CN111344284A - 用作异戊二烯半胱氨酸羧甲基转移酶抑制剂的化合物 - Google Patents
用作异戊二烯半胱氨酸羧甲基转移酶抑制剂的化合物 Download PDFInfo
- Publication number
- CN111344284A CN111344284A CN201880072698.4A CN201880072698A CN111344284A CN 111344284 A CN111344284 A CN 111344284A CN 201880072698 A CN201880072698 A CN 201880072698A CN 111344284 A CN111344284 A CN 111344284A
- Authority
- CN
- China
- Prior art keywords
- optionally substituted
- compound
- ring
- cancer
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 195
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 title description 10
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 title description 7
- 235000018417 cysteine Nutrition 0.000 title description 7
- 239000003112 inhibitor Substances 0.000 title description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 43
- 201000010099 disease Diseases 0.000 claims abstract description 40
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 38
- 201000011510 cancer Diseases 0.000 claims abstract description 33
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 108060001621 Isoprenylcysteine carboxyl methyltransferase Proteins 0.000 claims abstract description 13
- 150000004677 hydrates Chemical class 0.000 claims abstract description 11
- 239000012453 solvate Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 102000029740 protein-S-isoprenylcysteine O-methyltransferase Human genes 0.000 claims abstract description 4
- 102100035033 Protein-S-isoprenylcysteine O-methyltransferase Human genes 0.000 claims abstract 9
- 239000000203 mixture Substances 0.000 claims description 58
- 239000000651 prodrug Substances 0.000 claims description 41
- 229940002612 prodrug Drugs 0.000 claims description 41
- -1 methoxy, methyl Chemical group 0.000 claims description 40
- 125000005842 heteroatom Chemical group 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 29
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 23
- 125000001188 haloalkyl group Chemical group 0.000 claims description 21
- 125000003107 substituted aryl group Chemical group 0.000 claims description 21
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 20
- 208000025500 Hutchinson-Gilford progeria syndrome Diseases 0.000 claims description 19
- 208000007932 Progeria Diseases 0.000 claims description 19
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 19
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 19
- 125000002252 acyl group Chemical group 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
- 206010063493 Premature ageing Diseases 0.000 claims description 17
- 208000032038 Premature aging Diseases 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 108010014186 ras Proteins Proteins 0.000 claims description 15
- 102000016914 ras Proteins Human genes 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000001931 aliphatic group Chemical group 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 8
- 206010033128 Ovarian cancer Diseases 0.000 claims description 8
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 8
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 8
- 208000032839 leukemia Diseases 0.000 claims description 8
- 201000005202 lung cancer Diseases 0.000 claims description 8
- 208000020816 lung neoplasm Diseases 0.000 claims description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 201000002528 pancreatic cancer Diseases 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 230000011987 methylation Effects 0.000 claims description 6
- 238000007069 methylation reaction Methods 0.000 claims description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 230000035407 negative regulation of cell proliferation Effects 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 150000001945 cysteines Chemical class 0.000 claims 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 230000002028 premature Effects 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 152
- 238000002360 preparation method Methods 0.000 description 152
- 238000005160 1H NMR spectroscopy Methods 0.000 description 141
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 90
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 31
- 239000000243 solution Substances 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 230000002829 reductive effect Effects 0.000 description 20
- 239000012043 crude product Substances 0.000 description 19
- 235000002639 sodium chloride Nutrition 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 125000006413 ring segment Chemical group 0.000 description 17
- 239000012267 brine Substances 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 14
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 10
- 108010047294 Lamins Proteins 0.000 description 9
- 102000006835 Lamins Human genes 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000012528 membrane Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000005335 azido alkyl group Chemical group 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 210000005053 lamin Anatomy 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000002243 precursor Substances 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- KWFFEQXPFFDJER-UHFFFAOYSA-N 4-[3-(4-aminophenoxy)propoxy]aniline Chemical compound C1=CC(N)=CC=C1OCCCOC1=CC=C(N)C=C1 KWFFEQXPFFDJER-UHFFFAOYSA-N 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000002270 dispersing agent Substances 0.000 description 5
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- IGXFKKXJQUMKFH-UHFFFAOYSA-N 3-(2-methylimidazol-1-yl)phenol Chemical compound CC1=NC=CN1C1=CC=CC(O)=C1 IGXFKKXJQUMKFH-UHFFFAOYSA-N 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 4
- JMWGPGIENJZJMB-UHFFFAOYSA-N ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CC=NN1C Chemical compound ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CC=NN1C JMWGPGIENJZJMB-UHFFFAOYSA-N 0.000 description 4
- OVHLCLCOZRFQHN-CQSZACIVSA-N FC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C Chemical compound FC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C OVHLCLCOZRFQHN-CQSZACIVSA-N 0.000 description 4
- 102000007317 Farnesyltranstransferase Human genes 0.000 description 4
- 108010007508 Farnesyltranstransferase Proteins 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 102000015499 Presenilins Human genes 0.000 description 4
- 108010050254 Presenilins Proteins 0.000 description 4
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 3
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 3
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 3
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 description 3
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 description 3
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 description 3
- 125000006763 (C3-C9) cycloalkyl group Chemical group 0.000 description 3
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 3
- CAKCXSQYVATMMT-UHFFFAOYSA-N 3-(2-cyclopropylimidazol-1-yl)phenol Chemical compound OC1=CC=CC(N2C(=NC=C2)C2CC2)=C1 CAKCXSQYVATMMT-UHFFFAOYSA-N 0.000 description 3
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 3
- YZFFTLDUCWKOOJ-INIZCTEOSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@H](C)OC2=C(C=C(C#N)C=C2)OC)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@H](C)OC2=C(C=C(C#N)C=C2)OC)C=CC=1 YZFFTLDUCWKOOJ-INIZCTEOSA-N 0.000 description 3
- JXFFKZJXNNMYAJ-UHFFFAOYSA-N CC=1N(C=CN=1)C=1C=C(OC(C(C)=O)C)C=CC=1 Chemical compound CC=1N(C=CN=1)C=1C=C(OC(C(C)=O)C)C=CC=1 JXFFKZJXNNMYAJ-UHFFFAOYSA-N 0.000 description 3
- GYEFISSBZCOTGP-UHFFFAOYSA-N CC=1N(C=CN=1)C=1C=C(OCCOC=2C=CC(=NC=2)C#N)C=CC=1 Chemical compound CC=1N(C=CN=1)C=1C=C(OCCOC=2C=CC(=NC=2)C#N)C=CC=1 GYEFISSBZCOTGP-UHFFFAOYSA-N 0.000 description 3
- MYLHNIBKADVMPD-UHFFFAOYSA-N COC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound COC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)N1C(=NC=C1)C MYLHNIBKADVMPD-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 238000001516 cell proliferation assay Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 229940126545 compound 53 Drugs 0.000 description 3
- 229940125900 compound 59 Drugs 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 150000001944 cysteine derivatives Chemical class 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 210000000633 nuclear envelope Anatomy 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 235000019271 petrolatum Nutrition 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 230000004481 post-translational protein modification Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- HSNBGFVFXQYLMI-UHFFFAOYSA-N (3-cyanophenyl) acetate Chemical compound CC(=O)OC1=CC=CC(C#N)=C1 HSNBGFVFXQYLMI-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 2
- RRAYWYJIEOHYET-UHFFFAOYSA-N 3-(1,2-oxazol-4-yl)phenol Chemical compound OC1=CC=CC(C2=CON=C2)=C1 RRAYWYJIEOHYET-UHFFFAOYSA-N 0.000 description 2
- KYOGIWCQMNTTCC-UHFFFAOYSA-N 3-(2-methylpyrazol-3-yl)phenol Chemical compound CN1N=CC=C1C1=CC=CC(O)=C1 KYOGIWCQMNTTCC-UHFFFAOYSA-N 0.000 description 2
- OLRDBGKZQUNRIF-UHFFFAOYSA-N 4-[2-[3-(2-methylimidazol-1-yl)phenoxy]ethoxy]-3-(trifluoromethyl)benzonitrile Chemical compound CC=1N(C=CN=1)C=1C=C(OCCOC2=C(C=C(C#N)C=C2)C(F)(F)F)C=CC=1 OLRDBGKZQUNRIF-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- UGODENBRHGIBJR-UHFFFAOYSA-N BrC1=CC(=C(OCCOC2=CC(=NC=C2)C2=CC=NN2C)C=C1)F Chemical compound BrC1=CC(=C(OCCOC2=CC(=NC=C2)C2=CC=NN2C)C=C1)F UGODENBRHGIBJR-UHFFFAOYSA-N 0.000 description 2
- ZMBHEZDEAFRACF-UHFFFAOYSA-N BrC1=CC(=C(OCCOC2=CC(=NC=C2)N2C(=NC=C2)C)C=C1)F Chemical compound BrC1=CC(=C(OCCOC2=CC(=NC=C2)N2C(=NC=C2)C)C=C1)F ZMBHEZDEAFRACF-UHFFFAOYSA-N 0.000 description 2
- ITSOSUHHEDQNSP-UHFFFAOYSA-N C1(CC1)C=1N(C=CN=1)C1=NC=CC(=C1)OCCOC1=CC=C(C#N)C=C1 Chemical compound C1(CC1)C=1N(C=CN=1)C1=NC=CC(=C1)OCCOC1=CC=C(C#N)C=C1 ITSOSUHHEDQNSP-UHFFFAOYSA-N 0.000 description 2
- YBNMJBZOQYHINU-UHFFFAOYSA-N C1(CC1)C=1N(C=CN=1)C1=NC=CC(=C1)OCCOC1=NC=C(C#N)C=C1F Chemical compound C1(CC1)C=1N(C=CN=1)C1=NC=CC(=C1)OCCOC1=NC=C(C#N)C=C1F YBNMJBZOQYHINU-UHFFFAOYSA-N 0.000 description 2
- YZFFTLDUCWKOOJ-UHFFFAOYSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OCC(C)OC2=C(C=C(C#N)C=C2)OC)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OCC(C)OC2=C(C=C(C#N)C=C2)OC)C=CC=1 YZFFTLDUCWKOOJ-UHFFFAOYSA-N 0.000 description 2
- AZJIYOCNWUEQAE-UHFFFAOYSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 AZJIYOCNWUEQAE-UHFFFAOYSA-N 0.000 description 2
- YVCZUSRDXMRASG-LLVKDONJSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@@H](C)O)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@@H](C)O)C=CC=1 YVCZUSRDXMRASG-LLVKDONJSA-N 0.000 description 2
- YVCZUSRDXMRASG-NSHDSACASA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@H](C)O)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@H](C)O)C=CC=1 YVCZUSRDXMRASG-NSHDSACASA-N 0.000 description 2
- XDIRBTPBDYXDMK-UHFFFAOYSA-N C1(CC1)N1N=CC=C1C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 Chemical compound C1(CC1)N1N=CC=C1C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 XDIRBTPBDYXDMK-UHFFFAOYSA-N 0.000 description 2
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 description 2
- GWECOZCUPZHIJC-UHFFFAOYSA-N C1=CC(=CC(=N1)C=1N(N=CC=1)C)OCCOC1=NC=C(C=C1F)C#N Chemical compound C1=CC(=CC(=N1)C=1N(N=CC=1)C)OCCOC1=NC=C(C=C1F)C#N GWECOZCUPZHIJC-UHFFFAOYSA-N 0.000 description 2
- IDSKEAGECWZAGY-UHFFFAOYSA-N CC(O)COC1=CC(=CC=C1)C1=CC=NN1C Chemical compound CC(O)COC1=CC(=CC=C1)C1=CC=NN1C IDSKEAGECWZAGY-UHFFFAOYSA-N 0.000 description 2
- VKUAMEXUKSMYLJ-UHFFFAOYSA-N CC(O)COC1=CC(=CC=C1)N1C=CN=C1C Chemical compound CC(O)COC1=CC(=CC=C1)N1C=CN=C1C VKUAMEXUKSMYLJ-UHFFFAOYSA-N 0.000 description 2
- JYNKCBPIJLHKNS-UHFFFAOYSA-N CC1=NC=CN1C1=CC(OCCOC2=C(F)C=C(Cl)C=C2)=CC=C1 Chemical compound CC1=NC=CN1C1=CC(OCCOC2=C(F)C=C(Cl)C=C2)=CC=C1 JYNKCBPIJLHKNS-UHFFFAOYSA-N 0.000 description 2
- HGVZLUXMPFTAEY-UHFFFAOYSA-N CC1=NN=CN1C1=NC=CC(OCCOC2=C(F)C=C(C=C2)C#N)=C1 Chemical compound CC1=NN=CN1C1=NC=CC(OCCOC2=C(F)C=C(C=C2)C#N)=C1 HGVZLUXMPFTAEY-UHFFFAOYSA-N 0.000 description 2
- FBHSGQOFGHLBFV-UHFFFAOYSA-N CC=1N(C=CN=1)C1=NC=CC(=C1)OCCOC1=CC=C(C#N)C=C1 Chemical compound CC=1N(C=CN=1)C1=NC=CC(=C1)OCCOC1=CC=C(C#N)C=C1 FBHSGQOFGHLBFV-UHFFFAOYSA-N 0.000 description 2
- ZUFXKSUWYOEQKQ-UHFFFAOYSA-N CC=1N(C=CN=1)C=1C=C(OC(C(C)O)C)C=CC=1 Chemical compound CC=1N(C=CN=1)C=1C=C(OC(C(C)O)C)C=CC=1 ZUFXKSUWYOEQKQ-UHFFFAOYSA-N 0.000 description 2
- PJCHDBKPLXFLJC-UHFFFAOYSA-N CC=1N(C=CN=1)C=1C=C(OC(CO)C)C=CC=1 Chemical compound CC=1N(C=CN=1)C=1C=C(OC(CO)C)C=CC=1 PJCHDBKPLXFLJC-UHFFFAOYSA-N 0.000 description 2
- UCEQHMICHTXRIB-UHFFFAOYSA-N CN1N=CC=C1C=1C=C(OCCOC2=NC=C(C#N)C=C2)C=CC=1 Chemical compound CN1N=CC=C1C=1C=C(OCCOC2=NC=C(C#N)C=C2)C=CC=1 UCEQHMICHTXRIB-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- SJTHYRXGARVXJR-UHFFFAOYSA-N ClC1=CC(=C(OCCOC2=CC(=NC=C2)N2C(=NC=C2)C)C=C1)F Chemical compound ClC1=CC(=C(OCCOC2=CC(=NC=C2)N2C(=NC=C2)C)C=C1)F SJTHYRXGARVXJR-UHFFFAOYSA-N 0.000 description 2
- MFFNVARKRNIHMO-UHFFFAOYSA-N ClC1=CC=C(OCCOC=2C=C(C=CC=2)C2=CC=NN2C)C=C1 Chemical compound ClC1=CC=C(OCCOC=2C=C(C=CC=2)C2=CC=NN2C)C=C1 MFFNVARKRNIHMO-UHFFFAOYSA-N 0.000 description 2
- MNEOWBDGBJBREB-UHFFFAOYSA-N ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)N1C(=NC=C1)C1CC1 Chemical compound ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)N1C(=NC=C1)C1CC1 MNEOWBDGBJBREB-UHFFFAOYSA-N 0.000 description 2
- YIWXIYWGFHCVPW-UHFFFAOYSA-N ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=NC=C1)C1=CC=NN1C Chemical compound ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=NC=C1)C1=CC=NN1C YIWXIYWGFHCVPW-UHFFFAOYSA-N 0.000 description 2
- MDOHUGAFOIKFOT-AWEZNQCLSA-N ClC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C Chemical compound ClC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C MDOHUGAFOIKFOT-AWEZNQCLSA-N 0.000 description 2
- JWPXWMRZAXYJAT-UHFFFAOYSA-N ClC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=NC=C1)C1=CC=NN1C Chemical compound ClC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=NC=C1)C1=CC=NN1C JWPXWMRZAXYJAT-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- OONIKEZOOPCPRK-UHFFFAOYSA-N FC1=C(C=C(OCCOC2=CC=C(C#N)C=C2)C=C1)C1=CC=NN1C Chemical compound FC1=C(C=C(OCCOC2=CC=C(C#N)C=C2)C=C1)C1=CC=NN1C OONIKEZOOPCPRK-UHFFFAOYSA-N 0.000 description 2
- KNTJPQJUHVFUOE-UHFFFAOYSA-N FC1=C(C=C(OCCOC2=CC=C(C#N)C=C2)C=C1)N1C(=NC=C1)C Chemical compound FC1=C(C=C(OCCOC2=CC=C(C#N)C=C2)C=C1)N1C(=NC=C1)C KNTJPQJUHVFUOE-UHFFFAOYSA-N 0.000 description 2
- VLPNTJUTOQLFAP-UHFFFAOYSA-N FC1=C(C=C(OCCOC2=NC=C(C#N)C=C2)C=C1)N1C(=NC=C1)C Chemical compound FC1=C(C=C(OCCOC2=NC=C(C#N)C=C2)C=C1)N1C(=NC=C1)C VLPNTJUTOQLFAP-UHFFFAOYSA-N 0.000 description 2
- IIKUQLVVBNHCFA-UHFFFAOYSA-N FC1=C(OCCOC2=CC=C(C#N)C=C2)C=C(C=C1)C1=CC=NN1C Chemical compound FC1=C(OCCOC2=CC=C(C#N)C=C2)C=C(C=C1)C1=CC=NN1C IIKUQLVVBNHCFA-UHFFFAOYSA-N 0.000 description 2
- VZNOYSBRGYOEFV-UHFFFAOYSA-N FC=1C(=NC=C(C#N)C=1)OCCOC1=CC(=C(C=C1)F)C1=CC=NN1C Chemical compound FC=1C(=NC=C(C#N)C=1)OCCOC1=CC(=C(C=C1)F)C1=CC=NN1C VZNOYSBRGYOEFV-UHFFFAOYSA-N 0.000 description 2
- UGKXYSXTOXTUCV-UHFFFAOYSA-N FC=1C(=NC=C(C#N)C=1)OCCOC1=CC(=NC=C1)N1C(=NC=C1)C Chemical compound FC=1C(=NC=C(C#N)C=1)OCCOC1=CC(=NC=C1)N1C(=NC=C1)C UGKXYSXTOXTUCV-UHFFFAOYSA-N 0.000 description 2
- JUESZVNFEVXEOV-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC1=CC(=C(C=C1)F)C1=CC=NN1C Chemical compound FC=1C=C(C#N)C=CC=1OCCOC1=CC(=C(C=C1)F)C1=CC=NN1C JUESZVNFEVXEOV-UHFFFAOYSA-N 0.000 description 2
- IRNVYHYCXKVKGG-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC1=NC(=CC=C1)C1=CC=NN1C Chemical compound FC=1C=C(C#N)C=CC=1OCCOC1=NC(=CC=C1)C1=CC=NN1C IRNVYHYCXKVKGG-UHFFFAOYSA-N 0.000 description 2
- OVHLCLCOZRFQHN-AWEZNQCLSA-N FC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C Chemical compound FC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C OVHLCLCOZRFQHN-AWEZNQCLSA-N 0.000 description 2
