CN115322158B - As KRASG12CSubstituted quinazoline compounds of protein inhibitor - Google Patents
As KRASG12CSubstituted quinazoline compounds of protein inhibitor Download PDFInfo
- Publication number
- CN115322158B CN115322158B CN202210979546.0A CN202210979546A CN115322158B CN 115322158 B CN115322158 B CN 115322158B CN 202210979546 A CN202210979546 A CN 202210979546A CN 115322158 B CN115322158 B CN 115322158B
- Authority
- CN
- China
- Prior art keywords
- carcinoma
- pharmaceutically acceptable
- kras
- acceptable salt
- substituted quinazoline
- 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.)
- Active
Links
- 229940121649 protein inhibitor Drugs 0.000 title abstract description 4
- 239000012268 protein inhibitor Substances 0.000 title abstract description 4
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title description 3
- -1 quinazoline compound Chemical class 0.000 claims abstract description 51
- 102200006538 rs121913530 Human genes 0.000 claims abstract description 25
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 13
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims description 42
- 238000002360 preparation method Methods 0.000 claims description 24
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 201000009030 Carcinoma Diseases 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010039491 Sarcoma Diseases 0.000 claims description 5
- 210000004027 cell Anatomy 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 230000035772 mutation Effects 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 206010029260 Neuroblastoma Diseases 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 3
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims description 3
- 208000010667 Carcinoma of liver and intrahepatic biliary tract Diseases 0.000 claims description 3
- 208000030808 Clear cell renal carcinoma Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010014733 Endometrial cancer Diseases 0.000 claims description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 3
- 206010073069 Hepatic cancer Diseases 0.000 claims description 3
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 3
- 208000028018 Lymphocytic leukaemia Diseases 0.000 claims description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 claims description 3
- 208000008900 Pancreatic Ductal Carcinoma Diseases 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 3
- 208000008938 Rhabdoid tumor Diseases 0.000 claims description 3
- 206010073334 Rhabdoid tumour Diseases 0.000 claims description 3
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 3
- 208000034254 Squamous cell carcinoma of the cervix uteri Diseases 0.000 claims description 3
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 claims description 3
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 3
- 208000033781 Thyroid carcinoma Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 208000002517 adenoid cystic carcinoma Diseases 0.000 claims description 3
- 208000020990 adrenal cortex carcinoma Diseases 0.000 claims description 3
- 208000007128 adrenocortical carcinoma Diseases 0.000 claims description 3
- 206010005084 bladder transitional cell carcinoma Diseases 0.000 claims description 3
- 201000001528 bladder urothelial carcinoma Diseases 0.000 claims description 3
- 210000004556 brain Anatomy 0.000 claims description 3
- 210000000481 breast Anatomy 0.000 claims description 3
- 208000019065 cervical carcinoma Diseases 0.000 claims description 3
- 201000006612 cervical squamous cell carcinoma Diseases 0.000 claims description 3
- 201000010240 chromophobe renal cell carcinoma Diseases 0.000 claims description 3
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 3
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 claims description 3
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 3
- 208000030381 cutaneous melanoma Diseases 0.000 claims description 3
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 3
- 201000003914 endometrial carcinoma Diseases 0.000 claims description 3
- 201000005619 esophageal carcinoma Diseases 0.000 claims description 3
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 208000010749 gastric carcinoma Diseases 0.000 claims description 3
- 208000005017 glioblastoma Diseases 0.000 claims description 3
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 3
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 3
- 230000000366 juvenile effect Effects 0.000 claims description 3
- 201000002250 liver carcinoma Diseases 0.000 claims description 3
- 208000030173 low grade glioma Diseases 0.000 claims description 3
- 201000005296 lung carcinoma Diseases 0.000 claims description 3
- 201000005243 lung squamous cell carcinoma Diseases 0.000 claims description 3
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 3
- 201000008968 osteosarcoma Diseases 0.000 claims description 3
- 201000005292 ovarian small cell carcinoma Diseases 0.000 claims description 3
- 201000008129 pancreatic ductal adenocarcinoma Diseases 0.000 claims description 3
- 201000001514 prostate carcinoma Diseases 0.000 claims description 3
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 claims description 3
- 201000003708 skin melanoma Diseases 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 201000000498 stomach carcinoma Diseases 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 208000013077 thyroid gland carcinoma Diseases 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- 208000000172 Medulloblastoma Diseases 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- 229940001468 citrate Drugs 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- 230000008595 infiltration Effects 0.000 claims description 2
- 238000001764 infiltration Methods 0.000 claims description 2
- 229940001447 lactate Drugs 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 208000012988 ovarian serous adenocarcinoma Diseases 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 206010046766 uterine cancer Diseases 0.000 claims description 2
- 208000012991 uterine carcinoma Diseases 0.000 claims description 2
- 206010052399 Neuroendocrine tumour Diseases 0.000 claims 1
- 230000000968 intestinal effect Effects 0.000 claims 1
- 208000016065 neuroendocrine neoplasm Diseases 0.000 claims 1
- 201000011519 neuroendocrine tumor Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 230000002503 metabolic effect Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- 239000000203 mixture Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 20
- 102100030708 GTPase KRas Human genes 0.000 description 18
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 239000012453 solvate Substances 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000012636 effector Substances 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 102000016914 ras Proteins Human genes 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- LAYPMCGIWDGYKX-UHFFFAOYSA-N trichloromethyl hydrogen carbonate Chemical compound OC(=O)OC(Cl)(Cl)Cl LAYPMCGIWDGYKX-UHFFFAOYSA-N 0.000 description 4
