(s,1H),8.98(d,1H),8.23(s,1H),6.94(d,2H),6.65(d,1H),4.32(m,1H),3.78(s,6H),3.26-3.13(m,2H),3.12-2.97(m,2H),2.38-2.22(m,2H),2.00(s,3H);LC/MS(ESI):m/z=431.1[M+H]+.
实施例18:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(3-丁-2-炔酰胺基哌啶-1-基)-1H-吡唑[3,4-d]嘧啶(化合物18)的制备
用与实施例3相似的方法(中间体换为(S)-3-叔丁氧羰基氨基哌啶)得到化合物18(146mg,产率33%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.83(s,1H),8.46(s,1H),8.23(d,1H),6.94(d,2H),3.98-3.81(s,1H),3.78(s,6H)3.19-2.88(m,3H),2.80(m,1H),1.94(s,3H),1.88-1.80(m,1H),1.72(m,2H),1.33(m,1H);LC/MS(ESI):m/z=445.1[M+H]+.
实施例19:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丁-2-炔酰基吡咯烷-3-胺基)-1H-吡唑[3,4-d]嘧啶(化合物19)的制备
用与实施例3相似的方法(中间体换为(S)-1-叔丁氧羰基-3-氨基吡咯烷)得到化合物19(163mg,产率38%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.84(s,1H),8.23(s,1H),6.94-6.64(m,4H),4.53-4.11(m,3H)3.83-3.50(m,8H),2.34-2.18(m,1H),2.12-1.99(m,1H),1.97(s,3H);LC/MS(ESI):m/z=431.1[M+H]+.
实施例20:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丁-2-炔酰基哌啶-3-胺基)-1H-吡唑[3,4-d]嘧啶(化合物20)的制备
用与实施例3相似的方法(中间体换为(S)-1-叔丁氧羰基-3-氨基哌啶)得到化合物20(124mg,产率28%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.82(s,1H),8.23(s,1H),6.95-6.64(m,4H),3.97(s,1H)3.81-3.76(m,8H),3.31-3.00(m,2H),2.00(s,3H),1.77(m,1H),1.48(m,3H);LC/MS(ESI):m/z=445.2[M+H]+.
实施例21:(R)-3-(3,5-二甲氧基苯乙炔基)-4-(3-丁-2-炔酰胺基吡咯烷-1-基)-1H-吡唑[3,4-d]嘧啶(化合物21)的制备
用与实施例2相似的方法(中间体换为(R)-3-叔丁氧羰基氨基吡咯烷)得到化合物21(175mg,产率42%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.06(s,1H),8.98(d,1H),8.16(s,1H),6.94-6.54(m,4H),4.33-4.21(m,1H),3.77(s,6H),3.26-3.13(m,2H),3.12-2.97(m,2H),2.38-2.22(m,2H),2.00(s,3H);LC/MS(ESI):m/z=430.1[M+H]+.
实施例22:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(3-丁-2-炔酰胺基哌啶-1-基)-1H-吡唑[3,4-d]嘧啶(化合物22)的制备
用与实施例2相似的方法(中间体换为(S)-1-叔丁氧羰基-3-氨基哌啶)得到化合物22(128mg,产率29%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.08(s,1H),8.47(br s,1H),8.16(s,1H),6.95-6.75(m,4H),4.02(m,1H),3.77(s,6H)3.19-2.88(m,3H),2.80(m,1H),1.98(s,3H),1.88-1.80(m,1H),1.73(m,2H),1.34(m,1H);LC/MS(ESI):m/z=444.1[M+H]+.
实施例23:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丁-2-炔酰基吡咯烷-3-胺基)-1H-吡咯[3,4-d]嘧啶(化合物23)的制备
用与实施例2相似的方法(中间体换为(S)-1-叔丁氧羰基-3-氨基吡咯烷)得到化合物23(137mg,产率32%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.07(s,1H),8.16(s,1H),6.94-6.54(m,4H),4.53-4.11(m,3H)3.83-3.50(m,8H),2.34-2.18(m,1H),2.12-2.01(m,1H),1.98(s,3H);LC/MS(ESI):m/z=431.1[M+H]+.
