TWI757256B - 轉染過程重排之抑制劑 - Google Patents
轉染過程重排之抑制劑 Download PDFInfo
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- TWI757256B TWI757256B TW105135376A TW105135376A TWI757256B TW I757256 B TWI757256 B TW I757256B TW 105135376 A TW105135376 A TW 105135376A TW 105135376 A TW105135376 A TW 105135376A TW I757256 B TWI757256 B TW I757256B
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- TW
- Taiwan
- Prior art keywords
- methyl
- compound
- hydrogen
- pharmaceutically acceptable
- alkyl
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 185
- 238000000034 method Methods 0.000 claims abstract description 67
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- -1 C3 - C12cycloalkyl Chemical group 0.000 claims description 149
- 150000003839 salts Chemical class 0.000 claims description 70
- 229910052739 hydrogen Inorganic materials 0.000 claims description 68
- 239000001257 hydrogen Substances 0.000 claims description 68
- 230000008707 rearrangement Effects 0.000 claims description 56
- 238000001890 transfection Methods 0.000 claims description 54
- 230000008569 process Effects 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- 150000002431 hydrogen Chemical class 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 230000004927 fusion Effects 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 230000035772 mutation Effects 0.000 claims description 6
- 206010033701 Papillary thyroid cancer Diseases 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 208000009018 Medullary thyroid cancer Diseases 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims description 4
- 206010051747 multiple endocrine neoplasia Diseases 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 125000006413 ring segment Chemical group 0.000 claims description 3
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 150000003573 thiols Chemical group 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 95
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- 230000015572 biosynthetic process Effects 0.000 description 70
- 238000003786 synthesis reaction Methods 0.000 description 70
- 239000000243 solution Substances 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 125000003118 aryl group Chemical group 0.000 description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- 239000007787 solid Substances 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
- 238000004949 mass spectrometry Methods 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 18