- UDLWJRJHSHVPGS-UHFFFAOYSA-N 2-amino-5-hydroxy-4-methoxybenzoic acid Chemical compound COC1=CC(N)=C(C(O)=O)C=C1O UDLWJRJHSHVPGS-UHFFFAOYSA-N 0.000 description 3
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 206010069755 K-ras gene mutation Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 3
- 108091007960 PI3Ks Proteins 0.000 description 3
- 102000038030 PI3Ks Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000003281 allosteric effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000008297 liquid dosage form Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- PEMUGDMSUDYLHU-ZEQRLZLVSA-N 2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile Chemical compound ClC=1C=CC=C2C=CC=C(C=12)N1CC=2N=C(N=C(C=2CC1)N1C[C@@H](N(CC1)C(C(=C)F)=O)CC#N)OC[C@H]1N(CCC1)C PEMUGDMSUDYLHU-ZEQRLZLVSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 101100342473 Drosophila melanogaster Raf gene Proteins 0.000 description 2
- 102000018898 GTPase-Activating Proteins Human genes 0.000 description 2
- 108091006094 GTPase-accelerating proteins Proteins 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101100523543 Rattus norvegicus Raf1 gene Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 101100523549 Xenopus laevis raf1 gene Proteins 0.000 description 2
- 101150037250 Zhx2 gene Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229940124988 adagrasib Drugs 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 201000010329 small intestine neuroendocrine neoplasm Diseases 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- NXQKSXLFSAEQCZ-SFHVURJKSA-N sotorasib Chemical group FC1=CC2=C(N(C(N=C2N2[C@H](CN(CC2)C(C=C)=O)C)=O)C=2C(=NC=CC=2C)C(C)C)N=C1C1=C(C=CC=C1O)F NXQKSXLFSAEQCZ-SFHVURJKSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ZGNUEQDNAAGMNY-MRVPVSSYSA-N tert-butyl (2r)-4-carbonochloridoyl-2-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(Cl)=O)CCN1C(=O)OC(C)(C)C ZGNUEQDNAAGMNY-MRVPVSSYSA-N 0.000 description 2
- FMLPQHJYUZTHQS-MRVPVSSYSA-N tert-butyl (3r)-3-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-MRVPVSSYSA-N 0.000 description 2
- BSLGONYLMNUSQK-MRVPVSSYSA-N tert-butyl (3r)-4-carbonochloridoyl-3-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(Cl)=O BSLGONYLMNUSQK-MRVPVSSYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000005955 1H-indazolyl group Chemical group 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- DPELYVFAULJYNX-UHFFFAOYSA-N 2-amino-4-hydroxybenzoic acid Chemical compound NC1=CC(O)=CC=C1C(O)=O DPELYVFAULJYNX-UHFFFAOYSA-N 0.000 description 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FNDZIIJCKXGZJA-UHFFFAOYSA-N 4-hydroxy-2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1[N+]([O-])=O FNDZIIJCKXGZJA-UHFFFAOYSA-N 0.000 description 1
- DVZBWONCSHFMMM-UHFFFAOYSA-N 4-methoxy-2-nitrobenzoic acid Chemical compound COC1=CC=C(C(O)=O)C([N+]([O-])=O)=C1 DVZBWONCSHFMMM-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000031618 GDP binding proteins Human genes 0.000 description 1
- 108091009874 GDP binding proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 102100029974 GTPase HRas Human genes 0.000 description 1
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010067218 Guanine Nucleotide Exchange Factors Proteins 0.000 description 1
- 102000016285 Guanine Nucleotide Exchange Factors Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- 101150105104 Kras gene Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108091008611 Protein Kinase B Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 241000713810 Rat sarcoma virus Species 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 101000744436 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Trans-acting factor D Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 108010059447 Son of Sevenless Proteins Proteins 0.000 description 1
- 102000005588 Son of Sevenless Proteins Human genes 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 101710176296 Switch 2 Proteins 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 102100025093 Zinc fingers and homeoboxes protein 2 Human genes 0.000 description 1
- YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000007630 basic procedure Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 230000002710 gonadal effect Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000024312 invasive carcinoma Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 239000000401 methanolic extract Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical class CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960003552 other antineoplastic agent in atc Drugs 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 102000001720 ral Guanine Nucleotide Exchange Factor Human genes 0.000 description 1
- 108010029592 ral Guanine Nucleotide Exchange Factor Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 102200006531 rs121913529 Human genes 0.000 description 1
- 102200006539 rs121913529 Human genes 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 102000030938 small GTPase Human genes 0.000 description 1
- 108060007624 small GTPase Proteins 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940073531 sotorasib Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- ZGNUEQDNAAGMNY-QMMMGPOBSA-N tert-butyl (2S)-4-carbonochloridoyl-2-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(CCN1C(=O)OC(C)(C)C)C(Cl)=O ZGNUEQDNAAGMNY-QMMMGPOBSA-N 0.000 description 1
- DATRVIMZZZVHMP-MRVPVSSYSA-N tert-butyl (2r)-2-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-MRVPVSSYSA-N 0.000 description 1
- DATRVIMZZZVHMP-QMMMGPOBSA-N tert-butyl (2s)-2-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-QMMMGPOBSA-N 0.000 description 1
- BSLGONYLMNUSQK-QMMMGPOBSA-N tert-butyl (3S)-4-carbonochloridoyl-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(CCN1C(=O)Cl)C(=O)OC(C)(C)C BSLGONYLMNUSQK-QMMMGPOBSA-N 0.000 description 1
- FMLPQHJYUZTHQS-QMMMGPOBSA-N tert-butyl (3s)-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-QMMMGPOBSA-N 0.000 description 1
- BSLGONYLMNUSQK-UHFFFAOYSA-N tert-butyl 4-carbonochloridoyl-3-methylpiperazine-1-carboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)CCN1C(Cl)=O BSLGONYLMNUSQK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 229910052722 tritium Chemical group 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a substituted quinazoline compound serving as a KRAS G12C protein inhibitor, belonging to the field of biological medicine. The invention provides a substituted quinazoline compound with a structure shown in a general formula (I), which has good KRAS G12C protein inhibitory activity, and has better targeted inhibition selectivity under the condition of ensuring good KRAS G12C inhibitory activity and metabolic stability.
Description
Technical Field
The invention relates to a substituted quinazoline compound serving as a KRAS G12C protein inhibitor, belonging to the field of biological medicine.