实施例24:(S)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丁-2-炔酰基哌啶-3-胺基)-1H-吡咯[3,4-d]嘧啶(化合物24)的制备
用与实施例2相似的方法(中间体换为(S)-1-叔丁氧羰基-3-氨基哌啶)得到化合物24(146mg,产率33%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.08(s,1H),8.16(s,1H),6.94-6.54(m,5H),3.97(s,1H)3.82-3.76(m,8H),3.31-3.01(m,2H),2.04(s,3H),1.76(m,1H),1.49(m,3H);LC/MS(ESI):m/z=444.2[M+H]+.
实施例25:3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基哌啶-4-胺基)-1H-吡唑[3,4-d]嘧啶(化合物25)的制备
用与实施例1相似的方法(中间体换为1-叔丁氧羰基-4-氨基哌啶)得到化合物25(168mg,产率39%,此为最后一步产率,下同)为淡黄色固体。LC/MS(ESI):m/z=433.1[M+H]+.
实施例26:3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基哌啶-4-胺基)-1H-吡咯[3,4-d]嘧啶(化合物26)的制备
用与实施例2相似的方法(中间体换为1-叔丁氧羰基-4-氨基哌啶)得到化合物26(134mg,产率31%,此为最后一步产率,下同)为淡黄色固体。LC/MS(ESI):m/z=432.1[M+H]+.
实施例27:3-(3,5-二甲氧基苯乙炔基)-4-(3-丙烯酰胺基氮杂环丁烷-1-基)-1H-吡唑[3,4-d]嘧啶(化合物27)的制备
用与实施例1相似的方法(中间体换为3-叔丁氧羰基氨基氮杂环丁烷)得到化合物27(129mg,产率32%,此为最后一步产率,下同)为淡黄色固体。LC/MS(ESI):m/z=405.1[M+H]+.
实施例28:3-(3,5-二甲氧基苯乙炔基)-4-(3-丙烯酰胺基氮杂环丁烷-1-基)-1H-吡咯[3,4-d]嘧啶(化合物28)的制备
用与实施例2相似的方法(中间体换为3-叔丁氧羰基氨基氮杂环丁烷)得到化合物28(153mg,产率38%,此为最后一步产率,下同)为淡黄色固体。LC/MS(ESI):m/z=404.1[M+H]+.
实施例29:(R)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丁-2-炔酰基吡咯烷-1-胺基)-1H-吡唑[3,4-d]嘧啶(化合物29)的制备
用与实施例1相似的方法(中间体换为(R)-1-叔丁氧羰基-3-氨基吡咯烷)得到化合物29(133mg,产率32%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.84(s,1H),8.23(s,1H),6.94-6.64(m,4H),4.53-4.11(m,3H)3.83-3.50(m,8H),2.34-2.18(m,1H),2.12-1.99(m,1H),1.97(s,3H);LC/MS(ESI):m/z=431.1[M+H]+.
实施例30:(R)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基吡咯烷-1-胺基)-1H-吡唑[3,4-d]嘧啶(化合物30)的制备
用与实施例1相似的方法(中间体换为(R)-1-叔丁氧羰基-3-氨基吡咯烷)得到化合物30(159mg,产率38%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.82(s,1H),8.21(s,1H),6.94-6.64(m,4H),6.27(dd,1H),6.14(dd,1H),5.64(dd,1H),5.16(d,1H),4.34-4.10(m,1H)3.99-3.40(m,9H),2.34-2.18(m,1H),2.15-1.94(m,1H);LC/MS(ESI):m/z=419.2[M+H]+.
实施例31:3-(3,5-二甲氧基苯乙炔基)-4-(3-丙烯酰胺基吡咯烷-1-基)-1H-吡唑[3,4-d]嘧啶(化合物31)的制备
用与实施例1相似的方法(中间体换为3-叔丁氧羰基氨基吡咯烷)得到化合物31(134mg,产率32%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.82(s,1H),8.39(d,1H),8.21(s,1H),6.94(d,2H),6.65(d,1H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.58(dd,1H),4.45-4.30(m,1H),3.78(s,6H),3.30-3.23(m,2H),3.14-2.97(m,2H),2.38-2.22(m,2H);LC/MS(ESI):m/z=419.2[M+H]+.