- YLNCRIDPVKPVNS-UHFFFAOYSA-N FC=1C=C(OCCOC2=CC=C(C#N)C=C2)C=C(C=1)C1=CC=NN1C Chemical compound FC=1C=C(OCCOC2=CC=C(C#N)C=C2)C=C(C=1)C1=CC=NN1C YLNCRIDPVKPVNS-UHFFFAOYSA-N 0.000 description 2
- BBRIRVWQIPENRS-UHFFFAOYSA-N FC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound FC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=CC=C1)N1C(=NC=C1)C BBRIRVWQIPENRS-UHFFFAOYSA-N 0.000 description 2
- RAQUWPZZLUFAKZ-UHFFFAOYSA-N FC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=NC=C1)N1C(=NC=C1)C Chemical compound FC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=NC=C1)N1C(=NC=C1)C RAQUWPZZLUFAKZ-UHFFFAOYSA-N 0.000 description 2
- 101710113436 GTPase KRas Proteins 0.000 description 2
- 108091006109 GTPases Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101001019525 Homo sapiens Protein-S-isoprenylcysteine O-methyltransferase Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 101100193693 Kirsten murine sarcoma virus K-RAS gene Proteins 0.000 description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102000016397 Methyltransferase Human genes 0.000 description 2
- 108060004795 Methyltransferase Proteins 0.000 description 2
- 208000014767 Myeloproliferative disease Diseases 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- KUGYYESQIPZTBW-UHFFFAOYSA-N N1(N=NN=C1)C1=NC=CC(=C1)OCCOC1=C(C=C(C#N)C=C1)F Chemical compound N1(N=NN=C1)C1=NC=CC(=C1)OCCOC1=C(C=C(C#N)C=C1)F KUGYYESQIPZTBW-UHFFFAOYSA-N 0.000 description 2
- IVSGYIIXPBPQPN-UHFFFAOYSA-N NC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)N1C(=NC=C1)C1CC1 Chemical compound NC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)N1C(=NC=C1)C1CC1 IVSGYIIXPBPQPN-UHFFFAOYSA-N 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical compound C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 238000001378 electrochemiluminescence detection Methods 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000005291 haloalkenyloxy group Chemical group 0.000 description 2
- 102000056785 human ICMT Human genes 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- ZOAMBXDOGPRZLP-UHFFFAOYSA-N indole-3-acetamide Chemical compound C1=CC=C2C(CC(=O)N)=CNC2=C1 ZOAMBXDOGPRZLP-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004971 nitroalkyl group Chemical group 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 210000004940 nucleus Anatomy 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
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229940066842 petrolatum Drugs 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 230000013823 prenylation Effects 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 241000701447 unidentified baculovirus Species 0.000 description 2
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- OFVRLVNCLJSKGW-ZETCQYMHSA-N (2R)-2-(3-methylbuta-1,3-dienylamino)-3-sulfanylpropanoic acid Chemical compound CC(=C)C=CN[C@@H](CS)C(O)=O OFVRLVNCLJSKGW-ZETCQYMHSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical compound C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- QXOGPTXQGKQSJT-UHFFFAOYSA-N 1-amino-4-[4-(3,4-dimethylphenyl)sulfanylanilino]-9,10-dioxoanthracene-2-sulfonic acid Chemical compound Cc1ccc(Sc2ccc(Nc3cc(c(N)c4C(=O)c5ccccc5C(=O)c34)S(O)(=O)=O)cc2)cc1C QXOGPTXQGKQSJT-UHFFFAOYSA-N 0.000 description 1
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 1
- SHZZCMTYFATJGO-UHFFFAOYSA-N 3-(1,2,4-triazol-1-yl)phenol Chemical compound OC1=CC=CC(N2N=CN=C2)=C1 SHZZCMTYFATJGO-UHFFFAOYSA-N 0.000 description 1
- HGYDYAJSQGPQKI-UHFFFAOYSA-N 3-(1,2,4-triazol-4-yl)phenol Chemical compound OC1=CC=CC(N2C=NN=C2)=C1 HGYDYAJSQGPQKI-UHFFFAOYSA-N 0.000 description 1
- XGDNXKHAMRBELS-UHFFFAOYSA-N 3-(1,3-thiazol-5-yl)phenol Chemical compound OC1=CC=CC(C=2SC=NC=2)=C1 XGDNXKHAMRBELS-UHFFFAOYSA-N 0.000 description 1
- NPUKDXXFDDZOKR-UHFFFAOYSA-N 3-(1-phenylethyl)-4-imidazolecarboxylic acid ethyl ester Chemical compound CCOC(=O)C1=CN=CN1C(C)C1=CC=CC=C1 NPUKDXXFDDZOKR-UHFFFAOYSA-N 0.000 description 1
- ANOHXLVHSDDZBP-UHFFFAOYSA-N 3-(2-chloro-6-fluorophenyl)-5-methyl-n-(4-propan-2-ylphenyl)-1,2-oxazole-4-carboxamide Chemical compound C1=CC(C(C)C)=CC=C1NC(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl ANOHXLVHSDDZBP-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 1
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 1
- BNBOUFHCTIFWHN-UHFFFAOYSA-N 3-bromobutan-2-one Chemical compound CC(Br)C(C)=O BNBOUFHCTIFWHN-UHFFFAOYSA-N 0.000 description 1
- AHOTWDHPKDLXGE-UHFFFAOYSA-N 3-fluoro-5-(2-methylpyrazol-3-yl)phenol Chemical compound CN1N=CC=C1C1=CC(O)=CC(F)=C1 AHOTWDHPKDLXGE-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- SHXAUBCOXJAXEI-UHFFFAOYSA-N 4-(1,3-diazepan-1-yl)morpholine Chemical compound O1CCN(CC1)N1CNCCCC1 SHXAUBCOXJAXEI-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 1
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 1
- QKXIODLJOUCSOA-UHFFFAOYSA-N 4-methoxy-2-(2-methylimidazol-1-yl)pyridine Chemical compound COC1=CC=NC(N2C(=NC=C2)C)=C1 QKXIODLJOUCSOA-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- XGKVGTCKKHCMKF-UHFFFAOYSA-N 5-(2-methylpyrazol-3-yl)pyridin-3-ol Chemical compound CN1N=CC=C1C1=CN=CC(O)=C1 XGKVGTCKKHCMKF-UHFFFAOYSA-N 0.000 description 1
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- XTURYZYJYQRJDO-BNAHBJSTSA-N Acetyl-farnesyl-cysteine Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CSC[C@@H](C(O)=O)NC(C)=O XTURYZYJYQRJDO-BNAHBJSTSA-N 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- RIRCPVPIMGUFFZ-UHFFFAOYSA-N C1(=C(C=C(C=C1)C)C#N)OCCOC1=CC(=CC=C1)C=1N(N=CC=1)C Chemical compound C1(=C(C=C(C=C1)C)C#N)OCCOC1=CC(=CC=C1)C=1N(N=CC=1)C RIRCPVPIMGUFFZ-UHFFFAOYSA-N 0.000 description 1
- FWCKRRCNOBRCHS-UHFFFAOYSA-N C1(=CC=CC(=C1)OCCOC1=C(C=C(C=C1)C#N)OC(F)(F)F)N1C(=NC=C1)C Chemical compound C1(=CC=CC(=C1)OCCOC1=C(C=C(C=C1)C#N)OC(F)(F)F)N1C(=NC=C1)C FWCKRRCNOBRCHS-UHFFFAOYSA-N 0.000 description 1
- AFWXTPFNTYWQBR-UHFFFAOYSA-N C1(CC1)C=1N(C=CN=1)C1=NC=CC(=C1)OCCOC1=C(C=C(C#N)C=C1)F Chemical compound C1(CC1)C=1N(C=CN=1)C1=NC=CC(=C1)OCCOC1=C(C=C(C#N)C=C1)F AFWXTPFNTYWQBR-UHFFFAOYSA-N 0.000 description 1
- JADDTATXBOYWPS-UHFFFAOYSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OCC(C)OC2=C(C=C(C#N)C=C2)C)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OCC(C)OC2=C(C=C(C#N)C=C2)C)C=CC=1 JADDTATXBOYWPS-UHFFFAOYSA-N 0.000 description 1
- CNLDJPRZJYYHID-UHFFFAOYSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OCC(C)OC2=C(C=C(C#N)C=C2)F)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OCC(C)OC2=C(C=C(C#N)C=C2)F)C=CC=1 CNLDJPRZJYYHID-UHFFFAOYSA-N 0.000 description 1
- UUJRQSWCXIQHAA-UHFFFAOYSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OCCOC2=C(C=C(C#N)C=C2)F)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OCCOC2=C(C=C(C#N)C=C2)F)C=CC=1 UUJRQSWCXIQHAA-UHFFFAOYSA-N 0.000 description 1
- DWXGCKDWJLTTHP-UHFFFAOYSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OCCOC2=C(C=C(C#N)C=C2)OC)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OCCOC2=C(C=C(C#N)C=C2)OC)C=CC=1 DWXGCKDWJLTTHP-UHFFFAOYSA-N 0.000 description 1
- MMQACSOHGPLNRT-UHFFFAOYSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OCCOC2=NC=C(C#N)C=C2F)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OCCOC2=NC=C(C#N)C=C2F)C=CC=1 MMQACSOHGPLNRT-UHFFFAOYSA-N 0.000 description 1
- JADDTATXBOYWPS-QGZVFWFLSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@@H](C)OC2=C(C=C(C#N)C=C2)C)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@@H](C)OC2=C(C=C(C#N)C=C2)C)C=CC=1 JADDTATXBOYWPS-QGZVFWFLSA-N 0.000 description 1
- CNLDJPRZJYYHID-OAHLLOKOSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@@H](C)OC2=C(C=C(C#N)C=C2)F)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@@H](C)OC2=C(C=C(C#N)C=C2)F)C=CC=1 CNLDJPRZJYYHID-OAHLLOKOSA-N 0.000 description 1
- JADDTATXBOYWPS-KRWDZBQOSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@H](C)OC2=C(C=C(C#N)C=C2)C)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@H](C)OC2=C(C=C(C#N)C=C2)C)C=CC=1 JADDTATXBOYWPS-KRWDZBQOSA-N 0.000 description 1
- CNLDJPRZJYYHID-HNNXBMFYSA-N C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@H](C)OC2=C(C=C(C#N)C=C2)F)C=CC=1 Chemical compound C1(CC1)C=1N(C=CN=1)C=1C=C(OC[C@H](C)OC2=C(C=C(C#N)C=C2)F)C=CC=1 CNLDJPRZJYYHID-HNNXBMFYSA-N 0.000 description 1
- VTFZITMILOAABX-UHFFFAOYSA-N C1(CC1)N1N=CC=C1C=1C=C(OCCOC2=C(C=C(C#N)C=C2)F)C=CC=1 Chemical compound C1(CC1)N1N=CC=C1C=1C=C(OCCOC2=C(C=C(C#N)C=C2)F)C=CC=1 VTFZITMILOAABX-UHFFFAOYSA-N 0.000 description 1
- NNSLQODBIJVRPS-UHFFFAOYSA-N C1(CC1)N1N=CC=C1C=1C=C(OCCOC2=C(C=C(C#N)C=C2)F)C=CC=1F Chemical compound C1(CC1)N1N=CC=C1C=1C=C(OCCOC2=C(C=C(C#N)C=C2)F)C=CC=1F NNSLQODBIJVRPS-UHFFFAOYSA-N 0.000 description 1
- FXWCJHHIKOXSIO-UHFFFAOYSA-N C1=CC(=CC(=N1)C=1N(N=CC=1)C)OCCOC1=CC=C(C#N)C=C1 Chemical compound C1=CC(=CC(=N1)C=1N(N=CC=1)C)OCCOC1=CC=C(C#N)C=C1 FXWCJHHIKOXSIO-UHFFFAOYSA-N 0.000 description 1
- MKPWTRAKNFFCHZ-UHFFFAOYSA-N C=1(C2=CC(OCCOC3=NC=C(C=C3F)C#N)=CC=C2)N(N=CC=1)C Chemical compound C=1(C2=CC(OCCOC3=NC=C(C=C3F)C#N)=CC=C2)N(N=CC=1)C MKPWTRAKNFFCHZ-UHFFFAOYSA-N 0.000 description 1
- 102100022361 CAAX prenyl protease 1 homolog Human genes 0.000 description 1
- TWEGOTMTZGVOKG-UHFFFAOYSA-N CC1=NC=CN1C1=CC(OCCOC2=C(F)C=C(C)C=C2)=CC=C1 Chemical compound CC1=NC=CN1C1=CC(OCCOC2=C(F)C=C(C)C=C2)=CC=C1 TWEGOTMTZGVOKG-UHFFFAOYSA-N 0.000 description 1
- CXVZNKWVPVONIX-UHFFFAOYSA-N CC1=NC=CN1C1=CC(OCCOC2=C(F)C=C(C=C2)C#C)=CC=C1 Chemical compound CC1=NC=CN1C1=CC(OCCOC2=C(F)C=C(C=C2)C#C)=CC=C1 CXVZNKWVPVONIX-UHFFFAOYSA-N 0.000 description 1
- IPBPBSCFBQCSPR-UHFFFAOYSA-N CC1=NC=CN1C1=CC(OCCOC2=CC=C(C=C2)C#C)=CC=C1 Chemical compound CC1=NC=CN1C1=CC(OCCOC2=CC=C(C=C2)C#C)=CC=C1 IPBPBSCFBQCSPR-UHFFFAOYSA-N 0.000 description 1
- VLMFEKLLOJTSIM-UHFFFAOYSA-N CC1=NC=CN1C1=CC(OCCOC2=CC=C(Cl)C=C2)=CC=C1 Chemical compound CC1=NC=CN1C1=CC(OCCOC2=CC=C(Cl)C=C2)=CC=C1 VLMFEKLLOJTSIM-UHFFFAOYSA-N 0.000 description 1
- TUWQCPPXIFJAKW-UHFFFAOYSA-N CC1=NN=CN1C1=NC=CC(O)=C1 Chemical compound CC1=NN=CN1C1=NC=CC(O)=C1 TUWQCPPXIFJAKW-UHFFFAOYSA-N 0.000 description 1
- IPMAECGFJWTQDT-UHFFFAOYSA-N CC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)C1=CC=NN1C)C Chemical compound CC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)C1=CC=NN1C)C IPMAECGFJWTQDT-UHFFFAOYSA-N 0.000 description 1
- IPMAECGFJWTQDT-MRXNPFEDSA-N CC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)C1=CC=NN1C)C Chemical compound CC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)C1=CC=NN1C)C IPMAECGFJWTQDT-MRXNPFEDSA-N 0.000 description 1
- IPMAECGFJWTQDT-INIZCTEOSA-N CC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)C1=CC=NN1C)C Chemical compound CC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)C1=CC=NN1C)C IPMAECGFJWTQDT-INIZCTEOSA-N 0.000 description 1
- NHANFPUERUMOCY-UHFFFAOYSA-N CC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound CC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=CC=C1)N1C(=NC=C1)C NHANFPUERUMOCY-UHFFFAOYSA-N 0.000 description 1
- HCXQZHZIEDKDDV-UHFFFAOYSA-N CC=1N(C=CN=1)C1=CC=CC(=N1)O Chemical compound CC=1N(C=CN=1)C1=CC=CC(=N1)O HCXQZHZIEDKDDV-UHFFFAOYSA-N 0.000 description 1
- UKPNMDMNILQSCE-UHFFFAOYSA-N CC=1N(C=CN=1)C1=NC=CC(=C1)OCCOC1=NC=C(C#N)C=C1 Chemical compound CC=1N(C=CN=1)C1=NC=CC(=C1)OCCOC1=NC=C(C#N)C=C1 UKPNMDMNILQSCE-UHFFFAOYSA-N 0.000 description 1
- AUIUZUQYQPPUOK-UHFFFAOYSA-N CC=1N(C=CN=1)C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 Chemical compound CC=1N(C=CN=1)C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 AUIUZUQYQPPUOK-UHFFFAOYSA-N 0.000 description 1
- HLRFSLTWHZGOJN-UHFFFAOYSA-N CC=1N(C=CN=1)C=1C=C(OCCOC2=NC=C(C#N)C=C2)C=CC=1 Chemical compound CC=1N(C=CN=1)C=1C=C(OCCOC2=NC=C(C#N)C=C2)C=CC=1 HLRFSLTWHZGOJN-UHFFFAOYSA-N 0.000 description 1
- UHNRLQRZRNKOKU-UHFFFAOYSA-N CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O Chemical compound CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O UHNRLQRZRNKOKU-UHFFFAOYSA-N 0.000 description 1
- GXIHQESQRVSHRG-UHFFFAOYSA-N CN1N=CC=C1C1=CC=CC(=N1)O Chemical compound CN1N=CC=C1C1=CC=CC(=N1)O GXIHQESQRVSHRG-UHFFFAOYSA-N 0.000 description 1
- XEMNUZBYDAJPRX-UHFFFAOYSA-N CN1N=CC=C1C1=NC=CC(=C1)O Chemical compound CN1N=CC=C1C1=NC=CC(=C1)O XEMNUZBYDAJPRX-UHFFFAOYSA-N 0.000 description 1
- BPTINYSELMYFNX-UHFFFAOYSA-N CN1N=CC=C1C1=NC=CC(=C1)OCCOC1=NC=C(C#N)C=C1 Chemical compound CN1N=CC=C1C1=NC=CC(=C1)OCCOC1=NC=C(C#N)C=C1 BPTINYSELMYFNX-UHFFFAOYSA-N 0.000 description 1
- WEFGVRSITJKNAW-UHFFFAOYSA-N CN1N=CC=C1C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 Chemical compound CN1N=CC=C1C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 WEFGVRSITJKNAW-UHFFFAOYSA-N 0.000 description 1
- BQBULLXIMXLYFT-UHFFFAOYSA-N COC1=C(OCCOC2=CC=CC(=C2)N2C=CN=C2C)C=CC(Cl)=C1 Chemical compound COC1=C(OCCOC2=CC=CC(=C2)N2C=CN=C2C)C=CC(Cl)=C1 BQBULLXIMXLYFT-UHFFFAOYSA-N 0.000 description 1
- AQMBXKCUBLLNRF-UHFFFAOYSA-N COC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)C1=CC=NN1C)C Chemical compound COC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)C1=CC=NN1C)C AQMBXKCUBLLNRF-UHFFFAOYSA-N 0.000 description 1
- SILCBNWSDQDKBJ-UHFFFAOYSA-N COC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)N1C(=NC=C1)C)C Chemical compound COC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)N1C(=NC=C1)C)C SILCBNWSDQDKBJ-UHFFFAOYSA-N 0.000 description 1
- OPJOOOIXZATMQP-UHFFFAOYSA-N COC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CC=NN1C Chemical compound COC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CC=NN1C OPJOOOIXZATMQP-UHFFFAOYSA-N 0.000 description 1
- JQUZTYJSEDQHHI-UHFFFAOYSA-N COC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CN=CS1 Chemical compound COC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CN=CS1 JQUZTYJSEDQHHI-UHFFFAOYSA-N 0.000 description 1
- AQMBXKCUBLLNRF-OAHLLOKOSA-N COC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)C1=CC=NN1C)C Chemical compound COC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)C1=CC=NN1C)C AQMBXKCUBLLNRF-OAHLLOKOSA-N 0.000 description 1
- SILCBNWSDQDKBJ-OAHLLOKOSA-N COC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C Chemical compound COC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C SILCBNWSDQDKBJ-OAHLLOKOSA-N 0.000 description 1
- AQMBXKCUBLLNRF-HNNXBMFYSA-N COC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)C1=CC=NN1C)C Chemical compound COC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)C1=CC=NN1C)C AQMBXKCUBLLNRF-HNNXBMFYSA-N 0.000 description 1
- SILCBNWSDQDKBJ-HNNXBMFYSA-N COC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C Chemical compound COC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C SILCBNWSDQDKBJ-HNNXBMFYSA-N 0.000 description 1
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- VKEMNQJEDDELDN-UHFFFAOYSA-N ClC1=CC(=C(OCCOC2=CC(=NC=C2)C2=CC=NN2C)C=C1)F Chemical compound ClC1=CC(=C(OCCOC2=CC(=NC=C2)C2=CC=NN2C)C=C1)F VKEMNQJEDDELDN-UHFFFAOYSA-N 0.000 description 1
- DGGCLEBUSVGJCH-UHFFFAOYSA-N ClC1=CC=C(OCCOC2=CC(=NC=C2)N2C(=NC=C2)C)C=C1 Chemical compound ClC1=CC=C(OCCOC2=CC(=NC=C2)N2C(=NC=C2)C)C=C1 DGGCLEBUSVGJCH-UHFFFAOYSA-N 0.000 description 1
- MDOHUGAFOIKFOT-UHFFFAOYSA-N ClC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)N1C(=NC=C1)C)C Chemical compound ClC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)N1C(=NC=C1)C)C MDOHUGAFOIKFOT-UHFFFAOYSA-N 0.000 description 1
- SUPDUAUQKZYSFO-UHFFFAOYSA-N ClC=1C=C(C#N)C=CC=1OCC(C)OC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound ClC=1C=C(C#N)C=CC=1OCC(C)OC1=CC(=CC=C1)N1C(=NC=C1)C SUPDUAUQKZYSFO-UHFFFAOYSA-N 0.000 description 1
- FPUHZMYTSZZLDZ-UHFFFAOYSA-N ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CC=NN1C1CC1 Chemical compound ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CC=NN1C1CC1 FPUHZMYTSZZLDZ-UHFFFAOYSA-N 0.000 description 1
- VREHUGBMHGJMHP-UHFFFAOYSA-N ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CN=CS1 Chemical compound ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CN=CS1 VREHUGBMHGJMHP-UHFFFAOYSA-N 0.000 description 1