Background
Mutations in the KRAS gene (KIRSTEN RAT Sarcoma Viral Oncogene Homolog, kirsten rat sarcoma virus oncogene homolog) were first found in NSCLC gene in 1984, which encodes a GTP/GDP-binding protein belonging to the family of small gtpases, consisting of six β -sheets, five α -helices, with a KRAS protein size of 20kda, functioning as a molecular switch to turn on/off transduction in regulating tyrosine kinases and their associated cellular signaling pathways, and the molecules involved in signaling in the cellular signaling pathways in which KRAS protein participates being EGFR, raf, MEK, MAPK, PI3K, akt. Activation of KRAS is achieved after attachment to GTP under the influence of guanine nucleotide exchange factors (including SOS proteins, RAF, PI3K, etc.), inactivation of KRAS proteins being by attachment to GDP. When GTP is linked to KRAS proteins, the conformation of KRAS is altered, which facilitates interactions of KRAS with downstream signaling proteins such as: raf, PI3K, ral-GDS, etc., result in proliferation and growth of cancer cells. The inactivation of KRAS is achieved by the action of KRAS and GAPs (gtpase activating proteins), so that the connection of KRAS and GDP is achieved by enhancing the gtpase action of KRAS proteins, and by this mechanism, KRAS plays an important role in cell proliferation and regulation of cell signal transduction.
The KRAS protein consists of 188 amino acids in total of three domains with significant functional differences, which are respectively an effector region, an allosteric region and a hypervariable region. Wherein the effector region is a KRAS protein substrate binding unit which binds mainly to effector proteins and nucleotides, and is itself divided into three regions: loop area, switch1 area, switch2 area. The hypervariable region has 86% and 15% amino acid sequence homology with the allosteric region relative to the other RAS subtypes, respectively, with respect to the amino acid sequence of the effector region being highly conserved (100% homology among the different RAS subtypes), whereas the hypervariable region is involved in KRAS and recognition of the cell membrane by KRAS.
KRAS mutations are associated with 22% of human cancers, with lung cancer accounting for 17%, colon cancer accounting for 33%, and pancreatic cancer accounting for 61%.80% of KRAS mutations occur at codon 12, resulting in single amino acid substitutions, glycine to cysteine (G12C, 14%), aspartic acid (G12D, 36%), valine (G12V, 23%), wherein the RAS mutation for lung cancer is predominantly KRAS mutation (44%).
Due to the high expression of KRAS G12C mutations in tumor patients, the patients can also develop drug resistance to other targeted drugs, and KRAS G12C protein attracts more and more experts and scholars. However, over the last three decades of effort, the development of small molecule inhibitors directly against KRAS G12C targets for clinical use remains elusive, and thus there is an urgent need in the art for small molecules that target the RAS (e.g., KRAS, HRAS or NRAS) and use thereof to treat a variety of diseases, such as cancer.
Alexach corporation has obtained the first KRAS G12C inhibitor ARS-1620 for the allosteric site of KRAS G12C, followed by many types of KRAS G12C inhibitors built on the parent structure of ARS-1620, currently the only inhibitor of KRAS G12C marketed in bulk is Sotorasib (AMG-510) from Amgen corporation and another KRAS G12C inhibitor marketed in application is Adagrasib (MRTX 849).
Disclosure of Invention
In order to solve the above problems in the prior art, the present invention provides a compound having the general formula (I) (including stereoisomers and tautomers thereof) or pharmaceutically acceptable salts thereof, a pharmaceutical composition and uses thereof. The compound has the characteristic of targeted inhibition of KRAS G12C protein.
The invention aims to provide a substituted quinazoline compound with a structural general formula shown in formula 1, or optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
Wherein:
m is 1 or 2;
r 1 is selected from methoxy, hydroxy, amino, halogen (F, cl, br, I), methylamino, C1-C2 alkyl, C1-C2 alkoxy;
Y is an oxygen atom or a nitrogen atom;
R 2 is selected from aryl or heteroaryl, which may be substituted with 1 to 2 of the following groups: halogen, C1-C2 alkoxy, hydroxy, amino, cyano, C1-C2 alkyl, C3-C6 cycloalkyl;
r 3 is mono-to trisubstituted, selected from hydrogen, methyl, hydroxymethyl, or For/>
R 4 is independently selected from hydrogen, fluorine, methoxy;
R 5 is mono-to trisubstituted selected from hydrogen, methyl, hydroxymethyl; or alternatively For/>
In one embodiment of the invention, R 1 is selected from methoxy or methylamino.
In one embodiment of the invention, R 2 is selected from aryl or heteroaryl, which may be substituted with 1 of the following groups: halogen (fluorine, chlorine, bromine, iodine), C1-2 alkoxy, cyano.
In one embodiment of the present invention,Preferably/>Wherein R 3' and R 3" are each independently selected from hydrogen, methyl, hydroxymethyl; or/>For/>
In one embodiment of the invention, R 3' and R 3" are not both hydrogen.
In one embodiment of the invention, R 4 is hydrogen or fluorine.
In one embodiment of the present invention,R 5 in (B) is preferably methyl, hydroxymethyl, orFor/>
In one embodiment of the invention, Y is oxygen or nitrogen.
In one embodiment of the present invention, aryl refers to a substituted or unsubstituted benzene ring, naphthalene ring.
In one embodiment of the invention, heteroaryl means that the substituted or unsubstituted heteroaryl is a mono-or bicyclic aromatic ring system having 5 to 12 ring atoms, wherein at least one atom in the ring system is a heteroatom selected from N, O and S. The definition also includes ring systems in which heteroaryl groups are fused to a benzene ring. Examples of suitable "heteroaryl rings" or "heteroaryl groups" are furyl, furazanyl, imidazolyl, 1H-indazolyl, indolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, thiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl and thienyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazole, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl.
Preferably:
in certain embodiments of the present invention, m is selected to be 1.
In certain embodiments of the invention, Y is oxygen.
In certain embodiments of the invention, R 4 is independently selected from hydrogen.
In certain embodiments of the invention, R 1 is selected from methoxy.
In certain embodiments of the invention, R 2 is selected from halo (chlorofluoro) aryl, alkoxy (C1-C2) aryl, and the inventors have found that such groups result in better protein inhibitory activity due to more favorable hydrophobic interactions.
In certain embodiments of the invention, R 3 is selected from methyl.
In certain embodiments of the invention, R 5 is selected from hydrogen.