- 238000000746 purification Methods 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 18
- 235000011152 sodium sulphate Nutrition 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 238000003818 flash chromatography Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000004698 Polyethylene Substances 0.000 description 13
- 229920000573 polyethylene Polymers 0.000 description 13
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 12
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 12
- 125000005842 heteroatom Chemical group 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 238000010828 elution Methods 0.000 description 11
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- 108091000080 Phosphotransferase Proteins 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 102000020233 phosphotransferase Human genes 0.000 description 9
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- DVXBXZLZIBWDCO-UHFFFAOYSA-N 1-methoxy-4-[6-methyl-2-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl]cyclohexane-1-carboxylic acid Chemical compound COC1(CCC(CC1)C1=NC(=NC(=C1)C)NC1=NNC(=C1)C)C(=O)O DVXBXZLZIBWDCO-UHFFFAOYSA-N 0.000 description 6
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000001594 aberrant effect Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 235000011056 potassium acetate Nutrition 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000000039 congener Substances 0.000 description 5
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 5
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 5
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 102200006097 rs79658334 Human genes 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 238000004808 supercritical fluid chromatography Methods 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- 229910052725 zinc Inorganic materials 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000013065 commercial product Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- NZNMSOFKMUBTKW-UHFFFAOYSA-M cyclohexanecarboxylate Chemical compound [O-]C(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-M 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 4
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- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940049068 xalkori Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
Classifications
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-
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- 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