- WJVPADFVXZPWNZ-UHFFFAOYSA-N ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)N1C(=NC=C1)C WJVPADFVXZPWNZ-UHFFFAOYSA-N 0.000 description 1
- NMVVFJDZTPSSDI-UHFFFAOYSA-N ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=NC=C1)N1C(=NC=C1)C Chemical compound ClC=1C=C(C#N)C=CC=1OCCOC1=CC(=NC=C1)N1C(=NC=C1)C NMVVFJDZTPSSDI-UHFFFAOYSA-N 0.000 description 1
- SUPDUAUQKZYSFO-CQSZACIVSA-N ClC=1C=C(C#N)C=CC=1OC[C@@H](C)OC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound ClC=1C=C(C#N)C=CC=1OC[C@@H](C)OC1=CC(=CC=C1)N1C(=NC=C1)C SUPDUAUQKZYSFO-CQSZACIVSA-N 0.000 description 1
- SUPDUAUQKZYSFO-AWEZNQCLSA-N ClC=1C=C(C#N)C=CC=1OC[C@H](C)OC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound ClC=1C=C(C#N)C=CC=1OC[C@H](C)OC1=CC(=CC=C1)N1C(=NC=C1)C SUPDUAUQKZYSFO-AWEZNQCLSA-N 0.000 description 1
- MDOHUGAFOIKFOT-CQSZACIVSA-N ClC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C Chemical compound ClC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)N1C(=NC=C1)C)C MDOHUGAFOIKFOT-CQSZACIVSA-N 0.000 description 1
- UWOLTPSCWBQKEC-UHFFFAOYSA-N ClC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=NC=C1)N1C(=NC=C1)C Chemical compound ClC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=NC=C1)N1C(=NC=C1)C UWOLTPSCWBQKEC-UHFFFAOYSA-N 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- ZJWOXSOTQHARDZ-UHFFFAOYSA-N FC1=C(C=C(C=C1)O)C1=CC=NN1C Chemical compound FC1=C(C=C(C=C1)O)C1=CC=NN1C ZJWOXSOTQHARDZ-UHFFFAOYSA-N 0.000 description 1
- OQTAYBQCNBPDNH-UHFFFAOYSA-N FC1=C(C=C(C=C1)O)N1C(=NC=C1)C Chemical compound FC1=C(C=C(C=C1)O)N1C(=NC=C1)C OQTAYBQCNBPDNH-UHFFFAOYSA-N 0.000 description 1
- UEJWNOIVHZNPDL-UHFFFAOYSA-N FC1=C(OCCOC2=CC(=CC=C2)N2C=NN=C2)C=CC(=C1)C#N Chemical compound FC1=C(OCCOC2=CC(=CC=C2)N2C=NN=C2)C=CC(=C1)C#N UEJWNOIVHZNPDL-UHFFFAOYSA-N 0.000 description 1
- KGADOQOBCWWEKZ-UHFFFAOYSA-N FC1=C(OCCOC2=CC=CC(=C2)N2C=CN=C2C2CC2)C=CC(Cl)=C1 Chemical compound FC1=C(OCCOC2=CC=CC(=C2)N2C=CN=C2C2CC2)C=CC(Cl)=C1 KGADOQOBCWWEKZ-UHFFFAOYSA-N 0.000 description 1
- DQNRNDKMOOFZCB-UHFFFAOYSA-N FC1=CC(=C(OCCOC=2C=C(C=CC=2)C2=CC=NN2C)C=C1)C Chemical compound FC1=CC(=C(OCCOC=2C=C(C=CC=2)C2=CC=NN2C)C=C1)C DQNRNDKMOOFZCB-UHFFFAOYSA-N 0.000 description 1
- NXJBITZNACJKEI-UHFFFAOYSA-N FC=1C(=NC=C(C#N)C=1)OCCOC1=CC(=C(C=C1)F)N1C(=NC=C1)C Chemical compound FC=1C(=NC=C(C#N)C=1)OCCOC1=CC(=C(C=C1)F)N1C(=NC=C1)C NXJBITZNACJKEI-UHFFFAOYSA-N 0.000 description 1
- CVLTYVQYNWLSLX-UHFFFAOYSA-N FC=1C(=NC=C(C#N)C=1)OCCOC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound FC=1C(=NC=C(C#N)C=1)OCCOC1=CC(=CC=C1)N1C(=NC=C1)C CVLTYVQYNWLSLX-UHFFFAOYSA-N 0.000 description 1
- UXJHWFPZWORYJN-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OC(C)C(C)OC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound FC=1C=C(C#N)C=CC=1OC(C)C(C)OC1=CC(=CC=C1)N1C(=NC=C1)C UXJHWFPZWORYJN-UHFFFAOYSA-N 0.000 description 1
- SRIORFBFIYTBBO-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)C1=CC=NN1C)C Chemical compound FC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)C1=CC=NN1C)C SRIORFBFIYTBBO-UHFFFAOYSA-N 0.000 description 1
- FVFIXFBKAYTAEO-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)C1=CC=NO1)C Chemical compound FC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)C1=CC=NO1)C FVFIXFBKAYTAEO-UHFFFAOYSA-N 0.000 description 1
- OVHLCLCOZRFQHN-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)N1C(=NC=C1)C)C Chemical compound FC=1C=C(C#N)C=CC=1OC(COC1=CC(=CC=C1)N1C(=NC=C1)C)C OVHLCLCOZRFQHN-UHFFFAOYSA-N 0.000 description 1
- VDLLORJBOXXVQV-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCC(C)OC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound FC=1C=C(C#N)C=CC=1OCC(C)OC1=CC(=CC=C1)N1C(=NC=C1)C VDLLORJBOXXVQV-UHFFFAOYSA-N 0.000 description 1
- ZGSHFNYLQIYQHC-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC(=C1)C1=CC=NN1C)F Chemical compound FC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC(=C1)C1=CC=NN1C)F ZGSHFNYLQIYQHC-UHFFFAOYSA-N 0.000 description 1
- MWWAUTJYMUZOAG-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CC=NN1C Chemical compound FC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CC=NN1C MWWAUTJYMUZOAG-UHFFFAOYSA-N 0.000 description 1
- CZFOGHIVPVYALU-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CN=CS1 Chemical compound FC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C1=CN=CS1 CZFOGHIVPVYALU-UHFFFAOYSA-N 0.000 description 1
- TWSBBBIJGUPDPQ-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C=1C=NOC=1 Chemical compound FC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)C=1C=NOC=1 TWSBBBIJGUPDPQ-UHFFFAOYSA-N 0.000 description 1
- KWQXNAROOLFKIN-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound FC=1C=C(C#N)C=CC=1OCCOC1=CC(=CC=C1)N1C(=NC=C1)C KWQXNAROOLFKIN-UHFFFAOYSA-N 0.000 description 1
- RKLSHUCSPZPWMG-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC1=CC(=NC=C1)C1=CC=NN1C Chemical compound FC=1C=C(C#N)C=CC=1OCCOC1=CC(=NC=C1)C1=CC=NN1C RKLSHUCSPZPWMG-UHFFFAOYSA-N 0.000 description 1
- VTMBMJOYVBYQEK-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC1=CC(=NC=C1)N1C(=NC=C1)C Chemical compound FC=1C=C(C#N)C=CC=1OCCOC1=CC(=NC=C1)N1C(=NC=C1)C VTMBMJOYVBYQEK-UHFFFAOYSA-N 0.000 description 1
- JPZZKGIUOWXISH-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC1=NC(=CC=C1)N1C(=NC=C1)C Chemical compound FC=1C=C(C#N)C=CC=1OCCOC1=NC(=CC=C1)N1C(=NC=C1)C JPZZKGIUOWXISH-UHFFFAOYSA-N 0.000 description 1
- ALRDXTNTFXJTJH-UHFFFAOYSA-N FC=1C=C(C#N)C=CC=1OCCOC=1C=NC=C(C=1)C1=CC=NN1C Chemical compound FC=1C=C(C#N)C=CC=1OCCOC=1C=NC=C(C=1)C1=CC=NN1C ALRDXTNTFXJTJH-UHFFFAOYSA-N 0.000 description 1
- VDLLORJBOXXVQV-CQSZACIVSA-N FC=1C=C(C#N)C=CC=1OC[C@@H](C)OC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound FC=1C=C(C#N)C=CC=1OC[C@@H](C)OC1=CC(=CC=C1)N1C(=NC=C1)C VDLLORJBOXXVQV-CQSZACIVSA-N 0.000 description 1
- VDLLORJBOXXVQV-AWEZNQCLSA-N FC=1C=C(C#N)C=CC=1OC[C@H](C)OC1=CC(=CC=C1)N1C(=NC=C1)C Chemical compound FC=1C=C(C#N)C=CC=1OC[C@H](C)OC1=CC(=CC=C1)N1C(=NC=C1)C VDLLORJBOXXVQV-AWEZNQCLSA-N 0.000 description 1
- SRIORFBFIYTBBO-CQSZACIVSA-N FC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)C1=CC=NN1C)C Chemical compound FC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)C1=CC=NN1C)C SRIORFBFIYTBBO-CQSZACIVSA-N 0.000 description 1
- FVFIXFBKAYTAEO-CYBMUJFWSA-N FC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)C1=CC=NO1)C Chemical compound FC=1C=C(C#N)C=CC=1O[C@@H](COC1=CC(=CC=C1)C1=CC=NO1)C FVFIXFBKAYTAEO-CYBMUJFWSA-N 0.000 description 1
- SRIORFBFIYTBBO-AWEZNQCLSA-N FC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)C1=CC=NN1C)C Chemical compound FC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)C1=CC=NN1C)C SRIORFBFIYTBBO-AWEZNQCLSA-N 0.000 description 1
- FVFIXFBKAYTAEO-ZDUSSCGKSA-N FC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)C1=CC=NO1)C Chemical compound FC=1C=C(C#N)C=CC=1O[C@H](COC1=CC(=CC=C1)C1=CC=NO1)C FVFIXFBKAYTAEO-ZDUSSCGKSA-N 0.000 description 1
- RMFXXILPAKKPFM-UHFFFAOYSA-N FC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=CC=C1)C1=CC=NN1C Chemical compound FC=1C=CC(=C(C#N)C=1)OCCOC1=CC(=CC=C1)C1=CC=NN1C RMFXXILPAKKPFM-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010026288 GTP Phosphohydrolases Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101150012162 H-RAS gene Proteins 0.000 description 1
- 101001003584 Homo sapiens Prelamin-A/C Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108010021099 Lamin Type A Proteins 0.000 description 1
- 102000008201 Lamin Type A Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- TZXUSXHUBSYJAF-UHFFFAOYSA-N N#CC1=CC=C(OCCOC2=CC(=CC=C2)N2C=NC=N2)C=C1 Chemical compound N#CC1=CC=C(OCCOC2=CC(=CC=C2)N2C=NC=N2)C=C1 TZXUSXHUBSYJAF-UHFFFAOYSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 description 1
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- WQPGZYABUSWEQG-UHFFFAOYSA-N N1(C2=CC(OCCOC3=NN=C(C=C3)C#N)=CC=C2)C(=NC=C1)C Chemical compound N1(C2=CC(OCCOC3=NN=C(C=C3)C#N)=CC=C2)C(=NC=C1)C WQPGZYABUSWEQG-UHFFFAOYSA-N 0.000 description 1
- HOYHMAWZRZVTQF-UHFFFAOYSA-N N1(N=NN=C1)C1=NC=CC(=C1)O Chemical compound N1(N=NN=C1)C1=NC=CC(=C1)O HOYHMAWZRZVTQF-UHFFFAOYSA-N 0.000 description 1
- 229910003827 NRaRb Inorganic materials 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- HWGMSPOXTWENKL-UHFFFAOYSA-N O1N=CC(=C1)C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 Chemical compound O1N=CC(=C1)C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 HWGMSPOXTWENKL-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 102100026531 Prelamin-A/C Human genes 0.000 description 1
- 102000019337 Prenyltransferases Human genes 0.000 description 1
- 108050006837 Prenyltransferases Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 102000055027 Protein Methyltransferases Human genes 0.000 description 1
- 108700040121 Protein Methyltransferases Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 108020005067 RNA Splice Sites Proteins 0.000 description 1
- XXHGOFCKIYGSCD-UHFFFAOYSA-N S1C=NC=C1C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 Chemical compound S1C=NC=C1C=1C=C(OCCOC2=CC=C(C#N)C=C2)C=CC=1 XXHGOFCKIYGSCD-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 101710188297 Trehalose synthase/amylase TreS Proteins 0.000 description 1
- 108091009221 ZMPSTE24 Proteins 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005035 acylthio group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 1
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000006319 alkynyl amino group Chemical group 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000005124 aminocycloalkyl group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000005018 aryl alkenyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical group CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- JYZIHLWOWKMNNX-UHFFFAOYSA-N benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- OGODKNYCTJYXFF-UHFFFAOYSA-N bis(4-methylbenzoyl) 2,3-dihydroxybutanedioate Chemical compound C1=CC(C)=CC=C1C(=O)OC(=O)C(O)C(O)C(=O)OC(=O)C1=CC=C(C)C=C1 OGODKNYCTJYXFF-UHFFFAOYSA-N 0.000 description 1
- 208000002352 blister Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000012200 cell viability kit Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229940099352 cholate Drugs 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- IBAHLNWTOIHLKE-UHFFFAOYSA-N cyano cyanate Chemical compound N#COC#N IBAHLNWTOIHLKE-UHFFFAOYSA-N 0.000 description 1
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 description 1
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 description 1
- XSYZCZPCBXYQTE-UHFFFAOYSA-N cyclodecylcyclodecane Chemical compound C1CCCCCCCCC1C1CCCCCCCCC1 XSYZCZPCBXYQTE-UHFFFAOYSA-N 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 230000002367 endolytic effect Effects 0.000 description 1
- 230000003241 endoproteolytic effect Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 1
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000006126 farnesylation Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 150000002244 furazanes Chemical class 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000006456 halo alkyl cycloalkyl group Chemical group 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000000232 haloalkynyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004405 heteroalkoxy group Chemical group 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 125000004447 heteroarylalkenyl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 1
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- AOHCBEAZXHZMOR-ZDUSSCGKSA-N hypaphorine Chemical compound C1=CC=C2C(C[C@H]([N+](C)(C)C)C([O-])=O)=CNC2=C1 AOHCBEAZXHZMOR-ZDUSSCGKSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000010820 immunofluorescence microscopy Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- VOFUROIFQGPCGE-UHFFFAOYSA-N nile red Chemical compound C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=O)C2=C1 VOFUROIFQGPCGE-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 230000006548 oncogenic transformation Effects 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 208000030087 premature aging syndrome Diseases 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 230000019639 protein methylation Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- ZHNFLHYOFXQIOW-LPYZJUEESA-N quinine sulfate dihydrate Chemical compound [H+].[H+].O.O.[O-]S([O-])(=O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 ZHNFLHYOFXQIOW-LPYZJUEESA-N 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- MUUHXGOJWVMBDY-UHFFFAOYSA-L tetrazolium blue Chemical compound [Cl-].[Cl-].COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 MUUHXGOJWVMBDY-UHFFFAOYSA-L 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 201000011531 vascular cancer Diseases 0.000 description 1
- 206010055031 vascular neoplasm Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
本发明涉及通式(I)的化合物、和/或其互变异构体、对映异构体、溶剂化物、水合物和药学上可接受的盐。本发明还涉及用于治疗的式(I)化合物、治疗异戊二烯半胱氨酸羧甲基转移酶(ICMT)相关疾病的方法或式(I)化合物在制备用于治疗ICMT相关疾病的药物中的用途,其中所述疾病是癌症和/或早衰症。本发明还涉及合成式(I)化合物的方法。
Description
技术领域
本发明总体上涉及用作异戊二烯半胱氨酸羧甲基转移酶(ICMT)抑制剂的化合物。本发明还涉及用于治疗的化合物、治疗ICMT相关疾病的方法、或所述化合物在制备用于治疗ICMT相关疾病的药物中的用途。本发明还涉及合成所述化合物的方法。
背景技术
Ras信号分子家族的成员和以CaaX基序终止的其他蛋白质经历三步翻译后修饰以实现它们的细胞功能。在修饰的第一步中,15-碳法呢基或20-碳香叶基香叶基脂质(geranylgeranyl lipid)共价连接到Caax基序的半胱氨酸残基上。这通过法尼基转移酶(FTase)或香叶基香叶基转移酶(GGTase)I型酶进行。第二步包括通过膜结合的RceI(Ras转化酶1)蛋白酶切割三个氨基酸(即-aaX)。在修饰的最后步骤中,新暴露的异戊二烯化半胱氨酸残基通过ICMT甲基化。翻译后修饰增加了信号分子的疏水性并将其导向膜。
GTP酶(鸟苷三磷酸酶,GTPases)的Ras家族与肿瘤发生和肿瘤进展有关。K-Ras是人恶性肿瘤(尤其是实体恶性肿瘤)中发现的Ras的最常见突变形式。Ras中的活化突变已在几乎30%的所有癌症中发现,包括50%的结肠癌和高达90%的胰腺癌。Ras的转化能力需要通过异戊二烯化途径进行加工。因此,蛋白质异戊二烯转移酶是许多药物发现程序的重要靶标。过去已经研究了FTase抑制剂(FTI),但尚未在临床试验中证明有效。缺乏功效的原因之一可能是由于GGTase在缺乏FTase的情况下在翻译后修饰中有效的能力。
ICMT的遗传学和药理学失活定义了CAAX基序甲基化对Ras功能的特殊要求。ICMT是H-RAS、N-RAS和K-RAS的适当膜靶向所需的。研究表明,灭活小鼠成纤维细胞中的ICMT可抑制细胞生长和K-RAS诱导的致癌转化。此外,ICMT失活改善K-Ras诱导的骨髓增生性疾病(myeloproliferative disease)。因此,ICMT抑制剂可能是克服RAS蛋白与质膜结合的更好策略。
随着越来越多的证据表明ICMT催化的Caax蛋白甲基化在肿瘤发生中的重要性,显然需要特定的药理学试剂来靶向该过程。然而,迄今为止仅有的这类试剂是底物的类似物,如最小ICMT底物N-乙酰基-S-法呢基半胱氨酸异戊二烯半胱氨酸或基于吲哚的Icmt小分子抑制剂的类异戊二烯修饰的类似物。这些化合物要么效力低下、要么理化性质和PK性质差。
靶向ICMT的另一个基本原理包括治疗早衰样疾病(progeroid disorders)。哈钦森-吉尔福德早衰综合征(Hutchinson-Gilford progeria syndrome,HGPS)是一种模拟过早快速衰老的罕见的显性遗传病。这种疾病是由不能加工成成熟A型核纤层蛋白(lamin A)的A型核纤层蛋白前体(prelamin A)的突变形式的积聚所引起的。HGPS最常见的是由LMNA外显子11中的从头点突变引起的。发生在密码子608中的这种突变激活了一个隐蔽剪接位点,并导致在A型核纤层蛋白前体中50个氨基酸的框内缺失。该缺失使CAAX基序保持完整;因此,预测突变体A型核纤层蛋白前体(早衰蛋白,progerin)经历法尼基化、_AAX的释放和羧甲基化。然而,第二个内切蛋白酶水解切割(endoproteolytic cleavage)步骤的位点ZMPSTE24-识别位点通过缺失而被消除。
通过基因突变,ZMPSTE24蛋白酶活性的丧失导致了更严重形式的早衰症(progeria)。在所有形式的早衰症中,法尼基化和羧甲基化的A型核纤层蛋白前体的蛋白水解作用的缺乏,导致未完全加工的分子(称为早衰蛋白)积聚在核被膜(nuclear envelope)上,从而引发一系列导致早衰的分子干扰。早衰蛋白的存在不利地影响核纤层的完整性,导致畸形核和核泡(nuclear bleb)。
使用FTI测试了HGPS的可能的治疗策略。用遗传学上相同的原代小鼠胚胎成纤维细胞产生基因靶向的HGPS小鼠模型,然后检测FTI对核起泡的影响。使用免疫荧光显微术,观察到错误定位的早衰蛋白远离核被膜去往核质。迄今为止,在临床试验中仅观察到了适度的效果。
另一项策略是靶向早衰症中的ICMT。将ICMT的亚效等位基因(hypomorphicallele)引入早衰症的Zmpste24-/-小鼠模型中,可以很大程度上挽救过早的衰老表型和过早的死亡。因此,在药理学上减少异戊二烯半胱氨酸甲基化可能对早衰症患儿有帮助。
由于ICMT在蛋白质异戊二烯化途径(一种可靶向癌症和早熟衰老症的途径)中的作用,它已经成为药物发现的有希望的靶标。
因此,需要提供抑制ICMT并克服或至少改善上述一种或多种缺点的化合物。
发明内容
在本公开的一个方面,提供了具有下式(I)的化合物:
和/或其互变异构体、对映异构体、溶剂化物、水合物、前药和药学上可接受的盐;
其中:
环A为5元或6元碳环体系,其中1至4个碳原子可以任选地被杂原子替代;
B1、B2和B3独立地选自C、CH或N;
环C为5元或6元碳环体系,其中1至3个碳原子可以任选地被杂原子替代;
R1、R2和R3独立地不存在或选自H、OH、氰基、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基;
R4和R5独立地选自H或脂肪族;
n为选自0至5的整数,其中当n大于1时,环A上取代的每个R1可以相同或不同;
m为选自0至4的整数,其中当m大于1时,环B上取代的每个R2可以相同或不同;以及
p为选自0至5的整数,其中当p大于1时,环C上取代的每个R3可以相同或不同。
在本公开的另一方面,提供了具有下式(I)的化合物:
和/或其互变异构体、对映异构体、溶剂化物、水合物、前药和药学上可接受的盐;
其中:
环A为5元或6元碳环体系,其中1至4个碳原子可以任选地被杂原子替代;
B1、B2和B3独立地选自C、CH或N,其中当B1、B2或B3中的一个为N时,剩余的B1、B2或B3为C或CH;
环C为5元或6元碳环体系,其中1至3个碳原子可以任选地被杂原子替代;
R1不存在或选自H、OH、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基;
R2不存在或选自H、OH、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基;
R3不存在或选自H、OH、氰基、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基或任选取代的芳基;
R4和R5独立地选自H或脂肪族;
n为选自0至5的整数,其中当n大于1时,环A上取代的每个R1可以相同或不同;
m为选自0至4的整数,其中当m大于1时,环B上取代的每个R2可以相同或不同,并且当R2为卤素时,m为1;以及
p为选自0至5的整数,其中当p大于1时,环C上取代的每个R3可以相同或不同。