In certain embodiments of the invention, the compounds have the following structure and steric configuration:
In certain embodiments of the invention, to obtain better KRAS G12C protein inhibitory activity, the compounds preferably have the following structure and steric configuration:
in one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt, and the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, salicylate.
The invention also provides application of the substituted quinazoline compound or each optical isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof in preparing medicines for preventing or treating KRAS G12C protein-mediated diseases.
The invention also provides a pharmaceutical composition containing the substituted quinazoline compound, or each optical isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.
In one embodiment of the present invention, the pharmaceutical composition further comprises: a pharmaceutically acceptable carrier, excipient or diluent.
The invention also provides application of the substituted quinazoline compound or each optical isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof in preparing KRAS G12C mutation inhibitor.
The present invention also provides a method of treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or any combination of the foregoing, or a pharmaceutical composition of the foregoing.
The invention also provides a medicine for treating cancers, which comprises the substituted quinazoline compound, or optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof.
In one embodiment of the invention, the cancer is pancreatic ductal carcinoma, colorectal carcinoma, multiple myeloma, lung carcinoma, cutaneous melanoma, endometrial carcinoma, uterine sarcoma, thyroid carcinoma, acute myelogenous leukemia, bladder urothelial carcinoma, gastric carcinoma, cervical carcinoma, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung carcinoma, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenal cortical carcinoma, prostate carcinoma, neuroblastoma, brain low-grade glioma, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdoid tumor, sarcoma, small intestine neuroendocrine tumor, T cell juvenile lymphocytic leukemia.
The beneficial effects are that:
The compound with the structure shown in the general formula (I) provided by the invention has certain selectivity and novel structure under the condition of ensuring good KRAS G12C inhibitory activity and metabolic stability.
Detailed Description
The technical scheme of the present invention will be described in detail with reference to examples.
In the context of the present invention "(1-2C) alkyl" refers to a saturated branched or branched monovalent hydrocarbon radical of 1 to 2 carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl. "(1-3C) alkyl" is analogically defined, specific examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl.
In the present invention, "halogen" means fluorine, chlorine, bromine and iodine.
In the present invention, "pharmaceutically acceptable salts" refer to those salts which retain the biological effectiveness and properties of the parent compound. The term "salt" refers to any salt of a compound according to the invention prepared from an inorganic or organic acid or base and an internally formed salt. Typically, such salts have a physiologically acceptable anion or cation.
In the present invention, "administering" or "administering" a compound to an individual refers to providing a compound of the present invention to an individual in need of treatment.
Reference throughout this specification to "an embodiment" or "in another embodiment" or "in certain embodiments" or "in some embodiments" means that a particular reference element, structure, or feature described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" or "in some embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.
< Compound or pharmaceutically acceptable salt >
Further, the compounds of formula (I) or their salts may be isolated in the form of solvates, and thus any such solvates are within the scope of the invention.
The compounds of formula (I) also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of the invention include compounds in which one or more hydrogen atoms are replaced with deuterium or tritium or one or more carbon atoms are replaced with 13C-or 14C-enriched carbon, which are within the scope of the invention.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as solid formulations for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, and the like. In these solid dosage forms, the compounds of formula (I) according to the invention are mixed as active ingredient with at least one conventional inert excipient (or carrier), for example with sodium citrate or dicalcium phosphate. Or with the following components: (1) Fillers or solubilisers, for example starch, lactose, sucrose, glucose, mannitol, silicic acid and the like; (2) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like; (3) humectants, for example, glycerin, etc.; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and the like; (5) a slow solvent such as paraffin wax or the like; (6) absorption accelerators such as quaternary ammonium compounds and the like; (7) Wetting agents such as cetyl alcohol and glycerol monostearate, and the like; (8) adsorbents such as kaolin and the like; (9) Lubricants, for example, talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, and the like, or mixtures thereof. Buffers may also be included in capsules, tablets, pills.
The solid dosage forms, such as tablets, dragees, capsules, pills and granules, may be provided with coatings and shell materials such as enteric coatings and other materials known in the art in the form of crystalline coatings or microencapsulations. They may contain opacifying agents and the release of the active ingredient in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active ingredient may also be in the form of microcapsules with one or more of the above excipients, if desired.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like. In addition to the compounds of formula (I) or pharmaceutically acceptable salts thereof as active ingredients, liquid dosage forms may contain inert diluents commonly used in the art such as water and other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular cottonseed, groundnut, corn, olive, castor, sesame oils and the like or mixtures of these substances and the like. In addition to these inert diluents, the liquid dosage forms of the present invention can also include conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents and the like.
Such suspending agents include, for example, ethoxylated stearyl alcohol, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar-agar, and the like, or mixtures of these.
The compounds of the present invention and pharmaceutically acceptable salts thereof may be formulated in dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into dosage forms for topical administration, including, for example, ointments, powders, suppositories, drops, sprays, inhalants and the like. The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts as active ingredients are mixed under sterile conditions with physiologically acceptable carriers and optionally with preservatives, buffers and, if appropriate, propellants.
The pharmaceutical composition of the invention comprises a compound of a general formula (I) or pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable carriers, excipients and diluents. In preparing pharmaceutical compositions, the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention are typically admixed with a pharmaceutically acceptable carrier, excipient or diluent, in a unit dosage of formulation comprising from 0.05g to 210mg of a compound of formula (I) or pharmaceutically acceptable salt thereof, preferably from 0.1mg to 100mg of a compound of formula (I).
< Use >
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of KRAS G12C protein-related cancers.
A method for treating cancer in a mammal, including a human, by maintaining KRAS G12C in an inactive state to close a signal pathway that promotes proliferation of cancer cells, comprising administering to the mammal, including a human, a therapeutically effective amount of a compound of formula (I) above, or a pharmaceutically acceptable salt thereof.
A "therapeutically effective amount" is an amount of a compound of the invention effective to produce a biological or medical response (e.g., reduce or inhibit the activity of an enzymatically active protein, or ameliorate symptoms, alleviate a condition, slow or delay the progression of a disease, or prevent a disease) in an individual.