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- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
此處描述:抑制原生型轉染過程重排(wild-type RET)及其抗性突變體(resistant mutant)的化合物;藥劑組成物包括此種化合物,以及使用此種化合物和組成物的方法。
Description
本發明係有關於轉染過程重排(RET)之抑制劑,該抑制劑對於原生型轉染過程重排(wild-type RET)及其抗性突變體(resistant mutant)具有活性。
轉染過程重排(RET;rearranged during transfection)是一種受體酪氨酸激酶(receptor tyrosine kinase),它刺激活化包含在細胞增殖(cell proliferation)和細胞存活(survival)中的多重下游路徑(multiple downstream pathways);轉染過程重排融合物(RET fusions)關聯到數種癌症,包括甲狀腺乳突癌(papillary thyroid carcinoma)和非小細胞肺癌(non-small cell lung cancer)。一個在激酶融合物(kinase fusions)格局地景上的基因體學分析(genomics analysis)確認乳癌和大腸癌病人樣本的轉染過程重排融合物,提供治療基礎理論(therapeutic rationale)應用轉染過程重排抑制劑於複數的病人亞族群(patient subpopulations)。
鑑明轉染過程重排融合物在一些癌症中是驅動者,這件事促進了已核准之具有轉染過程重排抑制活性的多激酶抑制劑(multi-kinase inhibitor)的應用,用於治療腫瘤顯示一個轉染過程重排融合物蛋白質(RET fusion protein)的病人。然而,這些藥物無法一直維持在充分抑制轉染過程重排所需的血中濃度,肇因於除了在轉染過程重排,還有來自標靶抑制(inhibition of targets)所產生的毒性。再者,在癌症治療的最大挑戰之一是腫瘤細胞對於治療變成有抵抗性(resistant)的能力,透過突變的激酶再活化(kinase reactivation)是產生抵抗性(resistance)最常見的機轉,一旦發生抵抗性,病人的治療選項通常極為有限,且大多數例子中,癌症一直進展、不受抑制,因此,需要一些化合物可以抑制轉染過程重排以及其抗性突變體。
本發明提供轉染過程重排及轉染過程重排突變體亦即轉染過程重排抗性突變體《如同此處之定義》之抑制劑,如結構式(I)及其藥劑學上可接受的鹽類和組成分構成的抑制劑;本發明更進一步提供使用本發明之化合物及其藥劑學上可接受的鹽類和組成分的方法,抑制在一個細胞或病人中的轉染過程重排及轉染過程重排突變體的活性;本發明更進一步提供使用本發明之化合物及其藥劑學上可接受的鹽類和組成分的方法,治療一個患有因畸變轉染過程重排活性(aberrant RET activity)導致的狀況,亦即癌症的個體。
其中,環A、X1
、X2
、Y1
、Y2
、R1
、R2
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R8b
、R9
、m、n、o和『』的每一者,其定義係如此處所描述。 於另一個面向中,本發明提供藥劑組成物,包含一個結構式(I)的化合物或其一個藥劑學上可接受的鹽類和一個藥劑學上可接受的載體(carrier)。 於另一個面向中,本發明提供一個方法,用來抑制一個細胞或一個病人中的轉染過程重排的活性。在某些具體模式例中,所述之方法包含一個接觸細胞或投與一個結構式(I)的化合物或其一個藥劑學上可接受的鹽類或組成給一個病人的步驟。 於另一個面向中,本發明提供一個方法,用來治療一個患有因畸變的轉染過程重排活性介導的狀況亦即癌症的個體。在某些具體模式例中,所述之方法包含投與一個有效治療數量的一個結構式(I)的化合物或其一個藥劑學上可接受的鹽類或組成給該個體。 於另一個面向中,本發明提供一個方法,用來治療一個對一種癌症治療已產生抵抗性的個體。在某些具體模式例中,所述之方法包含投與一個有效治療數量的一個結構式(I)的化合物或其一個藥劑學上可接受的鹽類或組成給該個體。
化合物
於一個面向中,本發明特別描述一個化合物,具有結構式(A):(A), 或其一個藥劑學上可接受的鹽類,其中: 環A係一個芳基(aryl)或雜芳基(heteroaryl)環(ring); X1
和X2
的每一者係獨立選自N和C(R6
); Y1
和Y2
的每一者係獨立選自-CH2
-和-O-,其中Y1
或Y2
至多一個是-O-;
每一個R1
和每一個R7
係獨立選自C1
-C6
烷基(alkyl)、C2
-C6
烯基(alkenyl)、C2
-C6
炔基(alkynyl)、C1
-C6
烷氧基(alkoxy)、鹵代(halo)、C1
-C6
雜烷基(heteroalkyl)、環烷基(cycloalkyl)、芳基(aryl)、雜芳基(heteroaryl)、芳氧基(aryloxy)、芳代脂烷基(aralkyl)、雜環基(heterocyclyl)、雜環烷基(heterocyclylalkyl)、硝基(nitro)、氰基(cyano)、-C(O)R、-OC(O)R、-C(O)OR、‑(C1
-C6
亞烷基)-C(O)R(‑(C1
-C6
alkylene)-C(O)R)、-SR、-S(O)2
R、-S(O)2
-N(R)(R)、 ‑(C1
-C6
亞烷基)-S(O)2
R、‑(C1
-C6
亞烷基)-S(O)2
-N(R)(R)、-N(R)(R)、-C(O)-N(R)(R)、 -N(R)-C(O)R、-N(R)-C(O)OR、-(C1
-C6
亞烷基)‑N(R)‑C(O)R、-N(R)S(O)2