在本公开的又一方面,提供了药物组合物,其包含如本文所定义的化合物或其药学上可接受的形式或前药、以及药学上可接受的赋形剂。
在本公开的另一方面,提供了抑制由异戊二烯半胱氨酸羧甲基转移酶(ICMT)引起的异戊二烯化半胱氨酸(isoprenylated cysteine)或异戊二烯半胱氨酸(isoprenylcysteine)甲基化的方法,包括使如本文定义的化合物或如本文定义的药物组合物与ICMT接触。
在本公开的另一方面,提供了抑制细胞中的ICMT的方法,其包括使所述细胞与如本文所定义的化合物、或其药学上可接受的形式或前药、或如本文所定义的药物组合物接触。
在本公开的又一方面,提供了治疗ICMT相关疾病的方法,其包括向需要治疗的受试者施用如本文所定义的化合物、或如本文所定义的药物、或组合物。
在本公开的另一方面,提供了用于治疗的如本文所定义的化合物、或其药学形式或前药、或如本文所定义的组合物。
在本公开的另一方面,提供了用于治疗和/或预防癌症和/或早衰样疾病的如本文所定义的化合物、或其药学形式或前药、或如本文所定义的组合物。
在本公开的又一方面,提供了用于治疗ICMT相关疾病的如本文所定义的化合物、或其药学形式或前药、或如本文所定义的组合物。
在本公开的另一方面,提供了如本文所定义的化合物、或其药学形式或前药、或如本文所定义的组合物在制备用于治疗和/或预防癌症和/或早衰样疾病的药物中的用途。
在本公开的另一方面,提供了如本文所定义的化合物、或其药学形式或前药、或如本文所定义的组合物在制备用于治疗ICMT相关疾病的药物中的用途。
在本公开的又一方面,提供了用于合成如本文所定义的化合物的方法,其包括:
(a)使式(III)化合物:
其中R1、R2、R4、R5、B1、B2、B3、n和m如本文所定义,且R6为离去基团(leaving group),
在碱存在下,在有机溶剂中,与式(IV)化合物反应:
其中R3和p如本文所定义,且R7为-OH;
或者
(b)使式(III)化合物:
其中R1、R2、R4、R5、B1、B2、B3、n和m如本文所定义,且R6为OH或醇盐,
在碱存在下,在有机溶剂中,与式(IV)化合物反应:
其中R3和p如本文所定义,且R7为卤素。
有利地,本公开的化合物和包含它们的药物组合物可以以低浓度有效抑制ICMT。所述化合物和包含它们的药物组合物可用于预防和/或治疗与ICMT有关的疾病。有利地,包含它们的化合物或药物组合物可为以下疾病提供治疗:癌症、早熟衰老症或哈钦森-吉尔福德早衰综合征(HGPS),包括但不限于与突变型Ras过度活性相关的癌症,例如肝细胞癌、乳腺癌、卵巢癌、结肠直肠癌、肺癌、胰腺癌或白血病以及与高ICMT表达相关的其他疾病。
有利地,与现有技术的已知化合物相比,本公开的化合物可以显示出在ICMT抑制方面的高效性,并具有期望的优异抗增殖和抗衰老活性。本公开的化合物可以进一步被很好地加工成用于进一步药物测试的制剂。
定义
本文所用的以下词语和术语应具有所指示的含义:
“酰基(acyl)”是指R-C(=O)-基团,其中R基团可以为如本文所定义的任选取代的烷基、任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基基团。酰基的实例包括乙酰基、苯甲酰基和氨基酸衍生的氨酰基。该基团可以为端基或桥连基。如果该基团为端基,则其通过羰基碳键合到分子的其余部分。
“脂肪族(aliphatic)”是指其中碳和氢原子以饱和或不饱和直链或支链排列的有机部分,包括烷烃、烯烃和炔烃。
“烯基(alkenyl)”作为基团或基团的一部分表示含有至少一个碳-碳双键的脂肪族烃基,并且其可以为直链或支链的,优选在正链中具有2至12个碳原子、更优选2至10个碳原子、最优选2至6个碳原子。该基团可以在正链中含有多个双键,并且围绕每个双键的取向独立地为E或Z。示例性的烯基包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基和壬烯基。该基团可以为端基或桥连基。
“烷氧基(alkoxy)”是指烷基-O-基团,其中烷基如本文所定义。优选地,烷氧基为C1-C6烷氧基。实例包括但不限于甲氧基和乙氧基。该基团可以为端基或桥连基。术语烷氧基(alkoxy)可与术语“烷氧基(alkyloxy)”互换使用。
除非另有说明,“烷基(alkyl)”或“亚烷基(alkylene)”作为基团或基团的一部分是指直链或支链脂肪族烃基,优选C1-C12烷基、更优选C1-C10烷基、最优选C1-C6烷基。合适的直链和支链C1-C6烷基取代基的实例包括甲基、乙基、正丙基、2-丙基、正丁基、仲丁基、叔丁基、己基等。该基团可以为端基或桥连基。
“炔基(alkynyl)”作为基团或基团的一部分是指含有碳-碳三键的脂肪族烃基,其可以为直链或支链的,优选在正链中具有2至12个碳原子、更优选2至10个碳原子、更优选2至6个碳原子。示例性的结构包括但不限于乙炔基和丙炔基。该基团可以为端基或桥连基。
“氨基(amino)”是指–NRaRb形式的基团,其中Ra和Rb独立地选自包括但不限于以下的组:氢、任选取代的烷基、任选取代的烯基、任选取代的炔基和任选取代的芳基。
作为基团或基团的一部分的“芳基(aryl)”表示(i)优选每个环具有6至12个原子的任选取代的单环或稠合多环芳族碳环(具有环原子均为碳的环结构)。芳基的实例包括苯基、萘基等;(ii)任选取代的部分饱和的双环芳族碳环部分,其中苯基和C5-7环烷基或C5-7环烯基稠合在一起形成环状结构,例如四氢萘基(tetrahydronaphthyl)、茚基或茚满基。该基团可以为端基或桥连基。典型地,芳基为C6-C18芳基。
“叠氮基烷基(azidoalkyl)”是指其中烷基如本文所定义且被–N3基团取代的烷基。优选地,叠氮基烷基为C1-C6叠氮基烷基。实例包括但不限于叠氮基甲基和叠氮基乙基。
“碳环(carbocylic)”是指任何稳定的3、4、5、6或7元单环或双环或7、8、9、10、11、12或13元双环或三环体系,其中任何一个可以为饱和的、部分不饱和的或芳族的。此类碳环的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基、环辛基、[3.3.0]二环辛烷、[4.3.0]二环壬烷、[4.4.0]二环癸烷(萘烷)、[2.2.2]二环辛烷、芴基、苯基、萘基、茚满基、金刚烷基或四氢萘基(四氢化萘)。除非另有说明,优选的碳环为环丙基、环丁基、环戊基、环己基、苯基、萘基和茚满基。当使用术语“碳环”时,其旨在包括“芳基”。碳环可以任选被取代。
“环烯基(cycloalkenyl)”是指含有至少一个碳-碳双键并且优选每个环具有5-10个碳原子的非芳族单环或多环体系。示例性的单环环烯基环包括环戊烯基、环己烯基或环庚烯基。环烯基可以被一个或多个取代基取代。环烯基通常为C3-C12烯基基团。该基团可以为端基或桥连基。
除非另有说明,“环烷基(cycloalkyl)”是指饱和的单环或稠合或桥连或螺多环,碳环优选每个环含有3至9个碳原子,如环丙基、环丁基、环戊基、环己基等。它包括单环体系如环丙基和环己基、双环体系如萘烷以及多环体系如金刚烷。环烷基通常是C3-C12烷基。该基团可以为端基或桥连基。
“卤代烷基(haloalkyl)”是指其中烷基如本文所定义且烷基被至少一个卤素取代的烷基。优选烷基被1至5个卤素原子取代。优选地,烷氧基为C1-C6卤代烷基。实例包括但不限于氯甲基、氟甲基和三氟甲基。该基团可以为端基或桥连基。
“卤素(halogen)”或“卤代(halo)”表示氯、氟、溴或碘。
“杂芳基(heteroaryl)”单独或作为基团的一部分是指含有芳环(优选5元或6元芳环)的基团,该芳环具有一个或多个杂原子作为环原子的芳环,其余环原子为碳原子。合适的杂原子包括氮、氧和硫。杂芳基的实例包括噻吩、苯并噻吩、苯并呋喃、苯并咪唑、苯并噁唑、苯并噻唑、苯并异噻唑、萘并[2,3-b]噻吩、呋喃、异吲哚嗪(isoindolizine)、呫吨烯(xantholene)、phenoxatine、吡咯、咪唑、吡唑、吡啶、吡嗪、嘧啶、哒嗪、四唑、吲哚、异吲哚、1H-吲唑、嘌呤、喹啉、异喹啉、酞嗪、萘啶、喹喔啉、噌啉(cinnoline)、咔唑、菲啶、吖啶、吩嗪、噻唑、异噻唑、吩噻嗪、噁唑、异噁唑、呋咱(furazane)、吩噁嗪、2-吡啶基、3-吡啶基或4-吡啶基、2-喹啉基、3-喹啉基、4-喹啉基、5-喹啉基或8-喹啉基、1-异喹啉基、3-异喹啉基、4-异喹啉基或5-异喹啉基、1-吲哚基、2-吲哚基或3-吲哚基以及2-苯硫基或3-苯硫基。杂芳基基团通常为C1-C18杂芳基基团。杂芳基可包含3至8个环原子。杂芳基可以包含1至3个独立地选自N、O和S的杂原子。该基团可以为端基或桥连基。
“杂环基(heterocyclyl)”是指含有至少一个选自氮、硫和氧的杂原子作为环原子的饱和或部分不饱和的单环、双环或多环体系。杂环部分的实例包括杂环烷基和杂环烯基。
“杂环烯基(heterocycloalkenyl)”是指如本文所定义但含有至少一个双键的杂环烷基。杂环烯基通常为C2-C12杂环烯基。该基团可以为端基或桥连基。
“杂环烷基(heterocycloalkyl)”是指在至少一个环中含有至少一个选自氮、硫、氧的杂原子、优选1至3个杂原子的饱和单环、稠合或桥连或螺多环。每个环优选为3元至10元,更优选4元至7元。合适的杂环烷基取代基的实例包括吡咯烷基、四氢呋喃基、四氢硫代呋喃基(tetrahydrothiofuranyl)、哌啶基、哌嗪基、四氢吡喃基、吗啉代、1,3-二氮杂环庚烷(diazapane)、1,4-二氮杂环庚烷、1,4-氧杂氮杂环庚烷和1,4-氧杂硫杂环庚烷(oxathiapane)。杂环烷基基团通常为C2-C12杂环烷基。杂环烷基可包含3至9个环原子。杂环烷基可以包含1至3个独立地选自N、O和S的杂原子。该基团可以为端基或桥连基。
应当理解,包括在式(I)化合物家族中的是异构形式,包括“E”或“Z”构型异构体或E和Z异构体的混合物中的非对映异构体、对映异构体、互变异构体和几何异构体。还应当理解,一些异构体形式如非对映异构体、对映异构体和几何异构体可以由本领域技术人员通过物理和/或化学方法分离。
所公开的实施方案中的一些化合物可以作为单一立体异构体、外消旋体和/或对映异构体和/或非对映异构体的混合物存在。所有这样的单一立体异构体、外消旋体及其混合物都在所描述和要求保护的主题范围内。
本文所用的术语“任选取代的(optionally substituted)”是指该术语所指的基团可以为未取代的,或可以被独立地选自下述基团中的一个或多个基团取代:任选取代的芳基、任选取代的杂芳基、烷基(包括代表两个取代基的亚烷基桥)、烯基、炔基、硫代烷基、环烷基、氨基环烷基、环烷基烷基、环烯基、环烷基烯基、杂环烷基、环烷基杂烷基、环烷基氧基、环烷基氨基羰基、环烯基氧基、环氨基、卤代(halo)、羧基、卤代烷基、卤代烯基、卤代炔基、炔氧基、杂烷基、杂烷氧基、羟基、羟基烷基、烷氧基、烷氧基烷基、烷氧基烷氧基烷基、环烷基烷氧基烷基、硫代烷氧基、烯氧基、卤代烷氧基、卤代烯氧基、硝基、卤素(halogen)、氨基、氨基羰基、氨基羰基烷基、叠氮基烷基(azidoalkyl)、硝基烷基、硝基烯基、硝基炔基、硝基杂环基、烷基氨基、烷基氨基羰基、二烷基氨基、二烷基氨基烷基、烯基胺、烷基羰基氨基、氨基烷基、炔基氨基、酰基、氧代、烷氧基、烷氧基烷基、烷氧基芳基、烷氧基羰基、烷氧基环烷基、烷氧基杂芳基、烷氧基杂环烷基、烯酰基(alkenoyl)、炔酰基、酰氨基、二酰基氨基、酰氧基、烷基磺酰氧基、杂环基、杂环烯基、杂环烷基、杂环烷基烷基、杂环烷基烯基、杂环烷基杂烷基、杂环烷氧基、杂环烯氧基(heterocycloalkenyloxy)、杂环氧基、杂环氨基、卤代杂环烷基、烷基亚磺酰基(alkylsulfinyl)、烷基磺酰基(alkylsulfonyl)、烷基亚氧硫基(alkylsulfenyl)、烷基羰氧基、烷硫基、酰硫基、氨基磺酰基、含磷基团如膦酰基(phosphono)和氧膦基(phosphinyl)、亚磺酰基、亚磺酰基氨基、磺酰基、磺酰基氨基、烷基氨磺酰基(alkylsulfamoyl)、芳基、杂芳基、杂芳基烷基、杂芳基烯基、杂芳基杂烷基、杂芳基氨基、杂芳基氧基、芳基烯基、芳基烷基、烷基芳基、烷基杂芳基、芳氧基、芳基磺酰基、氰基、氰酸根(cyanate)、异氰酸根(isocyanate)、-C(O)NH(烷基)和-C(O)N(烷基)2。任选取代基的基团中碳原子和杂原子的数目如上述基团所定义,例如每个烷基或亚烷基部分可以为C1-C12烷基、甲基、乙基、正丙基、2-丙基等。因此,卤代烷氧基例如定义为被至少一个卤素原子取代的上述烷氧基。在任选取代基本身任选被取代的情况下,取代基可以选自任选取代基的列表,并且这样的取代基不被进一步取代。
优选的任选取代基定义为选自以下基团的1至3个基团:卤素、C1-C3烷基或C3-C7环烷基、硝基、卤素、具有1至5个卤素原子的C1-C4卤代烷基、C1-C4羟基烷基、任选卤素取代的C3-C7环烷基、氨基羰基-C1-C3烷基、具有5至6个环成员以及1至2个选自N或O的杂原子的任选C1-C3烷基取代的和/或卤素取代的杂芳基、或任选卤素、C1-C3烷基、C1-C4羟基烷基和/或叠氮基C1-C3烷基取代的苯基。优选的任选取代基也是形成任选C1-C3烷基取代的C1-C4亚烷基桥的两个取代基。
术语“药学上可接受的盐”是指保持上述化合物的所需生物活性的盐,并且包括药学上可接受的酸加成盐和碱加成盐。式(I)化合物的合适的药学上可接受的酸加成盐可以由无机酸或有机酸制备。这种无机酸的实例是盐酸、硫酸和磷酸。合适的有机酸可以选自脂肪族、脂环族、芳族、杂环羧酸和磺酸类有机酸,其实例为甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、富马酸、马来酸、烷基磺酸、芳基磺酸。关于药学上可接受的盐的其他信息可参见Remington's Pharmaceutical Sciences(《雷明顿药物科学》,第19版,Mack Publishing Co.(马克出版社),Easton,PA 1995。在试剂为固体的情况下,本领域技术人员应当理解,本发明的化合物、试剂和盐可以以不同的结晶或多晶型形式存在,所有这些都在本公开内容和特定结构式的范围内。
“前药(produrg)”是指在生物系统内通常通过代谢方式(例如通过水解、还原或氧化)转化为式(I)化合物的化合物。例如,含有羟基的式(I)化合物的酯前药可以通过体内水解转化为母体分子。含有羟基的式(I)化合物的合适酯类是例如甲酸酯、乙酸酯、柠檬酸酯、乳酸酯、酒石酸酯、丙二酸酯、草酸酯、水杨酸酯、丙酸酯、琥珀酸酯、富马酸酯、马来酸酯、亚甲基-双-β-羟基萘甲酸酯、龙胆酸酯、羟乙基磺酸酯(isethionate)、二-对甲苯酰基酒石酸酯、甲磺酸酯、乙磺酸酯、苯磺酸酯、对甲苯磺酸酯、环己基氨基磺酸酯和奎尼酸酯。作为另一个实例,含有羧基的式(I)化合物的酯前药可以通过体内水解转化为母体分子。(酯前药的实例是F.J.Leinweber,Drug Metab.Res.(《药物代谢研究》,18:379,1987中描述的那些)。类似地,含有氨基的式(I)化合物的酰基前药可以通过体内水解转化为母体分子(这些药物和其他官能团(包括胺类)的许多前药实例在Prodrugs:Challenges and Rewards(Parts 1and 2)(《前药:挑战和奖励》(第1部分和第2部分));Ed V.Stella,R.Borchardt,M.Hageman,R.Oliyai,H.Maag和J Tilley;Springer,2007)中有所描述。
在本发明的上下文中,术语“施用(administering)”以及该术语的变体包括“施用(administer、administration)”,包括通过任何合适的方式将本发明的化合物或组合物接触、应用、递送或提供至生物体或表面。
术语“治疗(treatment)”是指以任何方式治疗疾病状态或症状、预防疾病的建立或以任何方式预防、阻碍、延缓或逆转疾病或其他不良症状的进展的任何和所有用途。
词语“基本上(substantially)”不排除“完全(completely)”,例如“基本上不含(substantially free)”Y的组合物可以完全不含Y。必要时,词语“基本上”可以从本发明的定义中省略。
除非另外指明,否则术语“包括(comprising、comprise)”及其语法变体旨在表示“开放式”或“包括性”语言,使得它们包括所列举的要素,但也允许包括另外的未列举的要素。
如本文所用,在制剂组分浓度的上下文中,术语“约(about)”通常为所述值的+/-5%、更通常为所述值的+/-4%、更通常为所述值的+/-3%、更通常为所述值的+/-2%、甚至更通常为所述值的+/-1%、以及甚至更通常为所述值的+/-0.5%。
在整个本公开中,某些实施方案可以范围形式公开。应当理解,范围形式的描述仅仅是为了方便和简洁,而不应被解释为对所公开范围的范畴的僵化限制。因此,应当认为范围的描述已经具体公开了所有可能的子范围以及该范围内的各个数值。例如,对诸如1至6的范围的描述应当被认为已经具体公开了诸如1至3、1至4、1至5、2至4、2至6、3至6等的子范围,以及在该范围内的单个数字,例如1、2、3、4、5和6。无论范围的宽度如何,这都适用。
某些实施方案也可以在本文中广泛地和一般性地描述。落入一般公开内容内的每个较窄种类和亚类分组也形成本公开内容的一部分。这包括以从所述类中去除任何主题的附带条件或负面限制条件来一般性地说明本发明,不论所排除的内容是否在本文被具体地叙述。
附图说明
附图示出了所公开的实施方案,并用于解释所公开的实施方案的原理。然而,应当理解,附图仅仅是为了说明的目的而设计的,而不是作为对本发明的限制的定义。
图1
[图1]显示了剂量反应曲线,其显示了下述化合物对异戊二烯半胱氨酸羧甲基转移酶的酶活性的影响;化合物7(图1A);化合物71(图1B);化合物53(图1C);化合物70(图1D);化合物59(图1E);化合物69(图1F);以及化合物78(图1G)。
图2
[图2]显示了蛋白质印迹(Western blot)图像,其显示了用不同浓度的化合物59、69、70和71处理后MIAPaCa-2细胞中的A型核纤层蛋白前体的积聚。
图3
[图3]是显示下述化合物对MIAPaCa-2细胞生长的影响的剂量反应曲线;化合物71(图3A);化合物53(图3B);化合物70(图3C);化合物59(图3D);化合物69(图3E);化合物78(图3F)。
具体实施方式
本发明涉及具有下式(I)的化合物:
和/或其互变异构体、对映异构体、溶剂化物、水合物、前药和药学上可接受的盐;
其中:
环A为5元或6元碳环体系,其中1至4个碳原子可以任选地被杂原子替代;
B1、B2和B3独立地选自C、CH或N;
环C为5元或6元碳环体系,其中1至3个碳原子可以任选地被杂原子替代;
R1、R2和R3独立地不存在或选自H、OH、氰基、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基;
R4和R5独立地选自H或脂肪族;
n为选自0至5的整数,其中当n大于1时,环A上取代的每个R1可以相同或不同;
m为选自0至4的整数,其中当m大于1时,环B上取代的每个R2可以相同或不同;以及
p为选自0至5的整数,其中当p大于1时,环C上取代的每个R3可以相同或不同。
本发明还涉及具有下式(I)的化合物:
和/或其互变异构体、对映异构体、溶剂化物、水合物、前药和药学上可接受的盐;
其中:
环A为5元或6元碳环体系,其中1至4个碳原子可以任选地被杂原子替代;
B1、B2和B3独立地选自C、CH或N,其中当B1、B2或B3中的一个为N时,剩余的B1、B2或B3为C或CH;
环C为5元或6元碳环体系,其中1至3个碳原子可以任选地被杂原子替代;
R1不存在或选自H、OH、卤素、任选取代的烷基、任选取代的烯基、卤代烷基、CF3、CHF2、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基;
R2不存在或选自H、OH、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基;
R3不存在或选自H、OH、氰基、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基或任选取代的芳基;
R4和R5独立地选自H或脂肪族;
n为选自0至5的整数,其中当n大于1时,环A上取代的每个R1可以相同或不同;
m为选自0至4的整数,其中当m大于1时,环B上取代的每个R2可以相同或不同,并且当R2是卤素时,m是1;以及
p为选自0至5的整数,其中当p大于1时,环C上取代的每个R3可以相同或不同。
本发明还涉及具有下式(IA)的化合物:
和/或其互变异构体、对映异构体、溶剂化物、水合物、前药和药学上可接受的盐,其中:
A1、A2、A3、A4以及A5、R1、n、B1、B2、B3、R2、m、R4、R5、C1、C2、C3、C4、C5、C6、R3和p如本文所定义。
本发明还涉及下式(IE)或式(IF)的化合物:
和/或其互变异构体、对映异构体、溶剂化物、水合物、前药和药学上可接受的盐,其中:
A1、A2、A3、A4以及A5、R1、n、B1、B2、B3、R2、m、R4、R5、C1、C2、C3、C4、C5、C6、R3和p如本文所定义。
在本文公开的式中,环A可以具有式(aa):
其中:
*表示与环B的连接点;以及
A1、A2、A3、A4和A5独立地选自C、CH、N、O或S。
在本文公开的式中,环A可以具有式(ab):
其中:
*表示与环B的连接点;以及
A1为N或C;
A2为N、S、CH或C;
A3为C、CH、N或O;
A4为N;以及
A5为C、CH、O或N。
在本文公开的式中,环A可以具有式(ac):
其中:
*表示与环B的连接点;以及
A1为N或C;
A2为N、S、CH或C;
A3为C、CH、N或O;
A4为N;以及
A5为C、O或N。
在本文公开的式中,环A可以选自由式(a1)至(a8)组成的组:
在本文公开的式中,环A可以选自由式(a1')至(a8')组成的组:
在本文公开的式中,环A可以选自由式(a1”)至(a10””)组成的组:
其中*表示与环B的连接点。
在本文公开的式中,R1可以不存在或为H、OH、氰基、卤素(例如F、Cl、Br、I)、任选取代的烷基、卤代烷基、CF3、CHF2、CH2F、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基。
R1的任选取代的烷基可以为任选取代的C1-C12烷基、或任选取代的C1烷基、任选取代的C2烷基、任选取代的C3烷基、任选取代的C4烷基、任选取代的C5烷基、任选取代的C6烷基、任选取代的C7烷基、任选取代的C8烷基、任选取代的C9烷基、任选取代的C10烷基、任选取代的C11烷基或任选取代的C12烷基。R1的任选取代的烷基可以为甲基、乙基、丙基、丁基、戊基、己基或卤代烷基,例如CF3、CHF2或CH2F。R1的任选取代的烷氧基可以为任选取代的C1-C12烷氧基、或任选取代的C1烷氧基、任选取代的C2烷氧基、任选取代的C3烷氧基、任选取代的C4烷氧基、任选取代的C5烷氧基、任选取代的C6烷氧基、任选取代的C7烷氧基、任选取代的C8烷氧基、任选取代的C9烷氧基、任选取代的C10烷氧基、任选取代的C11烷氧基或任选取代的C12烷氧基。R1的任选取代的环烷基可以为任选取代的C3-C9环烷基、或任选取代的C3环烷基、任选取代的C4环烷基、任选取代的C5环烷基、任选取代的C6环烷基、任选取代的C7环烷基、任选取代的C8环烷基或任选取代的C9环烷基。任选取代的环烷基可以为环丙基。R1的任选取代的环烯基可以为任选取代的C3-C9环烯基、或任选取代的C3环烯基、任选取代的C4环烯基、任选取代的C5环烯基、任选取代的C6环烯基、任选取代的C7环烯基、任选取代的C8环烯基或任选取代的C9环烯基。R1的任选取代的杂环烷基可以为环原子数为3至8(例如环原子数为3、4、5、6、7、8)并且具有1至3个独立地选自由N、O和S组成的组的杂原子(例如1、2、3个杂原子)的任选取代的杂环烷基。R1的任选取代的芳基可以为任选取代的C6-C18芳基、或任选取代的C6芳基、任选取代的C7芳基、任选取代的C8芳基、任选取代的C9芳基、任选取代的C10芳基、任选取代的C11芳基、或任选取代的C12芳基、任选取代的C13芳基、任选取代的C14芳基、或任选取代的C15芳基、任选取代的C16芳基、任选取代的C17芳基、或任选取代的C18芳基。R1的任选取代的杂芳基可以为环原子数为3至8(例如环原子数为3、4、5、6、7、8)并且具有1至3个独立地选自由N、O和S组成的组的杂原子(例如1、2、3个杂原子)的任选取代的杂芳基。R1的任选取代的烯基可以为任选取代的C2-C12烯基、或任选取代的C2烯基、任选取代的C3烯基、任选取代的C4烯基、任选取代的C5烯基、任选取代的C6烯基、任选取代的C7烯基、任选取代的C8烯基、任选取代的C9烯基、任选取代的C10烯基、任选取代的C11烯基、或任选取代的C12烯基。R1的任选取代的炔基可以为任选取代的C2-C12炔基、或任选取代的C2炔基、任选取代的C3炔基、任选取代的C4炔基、任选取代的C5炔基、任选取代的C6炔基、任选取代的C7炔基、任选取代的C8炔基、任选取代的C9炔基、任选取代的C10炔基、任选取代的C11炔基或任选取代的C12炔基。
在本文公开的式中,R2可以不存在或为H、OH、氰基、卤素(例如F、Cl、Br、I)、任选取代的烷基、卤代烷基、CF3、CHF2、CH2F、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基。
R2的任选取代的烷基可以为任选取代的C1-C12烷基、或任选取代的C1烷基、任选取代的C2烷基、任选取代的C3烷基、任选取代的C4烷基、任选取代的C5烷基、任选取代的C6烷基、任选取代的C7烷基、任选取代的C8烷基、任选取代的C9烷基、任选取代的C10烷基、任选取代的C11烷基或任选取代的C12烷基。R2的任选取代的烷氧基可以为任选取代的C1-C12烷氧基、或任选取代的C1烷氧基、任选取代的C2烷氧基、任选取代的C3烷氧基、任选取代的C4烷氧基、任选取代的C5烷氧基、任选取代的C6烷氧基、任选取代的C7烷氧基、任选取代的C8烷氧基、任选取代的C9烷氧基、任选取代的C10烷氧基、任选取代的C11烷氧基或任选取代的C12烷氧基。R2的任选取代的环烷基可以为任选取代的C3-C9环烷基、或任选取代的C3环烷基、任选取代的C4环烷基、任选取代的C5环烷基、任选取代的C6环烷基、任选取代的C7环烷基、任选取代的C8环烷基或任选取代的C9环烷基。R2的任选取代的环烯基可以为任选取代的C3-C9环烯基、或任选取代的C3环烯基、任选取代的C4环烯基、任选取代的C5环烯基、任选取代的C6环烯基、任选取代的C7环烯基、任选取代的C8环烯基或任选取代的C9环烯基。R2的任选取代的杂环烷基可以为环原子数为3至8(例如环原子数为3、4、5、6、7、8)并且具有1至3个独立地选自由N、O和S组成的组的杂原子(例如1、2、3个杂原子)的任选取代的杂环烷基。R2的任选取代的芳基可以为任选取代的C6-C18芳基、或任选取代的C6芳基、任选取代的C7芳基、任选取代的C8芳基、任选取代的C9芳基、任选取代的C10芳基、任选取代的C11芳基、或任选取代的C12芳基、任选取代的C13芳基、任选取代的C14芳基、或任选取代的C15芳基、任选取代的C16芳基、任选取代的C17芳基、或任选取代的C18芳基。R2的任选取代的杂芳基可以为环原子数为3至8(例如环原子数为3、4、5、6、7、8)并且具有1至3个独立地选自由N、O和S组成的组的杂原子(例如1、2、3个杂原子)的任选取代的杂芳基。R2的任选取代的烯基可以为任选取代的C2-C12烯基、或任选取代的C2烯基、任选取代的C3烯基、任选取代的C4烯基、任选取代的C5烯基、任选取代的C6烯基、任选取代的C7烯基、任选取代的C8烯基、任选取代的C9烯基、任选取代的C10烯基、任选取代的C11烯基、或任选取代的C12烯基。R2的任选取代的炔基可以为任选取代的C2-C12炔基、或任选取代的C2炔基、任选取代的C3炔基、任选取代的C4炔基、任选取代的C5炔基、任选取代的C6炔基、任选取代的C7炔基、任选取代的C8炔基、任选取代的C9炔基、任选取代的C10炔基、任选取代的C11炔基或任选取代的C12炔基。R2可以为H或F。
在本文公开的式中,R3可以不存在或为H、OH、氰基、卤素(例如F、Cl、Br、I)、任选取代的烷基、卤代烷基、CF3、CHF2、CH2F、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基。
R3的任选取代的烷基可以为任选取代的C1-C12烷基、或任选取代的C1烷基、任选取代的C2烷基、任选取代的C3烷基、任选取代的C4烷基、任选取代的C5烷基、任选取代的C6烷基、任选取代的C7烷基、任选取代的C8烷基、任选取代的C9烷基、任选取代的C10烷基、任选取代的C11烷基或任选取代的C12烷基。R3的任选取代的烷氧基可以为任选取代的C1-C12烷氧基、或任选取代的C1烷氧基、任选取代的C2烷氧基、任选取代的C3烷氧基、任选取代的C4烷氧基、任选取代的C5烷氧基、任选取代的C6烷氧基、任选取代的C7烷氧基、任选取代的C8烷氧基、任选取代的C9烷氧基、任选取代的C10烷氧基、任选取代的C11烷氧基或任选取代的C12烷氧基。R3的任选取代的环烷基可以为任选取代的C3-C9环烷基、或任选取代的C3环烷基、任选取代的C4环烷基、任选取代的C5环烷基、任选取代的C6环烷基、任选取代的C7环烷基、任选取代的C8环烷基或任选取代的C9环烷基。R3的任选取代的环烯基可以为任选取代的C3-C9环烯基、或任选取代的C3环烯基、任选取代的C4环烯基、任选取代的C5环烯基、任选取代的C6环烯基、任选取代的C7环烯基、任选取代的C8环烯基或任选取代的C9环烯基。R3的任选取代的杂环烷基可以为环原子数为3至8(例如环原子数为3、4、5、6、7、8)并且具有1至3个独立地选自由N、O和S组成的组的杂原子(例如1、2、3个杂原子)的任选取代的杂环烷基。R3的任选取代的芳基可以为任选取代的C6-C18芳基、或任选取代的C6芳基、任选取代的C7芳基、任选取代的C8芳基、任选取代的C9芳基、任选取代的C10芳基、任选取代的C11芳基、或任选取代的C12芳基、任选取代的C13芳基、任选取代的C14芳基、或任选取代的C15芳基、任选取代的C16芳基、任选取代的C17芳基、或任选取代的C18芳基。R3的任选取代的杂芳基可以为环原子数为3至8(例如环原子数为3、4、5、6、7、8)并且具有1至3个独立地选自由N、O和S组成的组的杂原子(例如1、2、3个杂原子)的任选取代的杂芳基。R3的任选取代的烯基可以为任选取代的C2-C12烯基、或任选取代的C2烯基、任选取代的C3烯基、任选取代的C4烯基、任选取代的C5烯基、任选取代的C6烯基、任选取代的C7烯基、任选取代的C8烯基、任选取代的C9烯基、任选取代的C10烯基、任选取代的C11烯基、或任选取代的C12烯基。R3的任选取代的炔基可以为任选取代的C2-C12炔基、或任选取代的C2炔基、任选取代的C3炔基、任选取代的C4炔基、任选取代的C5炔基、任选取代的C6炔基、任选取代的C7炔基、任选取代的C8炔基、任选取代的C9炔基、任选取代的C10炔基、任选取代的C11炔基或任选取代的C12炔基。R3可以为卤素(如F、Cl、Br、I)、-CN、烷氧基(如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基)、氨基、卤代烷基(如-CF3、-CHF2、-CH2F)、卤代烷氧基(如-OCF3、-OCHF2、-OCH2F)或烷基(如甲基、乙基、丙基、丁基、戊基、己基)。
R3可以为氟、氯、溴、-CN、甲氧基、甲基、-NH2、-OCF3或-CF3。
R4可以为H或脂肪族。R4可以为H或任选取代的烷基。R4可以为H或任选取代的C1-C12烷基,任选取代的C1-C12烯基或任选取代的C1-C12炔基。R4可以为任选取代的C1烷基、任选取代的C2烷基、任选取代的C3烷基、任选取代的C4烷基、任选取代的C5烷基、任选取代的C6烷基、任选取代的C7烷基、任选取代的C8烷基、任选取代的C9烷基、任选取代的C10烷基、任选取代的C11烷基或任选取代的C12烷基。R4可以为任选取代的C2烯基、任选取代的C3烯基、任选取代的C4烯基、任选取代的C5烯基、任选取代的C6烯基、任选取代的C7烯基、任选取代的C8烯基、任选取代的C9烯基、任选取代的C10烯基、任选取代的C11烯基或任选取代的C12烯基。R4可以为任选取代的C2烯基、任选取代的C3烯基、任选取代的C4烯基、任选取代的C5烯基、任选取代的C6烯基、任选取代的C7烯基、任选取代的C8烯基、任选取代的C9烯基、任选取代的C10烯基、任选取代的C11烯基或任选取代的C12烯基。R4可以为H或甲基、乙基、丙基、丁基、戊基或己基。
R5可以为H或脂肪族。R5可以为H或任选取代的烷基。R5可以为H或任选取代的C1-C12烷基,任选取代的C1-C12烯基或任选取代的C1-C12炔基。R4可以为任选取代的C1烷基、任选取代的C2烷基、任选取代的C3烷基、任选取代的C4烷基、任选取代的C5烷基、任选取代的C6烷基、任选取代的C7烷基、任选取代的C8烷基、任选取代的C9烷基、任选取代的C10烷基、任选取代的C11烷基或任选取代的C12烷基。R5可以为任选取代的C2烯基、任选取代的C3烯基、任选取代的C4烯基、任选取代的C5烯基、任选取代的C6烯基、任选取代的C7烯基、任选取代的C8烯基、任选取代的C9烯基、任选取代的C10烯基、任选取代的C11烯基或任选取代的C12烯基。R5可以为任选取代的C2烯基、任选取代的C3烯基、任选取代的C4烯基、任选取代的C5烯基、任选取代的C6烯基、任选取代的C7烯基、任选取代的C8烯基、任选取代的C9烯基、任选取代的C10烯基、任选取代的C11烯基或任选取代的C12烯基。R5可以为H或甲基、乙基、丙基、丁基、戊基或己基。
R4和R5可以为H;或R4为H且R5为甲基;或R4为甲基且R5为H;或R4为甲基且R5为甲基。
在本文公开的式中,环B可以具有由式(bb1)或式(bb2)组成的组:
其中:
*表示与环A的连接点;以及
**表示与式(I)的–O(CHR4)-部分的连接点。
在本文公开的式中,环B可以选自由式(b1)至(b5)组成的组:
在本文公开的式中,环B可以选自由式(b1')至(b9')组成的组:
其中:
*表示与环A的连接点;以及
**表示与式(I)的–O(CHR4)-部分的连接点。
在本文公开的式中,环C可以具有式(ca):
其中:
***表示与式(I)的–O(CHR5)-部分的连接点;以及
C1、C2、C3、C4、C5和C6独立地选自C、CH或N。
在本文公开的式中,环C可以具有式(cb):
其中:
***表示与式(I)的–O(CHR5)-部分的连接点;
C1和C2独立地为C、CH或N;
C4、C5和C6独立地为C或CH;以及
C3为C。
在本文公开的式中,环C可以具有式(cc):
其中:
***表示与式(I)的–O(CHR5)-部分的连接点;
C1和C2独立地为CH或N;
C5为CH;以及
C3、C4和C6为C。
在本文公开的式中,环C可以选自由式(c1)至(c4)组成的组:
在本文公开的式中,环C可以选自由式(c1')至(c6')组成的组:
其中:
***表示与式(I)的–O(CHR5)-部分的连接点。
在本文公开的式中,环C可以选自由(c1”)至(c22”)组成的组:
其中:
***表示与式(I)的–O(CHR5)-部分的连接点。
环A可以为5元碳环体系,其中1至4(如1、2、3、4)个碳原子被杂原子替代;并且环B具有式(bb1)或式(bb2)。
环A可以为5元杂芳基,并且环B具有式(bb1)或式(bb2)。
本文公开的式的化合物可以选自由以下组成的组:
提供了包含本文公开的化合物或其药学上可接受的形式或前药和药学上可接受的赋形剂的药物组合物。
该组合物中化合物的量可以使得其有效地可测量地抑制生物样品或患者中的ICMT。可以配制该组合物以施用于需要这种组合物的患者。
在使用该化合物时,它们可以以可使化合物可生物利用的任何形式或模式施用。制备制剂领域的技术人员可以根据所选化合物的具体特征、所治疗的病症(condition)、所治疗病症的阶段和其他相关情况容易地选择合适的施用形式和方式。
术语“药学上可接受的赋形剂(pharmaceutically acceptable excipient)”可以指无毒载体、佐剂或媒介物,其不破坏与其一起配制的化合物的药理学活性。可用于本公开的组合物中的药学上可接受的载体、佐剂或媒介物可包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸、水、盐或电解质的偏甘油酯混合物如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇或羊毛脂。