实施例32:(R)-3-(3,5-二甲氧基苯乙炔基)-4-(3-丙烯酰胺基吡咯烷-1-基)-1H-吡唑[3,4-d]嘧啶(化合物32)的制备
用与实施例1相似的方法(中间体换为(R)-3-叔丁氧羰基氨基吡咯烷)得到化合物32(150mg,产率36%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:13.82(s,1H),8.39(d,1H),8.21(s,1H),6.94(d,2H),6.65(d,1H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.58(dd,1H),4.45-4.30(m,1H),3.78(s,6H),3.30-3.23(m,2H),3.14-2.97(m,2H),2.38-2.22(m,2H);LC/MS(ESI):m/z=419.2[M+H]+.
实施例33:(R)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丁-2-炔酰基吡咯烷-1-胺基)-1H-吡咯[3,4-d]嘧啶(化合物33)的制备
用与实施例1相似的方法(中间体换为(R)-1-叔丁氧羰基-3-氨基吡咯烷)得到化合物33(117mg,产率28%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.07(s,1H),8.16(s,1H),6.94-6.54(m,4H),4.53-4.11(m,3H)3.83-3.50(m,8H),2.34-2.18(m,1H),2.12-2.01(m,1H),1.98(s,3H);LC/MS(ESI):m/z=431.1[M+H]+.
实施例34:(R)-3-(3,5-二甲氧基苯乙炔基)-4-(1-丙烯酰基吡咯烷-3-胺基)-1H-吡咯[3,4-d]嘧啶(化合物34)的制备
用与实施例2相似的方法(中间体换为(R)-1-叔丁氧羰基-3-氨基吡咯烷)得到化合物33(108mg,产率26%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.07(s,1H),8.17(s,1H),6.94-6.64(m,4H),6.27(dd,1H),6.14(dd,1H),5.64(dd,1H),5.16(d,1H),4.34-4.10(m,1H)3.99-3.40(m,9H),2.34-2.18(m,1H),2.15-1.93(m,1H);LC/MS(ESI):m/z=418.1[M+H]+.
实施例35:3-(3,5-二甲氧基苯乙炔基)-4-(3-丙烯酰胺基吡咯烷-1-基)-1H-吡咯[3,4-d]嘧啶(化合物35)的制备
用与实施例2相似的方法(中间体换为(S)-3-叔丁氧羰基氨基吡咯烷)得到化合物35(133mg,产率31%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.06(s,1H),8.38(d,1H),8.16(s,1H),6.94-6.77(m,4H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.59(dd,1H),4.45-4.29(m,1H),3.77(s,6H),3.30-3.22(m,2H),3.14-2.96(m,2H),2.38-2.23(m,2H);LC/MS(ESI):m/z=419.2[M+H]+.
实施例36:(R)-3-(3,5-二甲氧基苯乙炔基)-4-(3-丙烯酰胺基吡咯烷-1-基)-1H-吡咯[3,4-d]嘧啶(化合物36)的制备
用与实施例1相似的方法(中间体换为(S)-3-叔丁氧羰基氨基吡咯烷)得到化合物36(134mg,产率32%,此为最后一步产率,下同)为淡黄色固体。1H NMR(400MHz,DMSO-d6)δ:12.06(s,1H),8.38(d,1H),8.16(s,1H),6.94-6.77(m,4H),6.33-6.20(m,1H),6.14-6.04(m,1H),5.59(dd,1H),4.45-4.29(m,1H),3.77(s,6H),3.30-3.22(m,2H),3.14-2.96(m,2H),2.38-2.23(m,2H);LC/MS(ESI):m/z=419.2[M+H]+.