Cancers contemplated by the present invention include pancreatic ductal carcinoma, colorectal carcinoma, multiple myeloma, lung carcinoma, cutaneous melanoma, endometrial carcinoma, uterine carcinoma sarcoma, thyroid carcinoma, acute myelogenous leukemia, bladder urothelial carcinoma, gastric carcinoma, cervical carcinoma, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung carcinoma, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver carcinoma, breast infiltration carcinoma, cervical squamous cell carcinoma, ovarian serous gonadal carcinoma, adrenocortical carcinoma, prostate carcinoma, neuroblastoma, brain low-grade glioma, glioblastoma, neuroblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdoid tumor, sarcoma, small intestine neuroendocrine tumor, T cell juvenile lymphocytic leukemia.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered to mammals, including humans, orally, rectally, parenterally (intravenous, intramuscular or subcutaneous), topically (powders, ointments, drops) or intratumorally.
The compounds of the present invention and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing such compounds or salts thereof, may be used in combination with other anti-neoplastic agents or therapies such as radiation or chemotherapy.
The following examples illustrate, but do not limit, the synthesis of compounds of formula (I).
The temperatures are in degrees celsius. Reagents were purchased from commercial suppliers and used without further purification, if not otherwise indicated. The structures of the final products, intermediates and starting materials are confirmed by standard analytical methods, such as spectroscopic characterization, MS, NMR, and abbreviations used are conventional in the art.
Preparation of intermediate a:
the preparation method of 4-chloro-2-methoxyquinazoline-7-acetate (intermediate A) comprises the following steps:
Step a, preparation of 4-hydroxy-2-nitrobenzoic acid:
4-methoxy-2-nitrobenzoic acid (20 g,101.5 mmol) was suspended in 100mL of 40% hydrobromic acid and 100mL of acetic acid. The reaction was carried out at 120℃for 20h, and the completion of the reaction was detected by TLC. Cooling the reaction system to room temperature, and concentrating under reduced pressure to obtain a crude product; the crude product was dissolved in 150mL of methylene chloride, saturated aqueous sodium bicarbonate was added, the aqueous phase was separated, the pH was adjusted to about 2 with 1M hydrochloric acid, extracted with ethyl acetate, the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and dried to give 20.2g of crude 2-amino-5-hydroxy 4-methoxybenzoic acid as a yellow solid.
Step b, preparation of 2-amino-4-hydroxybenzoic acid:
A mixture of 2-amino-5-hydroxy 4 methoxybenzoic acid (20.2 g,110.38 mmol) and 2g Pd-C (10%) in 100mL (V 1:V2 =1:1) of a mixed solvent of methanol-tetrahydrofuran was stirred for 3h at room temperature under hydrogen atmosphere, and the reaction was complete by TLC. Filtration, washing with methanol, combining methanol extracts, and evaporation of the solvent under reduced pressure gave the product as a black solid (10.47 g, 62% yield).
Step c, preparation of 2-methoxyquinazoline-4, 7-diol:
To a mixture of 2-amino-5-hydroxy 4 methoxybenzoic acid (10.47 g,68.43 mmol) and 2-methoxyethanol (150 mL) was added oxymethylisourea hydrochloride (15.12 g,136.86 mmol), and the mixture was heated to 125℃and reacted overnight, and the completion of the reaction was detected by TLC. The reaction solution is cooled and distilled under reduced pressure, the residue is poured into 250mL of water, ammonia water is added dropwise to adjust the pH value to 7, the filtration is carried out, a filter cake is washed by water, and the filter cake is dried in vacuum to obtain brown solid 2-methoxyquinazoline-4, 7-diol (8.93 g, yield 68%) for synthesizing the 4-hydroxy-2-methoxyquinazoline-7-yl acetate in the step d:
To a mixture of 2-methoxyquinazoline-4, 7-diol (8.93 g,46.53 mmol) and 65mL of acetic anhydride was added pyridine (7.36 g,93.06 mmol), heated to 80℃and reacted for 1h, and TLC detection was complete. The reaction solution was cooled and distilled under reduced pressure, and the residue was poured into 100mL of water, filtered, and the cake was dried under vacuum to give 4-hydroxy-2-methoxyquinazolin-7-yl acetate (10.57 g, yield 97%) as a gray solid.
Step e, preparation of 4-chloro-2-methoxyquinazolin-7-acetate:
To a mixture of 4-hydroxy-2-methoxyquinazoline-7-acetate (10.57 g,45.13 mmol) and 1, 2-dichloroethane (80 mL) was added dropwise 80mL of thionyl chloride followed by 2 drops of N, N' -dimethylformamide, and after the addition, the reaction was refluxed at 80℃and detected by TLC to be complete. The solvent was distilled off under reduced pressure, the residue was poured into 150mL of water, a saturated aqueous sodium hydrogencarbonate solution was slowly added dropwise to the residue under ice bath, the pH was adjusted to 8-9, filtration was carried out, the cake was washed with water, and the cake was dried under vacuum to give 4-chloro-2-methoxyquinazolin-7-yl acetate (9.89 g, yield 87%) as a white solid.
Preparing an intermediate B:
Preparation method of (S) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (intermediate B):
step f, (S) -preparation of tert-butyl 4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylate:
Pyridine (0.79 g,10.08 mmol) and a solution of tert-butyl (S) -3-methylpiperazine-1-carboxylate (0.67 g,3.36 mmol) in dichloromethane were added dropwise to a mixture of 20mL of anhydrous dichloromethane and trichloromethyl carbonate (1 g,3.36 mmol) at 0deg.C under nitrogen, and after the addition, the mixture was allowed to stand at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give yellow solid B (0.79 g, yield 90%) which was used in the next reaction without further purification.
Preparation of intermediate C:
preparation method of (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (intermediate C):
Step g preparation of (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester
Pyridine (0.96 g,12.15 mmol) and a solution of tert-butyl (R) -3-methylpiperazine-1-carboxylate (0.81 g,4.05 mmol) in dichloromethane were added dropwise to a mixture of 20mL of anhydrous dichloromethane and trichloromethyl carbonate (1.2 g,4.05 mmol) at 0deg.C under nitrogen, and the mixture was stirred overnight after the dropwise addition. The reaction mixture was concentrated under reduced pressure to give C (0.98 g, yield 93%) as a yellow solid, which was used in the next reaction without further purification.