R、和 -P(O)(R)(R);其中烷基、烯基、炔基、烷氧基、雜烷基、環烷基、芳基、雜芳基、芳氧基、芳代脂烷基、雜環基、和雜環烷基係各自獨立地以0-5個Ra
取代;或二個R1
或二個R7
以其所連結的碳原子相連一起形成一個可獨立地以0-5個Rb
取代的環烷基環和雜環基環; R2
《若出現的話》、R3a
、R3b
、R4
、R8a
和 R8b
《若出現的話》的每一者係各自獨立地選自氫、C1
-C6
烷基、C1
-C6
烷氧基(alkoxy)、鹵代、羥基(hydroxyl)、C1
-C6
雜烷基(heteroalkyl)、和-N(R)(R);其中每一個烷基、烷氧基、和雜烷基係選擇性地且獨立地以0-5個Ra
取代; 每一個R5
和R9
係各自獨立地選自氫、C1
-C6
烷基、和C1
-C6
雜烷基;其中每一個烷基和雜烷基係選擇性地且獨立地以0-5個Ra
取代; 每一個R6
係獨立地選自氫、C1
-C6
烷基、C1
-C6
烷氧基(alkoxy)、鹵代、C1
-C6
雜烷基、和-N(R)(R);其中每一個烷基、烷氧基、和雜烷基係選擇性地且獨立地以0-5個Ra
取代; 每一個R係獨立地選自氫、羥基、鹵代、巰基(thiol)、C1
-C6
烷基、C1
-C6
巰烷基(thioalkyl)、C1
-C6
烷氧基(alkoxy)、C1
-C6
雜烷基、環烷基、環烷基烷基(cycloalkylalkyl)、雜芳基烷基(heteroarylalkyl)、雜環基、和雜環基烷基(heterocyclylalkyl);其中每一個烷基、巰烷基、烷氧基、雜烷基、環烷基、環烷基烷基、雜芳基烷基、雜環基、和雜環基烷基係各自獨立地以0-5個Ra
取代,或二個R1
以其所連結的碳原子相連一起形成一個可獨立地以0-5個Rb
取代的環烷基環和雜環基環; 每一個Ra
和Rb
係獨立地選自C1
-C6
烷基、鹵代、羥基、C1
-C6
雜烷基、C1
-C6
烷氧基、環烷基、雜環基、或氰基(cyano);其中每一個烷基、雜烷基、烷氧基、環烷基、和雜環基係獨立地以0-5個R’取代; 每一個R’係獨立地選自C1
-C6
烷基、C1
-C6
雜烷基、鹵代、羥基、環烷基、或氰基;或二個R’以其所連結的碳原子相連一起形成一個環烷基和雜環基環; m係0、1、或2; n係0、1、2、或3;係表示一個單鍵或雙鍵; 若是一個雙鍵(double bond),則每個o是0;且 若是一個單鍵(single bond),則每個o是1。
於某些具體模式例中,該化合物係一個具有結構式(I)的化合物:(I),或其一個藥劑學上可接受的鹽類, 其中環A、X1
、X2
、R1
、R2
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R8b
、R9
、R、Ra
、Rb
、R’、m、和n的每一者係如同結構式(A)的化合物的描述。
於某些具體模式例中,表示一個單鍵且化合物具有結構式(Ia):(Ia), 或其一個藥劑學上可接受的鹽類, 其中環A、X1
、X2
、R1
、R2
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R8b
、R9
、R、Ra
、Rb
、R’、m、和n的每一者係如同結構式(A)的化合物的描述。
於某些具體模式例中,表示一個雙鍵且化合物具有結構式(Ib):(Ib), 或其一個藥劑學上可接受的鹽類, 其中環A、X1
、X2
、R1
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R9
、R、Ra
、Rb
、R’、m、和n的每一者係如同結構式(A)的化合物的描述。
於結構式A、I、Ia或Ib的任一者的某些具體模式例中,R1
係位在5-位置;於某些具體模式例中,R1
係位在4-位置;於某些具體模式例中,R1
係C1
-C4
烷基,烷基可選擇性地以0-3個Ra
取代;於某些具體模式例中,m係1或2;於某些具體模式例中,m係1;於某些具體模式例中,m係1,R1
係位在5-位置,。且R1
係C1
-C4
烷基,烷基可選擇性地以0-3個Ra
取代;於某些具體模式例中,R1
係‑CH3
。
於某些結構式I或Ia 的具體模式例中,R2
係選自氫、羥基、鹵代和O-C1
-C4
烷基;於某些具體模式例中,R2
係選自氫、羥基、氟代(fluoro)和‑OCH3
。
於結構式A、I、Ia或Ib的任一者的某些具體模式例中,R3a
、R3b
、R8a
和 R8b
《只出現在結構式I或Ia》的每一者係獨立地選自氫和C1
-C4
烷基,烷基可選擇性地以0-3個Ra
取代;於某些具體模式例中,R3a
、R3b
、R8a
和 R8b
的每一者係獨立地選自氫和‑CH3
;於某些具體模式例中,R3a
和R3b
、或R8a
和R8b
的至少一對係同時為氫。
於結構式A、I、Ia或Ib的任一者的某些具體模式例中,R4
係選自氫、C1
-C4
烷基、和O-C1
-C4
烷基;其中R4
的每一個烷基部分(alkyl portion)係可選擇性地以0-3個Ra
取代;於某些具體模式例中,R4
係選自氫、‑CH3
、‑CH2
CH3
、‑OCH3
和‑OCH2
CH3
。
於結構式A、I、Ia或Ib的任一者的某些具體模式例中,R5
係選自氫和C1
-C4
烷基,烷基可選擇性地以0-3個Ra
取代;於某些具體模式例中,R5
係選自氫和‑CH3
。
於結構式A、I、Ia或Ib的任一者的某些具體模式例中,每一個R6
係獨立地選自氫、鹵代、和C1
-C4
烷基,烷基可選擇性地以0-3個Ra
取代;於某些具體模式例中,每一個R6
係獨立地選自氫、氯代(chloro)、和‑CH3
;於某些具體模式例中,至多一個R6
是氫以外之物。 於結構式A、I、Ia或Ib的任一者的某些具體模式例中,環A是一個6-員單環型雜芳基(6-membered monocyclic heteroaryl),包含至少一個氮的環原子(nitrogen ring atom)。於某些具體模式例中,環A係選自和。