实施例37:对激酶FGFR1、FGFR2、FGFR3和FGFR4的体外活性抑制作用测试
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定FGFR1、FGFR2、FGFR3和FGFR4蛋白激酶活性。将化合物用DMSO溶解后用激酶缓冲液稀释,在384孔板中加入5μL的5倍反应终浓度的化合物(10%DMS0)。加入10μL的2.5倍酶(分别用FGFR1、FGFR2、FGFR3和FGFR4)溶液后在室温下孵育10分钟,再加入10μL的2.5倍底物(FAM-labeledpeptide and ATP)溶液。28℃下孵育30-60分钟后加25μL终止液(pH 7.5 100mM HEPES,0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA)终止反应。Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据。把转化率转化成抑制率数据(%抑制率=(max-样品转化率)/(max-min)*100)。其中max是指DMSO对照的转化率,min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标,绘制曲线,使用XLFit excel add-inversion4.3.1软件拟合曲线并计算IC50。测定结果见下表显示化合物1-28对于激酶FGFR1、FGFR2、FGFR3和FGFR4的活性数据。活性利用IC50表征,其中“A”表示IC50≤10nM;“B”表示10<IC50≤100nM;“C”表示100<IC50≤500nM;“D”表示500<IC50≤2000nM。
表1对FGFR1、FGFR2、FGFR3和FGFR4的抑制活性
实施例38:人肝癌细胞Hep3B存活试验
人肝癌Hep3B细胞株来源于ATCC。细胞用DMEM液体培养基培养,另外加入胎牛血清(10%FBS)、青霉素-链霉素(100,000U/L)。细胞在培养基中保持37℃、95%的湿度和5%的二氧化碳。实验时将Hep3B细胞以每孔3000个细胞的密度铺种于96孔板中,细胞悬液体积为每孔100PL,并培养细胞过夜,使细胞附着。次日,将各化合物以三倍梯度用DMSO稀释,将1PL化合物DMSO溶液加入细胞培养基中,同时以IM DMSO作为对照,每个化合物的各浓度均设三个平行副孔。之后将细胞置于37℃培养箱,经连续72小时化合物处理后,向细胞培养基中添加50μL CellTiter-Glo(Promega,Madison WI),并确定各孔的相对发光单位(RLU)并计算细胞存活率和化合物活性(IC50),其中“A”表示IC50≤10nM;“B”表示10<IC50≤100nM;“C”表示100<IC50≤500nM;“D”表示500<IC50≤2000nM。实施例化合物对Hep3B细胞抑制活性结果如下表2所示:
表2对Hep3B细胞的抑制活性
样品编号 | IC<sub>50</sub>(nM) |
1 | A |
9 | A |
11 | A |
19 | A |
23 | A |
27 | A |
31 | A |
Claims (7)
1.一种具有通式(I)所示的化合物或者其前药、稳定同位素衍生物、可药用的盐、多晶型物或异构体,
其中:
X1,X2,X3,X4可以独立地选自N、CR1;
环B为苯环或者5-6元杂芳环,其中上述的苯环和杂芳环任选被一个或多个G1所取代;
R1独立地选自H、氰基、卤素、C1-6烷基、COOH、CONH2、NHCOH、CONHR2、OR2或-NHR2;
R2独立地选自H、氰基、卤素、C1-6烷基、C3-6环烷基、3-6元杂环烷基、-OR3、-NR3R4、-C(O)NR3R4,其中所述的烷基、环烷基或杂环烷基任选被氰基、卤素、-OR5、-NR5R6、C1-6烷基、C3-6环烷基或3-6元杂环烷基;
U独立地选自-C0-4烷基-、-CR7R8-、-C1-2烷基(R7)(OH)-、-C(O)-、-CR7R8O-、-OCR7R8-、-SCR7R8-、-CR7R8S-、-NR7-、-NR7C(O)-、-C(O)NR7-、-NR7C(O)NR8-、-CF2-、-O-、-S-、-S(O)m-、-NR7S(O)2-、-S(O)2NR7-;
Y不存在或选C3-8环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基,其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G2所取代;
键a为双键或者三键;
当a为双键时,Ra、Rb和Rc各自独立地选自H、氰基,卤素、C1-6烷基、C3-6环烷基或3-6元杂环基。其中所述烷基,环烷基和杂环基任选被1个或多个G3所取代;
Ra和Rb或Rb和Rc任选与它们连接的碳原子共同形成一任选含有杂原子的3-6元环;
当键a为三键时,Ra和Rc不存在,Rb独立选自H、氰基,卤素、C1-6烷基、C3-6环烷基或3-6元杂环基被一个或多个G4所取代;
R9独立地选自H、C1-6烷基、C3-6环烷基或3-6元杂环基,其中所述烷基,环烷基和杂环基任选被1个或多个G5所取代;