Preparation of intermediate D:
Preparation method of (R) -4- (chlorocarbonyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (intermediate D):
Step h preparation of (R) -4- (chlorocarbonyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
Pyridine (0.79 g,10.08 mmol) and a solution of tert-butyl (R) -2-methylpiperazine-1-carboxylate (0.67 g,3.36 mmol) in dichloromethane were added dropwise to a mixture of 20mL of anhydrous dichloromethane and trichloromethyl carbonate (1 g,3.36 mmol) at 0deg.C under nitrogen, and after the addition, the mixture was allowed to stand at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give yellow solid D (0.78 g, 89% yield) which was used in the next reaction without further purification.
Preparation of intermediate E:
Preparation method of (S) -4- (chlorocarbonyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (intermediate E):
Preparation of step i
Pyridine (0.89 g,11.13 mmol) was added dropwise to a mixture of 20mL of anhydrous dichloromethane and trichloromethyl carbonate (1.1 g,3.71 mmol) at 0℃under nitrogen, followed by dropwise addition of a dichloromethane solution of tert-butyl (S) -2-methylpiperazine-1-carboxylate (0.74 g,3.71 mmol), and the mixture was allowed to stand at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give yellow oil E (0.88 g, 91% yield), which was used in the next reaction without further purification.
Example 1:4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -4-acryl-2-methylpiperazine-1-carboxylate
The synthetic route is as follows:
the preparation process comprises the following steps:
Step j, preparation of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazoline-7-acetate:
To 4-chloro-2-methoxyquinazoline-7-acetate (500 mg,1.98 mmol) was added 1, 4-dioxane (15 mL), N-diisopropylethylamine (0.27 g,2.15 mmol) was added dropwise in this order with stirring at 40℃and 1- (4-chlorophenyl) piperazine (0.42 g,2.15 mmol) was added and the mixture was stirred at 50℃for 1.5h. TLC monitored complete consumption of starting material. Standing, cooling the reaction system to room temperature, concentrating to dryness, adding 20mL of water, extracting with DCM (2X 10 mL), and combining organic phases. The organic phase was washed with water (1 x 15 ml), saturated sodium chloride (1 x10 ml), dried over anhydrous sodium sulfate, filtered off with suction and distilled under reduced pressure to give 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl acetate as a crude product (0.74 g,1.72mmol, 84% crude yield) which was taken directly to the next step without further treatment.
Step k, preparation of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-ol:
4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazoline-7-acetate (0.74 g,1.79 mmol) was dissolved in anhydrous methanol (10 mL), and anhydrous potassium carbonate solid (0.53 g,3.90 mmol) was added and stirred at room temperature overnight. TLC detection was complete. Distillation under reduced pressure gave a residue which was purified by column chromatography to give 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-ol (0.463 g,1.25mmol, yield 70%).
Step l, preparation of 4- (tert-butyl) 1- (4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl) (R) -2-methylpiperazine-1, 4-dicarboxylic acid ester:
To a reaction system of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-ol (0.463 g,1.25 mmol) and anhydrous potassium carbonate (0.345 g,2.5 mmol) in N, N-dimethylformamide (13 mL) was added (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.5 g,2.5 mmol) and the mixture was stirred overnight at room temperature. TLC detects the completion of the starting material reaction. The reaction was added dropwise to 60mL of ice water continuously stirred, stirred for 10min after the addition was completed, left standing for 10min, suction-filtered, and the cake was dried in a vacuum oven at 40℃for 3h to give 4- (tert-butyl) 1- (4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl) (R) -2-methylpiperazine-1, 4-dicarboxylic acid ester (4813 mg,0.81mmol, yield 65.8%).
Step m, preparation of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -2-methylpiperazine-1-carboxylate
To the compound 4- (tert-butyl) 1- (4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl) (R) -2-methylpiperazine-1, 4-dicarboxylic acid ester (481 mg,0.81 mmol) was added 15mL of a 4M hydrogen chloride-methanol solution, and the mixture was stirred at room temperature for 1h, and the reaction was completed by TLC. The compound 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -2-methylpiperazine-1-carboxylate hydrochloride (0.38 g,0.78mmol, 97% yield) was obtained by distillation under reduced pressure, and was directly fed to the next reaction without further treatment.
Step n, preparation of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -4-acryloyl-2-methylpiperazine-1-carboxylate
To the compound 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -2-methylpiperazine-1-carboxylate hydrochloride (0.38 g,0.78 mmol) was added dichloromethane (8.0 mL), N, N-diisopropylethylamine (403 mg,3.12 mmol), after dissolving, a solution of acryloyl chloride (211 mg,2.34 mmol) diluted with dichloromethane (0.5 mL) was added and stirred at-20℃for 30min. After TLC detection of the reaction of the starting materials, the reaction solution was moved to room temperature, 10mL of saturated sodium bicarbonate and 3mL of stirring were added for 30min, the solution was separated, the organic phase was washed with water (2X 10 mL), saturated sodium chloride solution (2X 10 mL) was washed, the organic phase was evaporated to dryness and then directly stirred and passed through a column to give 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -4-acryl-2-methylpiperazine-2-carboxylate (236 mg,0.43mmol, yield 56.3%).
MS(ESI)m/z:551[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.69(s,1H),7.62(s,1H),7.28(d,J=19.1Hz,1H),6.99(t,J=8.6Hz,2H),6.92(dd,J=9.1,4.6Hz,2H),6.56(t,J=13.6Hz,1H),6.41–6.33(m,1H),5.80–5.73(m,1H),4.64(s,1H),3.96(s,3H),3.90–3.83(m,4H),3.29(s,10H),1.31(s,3H).
The substituted quinazolines corresponding to examples 2-7 were synthesized following procedures similar to the basic procedure of example 1.