如上定义的组合物可以口服、肠胃外、通过吸入喷雾、局部、直肠、鼻、口腔、阴道或通过植入的储库施用。本文所用的术语“肠胃外(parenteral)”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。优选地,组合物通过口服、腹膜内或静脉内给药。本公开的组合物的无菌可注射形式可以为水性或油性悬浮液。这些悬浮液可以根据本领域已知的技术使用合适的分散剂或润湿剂和悬浮剂来配制。无菌可注射制剂还可以为在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为在1,3-丁二醇中的溶液。可以使用的可接受的载体和溶剂是水、林格氏溶液和等渗氯化钠溶液。此外,无菌的不挥发油通常用作溶剂或悬浮介质。
为此,可以使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。脂肪酸如油酸及其甘油酯衍生物可用于制备注射剂,天然的药学上可接受的油如橄榄油或蓖麻油,尤其是它们的聚氧乙烯化形式也可用于制备注射剂。这些油溶液或混悬液还可以含有长链醇稀释剂或分散剂,例如羧甲基纤维素或类似分散剂,其通常用于配制药学上可接受的剂型(包括乳剂和混悬液)。其他常用的表面活性剂,如Tweens、Spans和其他常用于制备药学上可接受的固体、液体或其他剂型的乳化剂或生物利用度增强剂也可用于配制目的。
如上定义的药学上可接受的组合物可以以任何口服可接受的剂型口服施用,包括但不限于胶囊、片剂、水性悬浮液或溶液。在口服片剂的情况下,通常使用的载体包括乳糖和玉米淀粉。通常还加入润滑剂,例如硬脂酸镁。对于胶囊形式的口服施用,有用的稀释剂包括乳糖和干玉米淀粉。当口服使用需要水性悬浮液时,将活性成分与乳化剂和悬浮剂组合。如果需要,也可以加入某些甜味剂、调味剂或着色剂。
用于肠胃外注射的药物组合物可以包含药学上可接受的无菌水性或非水性溶液、分散体、悬浮液或乳液以及用于在临用前重构为无菌可注射溶液或分散体的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)及其合适的混合物、植物油(如橄榄油)和可注射的有机酯如油酸乙酯。例如,通过使用包衣材料如卵磷脂,通过在分散体的情况下维持所需的粒度(particlesize),以及通过使用表面活性剂,可以维持适当的流动性。
这些组合物还可以含有佐剂如防腐剂、润湿剂、乳化剂和分散剂。通过包含各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚山梨酸等,可以确保防止微生物的作用。还希望包括等渗剂如糖、氯化钠等。通过包含延迟吸收的试剂如单硬脂酸铝和明胶,可以实现可注射药物形式的延长吸收。
如果需要并且为了更有效地分布,可将化合物掺入缓释或靶向递送系统如聚合物基质、脂质体和微球中。
可注射制剂可例如通过经细菌截留滤器过滤或通过掺入无菌固体组合物形式的灭菌剂来灭菌,所述灭菌剂可在临用前溶解或分散于无菌水或其他无菌可注射介质中。
或者,上述药学上可接受的组合物可以以用于直肠施用的栓剂形式施用。这些可以通过将药剂与合适的无刺激性赋形剂混合来制备,所述赋形剂在室温为固体,但在直肠温度为液体,因此将在直肠中熔化以释放药物。这些材料包括可可脂、蜂蜡和聚乙二醇。
如上定义的药学上可接受的组合物也可以局部施用,特别是当治疗目标包括通过局部施用容易接近的区域或器官时,包括眼睛、皮肤或下肠道的疾病。对于这些区域或器官的每一个,可以容易地制备合适的局部制剂。
下肠道的局部施用可以以直肠栓剂制剂(参见上文)或合适的灌肠制剂进行。也可以使用局部透皮贴剂。
对于局部应用,药学上可接受的组合物可以配制成含有悬浮或溶解在一种或多种载体中的活性组分的合适软膏剂。用于局部施用如上定义的化合物的载体可以包括但不限于矿物油、液体凡士林、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者,药学上可接受的组合物可以配制成含有悬浮或溶解在一种或多种药学上可接受的载体中的活性组分的合适洗剂或霜剂。合适的载体可以包括但不限于矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苯甲醇和水。
对于眼科用途,可将药学上可接受的组合物配制成在等渗的、pH调节的无菌盐水中的微粉化悬浮液,或优选配制成在等渗的、pH调节的无菌盐水中的溶液,含有或不含防腐剂如苯扎氯铵。或者,对于眼科用途,可将药学上可接受的组合物配制成软膏如凡士林。
如上定义的药学上可接受的组合物也可以通过鼻气雾剂或吸入施用。这样的组合物可以根据药物制剂领域公知的技术制备,并且可以使用苯甲醇或其他合适的防腐剂、提高生物利用度的吸收促进剂、碳氟化合物和/或其他常规增溶剂或分散剂制备为盐水的溶液。
最优选地,如上定义的药学上可接受的组合物可以配制用于口服施用。这样的制剂可以与食物一起或不与食物一起施用。在一些实施方案中,如上定义的药学上可接受的组合物可以不与食物一起施用。在其他实施方案中,如上定义的药学上可接受的组合物可以与食物一起施用。
可以与载体材料组合以产生单一剂型的组合物的化合物的量可以根据所治疗的宿主、具体的施用方式而变化。优选地,应当配制组合物,使得可以向接受这些组合物的患者施用0.01mg/kg至100mg/kg体重/天的抑制剂剂量。
还应当理解,任何具体患者的具体剂量和治疗方案将取决于各种因素,包括所用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、施用时间、排泄速率、药物组合以及治疗医师的判断和所治疗具体疾病的严重程度。组合物中本发明化合物的量还将取决于组合物中的具体化合物。
本发明提供了抑制由异戊二烯半胱氨酸羧甲基转移酶(ICMT)引起的异戊二烯化半胱氨酸或异戊二烯半胱氨酸甲基化的方法,包括使本文公开的化合物或本文公开的药物组合物与ICMT接触。
还提供了抑制细胞中的ICMT的方法,包括使所述细胞与本文公开的化合物、或其药学上可接受的形式或前药、或本文公开的药物组合物接触。
ICMT的抑制还可以包括细胞增殖的抑制。
还提供了治疗ICMT相关疾病的方法,包括向需要治疗的受试者施用本文公开的化合物、或本文公开的药物或组合物。该方法还可以包括向受试者施用另外的治疗剂的步骤。
所述疾病可以为癌症、早熟衰老症或哈钦森-吉尔福德早衰综合征(HGPS)。癌症可能与突变型Ras过度活性有关。癌症可以选自由肝细胞癌、乳腺癌、卵巢癌、结肠直肠癌、肺癌、胰腺癌或白血病组成的组。
还提供了用于治疗的本文公开的化合物、或其药学形式或前药、或本文公开的组合物。该化合物可以与另外的治疗剂组合施用。
还提供了用于治疗和/或预防癌症和/或早衰样疾病的本文公开的化合物、或其药学形式或前药、或本文公开的组合物。
还提供了用于治疗ICMT相关疾病的本文公开的化合物、或其药学形式或前药、或本文公开的组合物。所述疾病可以为癌症、早熟衰老症或哈钦森-吉尔福德早衰综合征(HGPS)。癌症可以为与突变型Ras过度活性相关的癌症。癌症可以为肝细胞癌、乳腺癌、卵巢癌、结肠直肠癌、肺癌、胰腺癌或白血病。
还提供了本文公开的化合物、或其药学形式或前药、或本文公开的组合物在制备用于治疗和/或预防癌症和/或早衰样疾病的药物中的用途。该药物可以与另外的治疗剂组合施用。
还提供了本文公开的化合物、或其药学形式或前药、或本文公开的组合物在制备用于治疗ICMT相关疾病的药物中的用途。所述疾病可以为癌症、早熟衰老症或哈钦森-吉尔福德早衰综合征。癌症可以为与突变型Ras过度活性相关的癌症。癌症可以为肝细胞癌、乳腺癌、卵巢癌、结肠直肠癌、肺癌、胰腺癌或白血病。
本发明的化合物可具有小于约5μM的ICMT IC50。本发明的化合物可具有约0.001μM至约5μM的ICMT IC50。
还提供了合成本文公开的化合物的方法,其包括:
(a)使式(III)化合物:
其中R1、R2、R4、R5、B1、B2、B3、n和m如本文所定义,并且R6为离去基团(leavinggroup),
在碱存在下,在有机溶剂中,与式(IV)化合物反应:
其中R3和p如本文所定义,且R7为-OH。
作为离去基团的R6可以为任何合适的离去基团,并且可以为甲磺酸酯(OMs)、甲苯磺酸酯(OTs)、全氟烷基磺酸酯(三氟甲磺酸酯)、溴化物或碘化物。
用于上述方法(a)的有机溶剂可以为N-甲基吡咯烷酮、二甲基甲酰胺、四氢呋喃、乙酸乙酯、丙酮、乙腈或二甲亚砜。
用于上述方法(a)的碱可以选自各种碱,包括无机碱或氮碱,例如三乙胺、吡啶、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铵、氢氧化钙、碳酸锂、碳酸钠、碳酸钾、碳酸铯、氢化钠或碳酸氢钠。
上述方法(a)可以在取决于所用溶剂和碱的类型的温度进行。作为指导,温度通常可以在约40℃至约80℃的范围。方法(a)可以在约40℃至约80℃、约45℃至约80℃、约50℃至约80℃、约55℃至约80℃、约60℃至约80℃、约65℃至约80℃、约70℃至约80℃、约75℃至约80℃、约40℃至约75℃、40℃至约70℃、约40℃至约65℃、约40℃至约60℃、约40℃至约55℃、约40℃至约50℃、约40℃至约45℃、或约40℃、约45℃、约50℃、约55℃、约60℃、约65℃、约70℃、约75℃、约80℃或其中的任何值或范围的温度范围进行。
上述方法(a)可以进行一段时间,这取决于所用溶剂和碱的类型。作为指导,持续时间通常可以在约12小时至约20小时的范围。方法(a)可以进行约12小时至约20小时、约13小时至约20小时、约14小时至约20小时、约15小时至约20小时、约16小时至约20小时、约17小时至约20小时、约18小时至约20小时、约19小时至约20小时、约12小时至约19小时、约12小时至约18小时、约12小时至约17小时、约12小时至约16小时、约12小时至约15小时、约12小时至约14小时、约12小时至约13小时、或约12小时、约13小时、约14小时、约15小时、约16小时、约17小时、约18小时、约19小时、约20小时或其中的任何值或范围。
还提供了用于合成本文公开的化合物的另一种方法,其包括:
(b)使式(III)化合物:
其中R1、R2、R4、R5、B1、B2、B3、n和m如本文所定义,并且R6为OH或醇盐,
在碱存在下,在有机溶剂中,与式(IV)化合物反应:
其中R3和p如本文所定义,且R7为卤素。
用于上述方法(b)的有机溶剂可以为N-甲基吡咯烷酮、二甲基甲酰胺、四氢呋喃、乙酸乙酯、丙酮、乙腈、二甲亚砜、碳酸丙烯酯或硝基甲烷。
用于上述方法(b)的碱可以选自各种碱,包括无机碱或氮碱,例如三乙胺、吡啶、氢氧化钠、氢氧化钾、氢氧化锂、碳酸锂、碳酸钠、碳酸钾或碳酸铯。
上述方法(b)可以在取决于所用溶剂和碱的类型的温度进行。作为指导,温度通常可以在约80℃至约120℃的范围。方法(b)可以在约80℃至约120℃、约85℃至约120℃、约90℃至约120℃、约95℃至约120℃、约100℃至约120℃、约105℃至约120℃、约110℃至约120℃、约115℃至约120℃、约80℃至约115℃、约80℃至约110℃、约80℃至约105℃、约80℃至约100℃、约80℃至约95℃、约80℃至约90℃、约80℃至约85℃、或约80℃、约85℃、约90℃、约95℃、约100℃、约105℃、约110℃、约115℃、约120℃或其中的任何值或范围的温度范围进行。
上述方法(b)可以进行一段时间,这取决于所用溶剂和碱的类型。作为指导,持续时间通常可以在约12小时至约20小时的范围内。方法(b)可以进行约12小时至约20小时、约13小时至约20小时、约14小时至约20小时、约15小时至约20小时、约16小时至约20小时、约17小时至约20小时、约18小时至约20小时、约19小时至约20小时、约12小时至约19小时、约12小时至约18小时、约12小时至约17小时、约12小时至约16小时、约12小时至约15小时、约12小时至约14小时、约12小时至约13小时、或约12小时、约13小时、约14小时、约15小时、约16小时、约17小时、约18小时、约19小时、约20小时或其中的任何值或范围。
实施例
通过参考具体实施例将进一步更详细地描述本发明的非限制性实施例,这些实施例不应被解释为以任何方式限制本发明的范围。
实施例1:ICMT酶的表达与纯化
通过用含有人ICMT cDNA的完整可读框的重组杆状病毒感染Sf9细胞制备重组人ICMT。简言之,将对数生长期的Sf9细胞稀释至1x 106细胞/ml,并以2的感染复数感染重组杆状病毒。感染后66小时收获产生ICMT的细胞。将细胞匀浆并重悬于5mM NaHPO4(pH 7.0)和蛋白酶抑制剂的混合物中。除去细胞核和碎片后,以100,000xg沉淀膜1小时。将膜以10mg/ml至12mg/ml重悬于含有5mM EDTA的5mM NaHPO4(pH 7.0)中。将悬浮液以多个等分试样储存在-80℃。
实施例2:ICMT生化测定
使用Promega的甲基转移酶-GloTM试剂开发了ICMT酶测定。在该测定中,ICMT通过将甲基从SAM转移到法尼基化的半胱氨酸来催化N-乙酰基-S-法尼基-L-半胱氨酸的甲基化,并进一步将SAM转化为SAH。通过使用将SAH转化为ATP的偶联酶,基于反应产生的SAH量来测量甲基转移酶的活性。然后MTase-Glo检测溶液催化ATP形成光。
为了测定IC50,将化合物与0.04μg/孔的来自Sf-9细胞的ICMT膜提取物一起孵育30分钟。加入终浓度为2.0μM和20μM的SAM和肽,并在室温下进一步孵育90分钟,然后加入MTase Glo和检测试剂。使用微板读数器在发光模式(Safire Tcan)上检测反应信号。使用GraphPad Prism 5.03版通过非线性回归确定IC50。
实施例3:A型核纤层蛋白前体积聚测定
将MIAPaCa-2细胞接种在6孔板中。接种24小时后,用DMSO或不同浓度的化合物处理细胞并孵育48小时。将细胞用胰蛋白酶消化并用RIPA缓冲液(Santa Cruz)提取裂解物。使用标准的Bradford测定法(Biorad蛋白测定,微孔板标准测定)对裂解物的总蛋白浓度进行定量。
在用不同浓度的化合物处理48小时的MIAPaCa细胞中,使用针对A型核纤层蛋白前体的抗体进行蛋白质印迹分析。将15.0μg细胞裂解物在SDS-PAGE上电泳,然后转移到硝酸纤维素膜上。然后将膜在封闭缓冲液[含有0.1%Tween 20和5%奶粉的PBS(磷酸盐缓冲盐水)]中于室温孵育1小时,接着与以1:2500稀释于PBS、0.1%Tween 20和5%奶粉中的A型核纤层蛋白前体抗体(大鼠单克隆抗体)于4℃孵育过夜,然后在第二天在PBS、0.1%Tween 20中洗涤三次(每次洗涤15分钟)。
然后将硝酸纤维素膜与二抗溶液于室温孵育1小时,洗涤3次,然后用增强化学发光(ECL)混合物(Amersham,Aylesbury,英国)显影,孵育5分钟并使用Fluorrchem E System仪器(Protein Simple)曝光。
实施例4:软琼脂测定
MIAPaCa-2细胞购自ATCC。对于软琼脂测定,将600μL的0.6%琼脂加入到24孔板中以形成基层。然后加入500μL 0.36%琼脂中间层(含有MIAPacCa-2细胞)。最后,在中间层上加入500μL新鲜生长培养基(含有相应的连续稀释的化合物)。将板在37℃与5%二氧化碳在潮湿的培养箱中孵育1至2周,每3天更换培养基。向各孔中加入70μL噻唑蓝溴化四唑(5mg/mL,Sigma Catalogue No:M5655),将板在室温下孵育过夜。用解剖显微镜(4X放大)对具有菌落的平板进行成像。然后用ImageJ软件分析图像的菌落计数,使用GraphPad Prism软件将菌落计数对化合物浓度作图。此外,该软件用于进行非线性曲线拟合和IC50的计算。
实施例5:细胞增殖测定
使用CellTiter-Glo发光法细胞活力检测试剂盒(Promega)按照制造商的说明书进行细胞增殖测定。用在培养基(DMEM)中连续稀释的化合物处理MIAPaCa-2细胞(ATCC)。将板在37℃在5%CO2中孵育3天。3天后,加入等体积的Cell Titer Glo试剂。将板在旋转器上摇动2小时。将每孔100μL转移到96孔不透明板中,并用Tecan Safire II测量发射的荧光。所选化合物的数据总结于表1中。
表1.所选化合物的MIAPaCa-2细胞增殖测定数据总结。
化合物 | GI<sub>50</sub>(μM) |
71 | 12.66 |
53 | 2.2 |
70 | 5.99 |
59 | 5.52 |
69 | 5.05 |
78 | 6.02 |
实施例6:苯酚中间体的制备
一般方法1
向充分搅拌的相应的卤化物1(1摩尔当量)在4:1比例的1,4-二噁烷-水(0.6M)中的溶液中,在室温依次添加硼酸2(1.2摩尔当量)、K3PO4(2摩尔当量)和Pd(dppf)Cl2.DCM(0.05摩尔当量),并用氩气脱气5分钟。将反应混合物在100℃加热16小时。将反应混合物冷却至室温,倒入冰水中并用乙酸乙酯萃取。将合并的有机物用水、盐水洗涤,经硫酸钠干燥,过滤并减压浓缩,得到粗产物。通过柱色谱法纯化该粗产物,得到所需产物3。
在80℃,将充分搅拌的3的过量HBr的乙酸溶液加热16小时。将反应混合物减压浓缩。将粗物质用饱和碳酸氢钠碱化并将pH调节至8并用乙酸乙酯萃取。合并的有机物用水和盐水溶液洗涤,经无水硫酸钠干燥,过滤,减压浓缩,得到所需的苯酚4。
3-(噻唑-5-基)苯酚的制备
1HNMR(400MHz,CDCl3)δ(ppm):8.75(s,1H),8.07(s,1H),7.33(t,J=8.0Hz,1H),7.20-7.15(m,1H),7.11(t,J=2.2Hz,1H),6.91-6.88(m,1H),3.86(s,3H)。MS(ESI)m/z178.2[C9H7NOS+H]+。
3-(1-甲基-1H-吡唑-5-基)苯酚的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.52(d,J=2.0Hz,1H),7.32-7.25(m,1H),6.96-6.86(m,3H),6.38(t,J=2.4Hz,1H),6.30(dd,J=6.8,2.0Hz,1H),3.93(s,3H)。MS(ESI)m/z175.2[C10H10N2O+H]+。
2-(1-甲基-1H-吡唑-5-基)吡啶-4-醇的制备
1H NMR(400MHz,CDCl3)δ(ppm):10.8(s,1H),8.49(d,J=6.0Hz,1H),7.49(s,1H),7.07(s,1H),6.79(t,J=2.0Hz,1H),6.54(s,1H),4.2(s,3H)。MS(ESI)m/z 176.2[C9H9N3O+H]+。
3-(异噁唑-4-基)苯酚的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.66(d,J=6.8Hz,1H),8.52(d,J=3.6Hz,1H),7.27(t,J=7.6Hz,1H),7.05(d,J=8.0Hz,1H),6.81(dd,J=8.4,2.0Hz,1H),4.98(s,1H)。MS(ESI)m/z 162.2[C9H7NO2+H]+。
3-(异噁唑-4-基)苯酚的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.66(d,J=6.8Hz,1H),8.52(d,J=3.6Hz,1H),7.27(t,J=7.6Hz,1H),7.05(d,J=8.0Hz,1H),6.81(dd,J=8.4,2.0Hz,1H),4.98(s,1H)。MS(ESI)m/z 162.2[C9H7NO2+H]+。
3-氟-5-(1-甲基-1H-吡唑-5-基)苯酚的制备
1H NMR(DMSO-d6,400MHz):δ10.527(brs,1H),7.434(d,1H,J=1.6Hz),6.765(d,1H,J=9.6Hz),6.715(s,1H),6.623(dd,1H,J=10.8&2.0Hz),6.379(d,1H,J=1.6Hz),3.815(s,3H)。MS(ESI)m/z 193.1[C10H9FN2O+H]+。
5-(1-甲基-1H-吡唑-5-基)吡啶-3-醇的制备
MS(ESI)m/z 176.1[C9H9N3O]+。
6-(1-甲基-1H-吡唑-5-基)吡啶-2-醇的制备
1H NMR(CDCl3,400MHz):δ7.542(t,0.5H,J=8.0Hz),7.444(t,0.5H,J=8.0Hz),7.082(d,0.5H,J=7.2Hz),6.924(d,0.5H,J=7.2Hz),6.735(d,0.5H,J=8.0Hz),6.703(d,0.5H,J=8.0Hz),4.462-4.440(m,2H),3.964-3.942(m,2H)。MS(ESI)m/z 176.1[C9H9N3O+H]+。
4-氟-3-(1-甲基-1H-吡唑-5-基)苯酚的制备
1H NMR(CDCl3,400MHz):δ7.54-7.53(d,J=1.6Hz,1H),7.10(t,J=9.0Hz,1H),6.97-6.93(m,1H),6.87-6.85(m,1H),6.32-6.31(d,J=2.0Hz,1H),4.09-4.07(m,2H),3.98-3.96(m,2H),3.82(s,3H)。MS(ESI)m/z 193.1[C10H9FN2O+H]+。
一般方法2
向充分搅拌的1-溴-3-甲氧基苯1(1摩尔当量)的DMF(0.85M)溶液中添加相应的胺1a(1.5摩尔当量)和碳酸铯(2摩尔当量)和碘化铜(I)(0.1摩尔当量)。将反应混合物在100℃加热16小时。冷却反应混合物,倒入水中,用乙酸乙酯萃取。将合并的有机物用水和盐水洗涤,经硫酸钠干燥并减压浓缩。通过柱色谱法纯化粗产物,得到所需中间体2。
在80℃,将充分搅拌的2的过量HBr的乙酸溶液加热16小时。将反应混合物减压浓缩。将粗物质用饱和碳酸氢钠碱化并将pH调节至8并用乙酸乙酯萃取。合并的有机物用水和盐水溶液洗涤,经无水硫酸钠干燥,过滤,减压浓缩,得到所需的苯酚3。
3-(1H-1,2,4-三唑-1-基)苯酚的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):9.97(s,1H),9.22(s,1H),8.19(s,1H),7.34-7.24(m,3H),6.80-6.78(m,1H)。MS(m/z):162.2[C8H7N3O+H]+。
3-(4H-1,2,4-三唑-4-基)苯酚的制备
1H NMR(400MHz,CDCl3)δ(ppm):9.94(s,1H),9.23(s,1H),8.19(s,1H),7.35-7.24(m,3H),6.93(dd,J=1.6Hz,8.0Hz,1H)。MS(ESI)m/z 162.2[C8H7N3O+H]+。
2-(3-甲基-4H-1,2,4-三唑-4-基)吡啶-4-醇的制备
MS(ESI)m/z 177.1[C8H8N4O]+。
2-(1H-四唑-1-基)吡啶-4-醇的制备
MS(ESI)m/z 177.1[C6H5N5O]+。
3-(2-甲基-1H-咪唑-1-基)苯酚的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):9.91(s,1H),7.32-7.28(m,1H),7.23(m,1H),6.68(m,1H),6.84-6.81(m,2H),6.75(m,1H),2.26(s,3H);MS(ESI)m/z 175.1[C10H10N2O+H]+。
4-甲氧基-2-(2-甲基-1H-咪唑-1-基)吡啶的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):11.08(s,1H),8.23(d,J=6.0Hz,1H),7.45(d,J=1.6Hz,1H),6.87-6.80(m,3H),2.23(s,3H)。MS(ESI)m/z 176.2[C9H9N3O+H]+。
6-(2-甲基-1H-咪唑-1-基)吡啶-2-醇的制备
MS(ESI)m/z 176.0[C9H9N3O]+。
3-(2-环丙基-1H-咪唑-1-基)苯酚的制备
1HNMR(400MHz,DMSO-d6)δ(ppm):9.89(s,1H),7.32(t,J=8.4Hz,1H),7.19(d,J=1.1Hz,1H),6.89(dd,J=1.4和2.5Hz,1H),6.84-6.82(m,3H),1.80-1.74(m,1H),0.88-0.82(m,4H)。MS(ESI)m/z 201.2[C12H12N2O+H]+。
4-氟-3-(2-甲基-1H-咪唑-1-基)苯酚的制备
1H NMR(DMSO,400MHz,)δ9.88(s,1H),7.27(t,J=9.4Hz,1H),7.22(s,1H),6.92(s,1H),6.91-6.87(m,1H),6.80-6.78(m,1H),2.17(s,3H)。MS(ESI)m/z 192.8[C10H9FN2O+H]+。
2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙酸乙酯的制备
向充分搅拌的3-(2-甲基-1H-咪唑-1-基)苯酚(1摩尔当量)的DMF(0.3M)溶液中添加2-溴丙酸乙酯(2摩尔当量)和K2CO3(3摩尔当量)。将反应混合物在100℃加热16小时。将反应混合物冷却并倒入水(200mL)中并用EtOAc(3x 200mL)萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并减压浓缩。通过柱色谱法纯化粗产物,得到2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙酸乙酯,为无色胶状液体。
1H NMR(400MHz,CDCl3)δ(ppm):7.37(t,J=8.0Hz,1H),7.01-6.89(m,4H),6.81(d,J=1.6Hz,1H),4.78-4.73(m,1H),4.25-4.20(s,2H),2.37(d,J=6.0Hz,3H),1.28(t,J=7.6Hz,3H)。
2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-1-醇的制备
向充分搅拌的2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙酸乙酯(0.07M)的THF(20mL)溶液中添加LAH(2M于THF中)(2摩尔当量)。将反应混合物在0℃冷却至室温16小时。将反应混合物冷却并用饱和NaSO4淬灭并用EtOAc萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并减压浓缩。通过柱色谱法纯化粗产物,得到2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-1-醇。
1H NMR(400MHz,CDCl3)δ(ppm):7.38(t,1H),7.05-6.90(m,4H),6.85(d,1H),4.58(m,1H),3.78(s,2H),2.37(s,3H),1.28(s,3H)。
1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-醇的制备
向充分搅拌的3-(1-甲基-1H-吡唑-5-基)苯酚(500mg,2.8mmol)的DMSO(0.5M)溶液中添加1-氯丙-2-醇(1.5摩尔当量)和K2CO3(3摩尔当量)。将反应混合物在100℃加热16小时。将反应混合物冷却,倒入水中,用EtOAc萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并减压浓缩。通过柱色谱法纯化粗产物,得到1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-醇。
1H NMR(400MHz,CDCl3)δ(ppm):7.50(d,J=1.6Hz,1H),7.39-7.24(m,1H),7.02-6.95(m,3H),6.29(d,J=2.0Hz,1H),4.25-4.20(m,1H),4.04-3.96(m,1H),3.96-3.82(m,4H),2.31(d,J=3.6Hz,1H),1.31-1.24(m,3H)。
1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-醇的制备
向充分搅拌的3-(2-甲基-1H-咪唑-1-基)苯酚(1当量)的DMSO(0.2M)溶液中添加1-氯丙-2-醇(2摩尔当量)和K2CO3(3摩尔当量)。将反应混合物在100℃加热16小时。将反应混合物冷却,倒入水中,用EtOAc萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并减压浓缩。通过柱色谱法纯化粗产物,得到1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-醇。
1H NMR(400MHz,CDCl3)δ(ppm):7.37(t,J=8.0Hz,1H),7.27(d,J=1.2Hz,1H),7.03-6.97(m,3H),6.89(d,J=1.2Hz,1H),4.89(d,J=4.4Hz,1H),3.97-3.84(m,3H),2.29(s,3H),1.15(d,J=6.4Hz,3H)。
(S)-1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-醇的制备
向充分搅拌的3-(2-环丙基-1H-咪唑-1-基)苯酚(1摩尔当量)的DMSO(0.3M)溶液中添加(S)-1-氯丙-2-醇(2摩尔当量)和K2CO3(3摩尔当量)。将反应混合物在100℃加热16小时。将反应混合物冷却,倒入水中,用EtOAc萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并减压浓缩。通过柱色谱法纯化粗产物,得到(S)-1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-醇。
1H NMR(400MHz,CDCl3)δ(ppm):7.41-7.36(m,1H),7.02(t,J=8.0Hz,4H),4.25-4.20(m,1H),3.97(dd,J=4.0,12.0Hz,1H),3.85(t,J=8.0Hz,1H),2.34(s,1H),1.82-1.75(m,1H),1.30(d,J=4.0Hz,3H),1.12-1.09(m,2H),0.92-0.87(m,2H);MS(ESI)m/z 259.21[C15H18N2O2+H]+。
(R)-1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-醇的制备
向充分搅拌的3-(2-环丙基-1H-咪唑-1-基)苯酚(1摩尔当量)的DMSO(0.3M)溶液中添加(R)-1-氯丙-2-醇(2摩尔当量)和K2CO3(3摩尔当量)。将反应混合物在100℃加热16小时。将反应混合物冷却,倒入水中,用EtOAc萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并减压浓缩。通过柱色谱法纯化粗产物,得到(R)-1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-醇。
1H NMR(400MHz,CDCl3)δ(ppm):7.41-7.36(m,1H),7.02(t,J=8.0Hz,4H),4.25-4.20(m,1H),3.97(dd,J=4.0,12.0Hz,1H),3.85(t,J=8.0Hz,1H),2.34(s,1H),1.82-1.75(m,1H),1.30(d,J=4.0Hz,3H),1.12-1.09(m,2H),0.92-0.87(m,2H);MS(ESI)m/z 259.21[C15H18N2O2+H]+。
3-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丁-2-酮的制备
向充分搅拌的3-(2-甲基-1H-咪唑-1-基)苯酚(1摩尔当量)的DMSO(0.14M)溶液中添加3-溴丁-2-酮(1.5摩尔当量)和K2CO3(3摩尔当量)。将反应混合物在100℃加热16小时。将反应混合物冷却,倒入水中,用EtOAc萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并减压浓缩。通过柱色谱法纯化粗产物,得到3-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丁-2-酮。
MS(ESI)m/z 245.2[C14H16N2O2+H]+。
3-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丁-2-醇的制备
在0℃至5℃向充分搅拌的3-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丁-2-酮(1摩尔当量)的甲醇(0.12M)溶液中添加NaBH4(1.5摩尔当量),并在室温搅拌反应混合物4小时。将反应混合物浓缩并用水稀释并萃取到EtOAc中。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并减压浓缩,得到粗产物。通过柱色谱法纯化该粗产物,得到3-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丁-2-醇。
MS(ESI)m/z 247.2[C14H18N2O2+H]+。
实施例7:最终化合物的制备
一般方法A
向充分搅拌的相应的苯酚1(1摩尔当量)的DMSO(0.25M)溶液中添加2-氯乙醇(2摩尔当量)和K2CO3(3摩尔当量)。将反应混合物在100℃加热16小时。反应完成后,将反应混合物冷却并倒入水中并用乙酸乙酯萃取。将合并的有机物用水和盐水洗涤,经硫酸钠干燥并减压浓缩。通过柱色谱法纯化粗产物,得到所需产物2。
在0℃,向相应的化合物2(1摩尔当量)的二氯甲烷(0.4M)溶液中加入三甲胺(3摩尔当量)和甲苯磺酰氯(1.5摩尔当量)。将反应混合物在室温下搅拌16小时。反应完成后,粗产物用二氯甲烷萃取并用水洗涤。将合并的有机物用硫酸钠干燥并减压浓缩,得到粗化合物,将其通过柱色谱法纯化,得到相应的甲苯磺酸盐3。
向充分搅拌的相应的酚4(1摩尔当量)的DMF(0.15M)溶液中添加相应的甲苯磺酸酯3(1.1摩尔当量)和K2CO3(3摩尔当量)。将反应混合物在60℃加热16小时。反应完成后,将反应混合物冷却至室温并减压浓缩。粗产物用乙酸乙酯稀释并用水洗涤。将合并的有机物用硫酸钠干燥并在减压下洗涤浓缩以获得粗产物,然后将其进一步通过柱色谱法纯化。
4-(2-(3-(1H-1,2,4-三唑-1-基)苯氧基)乙氧基)苄腈(化合物1)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.55(s,1H),8.11(s,1H),7.63-7.60(m,2H),7.43(t,J=8.0Hz,1H),7.34(t,J=2.4Hz,1H),7.29-7.28(m,1H),7.03-6.99(m,2H),6.97(dd,J=0.8and 5.6Hz,1H),4.42-4.41(m,4H)。MS(m/z):307.1[C17H14N4O2+H]+。
4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈(化合物2)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.62(d,J=8.8Hz,2H),7.40(t,J=8.0Hz,1H),7.02-6.98(m,3H),7.01(d,J=8.8Hz,2H),6.94-6.91(m,1H),6.87(t,J=2.0Hz,1H),4.41-4.37(m,4H),2.37(s,3H)。MS(m/z):320.2[C19H17N3O2+H]+。
4-(2-(3-(噻唑-5-基)苯氧基)乙氧基)苄腈(化合物3)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.76(s,1H),8.07(s,1H),7.62(d,J=8.8Hz,2H),7.35(t,J=8.0Hz,1H),7.22(d,J=7.6Hz,1H),7.16(s,1H),7.04(d,J=8.8Hz,2H),6.92(dd,J=2.4and 8.2Hz,1H),4.40(s,4H)。MS(m/z):322.9[C18H14N2O2S+H]+。