於結構式A、I、Ia或Ib的任一者的某些具體模式例中,R7
係雜芳基,可選擇性地以0-3個Rb
取代。於某些具體模式例中,R7
係選自4-氟吡唑-1-基(4-fluoropyrazol-1-yl)、4-氯吡唑-1-基(4-chloropyrazol-1-yl)、吡唑-1-基(pyrazol-1-yl)、和3,5二甲基吡唑-1-基,可選擇性地以0-3個Rb
取代。於某些具體模式例中,R7
係吡唑-1-基,可選擇性地以0-3個Rb
取代。於某些具體模式例中,n是1。於某些具體模式例中,n是1;而R7
係吡唑-1-基,可選擇性地以0-3個Rb
取代。
於結構式A、I、Ia或Ib的任一者的某些具體模式例中,R9
係選自氫和C1
-C4
烷基,可選擇性地以0-3個Ra
取代。於某些具體模式例中,R9
是氫;於某些具體模式例中,R9
是C1
-C4
烷基;於某些具體模式例中,R5
和R9
二者都是氫。 於某些具體模式例中,該化合物係一個具有結構式(Ic)的化合物:(Ic), 或其一個藥劑學上可接受的鹽類, 其中,環A、X1
、X2
、R1
、R2
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R8b
、R9
、m 和 n係如同結構式(A)的定義。
於某些具體模式例中,該化合物係一個具有結構式(Id)的化合物:(Id),或其一個藥劑學上可接受的鹽類, 其中,環A、X1
、X2
、R1
、R2
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R8b
、R9
、m 和 n係如同結構式(A)的定義。
於某些具體模式例中,該化合物係一個具有結構式(Ie)的化合物:(Ie) ,或其一個藥劑學上可接受的鹽類, 其中,環A、X1
、X2
、R1
、R2
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R9
、m 和 n係如同結構式(A)的定義。
於某些具體模式例中,該化合物係一個具有結構式(If)的化合物:(If) ,或其一個藥劑學上可接受的鹽類, 其中,環A、X1
、X2
、R1
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R9
、m 和 n係如同結構式(A)的定義。
本發明的另一個面向中,本發明特寫出一個化合物具有結構式(II):(II), 或其一個藥劑學上可接受的鹽類,其中: X1
係選自N、CH和C(鹵代); X2
係選自N和CH; X3
係選自N和CH; R12
係選自氫、羥基、鹵代和O-C1
-C4
烷基; R13a
、R13b
、R18a
和R18b
的每一者係獨立地選自氫和-C1
-C4
烷基; R14
係選自氫、-C1
-C4
烷基和‑O‑C1
-C4
烷基; R15
係選自氫和‑C1
-C4
烷基; R16
係選自氫和‑C1
-C4
烷基; R17b
係選自氫和鹵代;以及 R17a
和R17c
係獨立地選自氫和-C1
-C4
烷基。
在某些具體模式例中,X1
係選自N、CH和C(Cl);X2
係選自N和CH;X3
係選自N和CH;R12
係選自氫、羥基、氟代(fluoro)和‑O-CH3
;R13a
、R13b
、R18a
和R18b
的每一者係獨立地選自氫、甲基和乙基;且至少R13a
和R13b
、或R18a
和R18b
的一對係同時為氫;R14
係選自氫、‑CH3
、‑CH2
CH3
、‑OCH3
和 ‑OCH2
CH3
;R15
係選自氫和‑CH3
;R16
係選自氫和‑CH3
;R17b
係選自氫、氯代和氟代;R17a
和R17c
係同時為氫或‑CH3
,其中當R17a
和R17c
同時為‑CH3
時,R17b
是氫。
於某些具體模式例中,該化合物係一個具有結構式(IIa)的化合物:(IIa), 或其一個藥劑學上可接受的鹽類, 其中,X1
、X2
、X3
、R12
、R13a
、R13b
、R14
、R15
、R16
、R17a
、R17b
、R17c
、R18a
、 和 R18b
係如結構式(II)之定義。
於某些具體模式例中,該化合物係一個具有結構式(IIb)的化合物:(IIb), 或其一個藥劑學上可接受的鹽類, 其中,X1
、X2
、X3
、R12
、R13a
、R13b
、R14
、R15
、R16
、R17a
、R17b
、R17c
、R18a
、 和 R18b
係如結構式(II)之定義。
於某些具體模式例中,該化合物係一個具有結構式(IIIa)或結構式(IIIb)的化合物:(IIIa)(IIIb) 或其一個藥劑學上可接受的鹽類, 其中,環A、X1
、X2
、R1
、R2
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R8b
、R9
、R、Ra
、Rb
、R’、m、和n的每一者係如同結構式(A)的化合物所描述者,包括每一個前述變項(variables)的更特別的具體模式例和面向。
於結構式IIIb的某些具體模式例中,該化合物具有結構式IIIb-1:(IIIb),或其一個藥劑學上可接受的鹽類, 其中,環A、X1
、X2
、R1
、R2
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R8b
、R9
、R、Ra
、Rb
、R’、m、和n的每一者係如同結構式(A)的化合物所描述者,包括每一個前述變項(variables)的更特別的具體模式例和面向。
於結構式IIIb的某些具體模式例中,該化合物具有結構式IIIb-2:(IIIb-2),或其一個藥劑學上可接受的鹽類, 其中,環A、X1
、X2
、R1
、R2
、R3a
、R3b
、R4
、R5
、R6
、R7
、R8a
、R8b
、R9
、R、Ra
、Rb