Example 2: 2-methoxy-4- (4-phenylpiperazin-1-yl) quinazolin-7-yl (R) -4-acryloyl-2-methylpiperazine-1-carboxylate
Synthesis reference examples of 2-methoxy-4- (4-phenylpiperazin-1-yl) quinazolin-7-yl (R) -4-propenoyl-2-methylpiperazine-1-carboxylate 1.LC-MS(ESI)m/z:517[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.75(s,1H),7.35(s,1H),7.24(t,J=7.9Hz,2H),6.98(d,J=8.1Hz,2H),6.79(d,J=7.1Hz,1H),6.22–6.13(m,1H),5.75(s,1H),5.73(d,J=2.2Hz,1H),4.32(d,J=38.4Hz,1H),3.94(s,3H),3.83–3.80(m,4H),3.35(s,10H),1.24(s,3H).
Example 3: 2-methoxy-4- (4-phenylpiperazin-1-yl) quinazolin-7-yl (S) -4-acryloyl-2-methylpiperazine-1-carboxylate
Synthesis reference examples of 2-methoxy-4- (4-phenylpiperazin-1-yl) quinazolin-7-yl (S) -4-acryloyl-2-methylpiperazin-1-carboxylate 1.LC-MS(ESI)m/z:517[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.64(s,1H),7.31(s,1H),7.24(t,J=7.9Hz,2H),6.99(d,J=8.1Hz,2H),6.89(d,J=7.1Hz,1H),6.22–6.13(m,1H),5.75(s,1H),5.73(d,J=2.2Hz,1H),4.32(d,J=38.4Hz,1H),3.94(s,3H),3.83–3.80(m,4H),3.39(s,10H),1.77(s,3H).
Example 4:4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -4-acryloyl-3-methylpiperazine-1-carboxylate
Synthesis of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -4-acryloyl-3-methylpiperazine-1-carboxylate reference examples 1.MS(ESI)m/z:551[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.68(s,1H),7.62(s,1H),7.40(s,1H),7.26–7.21(m,2H),6.87(d,J=8.9Hz,2H),6.40(s,1H),6.17–6.05(m,1H),5.88–5.82(m,1H),5.80–5.75(m,1H),3.96(s,3H),3.92–3.87(m,4H),3.33(d,J=9.1Hz,8H),2.94–2.66(m,2H),1.32(s,3H).
Example 5:4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (S) -4-acryloyl-3-methylpiperazine-1-carboxylate
Synthesis of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (S) -4-acryloyl-3-methylpiperazine-1-carboxylate reference examples 1.MS(ESI)m/z:551[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.70(s,1H),7.62(d,J=6.6Hz,1H),7.32(s,1H),7.28–7.21(m,2H),6.88(d,J=8.6Hz,2H),6.58(dd,J=16.3,10.7Hz,1H),6.35(d,J=16.6Hz,1H),5.76(d,J=10.5Hz,1H),4.15(dd,J=17.6,10.0Hz,1H),3.96(s,3H),3.87(s,4H),3.42–2.99(m,8H),2.05(s,2H),1.37(d,J=14.9Hz,3H).
Example 6: 2-methoxy-4- (4- (4-methoxyphenyl) piperazin-1-yl) quinazolin-7-yl (R) -4-acryloyl-2-methylpiperazine-1-carboxylate
Synthesis reference examples of 2-methoxy-4- (4- (4-methoxyphenyl) piperazin-1-yl) quinazolin-7-yl (R) -4-acryloyl-2-methylpiperazine-1-carboxylate 1.MS(ESI)m/z:547[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.69(s,1H),7.63(d,J=6.9Hz,1H),7.32(s,1H),7.29–7.18(m,3H),6.89(d,J=8.7Hz,2H),6.59(d,J=16.9Hz,1H),6.35(d,J=11.5Hz,1H),5.74(d,J=4.8Hz,1H),3.96(s,6H),3.86(s,4H),3.34(s,10H),1.36(d,J=19.9Hz,3H).
Example 7: KRAS G12C -SOS1 protein complex inhibition rate test
The test concentration of the test compound was 500nM, diluted to 200-fold final concentration in 100% DMSO in 384 well plates. 50nl 200-fold final concentration of compound was transferred to the destination plate 384-well-plate using a dispenser Echo 550. 50nl of 100% DMSO is added to each of the negative control well and the positive control well, a 4-time final concentration of Tag1-SOS1 solution is prepared by using a reagent buffer, 2.5 μl of a 4-time final concentration of Tag1-SOS1 solution is added to a 384-well plate, and a 4-time final concentration of Tag2-KRAS-G12C solution is prepared by using a reagent buffer; 2.5 μl diluent buffer was added to the negative control wells. The 384-well plate was centrifuged at 1000rpm for 30 seconds, and incubated at room temperature for 15 minutes after shaking and mixing. The Detection buffer was prepared with 1-fold final concentration of Anti-Tag1-TB3+ solution and 1-fold final concentration of Anti-Tag2-XL665 solution, and after mixing the two solutions, 5. Mu.l of Mix solution was added to each well. The 384-well plate was centrifuged at 1000rpm for 30s, mixed with shaking, incubated at room temperature for 120min, and the readings were recorded with an Envision microplate reader. The specific results are shown in Table 1.
Table 1 specific inhibition (500 nM) of the examples and commercial compounds
Examples numbering | KRAS G12C -SOS1 protein complex inhibition rate (n=2) |
1 | 60.7%±3.2 |
2 | 45.7%±1.2 |
3 | 41.2%±0.7 |
4 | 63.1%±3.2 |
5 | 63.2%±3.5 |
6 | 93.8%±4.2 |
ARS-1620 | 81.7%±1.2 |
While the invention has been illustrated by the foregoing specific examples, it should not be construed as being limited thereto; but rather the invention encompasses the generic aspects previously disclosed. Various modifications and embodiments can be made without departing from the spirit and scope of the invention.
Claims (8)
1. A substituted quinazoline compound or pharmaceutically acceptable salt thereof, wherein the structure of the substituted quinazoline compound is as follows:
2. The substituted quinazoline compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an inorganic salt or an organic salt; inorganic salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, salicylate.
3. Use of a substituted quinazoline compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis or treatment of a KRAS G12C protein-mediated disease.