5-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)吡啶甲腈(化合物4)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):8.50(d,J=2.0Hz,1H),8.03(d,J=8.8Hz,1H),7.66(dd,J=5.2,2.4Hz,3H),7.45(t,J=8.4Hz,1H),7.28(s,1H),7.04(dd,J=16.4,7.2Hz,3H),6.90(s,1H),4.54-4.43(m,4H),2.29(s,3H);MS(ESI)m/z 321.23[C18H16N4O2+H]+。
3-氯-4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈(化合物5)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.67(d,J=1.9Hz,1H),7.57(dd,J=2.0and8.5Hz,1H),7.40(t,J=8.1Hz,1H),7.06(d,J=8.5Hz,1H),7.04-7.00(m,3H),6.96-6.90(m,1H),6.89(t,J=2.1Hz,1H),4.48-4.43(m,4H),2.37(s,3H)。MS(m/z):354.3[C19H16ClN3O2+H]+。
3-氟-4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈的制备。化合物6
1H NMR(400MHz,DMSO-d6)δ(ppm):7.85(d,J=11.2Hz,1H),7.70(d,J=8.4Hz,1H),7.45(t,J=8.8Hz,2H),7.29(s,1H),7.05(dd,J=17.6,6.8Hz,3H),6.90(s,1H),4.53(d,J=4.0Hz,2H),4.44(d,,J=3.2Hz,2H),2.30(s,3H)。MS(ESI)m/z338.20[C19H16FN3O2+H]+。
3-氯-4-(2-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈(化合物9)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.68(d,J=1.9Hz,1H),7.56(dd,J=1.9and8.5Hz,1H),7.41(t,J=7.8Hz,1H),7.07-6.98(m,6H),4.48-4.44(m,4H),1.82-1.75(m,1H),1.13-1.09(m,2H),0.92-0.86(m,2H);MS(m/z):380.3[C21H18ClN3O2+H]+。
3-氯-4-(2-(3-(噻唑-5-基)苯氧基)乙氧基)苄腈(化合物11)制备
1H NMR(400MHz,CDCl3)δ(ppm):8.76(s,1H),8.07(s,1H),7.68(d,J=2.0Hz,1H),7.57(dd,J=2.0and 8.5Hz,1H),7.36(t,J=7.9Hz,1H),7.21(dd,J=0.8and 7.7Hz,1H),7.15(t,J=2.2Hz,1H),7.07(d,J=8.5Hz,1H),6.96-6.93(m,1H),4.47(s,4H);MS(m/z):357.3[C18H13ClN2O2S+H]+。
3-氟-4-(2-(3-(噻唑-5-基)苯氧基)乙氧基)苄腈(化合物12)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.76(s,1H),8.07(s,1H),7.47-7.43(m,1H),7.40(dd,J=1.9and 10.4Hz,1H),7.35(t,J=7.9Hz,1H),7.23-7.20(m,1H),7.15(t,J=2.24Hz,1H),7.11(t,J=8.3Hz,1H),6.95-6.91(m,1H),4.50-4.47(m,2H),4.44-4.42(m,2H);MS(m/z):339.4[C18H13FN2O2S+H]+。
5-(3-(2-(4-氟-2-甲基苯氧基)乙氧基)苯基)-1-甲基-1H-吡唑(化合物27)的制备
1H NMR(400MHz,DMSO-d6))δ(ppm):7.45(d,J=2Hz,1H),7.41(t,J=8.2Hz,1H),7.11-7.09(m,2H),7.08-7.05(m,1H),7.03-6.93(m,3H),6.40(d,J=2Hz,1H),4.40-4.38(m,2H),4.32-4.30(m,2H),3.85(s,3H),2.12(s,3H);MS(ESI)m/z 327.1[C19H19FN2O2+H]+
1-(3-(2-(4-氯-2-氟苯氧基)乙氧基)苯基)-2-环丙基-1H-咪唑(化合物50)的制备
1H NMR(400MHz,DMSO-d6)δ7.48-7.42(m,2H),7.31-7.22(m,3H),7.10-7.07(m,3H),6.85(d,J=1.2Hz,1H),4.42(s,4H),1.85-1.79(m,1H),0.90-0.85(m,4H);MS(ESI)m/z373.1[C20H18ClFN2O2+H]+。
4-(2-(3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物57)的制备
1H NMR(400MHz,DMSO-d6)δ7.80-7.77(m,2H),7.45(d,J=2.0Hz,1H),7.42(t,J=8.0Hz,1H),7.19-7.16(m,2H),7.12-7.10(m,2H),7.07-7.04(m,1H),6.41(d,J=1.6Hz,1H),4.45-4.41(m,4H),3.85(s,3H);MS(ESI)m/z 320.1[C19H17N3O2+H]+。
1-(3-(2-(2-氟-4-甲基苯氧基)乙氧基)苯基)-2-甲基-1H-咪唑(化合物58)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.38(t,J=8.0Hz,1H),7.0(d,J=8.4Hz,3H),6.94-6.84(m,5H),4.37(d,J=5.2Hz,4H),2.37(s,3H),2.28(s,3H);MS(ESI)m/z 327.14[C19H19FN2O2+H]+。
4-(2-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈(化合物62)的制备
1H NMR(400MHz,DMSO-d6)δ7.80-7.78(m,2H),7.47(t,J=7.6Hz,1H),7.26(d,J=0.8Hz,1H),7.18-7.16(m,2H),7.10-7.07(m,3H),6.85(s,1H),4.44-4.43(m,4H),1.84-1.80(m,1H),0.90-0.85(m,4H);MS(ESI)m/z346.1[C21H19N3O2+H]+。
4-(2-(3-(异噁唑-4-基)苯氧基)乙氧基)苄腈(化合物67)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.66(s,1H),8.53(s,1H),7.61(d,J=8.8Hz,2H),7.35(t,J=8.4Hz,1H),7.10(d,J=7.6Hz,1H),7.05(dd,J=19.2,2.0Hz,3H),6.90(dd,J=8.4,1.6Hz,1H),4.39(m,4H);MS(ESI)m/z 307.22[C18H14N2O3+H]+。
4-(2-((2-(2-甲基-1H-咪唑-1-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物85)的制备
1H NMR(400MHz,CDCl3)δ8.41-8.40(m,1H),7.64-7.61(m,2H),7.25(s,1H),7.03-6.99(m,3H),6.89-6.86(m,2H),4.46-4.43(m,4H),2.60(s,3H);MS(ESI)m/z 321.1[C18H16N4O2+H]+。
3-氟-4-(2-((6-(2-甲基-1H-咪唑-1-基)吡啶-2-基)氧基)乙氧基)苄腈(化合物86)的制备
1H NMR(400MHz,DMSO-d6)δ7.95-7.87(m,1H),7.83(dd,J=11.2,1.6Hz,1H),7.72-7.65(m,1H),7.57(s,1H),7.48-7.40(m,1H),7.19(d,J=7.6Hz,1H),6.93-6.85(m,2H),4.75-4.65(m,2H),4.60-4.50(m,2H),2.54(s,3H);MS(ESI)m/z 339.1[C18H15N4O2+H]+。
5-氟-6-(2-(4-氟-3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)烟腈(化合物87)的制备
1H NMR(CDCl3,400MHz,)δ8.22-8.21(d,J=2.8Hz,1H),7.68-7.65(dd,J=6.8,2.8Hz,1H),7.24(t,J=6.0Hz,1H),7.19-7.17(m,1H),7.04-6.99(m,2H),6.88-6.86(m,1H),4.76(t,J=4.8Hz,1H),4.35(t,J=4.6Hz,1H),2.35(s,3H);MS(ESI)m/z 357.2[C18H14F2N4O2+H]+。
4-(2-(3-(1-环丙基-1H-吡唑-5-基)-4-氟苯氧基)乙氧基)-3-氟苄腈(化合物88)的制备
1H NMR(400MHz,DMSO-d6)δ7.88-7.84(dd,J=11.2,1.6Hz,1H),7.71-7.69(m,1H),7.48-7.41(m,2H),7.33-7.28(m,1H),7.14-7.09(m,2H),6.4(s,1H),4.52-4.51(m,2H),4.42(m,2H),3.60-3.55(m,1H),0.92-0.91(m,2H),0.9-0.87(m,2H);MS(ESI)m/z353.1[C19H17FN4O2+H]+。
4-(2-((2-(2-环丙基-1H-咪唑-1-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物89)的制备
1H NMR(400MHz,DMSO-d6)δ8.39(d,J=5.6Hz,1H),7.81-7.78(m,2H),7.49(s,1H),7.25(d,J=2.0Hz,1H),7.19-7.16(m,2H),7.11-7.09(m,1H),6.85(s.1H),4.56-4.55(m,2H),4.49-4.48(m,2H),2.40-2.34(m,1H),0.90-0.88(m,4H);MS(ESI)m/z 347.1[C20H18N4O2+H]+。
3-氟-4-(2-((5-(1-甲基-1H-吡唑-5-基)吡啶-3-基)氧基)乙氧基)苄腈(化合物92)的制备
1H NMR(400MHz,DMSO-d6)δ8.39-8.36(m,1H),7.88-7.85(m,1H),7.73-7.70(m,1H),7.63-7.62(m,1H),7.51(d,J=2.0Hz,1H),7.45(t,J=8.4Hz,1H),6.54(d,J=1.6Hz,1H),4.56(s,4H),3.89(s,3H);MS(ESI)m/z339.1[C18H15FN4O2]+。
4-(2-(3-氟-5-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物94)的制备
1H NMR(400MHz,DMSO-d6)δ7.80-7.78(m,2H),7.47(m,1H),7.18-7.16(m,2H),7.02-6.98(m,3H),6.48(s.1H),4.44(s,4H),3.88(m,3H);MS(ESI)m/z 338.1[C19H16FN3O2]+。
3-氟-4-(2-((2-(3-甲基-4H-1,2,4-三唑-4-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物95)的制备
1H NMR(400MHz,DMSO-d6)δ8.40(d,J=6.0Hz,1H),8.06(s,1H),7.88-7.85(m,1H),7.72-7.69(m,1H),7.45(t,J=8.4Hz,1H),7.39(d,J=2.4Hz,1H),7.13-7.11(m,1H),4.58(s,4H),2.74(s,3H);MS(ESI)m/z 340.1[C17H14FN5O2]+。
4-(2-(2-氟-5-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物96)的制备
1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.78(s,1H),7.46(s,1H),7.40-7.30(m,2H),7.18(s,1H),7.16(s,1H),7.14-7.08(m,1H),6.42(s,1H),4.55-4.50(m,2H),4.50-4.45(m,2H),3.85(s,3H);MS(ESI)m/z338.1[C19H16FN3O2+H]+。
5-氟-6-(2-((2-(1-甲基-1H-吡唑-5-基)吡啶-4-基)氧基)乙氧基)烟腈(化合物97)的制备
1H NMR(CDCl3,400MHz):δ8.54-8.53(d,J=4.8Hz,1H),8.49-8.43(m,2H),7.46(d,J=2.0Hz,1H),7.37(d,J=2.0Hz,1H),7.04-7.02(m,1H),6.82(d,J=1.6Hz,1H),4.77-4.75(m,2H),4.56-4.54(m,2H),4.12(s,3H);MS(ESI)m/z 340.16[C17H14FN5O2+H]+。
4-(2-(4-氯-2-氟苯氧基)乙氧基)-2-(1-甲基-1H-吡唑-5-基)吡啶(化合物101)的制备
1H NMR(400MHz,DMSO-d6)δ8.49(d,J=6.0Hz,1H),7.47-7.43(m,2H),7.38(d,J=2.4Hz,1H),7.31-7.22(m,2H),7.04-7.01(m,1H),6.82(d,J=2.0Hz,1H),4.53-4.51(m,2H),4.46-4.43(m,1H),4.13(s,3H);MS(ESI)m/z348.0[C17H15ClFN3O2+H]+。
1-(3-(2-(4-氯-2-氟苯氧基)乙氧基)苯基)-2-甲基-1H-咪唑(化合物102)的制备
1H NMR(400MHz,DMSO-d6)δ7.42-7.45(m,2H),7.21-7.30(m,3H),7.00-7.07(m,3H),6.89(s,1H),4.41(s,4H),2.29(s,3H);MS(ESI)m/z347.0[C18H16ClFN2O2+H]+。
4-(2-(4-氯-2-氟苯氧基)乙氧基)-2-(2-甲基-1H-咪唑-1-基)吡啶(化合物103)的制备
1H NMR(400MHz,DMSO-d6)δ8.37(d,J=5.6Hz,1H),7.56(d,J=1.2Hz,1H),7.45(dd,J=11.2,2.4Hz,1H),7.32-7.18(m,3H),7.10-7.03(m,1H),6.90(d,J=1.2Hz,1H),4.60-4.50(m,2H),4.50-4.40(m,2H),2.49(s,3H);MS(ESI)m/z 348.1[C17H15ClFN3O2+H]+。
4-(2-(4-溴-2-氟苯氧基)乙氧基)-2-(2-甲基-1H-咪唑-1-基)吡啶(化合物104)的制备
1H NMR(400MHz,DMSO-d6)δ8.37(d,J=6.0Hz,1H),7.60-7.50(m,2H),7.40-7.32(m,1H),7.28-7.20(m,2H),7.10-7.03(m,1H),6.90(d,J=1.6Hz,1H),4.60-4.50(m,2H),4.50-4.40(m,2H),2.49(s,3H);MS(ESI)m/z394.0[C17H15BrFN3O2+H]+。
5-氟-6-(2-(4-氟-3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)烟腈(化合物107)的制备
1H NMR(CDCl3,400MHz)δ8.21(d,J=3.2Hz,1H),7.67-7.64(dd,J=3.2,7.2Hz,1H),7.53(d,J=1.6Hz,1H),7.11(t,J=9.2Hz,1H),7.01-6.97(m,1H),6.89-6.87(dd,J=3.2,5.6Hz,1H),6.32-6.31(d,J=2.0Hz,1H),4.75(t,J=4.8Hz,2H),4.34(t,J=5.0Hz,2H),3.82-3.81(d,J=1.2Hz,1H);MS(ESI)m/z 357.1[C18H14F2N4O2+H]+。
6-(2-(4-氟-3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)烟腈(化合物109)的制备
1H NMR(CDCl3,400MHz,)δ8.48(d,J=2.4Hz,1H),7.82-7.80(dd,J=8.8,2.4Hz,1H),7.18(t,J=9.2Hz,1H),7.05(s,1H),7.01-6.96(m,1H),6.95(s,1H),6.89-6.87(d,J=8.4Hz,1H),6.86-6.85(m,1H),4.74(t,J=4.6Hz,1H),4.31(t,J=4.8Hz,1H),2.30(s,3H);MS(ESI)m/z 339.1[C18H15FN4O2+H]+。
5-(3-(2-(4-氯苯氧基)乙氧基)苯基)-1-甲基-1H-吡唑(化合物110)的制备
1H NMR(400MHz,DMSO-d6)δ7.51(d,J=2.0Hz,1H),7.38-7.36(m,1H),7.26-7.24(m,2H),7.04-7.02(m,1H),7.01-6.98(m,2H),6.90-6.88(m,2H),6.3(d,J=1.6Hz,1H),4.35-4.32(m,4H),3.89(s,3H);MS(ESI)m/z 329.1[C18H17ClN2O2+H]+。
1-(3-(2-(4-氯苯氧基)乙氧基)苯基)-2-甲基-1H-咪唑(化合物112)的制备
1H NMR(CDCl3,400MHz)δ7.41(t,J=8.1Hz,1H),7.28-7.26(m,2H),7.04-7.03(m,3H),6.94-6.89(m,4H),4.37-4.33(m,4H),2.39(s,3H)。MS(ESI)m/z 329.2[C18H17ClN2O2+H]+。
3-氟-4-(2-(4-氟-3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物113)的制备
1H NMR(CDCl3,400MHz)δ7.56(d,1H,J=2.0Hz),7.44(dt,1H,J=8.8&0.8Hz),7.39(dd,1H,J=10.4&2.0Hz),7.15-7.07(m,2H),6.984(dt,1H,J=8.8&3.6Hz),6.89(dd,1H,J=6.0&3.0Hz),4.47-4.45(m,2H),4.38-4.36(m,2H),3.83(d,3H,J=1.2Hz);MS(ESI)m/z 356.1[C19H15F2N3O2+H]+。
4-(2-(4-氯苯氧基)乙氧基)-2-(2-甲基-1H-咪唑-1-基)吡啶(化合物115)的制备
1H NMR(400MHz,DMSO-d6)δ8.38-8.36(d,J=6.0Hz,1H),7.57(d,J=1.2Hz,1H),7.35-7.32(m,2H),7.21-7.20(d,J=1.2Hz,1H),7.09-7.07(dd,J=6.0,1.2Hz,1H),7.03-7.00(m,2H),6.92(d,J=1.2Hz,1H),4.53-4.51(m,2H),4.37-4.34(m,2H);MS(ESI)m/z330.1[C17H16ClN3O2+H]+。
5-氟-2-(2-((2-(2-甲基-1H-咪唑-1-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物119)的制备
1H NMR(400MHz,DMSO-d6)δ8.38-8.37(d,J=5.6Hz,1H),7.77-7.74(dd,J=8.4,2.8Hz,1H),7.62-7.57(m,2H),7.39-7.35(dd,J=9.2,4.0Hz,1H),7.23-7.22(d,J=2.4Hz,1H),7.10-7.08(dd,J=6.0,2.4Hz,1H),6.96-6.95(d,J=1.6Hz,1H),4.58-4.56(m,2H),4.54-4.53(m,2H);MS(ESI)m/z 339.2[C18H15FN4O2+H]+。
4-(2-((2-(1H-四唑-1-基)吡啶-4-基)氧基)乙氧基)-3-氟苯甲腈(化合物120)的制备
1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.47(t,J=6.0Hz,1H),7.88-7.85(m,1H),7.73-7.70(m,1H),7.65(d,J=2.4Hz,1H),7.45(t,J=8.8Hz,1H),7.28-7.26(m,1H),4.67-4.65(m,2H),4.60-4.58(m,2H);MS(ESI)m/z 327.1[C15H11FN6O2+H]+。
4-(2-(4-溴-2-氟苯氧基)乙氧基)-2-(1-甲基-1H-吡唑-5-基)吡啶(化合物121)的制备
1H NMR(CDCl3,400MHz,)δ8.51(d,J=6Hz,1H),7.50(d,J=2Hz,1H),7.28-7.25(m,2H),7.23-7.20(m,1H),7.12(d,J=2.4Hz,1H),6.91(t,J=8.4Hz,1H),6.83(dd,J=6Hz,2.4Hz,1H),6.55(d,J=2Hz,1H),4.45-4.40(m,4H),4.20(s,3H);MS(ESI)m/z 392.1[C17H15BrFN3O2+H]+。
一般方法B
向充分搅拌的相应的苯酚1(1摩尔当量)的DMSO(0.25M)溶液中加入2-氯乙醇(2摩尔当量)和K2CO3(3摩尔当量)。将反应混合物在100℃加热16小时。反应完成后,将反应混合物冷却并倒入水中并用乙酸乙酯萃取。将合并的有机物用水和盐水洗涤,经硫酸钠干燥并减压浓缩。通过柱色谱法纯化粗产物,得到所需产物2。
向充分搅拌的2(1摩尔当量)的DMF(0.1M)溶液中添加相应的氟化合物3(1.3摩尔当量)和Cs2CO3(3.2摩尔当量)。将反应混合物在100℃加热16小时。冷却反应混合物,倒入水中,用乙酸乙酯萃取。将合并的有机物用水和盐水洗涤,经硫酸钠干燥并减压浓缩,得到粗产物。通过柱色谱法纯化该粗产物,得到所需产物。
3-氯-4-(2-(3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物7)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):8.02(d,J=2.0Hz,1H),7.84(dd,J=8.4,2.0Hz,1H),7.45-7.39(m,3H),),7.12-7.05(m,3H),6.40(d,J=1.2Hz,1H),4.55(dd,J=4.8,3.6Hz,2H),4.45(dd,J=6.4,2.0Hz,2H),3.85(s,3H);MS(ESI)m/z 354.21[C19H16ClN3O2+H]+。
3-甲氧基-4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈(化合物8)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.46-7.41(m,3H),7.29(d,J=0.8Hz,1H),7.20(d,J=8.4Hz,1H),7.07-7.01(m,3H),6.89(d,J=0.8Hz,1H),4.54-4.31(m,4H),3.78(s,3H),2.30(s,3H);MS(ESI)m/z 350.28[C20H19N3O3+H]+。
6-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)烟腈(化合物10)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):8.70(d,J=1.6Hz,1H),8.17(d,J=8.8,2.0Hz,1H),7.44(t,J=16Hz,1H),7.28(s,1H),7.07-7.01(m,4H),6.90(s,1H),4.68(d,J=4.4Hz,2H),4.41(d,J=4.4Hz,2H),2.29(s,3H);MS(ESI)m/z 321.23[C18H16N4O2+H]+。
5-甲基-2-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈(化合物13)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.53-7.42(m,3H),7.31(s,1H),7.23(d,J=8.8,Hz,1H),7.10-7.02(m,3H),6.93(s,1H),4.46(d,J=4.8Hz,2H),4.43(d,J=5.6Hz,2H),2.32(s,6H);MS(ESI)m/z 334.26[C20H19N3O2+H]+。
3-氟-4-(2-(3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物14)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.92-7.84(m,1H),7.75-7.69(t,J=16.4Hz,1H),),7.57-7.39(m,3H),),7.12-7.05(m,3H),6.40(d,J=2.0Hz,1H),4.53(dd,J=4.4,3.6Hz,2H),4.43(dd,J=6.0,2.0Hz,2H),3.85(s,3H);MS(ESI)m/z 338.27[C19H16FN3O2+H]+。
3-甲氧基-4-(2-(3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物15)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.46-7.39(m,4H),7.20(d,J=7.6Hz,1H),7.12-7.04(m,3H),6.41(d,J=1.2Hz,1H),4.41(m,4H),3.80(s,6H);MS(ESI)m/z 350.28[C20H19N3O3+H]+。
3-甲氧基-4-(2-(3-(噻唑-5-基)苯氧基)乙氧基)苄腈(化合物16)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):9.08(s,1H),8.35(s,1H),7.45-7.43(m,3H),7.31-7.20(m,3H),7.01-6.99(dd,J=2.0,2.0Hz,1H),4.42(m,4H),3.79(s,3H);MS(ESI)m/z 353.16[C19H16N2O3S+H]+。
4-(2-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)乙氧基)-3-氟苯甲腈(化合物17)的制备
1H NMR(400MHz,DMSO-d6)δ7.88-7.85(m,1H),7.70(d,J=8.4Hz,1H),7.48-7.42(m,2H),7.26(d,J=1.2Hz,1H),7.10-7.06(m,3H),6.85((d,J=1.2Hz,1H),4.55-4.53(m,2H),4.46-4.44(m,2H),1.84-1.80(m,1H),0.90-0.84(m,4H);MS(ESI)m/z 364.1[C21H18FN3O2]+。
5-甲基-2-(2-(3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物18)的制备
1H NMR(400MHz,DMSO–d6)δ7.54(s,1H),7.49(d,J=8.8Hz,1H),7.46(d,J=1.6Hz,1H),7.42(t,J=8Hz,1H),7.24(d,J=8.8Hz,1H),7.12-7.10(m,2H),7.09-7.06(m,1H),6.41(d,J=1.6Hz,1H),4.49-4.47(m,2H),4.43-4.41(m,2H),3.95(s,3H),2.27(s,3H);MS(ESI)m/z 334.4[C20H19N3O2+H]+
4-(2-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)乙氧基)-3-甲氧基苄腈(化合物19)的制备
1H NMR(400MHz,DMSO–d6)δ7.50-7.38(m,3H),7.27(d,J=0.8Hz,1H),7.23-7.17(m,1H),7.15-7.05(m,3H),6.85(d,J=0.8Hz,1H),4.43(s,4H),3.78(s,3H),1.90-1.80(m,1H),0.95-0.80(m,4H);MS(ESI)m/z 376.1[C22H21N3O3+H]+
4-(2-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈(化合物20)的制备
1H NMR(400MHz,DMSO-d6)δ7.79(d,J=8.8Hz,2H),7.46(t,J=8.0Hz,1H),7.27(d,J=1.6Hz,1H),7.20-7.13(m,2H),7.13-7.05(m,3H),6.85(d,J=1.2Hz,1H),4.50-4.40(m,4H),1.85-1.75(m,1H),0.95-0.80(m,4H);MS(ESI)m/z 346.1[C21H19N3O2+H]+
-(4H-1,2,4-三唑-4-基)苯氧基)乙氧基)苄腈(化合物21)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.54(s,1H),8.09(s,1H),7.60(d,J=8.8Hz,2H),7.42(t,J=8.0Hz,1H),7.33-7.25(m,2H),7.02-6.96(m,3H),4.43-4.39(m,4H);MS(ESI)m/z 307.29[C17H14N4O2+H]+。
3-氯-4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙氧基)苄腈(化合物22)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.99(d,J=1.2Hz,1H),7.81(d,J=8.0Hz,1H),7.42(dd,J=16.8,16.4Hz,2H),7.25(s,1H),7.05(d,J=6.4Hz,2H),7.00(d,J=8.0Hz,1H),6.88(s,1H),5.01-4.98(m,1H),4.38(dd,J=16.8,16Hz,2H),2.27(s,3H),1.39(d,J=5.6Hz,3H);MS(ESI)m/z 368.33[C20H18ClN3O2+H]+。
3-氟-4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙氧基)苄腈(化合物23)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.81(d,J=11.2Hz,1H),7.66(d,J=8.8Hz,1H),7.41(d,J=8.4Hz,2H),7.25(s,1H),7.05(d,J=8.4Hz,2H),6.98(d,J=8.4Hz,1H),6.88(s,1H),5.01-4.64(m,1H),4.38(t,J=2.4Hz,2H),2.27(s,3H),1.38(d,J=6.4Hz,3H);MS(ESI)m/z 352.12[C20H18FN3O2+H]+。
3-氯-4-(2-((2-(2-甲基-1H-咪唑-1-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物24)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):8.41(d,J=5.6Hz,1H),8.03(d,J=2.0Hz,1H),7.86-7.84(dd,J=2.0Hz,1H),7.75(s,1H),7.41(d,J=8.8Hz,1H),7.32(d,J=2.0Hz,1H),7.21-7.26(m,2H),4.62-4.58(dd,J=4.8,5.2Hz,4H),2.58(s,3H);MS(ESI)m/z 355.27[C18H15ClN4O2+H]+。
3-氟-4-((1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)苄腈(化合物25)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.42-7.35(m,3H),7.14(t,J=8.4Hz,1H),7.02-6.89(m,4H),6.81(t,J=2.0Hz,1H),2.36(s,3H),1.50(d,J=6.4Hz,3H);MS(ESI)m/z352.14[C20H18FN3O2+H]+。
1-(3-(2-(4-乙炔基苯氧基)乙氧基)苯基)-2-甲基-1H-咪唑(化合物26)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.47-7.39(m,3H),7.28(d,J=1.6Hz,1H),7.10-6,96(m,5H),6.89(d,J=1.2Hz,1H),4.45-4.30(m,4H),4.01(s,1H),2.30(s,3H);MS(ESI)m/z 319.1[C20H18N2O2+H]+。
4-((1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)-3-氟苯甲腈(化合物28)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.80(dd,J=11.2Hz,2.0Hz,1H),7.64(d,J=8.4Hz,1H),7.49-7.39(m,2H),7.22(s,1H),7.06-6.98(m,3H),6.82(s,1H),5.90-5.05(m,1H),4.29-4.21(m,2H),1.80-1.73(m,1H),1.36(t,J=6.4Hz,3H),0.91-0.79(m,4H);MS(ESI)m/z 378.21[C22H20FN3O2+H]+。
3-甲氧基-4-((1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)苄腈(化合物29)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.36(t,J=8.0Hz,1H),7.26-7.24(m,1H),7.10(d,J=8.8Hz,1H),7.06-6.88(m,5H),6.83(s,1H),4.86-4.82(m,1H),4.26-4.22(m,1H),4.12-4.09(m,1H),3.84(s,3H),2.36(s,3H)1.49(d,J=6.4Hz,3H);MS(ESI)m/z 364.16[C21H21N3O3+H]+。
3-甲基-4-((1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物30)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.50-7.42(m,3H),7.38-7.34(m,1H),7.03-6.92(m,4H),),6.28(d,J=2.0Hz,1H),4.87-4.82(dd,J=6.4,5.6Hz,1H),4.23-4.19(dd,J=6.4,5.6Hz,1H),4.11-3.88(d,J=4.4Hz,1H),3.88(s,3H),2.19(s,3H),1.48(d,J=6.4Hz,3H);MS(ESI)m/z 348.29[C21H21N3O2+H]+。