、R’、m、和n的每一者係如同結構式(A)的化合物所描述者,包括每一個前述變項(variables)的更特別的具體模式例和面向。
於結構式IIIa 、IIIb、 IIIb-1和IIIb-2的某些具體模式例中,每一個X1
和X2
是C(R6
);這些具體模式例的一個面向中,每一個X1
和X2
是CH。
於結構式IIIb的某些具體模式例中,該化合物具有結構式IIIb-3或IIIb-4:(IIIb-3)(IIIb-4), 或其一個藥劑學上可接受的鹽類, 其中,R12
、R13a
、R13b
、R14
、R15
、R16
、R17a
、R17b
、R17c
、R18a
and R18b
的每一者係如同結構式(A)的化合物所描述者,包括每一個前述變項(variables)的更特別的具體模式例和面向。
於某些具體模式例中,本發明特別描述一個化合物,係選自表1所列的任一化合物。 在另一個面向中,本發明特別描述一個藥劑組成物,包含一個此處描述之結構式A、I、Ia、Ib、Ic、Id、II、IIa、IIb、IIIa、IIIb、IIIb-1、IIIb-2、IIIb-3、或 IIIb-4的化合物《亦即,表1中的一個化合物》或其一個藥劑學上可接受的鹽類,以及一個藥劑學上可接受的載體。 在另一個面向中,本發明特別描述一個方法,用來抑制在一個細胞中或在一個病人的轉染過程重排活性,包含接觸細胞的步驟或投與病人一個此處描述的化合物《亦即,表1中的一個化合物》或其一個藥劑學上可接受的鹽類,或一個藥劑學上可接受的載體。
在另一個面向中,本發明特別描述一個方法,用來治療一個患有因畸變的轉染過程重排活性(aberrant RET activity)介導的狀況的個體,包含投與該個體一個治療上有效的數量的此處描述之化合物《亦即,表1中的一個化合物》或其一個藥劑學上可接受的鹽類,或一個藥劑學上可接受的載體。
在另一個面向中,本發明特別描述一個方法,用來治療一個已對癌症治療產生抵抗性的個體,包含投與該個體一個治療上有效的數量的此處描述之化合物《亦即,表1中的一個化合物》或其一個藥劑學上可接受的鹽類,或其一個藥劑組成物。
定義
如本文所用,名詞『病人(patient)』、『個體(subject)』、『個人(individual)』、和『宿主(host)』表示一個人類或一個非人類動物之任一者患有或懷疑患有一個與畸變的轉染過程重排活性《亦即,透過轉染過程重排發信號引發增加的轉染過程重排活性》或生物學活性相關的疾病或違常狀況(disorder)。
『治療(Treat)』和『做治療(treating)』此種疾病或違常,表示改善該疾病或違常至少一個徵狀(symptom)。這些用語,用在與一種情況例如癌症相關時,係表示一個或多個以下情形:阻止癌症生長、使癌症重量或體積萎縮、延長病人的預期存活時間、抑制腫瘤生長、漸少腫瘤團塊、減少轉移病灶(metastatic lesions)的大小或數目、抑制新轉移病灶的發展、延長存活期、延長無惡化存活期(progression- free survival)、延長腫瘤惡化的時間(time to progression),及/或加強生活品質。
用語『治療效果(therapeutic effect)』表示在一個動物,特別是哺乳動物(mammal)、且更特定為人類,的一個有效益的局部或系統作用,該作用係由投與本發明的一個化合物或組成物(composition)所產生。片語『治療上有效數量(therapeutically-effective amount)』意指本發明的一個化合物或組成物的數量在治療一個因轉染過程重排過度表達(over expression)或畸變的轉染過程重排活性(aberrant RET activity)所引起的疾病或違常狀況於一個合理的效益風險比(benefit/risk ratio)是有效的;這類物質的治療上有效數量會因個體和治療的疾病情況、該個體的體重和年齡、疾病情況的嚴重程度、投藥方式等等而改變,本領域的專業人員能夠很快地決定這些情形。
如本文所用,『發生抵抗性(developing resistance)』意指:當一個藥物第一次投與給一個病人,無論是以腫瘤體積減少、新病灶數目減少、或醫師用來評斷疾病進展(disease progression)的一些其他方法來量測,病人的徵狀有改善;然而,這些徵狀停止改善、或甚至在某些地方更壞,於此時點,該病人被稱為已經對該藥物發生抵抗性。
『脂族基(Aliphatic group)』意指一個直鏈、分枝鏈、或環狀碳氫基(hydrocarbon group)並包括飽和和不飽和基,例如一個烷基、一個烯基、和一個炔基。 『烯烴基(Alkylene)』表示一個烷基的一個二價基團(divalent radical),亦即:-CH2
-’ -CH2
CH2
-’ 和 ‑CH2
CH2
CH2
-。 『烯基(Alkenyl)』意指一個脂族基含有至少一個雙鍵(double bond)。
『烷氧基(Alkoxyl或alkoxy)』意指一個烷基,具有一個氧自由基(oxygen radical)附屬於其上。代表性的烷氧基包括甲氧基(methoxy)、乙氧基(ethoxy)、丙氧基(propyloxy)、特-丁氧基(tert-butoxy)及其他相似物。名詞『鹵代烷氧基(haloalkoxy)』表示一個烷氧基,其中一個或多個氫原子被鹵素取代,也包括全部氫原子被鹵素取代的烷氧基部分(alkoxy moieties)《例如,全氟烷氧基(perfluoroalkoxy)》。
『烷基(Alkyl)』表是一個飽和直鏈或分枝鏈碳氫化合物(hydrocarbon)的一個單價基(monovalent radical),例如一個1-12、1-10、或1-6個碳原子的直鏈或分枝鏈基團,如本文中提及,分別是C1
‑C12
烷基、C1
‑C10
烷基、和C1
‑C6