G1、G2、G3、G4和G5各自独立选自氰基,卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR10、-OC(O)NR10R11、-C(O)OR10、-C(O)NR10R11、-C(O)R10、-NR10R11、-NR10C(O)R11、-NR10C(O)NR11R12、-S(O)mR10或-NR10S(O)mR11,其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氰基,卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR13、-OC(O)NR13R14、-C(O)OR13、-C(O)NR13R14、-C(O)R13、-NR13R14、-NR13C(O)R14、-NR13C(O)NR14R15、-S(O)mR13或-NR13S(O)mR14的取代基所取代;
R3、R4、R5、R6、R7、R8、R10、R11、R12、R13、R14和R15各自独立选自氢、氰基、卤素、C1-6烷基、C3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基;且
m为1或2。
2.根据权利要求1所述的化合物或其前药、稳定同位素衍生物、药学上可接受的盐,多晶型物或异构体及其混合物形式。
4.一种药物组合物,包含权利要求1-3所述的化合物或其前药、稳定同位素衍生物、药学上可接受的盐、溶剂化物、多晶型物或异构体,以及药学上可接受的载体。
5.根据权利要求中任一项所述的化合物或其前药、稳定同位素衍生物、药学上可接受的盐、溶剂化物、多晶型物或异构体在制备用来治疗FGFR介导的疾病的药物中的用途。
6.根据权利要求5所述的用途,其中所述FGFR介导的疾病为非小细胞肺癌、食管癌、黑色素瘤、胃癌、多发性骨髓瘤、肝癌、胆管癌、***癌、皮肤癌、卵巢癌、子宫内膜癌、***、膀胱癌、乳腺癌、结肠癌、胶质瘤、以及横纹肌肉瘤中的一种或多种。
7.根据权利要求5中的任一项的化合物或其前药、稳定同位素衍生物、药学上可接受的盐、溶剂化物、多晶型物或异构体,以及药学上可接受的载体,其用作药物使用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110118468.0A CN114805359B (zh) | 2021-01-28 | 2021-01-28 | 炔代杂环化合物fgfr抑制剂的制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110118468.0A CN114805359B (zh) | 2021-01-28 | 2021-01-28 | 炔代杂环化合物fgfr抑制剂的制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114805359A true CN114805359A (zh) | 2022-07-29 |
CN114805359B CN114805359B (zh) | 2023-10-27 |
Family
ID=82525607
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110118468.0A Active CN114805359B (zh) | 2021-01-28 | 2021-01-28 | 炔代杂环化合物fgfr抑制剂的制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114805359B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024083111A1 (zh) * | 2022-10-18 | 2024-04-25 | 首药控股(北京)股份有限公司 | 一种新型杂环化合物 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103958512A (zh) * | 2012-01-19 | 2014-07-30 | 大鹏药品工业株式会社 | 3,5-双取代炔基苯化合物及其盐 |
US20160136168A1 (en) * | 2013-07-18 | 2016-05-19 | Taiho Pharmaceutical Co., Ltd. | Therapeutic agent for fgfr inhibitor-resistant cancer |
US20190183897A1 (en) * | 2013-07-18 | 2019-06-20 | Taiho Pharmaceutical Co., Ltd. | Antitumor drug for intermittent administration of fgfr inhibitor |
US20190350932A1 (en) * | 2016-03-04 | 2019-11-21 | Taiho Pharmaceutical Co., Ltd. | Preparation and composition for treatment of malignant tumors |
WO2020170355A1 (ja) * | 2019-02-20 | 2020-08-27 | 大鵬薬品工業株式会社 | Fgfr1変異腫瘍の治療方法 |
-
2021
- 2021-01-28 CN CN202110118468.0A patent/CN114805359B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103958512A (zh) * | 2012-01-19 | 2014-07-30 | 大鹏药品工业株式会社 | 3,5-双取代炔基苯化合物及其盐 |