3-甲氧基-4-((1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物31)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.50(d,J=1.6Hz,1H),7.37-7.31(m,1H),7.26(s,1H)7.09(d,J=1.2Hz,1H),7.04-6.99(m,2H),6.93(d,J=7.6Hz,2H),6.28(d,J=1.2Hz,1H),4.84(dd,J=6.0,2.0Hz,1H),4.26(dd,J=9.6,6.4Hz,1H),4.13-4.09(m,1H),3.88(s,3H),3.84(s,3H),1.50(d,J=6.4Hz,3H);MS(ESI)m/z 364.26[C21H21N3O3+H]+。
(R)-3-氯-4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙氧基)苄腈(化合物32)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.99(d,J=1.2Hz,1H),7.81(d,J=8.0Hz,1H),7.42(dd,J=16.8,16.4Hz,2H),7.25(s,1H),7.05(d,J=6.4Hz,2H),7.00(d,J=8.0Hz,1H),6.88(s,1H),5.01-4.98(m,1H),4.38(dd,J=16.8,16Hz,2H),2.27(s,3H),1.39(d,J=5.6Hz,3H);MS(ESI)m/z 368.33[C20H18ClN3O2+H]+。
(S)-3-氯-4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙氧基)苄腈(化合物33)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.99(d,J=1.2Hz,1H),7.81(d,J=8.0Hz,1H),7.42(dd,J=16.8,16.4Hz,2H),7.25(s,1H),7.05(d,J=6.4Hz,2H),7.00(d,J=8.0Hz,1H),6.88(s,1H),5.01-4.98(m,1H),4.38(dd,J=16.8,16Hz,2H),2.27(s,3H),1.39(d,J=5.6Hz,3H);MS(ESI)m/z 368.33[C20H18ClN3O2+H]+。
(R)-3-氟-4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙氧基)苄腈(化合物34)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.84(dd,J=11.6,1.6Hz,1H),7.68(d,J=8.8Hz,1H),7.44-7.39(m,2H),7.26(d,J=1.2Hz,1H),7.05-6.98(m,3H),6.89(d,J=1.2Hz,1H),5.01-4.97(m,1H),4.38-4.31(m,2H),2.28(s,3H),1.37(d,J=6.0Hz,3H);MS(ESI)m/z 352.25[C20H18FN3O2+H]+。
(S)-3-氟-4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙氧基)苄腈(化合物35)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.84(dd,J=11.6,1.6Hz,1H),7.68(d,J=8.8Hz,1H),7.44-7.39(m,2H),7.26(d,J=1.2Hz,1H),7.05-6.98(m,3H),6.89(d,J=1.2Hz,1H),5.01-4.97(m,1H),4.38-4.31(m,2H),2.28(s,3H),1.37(d,J=6.0Hz,3H);MS(ESI)m/z 352.25[C20H18FN3O2+H]+。
4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)-3-(三氟甲氧基)苄腈(化合物36)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.78-7.69(m,2H),7.49-7.39(m,2H),7.18(d,J=1.2Hz,1H),7.13-7.08(m,1H),7.02-6.95(m,3H),4.60-4.50(m,2H),4.50-4.40(m,2H),2.33(m,3H);MS(ESI)m/z 404.1[C20H16F3N3O3+H]+。
4-(2-(3-(4H-1,2,4-三唑-4-基)苯氧基)乙氧基)-3-氟苯甲腈(化合物38)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.54(s,1H),8.09(s,1H),7.45-7.26(m,5H),7.10(t,J=8.4Hz,1H),6.97(dd,J=2.0,8.0Hz,1H),4.49-4.45(m,4H);MS(ESI)m/z 325.10[C17H13FN4O2+H]+。
3-氟-4-((1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物37)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.50(d,J=2.0Hz,1H),7.42-7.34(m,3H),7.17(t,3H),7.03-6.99(m,1H),6.92-6.91(m,2H),6.28(d,J=1.6Hz,1H),4.91-4.87(dd,J=10.8,6.4Hz,1H),4.25-4.21(m,1H),4.14-4.10(m,1H),3.88(d,J=4.4Hz,1H),1.55-1.47(m,3H);MS(ESI)m/z352.25[C20H18FN3O2+H]+。
(R)-3-甲基-4-((1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物39)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.50-7.42(m,3H),7.38-7.34(m,1H),7.03-6.92(m,4H),),6.28(d,J=2.0Hz,1H),4.87-4.82(dd,J=6.4,5.6Hz,1H),4.23-4.19(dd,J=6.4,5.6Hz,1H),4.11-3.88(d,J=4.4Hz,1H),3.88(s,3H),2.19(s,3H),1.48(d,J=6.4Hz,3H);MS(ESI)m/z 348.29[C21H21N3O2+H]+。
(S)-3-甲基-4-((1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物40)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.50-7.42(m,3H),7.38-7.34(m,1H),7.03-6.92(m,4H),),6.28(d,J=2.0Hz,1H),4.87-4.82(dd,J=6.4,5.6Hz,1H),4.23-4.19(dd,J=6.4,5.6Hz,1H),4.11-3.88(d,J=4.4Hz,1H),3.88(s,3H),2.19(s,3H),1.48(d,J=6.4Hz,3H);MS(ESI)m/z 348.29[C21H21N3O2+H]+。
(R)-4-(1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-基氧基)-3-氟苯甲腈(化合物41)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.41-7.36(m,1H),7.02(t,J=8.0Hz,4H),4.25-4.20(m,1H),3.97(dd,J=4.0,12.0Hz,1H),3.85(t,J=8.0Hz,1H),2.34(s,1H),1.82-1.75(m,1H),1.30(d,J=4.0Hz,3H),1.12-1.09(m,2H),0.92-0.87(m,2H);MS(ESI)m/z 259.21[C15H18N2O2+H]+。
(S)-4-((1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)-3-氟苯甲腈(化合物42)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.84(dd,J=2.0Hz,11.2Hz,1H),7.66(d,J=8.0Hz,1H),7.52-7.42(m,2H),7.26(d,J=0.8Hz,1H),7.09-7.01(m,3H),6.86(s,1H),5.11-5.07(m,1H),4.31-4.23(m,2H),1.81-1.77(m,1H),1.39(d,J=6.4Hz,3H),0.91-0.82(m,4H);MS(ESI)m/z378.26[C22H20FN3O2+H]+。
(S)-4-((1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)-3-甲氧基苄腈(化合物43)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.43-7.35(m,3H),7.23(dd,J=2.0Hz,3.2Hz,2H),7.06-6.99(m,3H),6.82(s,1H),4.95(dd,J=13.2Hz,11.2Hz,1H),4.22(d,J=4.4Hz,2H),3.73(s,3H),1.79-1.75(m,1H),1.34(dd,J=8.0,11.2Hz,3H),0.88-0.79(m,4H);MS(ESI)m/z 390.27[C23H23N3O3+H]+。
3-氯-4-((1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)苄腈(化合物44)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.66(d,J=2.0Hz,1H),7.53(dd,J=2.0Hz,8.8Hz,1H),7.37(t,J=8.4Hz,1H),7.15(d,J=8.8Hz,1H),7.01-6.90(m,4H),6.82(s,1H),4.91-4.87(m,1H),4.27-4.23(m,1H),4.15-4.12(m,1H),2.36(s,3H),1.54(d,J=13.2Hz,3H);MS(ESI)m/z 368.11[C20H18ClN3O2+H]+。
1-(3-(2-(4-氯-2-甲氧基苯氧基)乙氧基)苯基)-2-甲基-1H-咪唑(化合物45)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.92-7.84(m,1H),7.75-7.69(t,J=16.4Hz,1H),),7.57-7.39(m,3H),),7.12-7.05(m,3H),6.40(d,J=2.0Hz,1H),4.53(dd,J=4.4,3.6Hz,2H),4.43(dd,J=6.0,2.0Hz,2H),3.85(s,3H);MS(ESI)m/z 338.27[C19H16FN3O2+H]+。
(R)-3-氟-4-((1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物46)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.51(d,J=2.0Hz,1H),7.43-7.34(m,3H),7.17-7.13(m,3H),7.03-7.01(m,1H),6.92-6.91(m,2H),6.29(d,J=1.6Hz,1H),4.91-4.87(dd,J=10.8,6.4Hz,1H),4.26-4.21(m,1H),4.14-4.11(m,1H),3.89(d,J=4.4Hz,1H),1.52-1.47(m,3H);MS(ESI)m/z 352.25[C20H18FN3O2+H]+。
(S)-3-氟-4-((1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物47)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.51(d,J=2.0Hz,1H),7.43-7.34(m,3H),7.17-7.13(m,3H),7.03-7.01(m,1H),6.92-6.91(m,2H),6.29(d,J=1.6Hz,1H),4.91-4.87(dd,J=10.8,6.4Hz,1H),4.26-4.21(m,1H),4.14-4.11(m,1H),3.89(d,J=4.4Hz,1H),1.52-1.47(m,3H);MS(ESI)m/z 352.25[C20H18FN3O2+H]+。
(R)-3-甲氧基-4-((1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物48)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.51(s,1H),7.36(t,1H),7.26(s,1H),7.10(s,1H),7.04-7.01(m,2H),6.96-6.92(m,2H),6.29(s,2H),4.90-4.83(m,1H),4.26(dd,J=10.0,6.4Hz,1H),4.11(dd,J=10.0,4.4Hz,1H),3.89(s,1H),3.84(s,3H),1.51(d,J=6.4Hz,3H);MS(ESI)m/z 364.26[C21H21N3O3+H]+。
(S)-4-((1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)-3-甲基苄腈(化合物49)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.62(t,J=8.4Hz,2H),7.43(t,J=8.0Hz,1H),7.24(d,J=7.6Hz,2H),7.05(t,J=10.8Hz,3H),6.84(s,1H),4.99(d,J=4.4Hz,1H),4.27(d,J=13.2Hz,2H),2.09(s,3H),1.76(dd,J=4.8,10Hz,1H),1.37(d,J=6.4Hz,3H),0.88-0.80(m,4H);MS(ESI)m/z374.30[C23H23N3O2+H]+。
1-(3-(2-(4-乙炔基-2-氟苯氧基)乙氧基)苯基)-2-甲基-1H-咪唑(化合物51)的制备
1H NMR(400MHz,DMSO–d6)δ7.44(t,J=8.2Hz,1H),7.37(dd,J=1.6,2Hz,1H),7.31-7.22(m,3H),7.08-7.06(m,2H),7.02(d,J=8.4Hz,1H),6.89(d,J=0.8Hz,1H),4.45-4.41(m,4H),4.13(s,1H),2.30(s,3H);MS(ESI)m/z 337.1[C20H17FN2O2+H]+
3-氨基-4-(2-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈(化合物52)的制备
1H NMR(400MHz,DMSO-d6)δ7.47(t,J=8.0Hz,1H),7.17-7.05(m,4H),7.03-6.95(m,3H),6.88-6.92(m,1H),4.50-4.40(m,4H),1.90-1.75(m,1H),1.00-0.85(m,4H);MS(ESI)m/z 361.1[C21H20N4O2+H]+。
3-氟-4-(2-((2-(2-甲基-1H-咪唑-1-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物53)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):8.37(d,J=6.0Hz,1H),7.84-7.85(dd,J=1.6,11.2Hz,1H),7.71(d,J=8.0Hz,1H),7.56(s,1H),7.44(t,1H),7.21(d,J=2.0Hz,1H),7.09-7.07(dd,J=2.0,6.0Hz,1H),6.91(s,1H),4.58-4.57(m,4H),3.31(s,3H);MS(ESI)m/z 339.23[C18H15FN4O2+H]+。
5-氟-2-(2-(3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物54)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.50(d,J=1.6Hz,1H),7.38(t,J=7.6Hz,1H),7.29(s,1H),7.26(d,J=7.2Hz,1H),7.05-6.97(m,4H),6.30(d,J=2.0Hz,1H),4.43(q,J=2.8Hz,4H),3.89(s,3H);MS(ESI)m/z 338.26[C19H16FN3O2+H]+。
(R)-3-氯-4-((1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)苄腈(化合物55)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.66(d,J=2.0Hz,1H),7.53(dd,J=2.0Hz,8.8Hz,1H),7.37(t,J=8.4Hz,1H),7.15(d,J=8.8Hz,1H),7.01-6.90(m,4H),6.82(s,1H),4.91-4.87(m,1H),4.27-4.23(m,1H),4.15-4.12(m,1H),2.36(s,3H),1.54(d,J=13.2Hz,3H);MS(ESI)m/z 368.11[C20H18ClN3O2+H]+。
(S)-3-氯-4-((1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)苄腈(化合物56)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.66(d,J=2.0Hz,1H),7.53(dd,J=2.0Hz,8.8Hz,1H),7.37(t,J=8.4Hz,1H),7.15(d,J=8.8Hz,1H),7.01-6.90(m,4H),6.82(s,1H),4.91-4.87(m,1H),4.27-4.23(m,1H),4.15-4.12(m,1H),2.36(s,3H),1.54(d,J=13.2Hz,3H);MS(ESI)m/z 368.11[C20H18ClN3O2+H]+。
4-(2-((2-(1-甲基-1H-吡唑-5-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物59)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.52(d,J=9.6Hz,1H),7.61(d,J=8.8Hz,2H),7.49(s,1H),7.11(s,1H),7.03(d,J=8.8Hz,2H),6.82(d,J=4.0Hz,1H),6.53(s,1H),4.42(d,J=6.4Hz,4H),4.20(s,3H);MS(ESI)m/z321.30[C18H16N4O2+H]+。
(S)-3-甲氧基-4-((1-(3-(1-甲基-1H-吡唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物60)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.50(d,J=1.6Hz,1H),7.37-7.31(m,1H),7.26(s,1H)7.09(d,J=1.2Hz,1H),7.04-6.99(m,2H),6.93(d,J=7.6Hz,2H),6.28(d,J=1.2Hz,1H),4.84(dd,J=6.0,2.0Hz,1H),4.26(dd,J=9.6,6.4Hz,1H),4.13-4.09(m,1H),3.88(s,3H),3.84(s,3H),1.50(d,J=6.4Hz,3H);MS(ESI)m/z 364.26[C21H21N3O3+H]+。
4-((1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)-3-甲基苄腈(化合物61)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.62(t,J=8.4Hz,2H),7.43(t,J=8.0Hz,1H),7.24(d,J=7.6Hz,2H),7.05(t,J=10.8Hz,3H),6.84(s,1H),4.99(d,J=4.4Hz,1H),4.27(d,J=13.2Hz,2H),2.09(s,3H),1.76(dd,J=4.8,10Hz,1H),1.37(d,J=6.4Hz,3H),0.88-0.80(m,4H);MS(ESI)m/z374.30[C23H23N3O2+H]+。
3-氟-4-(3-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丁-2-基氧基)苄腈(化合物63)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.40-7.33(m,3H),7.11-7.03(m,3H),6.98-6.87(m,2H),6,81(t,J=2.4Hz,1H),4.65-4.56(m,2H),2.37(d,J=5.2Hz,3H),1.57-1.40(m,6H);MS(ESI)m/z 366.15[C21H20FN3O2+H]+。
3-氟-4-((1-(3-(异噁唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物64)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):8.62(d,J=4.0Hz,1H),7.82(dd,J=2.0,11.6Hz,1H),7.65(d,J=8.8Hz,1H),7.51-7.39(m,4H),7.04(dd,i=1.6,5.2Hz 2H),5.10-5.06(m,1H),4.30-4.23(m,2H),1.35(d,J=5.6Hz,3H);MS(ESI)m/z 339.19[C19H15FN3O2+H]+。
(R)-3-氟-4-((1-(3-(异噁唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物65)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):8.62(d,J=4.0Hz,1H),7.82(dd,J=2.0,11.6Hz,1H),7.65(d,J=8.8Hz,1H),7.51-7.39(m,4H),7.04(dd,J=1.6,5.2Hz 2H),5.10-5.06(m,1H),4.30-4.23(m,2H),1.35(d,J=5.6Hz,3H);MS(ESI)m/z 339.19[C19H15FN3O2+H]+。
(S)-3-氟-4-((1-(3-(异噁唑-5-基)苯氧基)丙-2-基)氧基)苄腈(化合物66)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):8.62(d,J=4.0Hz,1H),7.82(dd,J=2.0,11.6Hz,1H),7.65(d,J=8.8Hz,1H),7.51-7.39(m,4H),7.04(dd,J=1.6,5.2Hz 2H),5.10-5.06(m,1H),4.30-4.23(m,2H),1.35(d,J=5.6Hz,3H);MS(ESI)m/z 339.19[C19H15FN3O2+H]+。
(R)-4-((1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)-3-甲基苄腈(化合物68)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):7.62(t,J=8.4Hz,2H),7.43(t,J=8.0Hz,1H),7.24(d,J=7.6Hz,2H),7.05(t,J=10.8Hz,3H),6.84(s,1H),4.99(d,J=4.4Hz,1H),4.27(d,J=13.2Hz,2H),2.09(s,3H),1.76(dd,J=4.8,10Hz,1H),1.37(d,J=6.4Hz,3H),0.88-0.80(m,4H);MS(ESI)m/z374.30[C23H23N3O2+H]+。
3-氟-4-(2-((2-(1-甲基-1H-吡唑-5-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物69)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.52(d,J=6.0Hz,1H),7.5(d,J=1.6Hz,1H),7.41(dd,J=8.8Hz,19.6Hz,2H),7.12-7.07(m,2H),6.83-6.81(m,1H),6.54(d,J=2Hz,1H),4.48(s,4H),4.20(s,3H);MS(ESI)m/z339.19[C18H15FN4O2+H]+。
6-(2-((2-(2-甲基-1H-咪唑-1-基)吡啶-4-基)氧基)乙氧基)烟腈(化合物70)的制备
1H NMR(400MHz,DMSO-d6)δ(ppm):8.72(d,J=2.0Hz,1H),8.37(d,J=5.6Hz,1H),8.19-8.17(dd,J=2.4,8.8Hz,1H),7.57(s,1H),7.21(d,J=2.0Hz,1H),7.08-7.06(m,2H),6.93(s,1H),4.73-4.71(m,2H),4.56-4.54(m,2H),2.50(s,3H);MS(ESI)m/z 322.29[C17H15N5O2+H]+
6-(2-((2-(1-甲基-1H-吡唑-5-基)吡啶-4-基)氧基)乙氧基)烟腈(化合物71)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.60(d,J=5.6Hz,2H),7.8(dd,J=1.6,8Hz,1H),7.49(d,J=1.6Hz,1H),7.12(d,J=2.0Hz,1H),6.88(d,J=4.8Hz,1H),6.81(t,J=6.0Hz,1H),6.53(d,J=2.0Hz,1H),4.78(t,J=4.4Hz,2H),4.42(t,J=4.8Hz,2H),4.20(s,3H);(.MS(ESI)m/z322.12[C17H15N5O2+H]+。
(S)-3-甲氧基-4-((1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)苄腈(化合物72)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.36(t,J=8.0Hz,1H),7.26-7.24(m,1H),7.10(d,J=8.8Hz,1H),7.06-6.88(m,5H),6.83(s,1H),4.86-4.82(m,1H),4.26-4.22(m,1H),4.12-4.09(m,1H),3.84(s,3H),2.36(s,3H)1.49(d,J=6.4Hz,3H);MS(ESI)m/z 364.16[C21H21N3O3+H]+。
6-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)哒嗪-3-甲腈(化合物73)的制备
1H NMR(400MHz,DMSO-d6)δ8.25(d,J=9.2Hz,1H),7.56(d,J=9.2Hz,1H),7.44(t,J=8.8Hz,1H),7.28(d,J=1.2Hz,1H),7.08-7.07(m,2H),7.02(d,J=8.4Hz,1H),6.89(d,J=1.2Hz,1H),4.89(d,J=4.0Hz,2H),4.48(d,J=4.4Hz,2H),2.30(s,3H);MS(ESI)m/z321.9[C17H15N5O2+H]+。
5-氟-6-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)烟腈(化合物74)的制备
1H NMR(400MHz,DMSO-d6)δ8.53(d,J=3.2Hz,1H),8.45-8.43(m,1H),7.44(t,J=8.0Hz,1H),7.28(d,J=1.2Hz,1H),7.08-7.01(m,3H),6.89(d,J=1.2Hz,1H),4.74(t,J=4.0Hz,2H),4.44(t,J=5.2Hz,2H),2.29(s,3H);MS(ESI)m/z 339.9[C18H15FN4O2+H]+。
6-(2-(3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)烟腈(化合物75)的制备
1H NMR(400MHz,DMSO-d6)δ8.71(d,J=2.0Hz,1H),8.19-8.16(m,1H),7.46-7.39(m,2H),7.11-7.04(m,4H),6.40(d,J=2.0Hz,1H),4.70(d,J=4.4Hz,2H),4.41(d,J=4.4Hz,2H),3.85(s,3H);MS(ESI)m/z320.9[C18H16N4O2+H]+。
4-(2-((2-(2-环丙基-1H-咪唑-1-基)吡啶-4-基)氧基)乙氧基)-3-氟苯甲腈(化合物76)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.42(d,J=5.6Hz,1H),7.46-7.38(m,2H),7.29(d,J=1.2Hz,1H),7.08(t,J=8.4Hz,2H),6.98-6.97(m,1H),6.88(dd,J=2.4,6.0Hz,1H),4.50(s,4H),2.19-2.14(m,1H),1.17-1.13(m,2H),0.98-0.94(m,2H);MS(ESI)m/z 365.23[C20H17FN4O2+H]+。
(R)-3-甲氧基-4-((1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)苄腈(化合物77)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.36(t,J=8.0Hz,1H),7.26-7.24(m,1H),7.10(d,J=8.8Hz,1H),7.06-6.88(m,5H),6.83(s,1H),4.86-4.82(m,1H),4.26-4.22(m,1H),4.12-4.09(m,1H),3.84(s,3H),2.36(s,3H)1.49(d,J=6.4Hz,3H);MS(ESI)m/z 364.16[C21H21N3O3+H]+。
(R)-3-氟-4-((1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)苄腈(化合物78)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.42-7.35(m,3H),7.14(t,J=8.4Hz,1H),7.02-6.89(m,4H),6.81(t,J=2.0Hz,1H),2.36(s,3H),1.50(d,J=6.4Hz,3H);MS(ESI)m/z352.14[C20H18FN3O2+H]+。
(S)-3-氟-4-((1-(3-(2-甲基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)苄腈(化合物79)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.42-7.35(m,3H),7.14(t,J=8.4Hz,1H),7.02-6.89(m,4H),6.81(t,J=2.0Hz,1H),2.36(s,3H),1.50(d,J=6.4Hz,3H);MS(ESI)m/z352.14[C20H18FN3O2+H]+。
4-((1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)-3-甲氧基苄腈(化合物80)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.41-7.36(m,1H),7.04-6.96(m,4H),4.25-4.20(m,1H),3.95(dd,J=3.2,9.2Hz,1H),3.85(t,J=8.0Hz,1H),2.37(s,1H),1.82-1.75(m,1H),1.30(d,J=6.4Hz,3H),1.12-1.08(m,2H),0.92-0.87(m,2H);MS(ESI)m/z 259.21[C15H18N2O2+H]+。
(S)-4-((1-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)丙-2-基)氧基)-3-甲氧基苄腈(化合物81)的制备
1H NMR(400MHz,CDCl3)δ(ppm):7.41-7.36(m,1H),7.04-6.96(m,4H),4.25-4.20(m,1H),3.95(dd,J=3.2,9.2Hz,1H),3.85(t,J=8.0Hz,1H),2.37(s,1H),1.82-1.75(m,1H),1.30(d,J=6.4Hz,3H),1.12-1.08(m,2H),0.92-0.87(m,2H);MS(ESI)m/z 259.21[C15H18N2O2+H]+。
5-氟-6-(2-(3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)烟腈(化合物82)的制备
1H NMR(400MHz,DMSO-d6)δ8.53(d,J=3.2Hz,1H),8.45-8.42(m,1H),7.46-7.39(m,2H),7.12-7.05(m,3H),6.41(d,J=1.6Hz,1H),4.74(d,J=4.0Hz,2H),4.43(d,J=4.8Hz,2H),3.85(s,3H);MS(ESI)m/z 339.1[C18H15FN4O2+H]+。
6-(2-(3-(2-环丙基-1H-咪唑-1-基)苯氧基)乙氧基)-5-氟烟腈(化合物83)的制备
1H NMR(400MHz,DMSO-d6)δ8.53(d,J=3.2Hz,1H),8.45-8.42(m,1H),7.46(t,J=7.6Hz,1H),7.26(d,J=1.2Hz,1H),7.10-7.08(m,3H),6.84(d,J=0.8Hz,1H),4.74(t,J=4.0Hz,1H),4.45(t,J=4.4Hz,1H);MS(ESI)m/z 365.1[C20H17FN4O2+H]+。
3-氟-4-(2-(3-(异噁唑-4-基)苯氧基)乙氧基)苄腈(化合物84)的制备
1H NMR(400MHz,CDCl3)δ(ppm):8.66(s,1H),8.54(s,1H),7.45-7.33(m,3H),7.08(dd,J=17.6,8.0Hz,3H),6.90(dd,J=8.4,1.2Hz,1H),4.49(t,J=3.6Hz,2H),4.42(t,J=4.8Hz,2H);MS(ESI)m/z 325.24[C18H13FN2O3+H]+。
6-(2-((2-(2-环丙基-1H-咪唑-1-基)吡啶-4-基)氧基)乙氧基)-5-氟烟腈(化合物90)的制备
1H NMR(400MHz,DMSO-d6)δ8.54(d,J=2.8Hz,1H),8.46-8.43(m,1H),8.39(d,J=6.0Hz,1H),7.48(s,1H),7.24(d,J=2.0Hz,1H),7.11-7.10(m,1H),6.85(s,1H),4.77(t,J=4.0Hz,2H),4.59(t,J=4.0Hz,2H),2.37-2.33(m,1H),0.90-0.87(m,4H);MS(ESI)m/z366.1[C19H16FN5O2+H]+。
5-氟-6-(2-((2-(2-甲基-1H-咪唑-1-基)吡啶-4-基)氧基)乙氧基)烟腈(化合物91)的制备