烷基。例示的烷基包括,但非侷限:甲基、乙基、丙基、異丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、異丁基、特-丁基、戊基、異戊基、新戊基(neopentyl)、己基、庚基(heptyl)、辛基(octyl)等等。
『亞烯基(Alkenylene)』表示一個烯基(alkenyl group)具有兩個連接點;例如,『亞乙烯基(ethenylene)』表示-CH=CH-化學基。亞烯基可以是又一個或多個取代物的不飽和型式也可以是飽和型式。
『炔基(Alkynyl)』表示一個直鏈或分枝鏈的碳氫鏈包含2-12個碳原子並具有一個或多個三鍵(triple bonds)為特徵。炔基的實例包括但非侷限,有:乙炔基(ethynyl)、丙炔基(propargyl)、和3-己炔基(3-hexynyl)。三鍵的碳原子的其中之一可以選擇性地作為炔基取代基(alkynyl substituent)的附著點(point of attachment)。
『亞炔基(Alkynylene)』表示一個炔基具有兩個接點(connecting points),例如『亞乙炔基(ethynylene)』代表化學基-C≡C-。亞炔基也可以是一個無取代型式、或一個有一或多個取代基的有取代型式。
『芳香環系統(Aromatic ring system)』係本領域所公認(art‑recognized),表示一個單環、雙環、或多環的碳氫環系統,其中至少一個環是芳香環。
『芳基(Aryl)』係指一個芳香環系統的一個單價基(monovalent radical)。代表性的芳基包括完全芳香環系統(fully aromatic ring systems),例如苯基(phenyl)、萘基(naphthyl)、和蒽基(anthracenyl);及,其他的環系統,其中一個芳香碳環融合一或多個非芳香碳環,例如二氫茚基(indanyl)、酞醯亞胺基(phthalimidyl)、萘醯亞胺基(naphthimidyl)、或四氫萘基(tetrahydronaphthyl)、及同類物。
『芳基烷基(Arylalkyl)』或『芳代脂烷基(aralkyl)』表示一個烷基部分(alkyl moiety),其中一個烷基氫原子被一個芳基取代;芳代脂烷基包括超過一個氫原子被一個芳基取代的族群。『芳基烷基』或『芳代脂烷基』的實例包括苄基(benzyl)、2-苯基乙基、3-苯基丙基、9-芴基(fluorenyl)、二苯甲基(benzhydryl)、和三苯甲基(trityl)的族群。 『芳氧基(Aryloxy)』表示-O-(芳基),其中芳香雜環部分(heteroaryl moiety)如本文所定義。 『鹵代(Halo)』係指一個任何鹵素的自由基,例如:氟(‑F)、氯(‑Cl)、溴(‑Br)、或碘(–I)。
『雜烷基(Heteroalkyl)』表示一個可選擇地被取代的烷基,其一個或多個的骨架鏈原子選自碳以外的原子,例如氧、氮、硫、磷或併用這些原子。給予一個數值範圍(numerical range)例如C1
-C6
雜烷基表示化學鏈上的碳原子數,與此實例係包括1至6個碳原子。舉例來說,一個–CH2
OCH2
CH3
自由基表示一個『三碳(C3
)』雜烷基,可以用一個雜原子(heteroatom)或一個在雜烷基鏈上的碳原子與分子的其餘部分連接。『雜烯烴基(Heteroalkylene)』表示一個雙價的可選擇地被取代的烷基,其一個或多個的骨架鏈原子選自碳以外的原子,例如氧、氮、硫、磷或併用這些原子。
『碳環系統(Carbocyclic ring system)』表示一個單環、雙環、或多環的碳氫環系統,其中每一個還可以是完全飽和或含有一個或多個不飽和單元,但沒有一個環屬芳香族。 『碳環基(Carbocyclyl)』表示一個碳環系統的一個單環自由基。代表性的碳環基族群包括環烷基類(cycloalkyl)《例如:環丙基、環丁基、環戊基、環己基和其同類物》、和環烯類(cycloalkenyl)《例如:環戊烯基(cyclopentenyl)、環己烯基、環戊二烯基(cyclopentadienyl)和其同類物》。
『環烷基(Cycloalkyl)』表示一個具有3至12個碳原子的單環、雙環、三環、或多環的非芳香族碳氫化合物類。任何可被取代的環原子都可以被取代《例如,被一個或多個取代基取代》,環烷基類可以包含融合的或螺旋形環(fused or spiro rings),融合的環係共用一個相同的碳原子。環烷基部分的實例包括但非侷限於此,有:環丙基、環己基、甲基環己基、金剛烷基(adamantyl)、和降莰基(norborny)。 『環烷基烷基(Cycloalkylalkyl)』表示一個-(環烷基)-烷基的自由基,其中環烷基和烷基如本文所揭示。『環烷基烷基』係藉由環烷基與原體分子結構(parent molecular structure)鍵結。
『雜芳香環系統(Heteroaromatic ring system)』係本領域所公認(art‑recognized),且係指一個單環、雙環、或多環的系統,其中至少一個環不但是芳香環而且包含至少一個雜原子《例如氮、氧、或硫》;且其中也沒有其他環是雜環(heterocyclyl)《定義如下》。於某些例子中,有一個環是芳香環且包含一個雜原子,這樣的環中含有1、2、3、或4環雜原子。