US20160136168A1 (en) * | 2013-07-18 | 2016-05-19 | Taiho Pharmaceutical Co., Ltd. | Therapeutic agent for fgfr inhibitor-resistant cancer |
US20190183897A1 (en) * | 2013-07-18 | 2019-06-20 | Taiho Pharmaceutical Co., Ltd. | Antitumor drug for intermittent administration of fgfr inhibitor |
US20190350932A1 (en) * | 2016-03-04 | 2019-11-21 | Taiho Pharmaceutical Co., Ltd. | Preparation and composition for treatment of malignant tumors |
WO2020170355A1 (ja) * | 2019-02-20 | 2020-08-27 | 大鵬薬品工業株式会社 | Fgfr1変異腫瘍の治療方法 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024083111A1 (zh) * | 2022-10-18 | 2024-04-25 | 首药控股(北京)股份有限公司 | 一种新型杂环化合物 |
Also Published As
Publication number | Publication date |
---|---|
CN114805359B (zh) | 2023-10-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN115073469B (zh) | 吡咯并嘧啶类化合物作为激酶抑制剂的制备及其应用 | |
JP2019520367A (ja) | 新規なヘテロサイクリック誘導体化合物およびその用途 | |
CN115073450A (zh) | Krasg12c突变蛋白抑制剂的制备及其应用 | |
CN114805359A (zh) | 炔代杂环化合物fgfr抑制剂的制备方法和用途 | |
CN115028633B (zh) | 吡咯并嘧啶类化合物的制备及其应用 | |
CN112851587A (zh) | 一种用于治疗癌症的炔类杂环化合物及其制备方法与用途 | |
CN115181106B (zh) | 喹唑啉类krasg12d突变蛋白抑制剂的制备及其应用 | |
CN114853723B (zh) | 吲哚类化合物btk抑制剂的制备及其应用 | |
CN112939982A (zh) | 一种炔类杂环btk抑制剂及其制备方法和用途 | |
CN114057749B (zh) | 不可逆炔类杂环化合物fgfr抑制剂的制备方法和用途 | |
CN115073451A (zh) | Krasg12d突变蛋白抑制剂的制备及其应用 | |
CN114853739B (zh) | 一种炔代吡嗪类fgfr抑制剂及其制备方法和用途 | |
CN115028634B (zh) | 一种炔代吡嗪并杂环类fgfr抑制剂及其制备方法和用途 | |
CN114853752B (zh) | Btk抑制剂吡啶并杂环类化合物的制备及其应用 | |
CN114853740B (zh) | 炔类嘧啶化合物作为fgfr抑制剂的制备方法和用途 | |
CN115215868A (zh) | 杂环化合物fgfr抑制剂的制备方法和用途 | |
CN114957242B (zh) | 吡啶并杂环类化合物作为激酶抑制剂的制备及其应用 | |
CN115043832B (zh) | 一种fgfr抑制剂炔代杂环类化合物及其制备方法和用途 | |
CN114957241B (zh) | 杂环类化合物作为激酶抑制剂的制备及其应用 | |
CN115141176B (zh) | 炔代吲哚类fgfr抑制剂及其制备方法和用途 | |
CN115073468B (zh) | 咪唑并吡嗪类btk抑制剂的制备及用途 | |
CN115043841B (zh) | 一种作为btk抑制剂杂环类化合物的制备及其应用 | |
CN115368381B (zh) | 杂环类抑制剂的制备及其应用 | |
CN115433190A (zh) | 不可逆杂环化合物fgfr抑制剂的制备方法和用途 | |
CN117229261A (zh) | 一种egfr抑制剂的制备及其应用 |
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 | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20240122 Address after: 650201 No. 871, Longquan Road, Panlong District, Kunming City, Yunnan Province Patentee after: Yunnan Wanhong Pharmaceutical Technology Co.,Ltd. Country or region after: China Address before: 201800 room 2042, No.37, Lane 588, Shuping Road, Juyuan New District, Jiading District, Shanghai Patentee before: YAOYA TECHNOLOGY (SHANGHAI) Co.,Ltd. Country or region before: China |