1H NMR(400MHz,CDCl3)δ8.39(d,J=6.0Hz,1H),8.23(d,J=2.8Hz,1H),7.69-7.67(m,1H),7.26-7.25(m,1H),7.01(d,J=1.6Hz,1H),6.89-6.87(m,1H),6.84(d,J=0.8Hz,1H),4.80(t,J=4.4Hz,2H),4.47(t,J=4.8Hz,2H),2.59(s,3H);MS(ESI)m/z 340.1[C17H14FN5O2]+。
4-(2-(4-氟-3-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物93)的制备
1H NMR(CDCl3,400MHz):δ7.61(d,J=8.8Hz,2H),7.54(s,1H),7.12(t,J=9.2Hz,1H),7.02-6.88(m,4H),6.31(s,1H),4.35(d,J=7.2Hz,4H),3.81(s,3H);MS(ESI)m/z338.12[C19H16FN3O2+H]+。
5-氯-2-(2-((2-(1-甲基-1H-吡唑-5-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物98)的制备
1H NMR(400MHz,DMSO-d6)δ8.50(d,J=6.0Hz,1H),7.92(d,J=2.4Hz,1H),7.77-7.75(m,1H),7.47(d,J=2.0Hz,1H),7.40-7.37(m,2H),7.05-7.03(m,1H),6.82(d,J=2.0Hz,1H),4.55(s,4H),4.12(s,3H);MS(ESI)m/z 355.1[C18H15ClN4O2+H]+。
5-氯-2-(2-((2-(2-甲基-1H-咪唑-1-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物99)的制备
1H NMR(400MHz,CDCl3)δ8.41(d,J=5.6Hz,1H),7.56-7.52(m,2H),7.27(s,1H),7.05(s,1H),6.99(d,J=8.8Hz,1H),6.92(d,J=6.0Hz,1H),6.86(s,1H),4.52-4.51(m,2H),4.48-4.47(m,2H),2.63(s,3H);MS(ESI)m/z 355.0[C18H15ClN4O2+H]+。
3-氯-4-(2-((2-(1-甲基-1H-吡唑-5-基)吡啶-4-基)氧基)乙氧基)苄腈(化合物100)的制备
1H NMR(400MHz,DMSO-d6)δ8.50(d,J=5.6,1H),8.03(d,J=1.6Hz,1H),7.88-7.80(m,1H),7.50-7.39(m,3H),7.06-7.00(s,1H),6.83(d,J=2.0Hz,1H),4.58(s,4H),4.12(s,3H);MS(ESI)m/z355.1[C18H15ClN4O2+H]+。
3-氟-4-(2-(3-氟-5-(1-甲基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物105)的制备
1H NMR(CDCl3,400MHz):δ7.508(d,1H,J=2.0Hz),7.460-7.376(m,2H),7.092(t,1H,J=8.4Hz),6.783-6.700(m,3H),6.310(d,1H,J=1.6Hz),4.485-4.463(m,2H),4.413-4.391(m,2H),3.902(s,3H);MS(ESI)m/z 356.1[C19H15F2N3O2+H]+。
3-氟-4-(2-((6-(1-甲基-1H-吡唑-5-基)吡啶-2-基)氧基)乙氧基)苄腈(化合物106)的制备
1H NMR(CDCl3,400MHz)δ7.662(dd,1H,J=7.6&7.2Hz),7.497(d,1H,J=2.0Hz),7.418(dt,1H,J=8.4&2.0Hz),7.375(dd,1H,J=10.4&2.0Hz),7.225(dd,1H,J=7.6&0.8Hz),7.086(t,1H,J=8.0Hz),6.747(dd,1H,J=8.0&0.8Hz),6.578(d,1H,J=2.0Hz),4.772(t,2H,J=4.8Hz),4.481(t,2H,J=4.8Hz),4.238(s,3H);MS(ESI)m/z 339.1[C18H15FN4O2+H]+。
4-(2-(4-氟-3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈(化合物108)的制备
1H NMR(CDCl3,400MHz,)δ7.62(m,1H),7.60(m,1H),7.19(t,J=9.2Hz,1H),7.06-7.05(d,J=1.2Hz,1H),7.02-6.97(m,3H),6.95(s,1H),6.87-6.85(dd,J=6.4,3.0Hz,1H),4.36(m,2H),4.34(m,2H),2.31(s,3H);MS(ESI)m/z 338.2[C19H16FN3O2+H]+。
4-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)-3-(三氟甲基)苄腈(化合物111)的制备
1H NMR(CDCl3,400MHz):δ7.89-7.88(d,J=2.0Hz,1H),7.84-7.81(dd,J=8.4,2.0Hz,1H),7.40(t,J=8.2Hz,1H),7.18-7.16(d,J=8.8Hz,1H),7.03-6.99(m,3H),6.92-6.91(m,1H),6.84(t,J=2.2Hz,1H),4.55-4.50(m,2H),4.49-4.40(m,2H),2.37(s,3H)。MS(ESI)m/z 388.1[C20H16F3N3O2+H]+。
5-氟-2-(2-(3-(2-甲基-1H-咪唑-1-基)苯氧基)乙氧基)苄腈(化合物114)的制备
1H NMR(DMSO-d6,400MHz):δ7.77-7.74(dd,J=8.0,3.2Hz,1H),7.61-7.56(dt,J=8.8,3.2Hz,1H),7.44(t,J=8.0Hz,1H),7.39-7.35(dd,J=9.2,4.0Hz,1H),7.29(d,J=1.2Hz,1H),7.09-7.01(m,3H),6.90(s,1H),4.51-4.49(m,2H),4.43-4.41(m,2H),2.29(s,3H);MS(ESI)m/z 338.2[C19H16FN3O2+H]+。
4-(2-(3-(1-环丙基-1H-吡唑-5-基)苯氧基)乙氧基)-3-氟苯甲腈(化合物116)的制备
1H NMR(DMSO-d6,400MHz):δ7.88-7.84(dd,J=11.4,2.0,1H),(td,J=8.8,1.4,1H),4.47-7.30(m,3H),7.24-7.22(m,2H),7.06-7.03(m,1H),6.43-6.42(d,J=1.6,1H),4.55-4.52(m,2H),4.44-4.42(m,2H),3.77-3.72(m,1H),0.97-0.91(m,4H);MS(ESI)m/z364.2[C21H18FN3O2+H]+。
4-(2-(3-(1-环丙基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物117)的制备
1H NMR(DMSO-d6,400MHz):δ7.63-7.61(d,J=8.8,2H),7.47(s,1H),7.40(t,J=8.0,1H),7.22-7.20(d,J=7.6,1H),7.14(s,1H),7.04-7.02(d,J=8.8,2H),7.01-6.98(d,J=8.8,1H),6.32(s,1H),4.41(s,4H),3.62(m,1H),1.17(m,2H),0.98-0.97(m,2H);MS(ESI)m/z 346.2[C21H19N3O2+H]+。
3-氯-4-(2-(3-(1-环丙基-1H-吡唑-5-基)苯氧基)乙氧基)苄腈(化合物118)的制备
1H NMR(DMSO-d6,400MHz):δ7.69-7.68(d,J=1.6,1H),7.59-7.56(dd,J=8.4,1.6,1H),7.47(s,1H),7.40(t,J=8.0,1H),7.23-7.21(d,J=7.2,1H),7.16(s,1H),7.09-7.07(d,J=8.8,1H),7.02-7.00(d,J=7.6,1H),6.32(s,1H),4.48(s,4H),3.62(m,1H),1.17(m,2H),0.98-0.97(m,2H);MS(ESI)m/z380.2[C21H18ClN3O2+H]+。
实施例8:化合物列表
下表2示出了代表本公开的示例性化合物的列表以及生物活性数据。
表2.列出了示例性化合物的结构和IC50的表
工业实用性
如上定义的化合物可以发现多种应用,其中它们抑制甲基转移酶如ICMT的能力是有用的。所述化合物还可以用于治疗或预防其中蛋白甲基转移酶和/或其辅因子和/或通过非指明的机制的抑制预防、抑制或改善病症的病理学或症状学的病症或疾病。所述病症或疾病可以为癌症或早衰样疾病。所述化合物可特别用于治疗癌症如乳腺癌、卵巢癌、胰腺癌、白血病、结肠直肠癌、肺癌、肝细胞癌和其他高血管肿瘤以及血管生成性疾病。
显然,在阅读了上述公开内容之后,在不脱离本发明的精神和范围的情况下,本发明的各种其他修改和修改对于本领域技术人员来说是显而易见的,并且所有这些修改和修改都落入所附权利要求的范围内。
Claims (54)
1.一种具有下式(I)的化合物:
和/或其互变异构体、对映异构体、溶剂化物、水合物、前药和药学上可接受的盐;
其中:
环A为5元或6元碳环体系,其中1至4个碳原子可以任选地被杂原子替代;
B1、B2和B3独立地选自C、CH或N;
环C为5元或6元碳环体系,其中1至3个碳原子可以任选地被杂原子替代;
R1、R2和R3独立地不存在或选自H、OH、氰基、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基;
R4和R5独立地选自H或脂肪族;
n为选自0至5的整数,其中当n大于1时,环A上取代的每个R1可以相同或不同;
m为选自0至4的整数,其中当m大于1时,环B上取代的每个R2可以相同或不同;以及
p为选自0至5的整数,其中当p大于1时,环C上取代的每个R3可以相同或不同。
2.一种具有下式(I)的化合物:
和/或其互变异构体、对映异构体、溶剂化物、水合物、前药和药学上可接受的盐;
其中:
环A为5元或6元碳环体系,其中1至4个碳原子可以任选地被杂原子替代;
B1、B2和B3独立地选自C、CH或N,其中当B1、B2或B3中的一个为N时,剩余的B1、B2或B3为C或CH;
环C为5元或6元碳环体系,其中1至3个碳原子可以任选地被杂原子替代;
R1不存在或选自H、OH、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基;
R2不存在或选自H、OH、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基;
R3不存在或选自H、OH、氰基、卤素、任选取代的烷基、卤代烷基、CF3、CHF2、任选取代的烯基、任选取代的炔基、任选取代的烷氧基、任选取代的氨基、任选取代的酰基、任选取代的环烷基、任选取代的环烯基、任选取代的杂环烷基或任选取代的芳基;
R4和R5独立地选自H或脂肪族;
n为选自0至5的整数,其中当n大于1时,环A上取代的每个R1可以相同或不同;
m为选自0至4的整数,其中当m大于1时,环B上取代的每个R2可以相同或不同,并且当R2是卤素时,m是1;以及
p为选自0至5的整数,其中当p大于1时,环C上取代的每个R3可以相同或不同。
8.根据权利要求1至7中任一项所述的化合物,其中R1为烷基或环烷基。
9.根据权利要求1至8中任一项所述的化合物,其中R1为甲基或环丙基。
12.根据权利要求1至11中任一项所述的化合物,其中环A为5元碳环体系,其中1至4个碳原子被杂原子替代;并且环B具有式(bb1)或式(bb2)。
14.根据权利要求1至13中任一项所述的化合物,其中R2为H或F。
21.根据权利要求1至20中任一项所述的化合物,其中R3为卤素、-CN、烷氧基、氨基、卤代烷基、卤代烷氧基或烷基。
22.根据权利要求1至21中任一项所述的化合物,其中R3为氟、氯、溴、-CN、甲氧基、甲基、-NH2、-OCF3、CF3或CHF2。
24.根据权利要求1至23中任一项所述的化合物,其中R4和R5独立地为H或烷基。
25.根据权利要求1至24中任一项的化合物,其中R4和R5独立地为H或甲基、乙基、丙基或丁基。
26.根据权利要求1至25中任一项所述的化合物,其中R4和R5为H;或R4为H且R5为甲基;或R4为甲基且R5为H;或R4为甲基且R5为甲基。
30.一种药物组合物,其包含权利要求1至29中任一项所述的化合物或其药学上可接受的形式或前药以及药学上可接受的赋形剂。
31.一种抑制由异戊二烯半胱氨酸羧甲基转移酶(ICMT)引起的异戊二烯化半胱氨酸或异戊二烯半胱氨酸甲基化的方法,所述方法包括使权利要求1至29中任一项所述的化合物或权利要求30所述的药物组合物与ICMT接触。
32.一种抑制细胞中的ICMT的方法,所述方法包括使所述细胞与权利要求1至29中任一项所述的化合物、或其药学上可接受的形式或前药、或权利要求30所述的药物组合物接触。
33.根据权利要求32所述的方法,其中所述ICMT的抑制还包括细胞增殖的抑制。
34.一种治疗ICMT相关疾病的方法,所述方法包括向需要治疗的受试者施用权利要求1至29中任一项所述的化合物、或权利要求30所述的药物、或组合物。
35.根据权利要求34所述的方法,其中所述疾病是癌症、早熟衰老症或哈钦森-吉尔福德早衰综合征(HGPS)。
36.根据权利要求35所述的方法,其中所述癌症是与突变型Ras过度活性相关的癌症。
37.根据权利要求35所述的方法,其中所述癌症选自由以下组成的组:肝细胞癌、乳腺癌、卵巢癌、结肠直肠癌、肺癌、胰腺癌或白血病。
38.根据权利要求33至37中任一项所述的方法,进一步包括向所述受试者施用另外的治疗剂的步骤。
39.根据权利要求1至29中任一项所述的化合物、或其药学形式或前药、或根据权利要求30所述的组合物,其用于治疗。
40.根据权利要求1至29中任一项所述的化合物、或其药学形式或前药、或权利要求30所述的组合物,其用于治疗和/或预防癌症和/或早衰样疾病。
41.根据权利要求1至29中任一项所述的化合物、或其药学形式或前药、或根据权利要求30所述的组合物,其用于治疗ICMT相关疾病。
42.根据权利要求41所述的化合物或其药学上可接受的形式或前药,其中所述疾病为癌症、早熟衰老症或哈钦森-吉尔福德早衰综合征(HGPS)。
43.根据权利要求42所述的化合物或其药学形式或前药,其中所述癌症是与突变型Ras过度活性相关的癌症。
44.根据权利要求42或43所述的化合物或其药学上可接受的形式或前药,其中所述癌症是肝细胞癌、乳腺癌、卵巢癌、结肠直肠癌、肺癌、胰腺癌或白血病。
45.根据权利要求39至44中任一项所述的化合物或其药学形式或前药,其中所述化合物将与另外的治疗剂组合施用。
46.根据权利要求1至29中任一项所述的化合物、或其药学形式或前药、或权利要求30所述的组合物在制备用于治疗和/或预防癌症和/或早衰样疾病的药物中的用途。
47.根据权利要求1至29中任一项所述的化合物、或其药学形式或前药、或权利要求30所述的组合物在制备用于治疗ICMT相关疾病的药物中的用途。
48.根据权利要求47所述的用途,其中所述疾病是癌症、早熟衰老症或哈钦森-吉尔福德早衰综合征(HGPS)。
49.根据权利要求48所述的用途,其中所述癌症是与突变型Ras过度活性相关的癌症。
50.根据权利要求48或49所述的用途,其中所述癌症是肝细胞癌、乳腺癌、卵巢癌、结肠直肠癌、肺癌、胰腺癌或白血病。
51.根据权利要求46至50中任一项所述的用途,其中所述药物与另外的治疗剂组合施用。
52.根据权利要求1至29中任一项所述的化合物,其具有小于约5μM的ICMTIC50。
53.根据权利要求1至29中任一项所述的化合物,其具有约0.001μM至约5μM的ICMTIC50。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SG10201707444W | 2017-09-12 | ||
SG10201707444W | 2017-09-12 | ||
PCT/SG2018/050466 WO2019054944A1 (en) | 2017-09-12 | 2018-09-12 | COMPOUNDS USEFUL AS INHIBITORS OF ISOPRENYLCYSTEINE CARBOXYL METHYLTRANFERASE |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111344284A true CN111344284A (zh) | 2020-06-26 |
CN111344284B CN111344284B (zh) | 2024-03-12 |
Family
ID=65722547
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880072698.4A Active CN111344284B (zh) | 2017-09-12 | 2018-09-12 | 用作异戊二烯半胱氨酸羧甲基转移酶抑制剂的化合物 |
Country Status (8)
Country | Link |
---|---|
US (1) | US11834430B2 (zh) |
EP (1) | EP3681878A4 (zh) |
JP (1) | JP7334979B2 (zh) |
KR (1) | KR20200090747A (zh) |
CN (1) | CN111344284B (zh) |
AU (1) | AU2018332634A1 (zh) |
SG (1) | SG11202002267UA (zh) |
WO (1) | WO2019054944A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023205465A1 (en) * | 2022-04-22 | 2023-10-26 | Vertex Pharmaceuticals Incorporated | Heteroaryl compounds for the treatment of pain |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0135838A2 (de) * | 1983-09-02 | 1985-04-03 | BASF Aktiengesellschaft | 3-Phenyl-4-methoxycarbonylpyrazole, Verfahren zu ihrer Herstellung und ihre Verwendung zur Bekämpfung unerwünschten Pflanzenwuchses |
CN1432013A (zh) * | 2000-06-28 | 2003-07-23 | Ss制药株式会社 | 咪唑衍生物或其盐以及含有该衍生物或其盐的药物 |
CN1505625A (zh) * | 2001-04-30 | 2004-06-16 | 用于治疗由过度细胞因子活性引起的疾病的三唑化合物 | |
CN1944383A (zh) * | 2005-01-11 | 2007-04-11 | 中国医学科学院药物研究所 | α-烷氧丙酸类化合物及其制法和药物用途 |
CN102574787A (zh) * | 2009-07-30 | 2012-07-11 | 新加坡国立大学 | 具有潜在的抗癌活性的小分子异戊二烯基半胱氨酸羧基甲基转移酶抑制剂 |
WO2014041349A1 (en) * | 2012-09-12 | 2014-03-20 | Cancer Therapeutics Crc Pty Ltd | Tetrahydropyran-4-ylethylamino- or tetrahydropyranyl-4-ethyloxy-pyrimidines or -pyridazines as isoprenylcysteincarboxymethyl transferase inhibitors |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2248491A (en) * | 1941-07-08 | Chs-chs | ||
US2196576A (en) * | 1938-12-16 | 1940-04-09 | Dow Chemical Co | Glycol ether |
IL111959A (en) | 1993-12-17 | 2000-07-16 | Tanabe Seiyaku Co | N-(polysubstituted pyrimidin-4-yl) benzenesulfonamide derivatives their preparation and pharmaceutical compositions containing them |
US6204293B1 (en) * | 1995-11-06 | 2001-03-20 | University Of Pittsburgh | Inhibitors of protein isoprenyl transferases |
US6465467B1 (en) | 1999-05-21 | 2002-10-15 | Biovitrum Ab | Certain aryl-aliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases |
KR20030026979A (ko) * | 2000-07-18 | 2003-04-03 | 야마노우치세이야쿠 가부시키가이샤 | 디시아노피리딘 유도체를 포함하는 의약 |
MY140724A (en) * | 2000-07-21 | 2010-01-15 | Actelion Pharmaceuticals Ltd | Novel arylethene-sulfonamides |
AU2003234606A1 (en) | 2002-05-16 | 2003-12-02 | Pharmacia Corporation | Using a selective iNOS inhibitor for the treatment of respiratory diseases and conditions |
JP2004262890A (ja) | 2003-03-04 | 2004-09-24 | Taisho Pharmaceut Co Ltd | 20−hete産生阻害作用を有するアゾール誘導体 |
US8088935B2 (en) * | 2003-12-23 | 2012-01-03 | Ironwood Pharmaceuticals, Inc. | Compounds and methods for the treatment of asthma |
JP2005298406A (ja) * | 2004-04-12 | 2005-10-27 | Fuji Photo Film Co Ltd | 5−アミノピラゾール化合物、及び該化合物を含む記録材料 |
US7803822B2 (en) * | 2005-04-06 | 2010-09-28 | Takeda Pharmaceutical Company Limited | Triazole derivative and use thereof |
JP2009545597A (ja) | 2006-08-01 | 2009-12-24 | プリーシス・ファーマシューティカルズ・インコーポレイテッド | スフィンゴシン−1−ホスフェート受容体(slp)のアゴニスト |
PL2116530T3 (pl) * | 2007-02-26 | 2013-03-29 | Santen Pharmaceutical Co Ltd | Nowa pochodna pirolu zawierająca jako podstawniki grupę ureidową i grupę aminokarbonylową |
BRPI0810523A2 (pt) * | 2007-04-11 | 2014-10-21 | Kissei Pharmaceutical | Derivado heterocíclico de 5 membros e uso do mesmo para propósitos médicos. |
KR20090077091A (ko) * | 2008-01-10 | 2009-07-15 | 일동제약주식회사 | 신규 퍼옥시좀 증식자-활성화 수용체 효능제인 화합물 및그 제조방법 |
US8883809B2 (en) | 2008-11-19 | 2014-11-11 | Council Of Scientific & Industrial Research | Isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids as potential anticancer agents and process for the preparation thereof |
EP2670739B1 (en) | 2011-02-04 | 2015-04-01 | Council Of Scientific & Industrial Research | Benzothiazole hybrids useful as anticancer agents and process for the preparation thereof |
SG11201600108PA (en) | 2013-07-17 | 2016-02-26 | Otsuka Pharma Co Ltd | Cyanotriazole compounds |
US20170283400A1 (en) | 2014-09-17 | 2017-10-05 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
KR20230119040A (ko) * | 2015-01-20 | 2023-08-14 | 아비나스 오퍼레이션스, 인코포레이티드 | 안드로겐 수용체의 표적화된 분해를 위한 화합물 및방법 |
WO2017136699A1 (en) | 2016-02-05 | 2017-08-10 | Epizyme, Inc | Arginine methyltransferase inhibitors and uses thereof |
US11191741B2 (en) | 2016-12-24 | 2021-12-07 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of enhancer of zeste homolog 2 polypeptide |
-
2018
- 2018-09-12 CN CN201880072698.4A patent/CN111344284B/zh active Active
- 2018-09-12 KR KR1020207010540A patent/KR20200090747A/ko not_active Application Discontinuation
- 2018-09-12 EP EP18856093.2A patent/EP3681878A4/en active Pending
- 2018-09-12 AU AU2018332634A patent/AU2018332634A1/en not_active Abandoned
- 2018-09-12 JP JP2020515184A patent/JP7334979B2/ja active Active
- 2018-09-12 US US16/646,693 patent/US11834430B2/en active Active
- 2018-09-12 SG SG11202002267UA patent/SG11202002267UA/en unknown
- 2018-09-12 WO PCT/SG2018/050466 patent/WO2019054944A1/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0135838A2 (de) * | 1983-09-02 | 1985-04-03 | BASF Aktiengesellschaft | 3-Phenyl-4-methoxycarbonylpyrazole, Verfahren zu ihrer Herstellung und ihre Verwendung zur Bekämpfung unerwünschten Pflanzenwuchses |
CN1432013A (zh) * | 2000-06-28 | 2003-07-23 | Ss制药株式会社 | 咪唑衍生物或其盐以及含有该衍生物或其盐的药物 |
CN1505625A (zh) * | 2001-04-30 | 2004-06-16 | 用于治疗由过度细胞因子活性引起的疾病的三唑化合物 | |
CN1944383A (zh) * | 2005-01-11 | 2007-04-11 | 中国医学科学院药物研究所 | α-烷氧丙酸类化合物及其制法和药物用途 |
CN102574787A (zh) * | 2009-07-30 | 2012-07-11 | 新加坡国立大学 | 具有潜在的抗癌活性的小分子异戊二烯基半胱氨酸羧基甲基转移酶抑制剂 |
WO2014041349A1 (en) * | 2012-09-12 | 2014-03-20 | Cancer Therapeutics Crc Pty Ltd | Tetrahydropyran-4-ylethylamino- or tetrahydropyranyl-4-ethyloxy-pyrimidines or -pyridazines as isoprenylcysteincarboxymethyl transferase inhibitors |
Non-Patent Citations (1)
Title |
---|
TASNEEM A. KHWAJA等: "Comparison of Quantitative Structure-Activity Relationships of the Inhibition of Leukemia Cells in Culture with the Inhibition of Dihydrofolate Reductase from Leukemia Cells and Other Cell Types", 《J. MED.CHEM.》 * |
Also Published As
Publication number | Publication date |
---|---|
EP3681878A4 (en) | 2021-02-24 |
US20210130317A1 (en) | 2021-05-06 |
SG11202002267UA (en) | 2020-04-29 |
WO2019054944A1 (en) | 2019-03-21 |
EP3681878A1 (en) | 2020-07-22 |
CN111344284B (zh) | 2024-03-12 |
AU2018332634A1 (en) | 2020-04-30 |
JP2020533386A (ja) | 2020-11-19 |
US11834430B2 (en) | 2023-12-05 |
KR20200090747A (ko) | 2020-07-29 |
JP7334979B2 (ja) | 2023-08-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113316574B (zh) | Shp2抑制剂及其应用 | |
AU2009331179B2 (en) | Novel bicyclic heterocyclic compound | |
KR102219441B1 (ko) | 메틸 변형 효소 조절제, 이의 조성물 및 용도 | |
EP1786773B1 (en) | Isoindolin-1-one derivatives | |
RU2669695C2 (ru) | Циклические амидные производные как ингибиторы 11-бета-гидроксистероид-дегидрогеназы и их применение | |
SK283413B6 (sk) | 2-Tioindoly, 2-indolíntióny a polysulfidy, ich selénové analógy a farmaceutické prostriedky na ich báze | |
EA011719B1 (ru) | Ингибитор высвобождения воспалительного цитокина | |
KR19990045726A (ko) | 선택적 β3 아드레날린 효능제 | |
KR20060015283A (ko) | 신규한 피리도피라진 및 키나제 억제제로서의 이의 용도 | |
CA2176668C (fr) | Nouveaux composes spiro heterocycliques, leur procede de preparation et les compositions pharmaceutiques les contenant | |
JP7187575B2 (ja) | Rhoキナーゼ阻害剤としてのベンゾピラゾール系化合物 | |
EA009051B1 (ru) | О-замещенные гидроксиарильные производные | |
KR20010110810A (ko) | Mek 효소의 억제제로서의 퀴놀린 유도체 | |
PT779887E (pt) | Novos derivados do benzimidazolo tendo uma actividade inibidora fosfodisterase cgmp | |
DK2364298T3 (en) | Quinolone AND PHARMACEUTICAL COMPOSITION | |
WO2018151678A1 (en) | Compounds for treatment of cancer and epigenetics | |
EP0350403A1 (fr) | Dérivés de (aza)naphtalènesultame, leurs procédés de préparation et les médicaments les contenant | |
CA2834101A1 (en) | Novel indole or indazole derivative or salt thereof | |
CN111344284B (zh) | 用作异戊二烯半胱氨酸羧甲基转移酶抑制剂的化合物 | |
JP2002510293A (ja) | 抗潰瘍剤として新規なベンゾイミダゾール誘導体、それらの製造方法、及びそれらを含有する薬学的組成物 | |
CZ85797A3 (cs) | Deriváty chinoxalinu, způsob a meziprodukty pro jejich výrobu, jejich použití a farmaceutické prostředky na jejich bázi | |
EP1908752A1 (en) | Novel 2-quinolone derivative | |
JP5769504B2 (ja) | 医薬 | |
KR20240042619A (ko) | 유기 피리딘-피라졸 화합물 및 이의 용도 | |
EP3189044B1 (en) | Crystalline (2s)-3-[(3s,4s)-3-[(1r)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl) -3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol |
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 |