4. A pharmaceutical composition comprising a substituted quinazoline compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition of claim 4, further comprising: a pharmaceutically acceptable carrier, excipient or diluent.
6. Use of a pharmaceutical composition of a substituted quinazoline compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, in the preparation of a KRAS G12C mutation inhibitor.
7. A medicament for the treatment of cancer comprising a substituted quinazoline compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof.
8. The medicament for treating cancer according to claim 7, wherein the cancer is pancreatic ductal carcinoma, colorectal carcinoma, multiple myeloma, lung carcinoma, cutaneous melanoma, endometrial carcinoma, uterine carcinoma sarcoma, thyroid carcinoma, acute myelogenous leukemia, bladder urothelial carcinoma, gastric carcinoma, cervical carcinoma, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung carcinoma, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver carcinoma, breast infiltration carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenocortical carcinoma, prostate carcinoma, neuroblastoma, brain low-grade glioma, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdoid tumor, sarcoma, small intestinal neuroendocrine tumor, T cell juvenile lymphocytic leukemia.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210979546.0A CN115322158B (en) | 2022-08-16 | 2022-08-16 | As KRASG12CSubstituted quinazoline compounds of protein inhibitor |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210979546.0A CN115322158B (en) | 2022-08-16 | 2022-08-16 | As KRASG12CSubstituted quinazoline compounds of protein inhibitor |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115322158A CN115322158A (en) | 2022-11-11 |
CN115322158B true CN115322158B (en) | 2024-04-30 |
Family
ID=83923361
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210979546.0A Active CN115322158B (en) | 2022-08-16 | 2022-08-16 | As KRASG12CSubstituted quinazoline compounds of protein inhibitor |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115322158B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024083120A1 (en) * | 2022-10-18 | 2024-04-25 | 南京明德新药研发有限公司 | Benzylaminoquinoline compound and preparation method therefor |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111848584A (en) * | 2020-07-10 | 2020-10-30 | 江南大学 | Polysubstituted quinazoline compound and application thereof |
CN114656411A (en) * | 2022-04-12 | 2022-06-24 | 江南大学 | Polysubstituted quinazoline compound serving as EGFR/HER2 double-target-point inhibitor and application thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20220152026A1 (en) * | 2019-02-12 | 2022-05-19 | Novartis Ag | Pharmaceutical combination comprising tno155 and a krasg12c inhibitor |
-
2022
- 2022-08-16 CN CN202210979546.0A patent/CN115322158B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111848584A (en) * | 2020-07-10 | 2020-10-30 | 江南大学 | Polysubstituted quinazoline compound and application thereof |
CN113307797A (en) * | 2020-07-10 | 2021-08-27 | 江南大学 | Polysubstituted quinazoline compound and application thereof |
CN114656411A (en) * | 2022-04-12 | 2022-06-24 | 江南大学 | Polysubstituted quinazoline compound serving as EGFR/HER2 double-target-point inhibitor and application thereof |
Non-Patent Citations (2)
Title |
---|
KRASG12C 共价抑制剂ARS-1620 的 合成工艺研究;韩忝甫,等;《化工时刊》;第35卷(第5期);22-27 * |
以SOS1 为靶标的抗肿瘤小分子调节剂研究进展;范懿庆,等;《中国新药杂志》;第31卷(第11期);1072-1079 * |
Also Published As
Publication number | Publication date |
---|---|
CN115322158A (en) | 2022-11-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018222073B2 (en) | O-aminoheteroaryl alkynyl-containing compound, preparation method therefor, and use thereof | |
CN105524048B (en) | As the indazole compounds of FGFR kinase inhibitor and its preparation and application | |
EP3325481B1 (en) | Compounds useful for treating disorders related to kit and pdgfr | |
WO2020259432A1 (en) | Kras-g12c inhibitor | |
JP6231556B2 (en) | N- [5- (3,5-difluoro-benzyl) -1H-indazol-3-yl] -4- (4-methyl-piperazin-1-yl) -2- (tetrahydro-pyran-4-ylamino)- Method for preparing benzamide | |
WO2017152707A1 (en) | Crystalline forms of mesylate salt of pyridinyl amino pyrimidine derivative, preparation methods therefor, and applications thereof | |
CN111961034A (en) | Compounds useful as RET kinase inhibitors and uses thereof | |
CN113454081A (en) | Imidazopyridinyl compounds and their use for the treatment of proliferative diseases | |
WO2018121400A1 (en) | Amide and thioamide derivatives and preparation method therefor and use thereof | |
CN115322158B (en) | As KRASG12CSubstituted quinazoline compounds of protein inhibitor | |
CN113336774B (en) | Substituted chiral diaryl macrocyclic compounds as TRK inhibitors | |
CN108239069B (en) | Inhibitor for fibroblast growth factor receptor and application thereof | |
WO2019029554A1 (en) | Sulfonamide derivative, preparation method thereof, and use of same in medicine | |
CN110407839B (en) | Preparation and application of triazole heterocyclic compound containing heteroaryl amide structure | |
CN113527311A (en) | FGFR4 inhibitor, composition and application thereof in preparation of medicines | |
JP7110335B2 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
CN115894486B (en) | Hydrogenated pyridoquinazoline compound, composition and application thereof | |
CN113527215B (en) | Quinazoline compound, preparation method and application thereof | |
RU2797694C2 (en) | O-aminoheteroarylalkynyl containing compound, method for its production and its use | |
TWI820414B (en) | Quinazoline compounds, preparation method and use thereof | |
CN113563341B (en) | Substituted pyrazolo [1,5-a ] pyrimidine compounds as Trk inhibitors | |
WO2023010354A1 (en) | Small molecule compound having egfr inhibitory activity, and preparation method therefor and use thereof | |
CN118221696A (en) | Pyrimidine heterocyclic compound containing N-methylpiperazine structure, and preparation method and application thereof | |
WO2022017524A1 (en) | Pyridone compound, preparation method therefor, and application thereof | |
WO2023246837A1 (en) | Class of compounds having pyrimido-six-membered ring structure, pharmaceutical compositions comprising same, and use thereof |
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 |