『雜芳基(Heteroaryl)』係一個雜芳香環系統的一個單價自由基(monovalent radical)。代表性的雜芳基族群包括以下:(i)每一個環包含一個雜原子且是芳香環,例如,咪唑基(imidazolyl)、噁唑基(oxazolyl)、噻唑基(thiazolyl)、三唑基(triazolyl)、吡咯基(pyrrolyl)、呋喃基(furanyl)、苯硫基(thiophenyl)、吡唑基(pyrazolyl)、吡啶基(pyridinyl)、吡嗪基(pyrazinyl)、噠嗪基(pyridazinyl)、嘧啶基(pyrimidinyl)、吲哚嗪基(indolizinyl)、嘌呤基(purinyl)、萘啶基(naphthyridinyl)、和喋啶基(pteridinyl);(ii)每一個環是芳香環或碳環,至少一個芳香環包含一個雜原子且至少另一個環是碳氫環或例如吲哚基(indolyl)、異吲哚基(isoindolyl)、苯噻嗯基(benzothienyl)、苯並呋喃基(benzofuranyl)、二苯並呋喃基(dibenzofuranyl)、吲唑基(indazolyl)、苯並咪唑基(benzimidazolyl)、苯並噻唑基(benzthiazolyl)、喹啉基(quinolyl)、異喹啉基(isoquinolyl)、㖕啉基(cinnolinyl)、呔嗪基(phthalazinyl)、喹唑啉基(quinazolinyl)、喹喔啉基(quinoxalinyl)、氮芴基(carbazolyl)、吖啶基(acridinyl)、吩嗪基(phenazinyl)、吩噻嗪基(phenothiazinyl)、吩噁嗪基(phenoxazinyl)、吡啶並[2,3‑b]- 1,4‑噁嗪-3-(4氫)-酮(pyrido[2,3‑b]‑1,4‑oxazin‑3-(4H)‑one)、5,6,7,8‑四氫喹啉基(5,6,7,8‑tetrahydroquinolinyl)和5,6,7,8‑四氫異喹啉基(5,6,7,8‑tetrahydroisoquinolinyl);(iii)每一個環是芳香環或碳環,且至少一個芳香環與另一個芳香環共用一個橋頭雜原子(bridgehead heteroatom),例如4H-喹嗪基(4H‑quinolizinyl)。
『雜環系統(Heterocyclic ring system)』係指單環、雙環和多環系統,其中至少一個環是飽和的或部分不飽和的環(partially unsaturated)《但不是芳香環》且該環包含至少一個雜原子。一個雜環系統可以在任何形成穩定結構的雜原子或碳原子處附加其側基(pendant group)且任何該環的原子可以選擇性地被取代。
『雜環基(Heterocyclyl)』係指一個雜環系統的一個單價自由基。代表性的雜環基包括的環系統有(i)每一個環係非芳香環且至少一個環包含一個雜原子,例如四氫呋喃基(tetrahydrofuranyl)、四氫吡喃基(tetrahydropyranyl)、四氫噻吩基(tetrahydrothienyl)、吡咯烷基(pyrrolidinyl)、吡咯烷酮基(pyrrolidonyl)、哌啶基(piperidinyl)、吡咯啉基(pyrrolinyl)、十氫喹啉基(decahydroquinolinyl)、噁唑烷基(oxazolidinyl)、哌嗪基(piperazinyl)、二噁烷基(dioxanyl)、二噁茂烷基(dioxolanyl)、二氮雜基(diazepinyl)、噁氮雜基(oxazepinyl)、噻氮雜基(thiazepinyl)、嗎啉基(morpholinyl)、和奎寧環基(quinuclidinyl);(ii)至少一個環係非芳香環且包含一個雜原子且至少一個其他環是一個芳香碳環,例如1,2,3,4‑四氫喹啉基(1,2,3,4‑tetrahydroquinolinyl)、1,2,3,4‑四氫異喹啉基(1,2,3,4‑tetrahydroisoquinolinyl);以及(iii)至少一個環係非芳香環且包含一個雜原子且至少一個其他環是一個芳香環並包含一個雜原子,例如二氫-1H-吡喃並[4,3‑c]吡啶(3,4‑dihydro‑1H‑pyrano[4,3‑c]pyridine),和1,2,3,4‑四氫‑2,6‑萘啶(1,2,3,4‑tetrahydro‑2,6‑naphthyridine)。
『雜環烷基(Heterocyclylalkyl)』表示一個烷基被一個雜環基取代。 『氰基(Cyano)』表示一個–CN自由基。 『硝基(Nitro)』表示–NO2
。 『羥基(Hydroxy或hydroxyl)』表示–OH。 如本文所用,每一個用詞的定義,例如烷基、m、n等在任何結構中出現一次以上時,意指獨立於其在相同結構中別處的定義。
本發明的某些化合物可能存在於特定的幾何(geometric)或立體異構(stereoisomeric)型式,本發明預期所有這些化合物,只要落入本發明範圍內者,包括順式(cis‑)和反式(trans‑)異構物(isomer)、右型《順時針》和左型《逆時針》鏡像異構物(R‑ and S‑enantiomers)、非鏡像異構物(diastereomers)、右式異構物((D)‑isomers)、左式異構物((L)‑isomers)、其消旋混合物(racemic mixtures)、和其他混合物。額外的不對稱碳原子可能出現在一個取代物如烷基中,所有這類異構物以及其混合物都主張被包括在本發明中。
舉例來說,如果想要一個本發明化合物的特別的鏡像異構物,可以藉由不對稱合成(asymmetric synthesis)、或藉由手性助劑(chiral auxiliary)衍生來製備,其中產生的非鏡像異構混合物被分離而助劑被切開,生成單純想要的鏡像異構物。另外,若分子含有一個鹼性功能基例如氨基(amino)、或一個酸性功能基例如羧基(carboxyl),則用一個適當的光學活性的酸或鹼可以形成非鏡像異構物鹽類,然後藉由本領域所熟知的分次結晶(fractional crystallization)或色層分析方法(chromatographic means)溶解形成的非鏡像異構物,逐步重獲純淨鏡像異構物。
除非另有說明,當一個揭露的化合物以一個結構被命名或描述而無具體說明立體化學(stereochemistry)且具有一或多個對掌中心(chiral centers),可理解係代表該化合物的所有可能的立體異構物、及其非鏡像異構物的混合物。
一個化合物的『鏡像異構物過量值(enantiomeric excess)』或『鏡像異構物過量值百分比(% enantiomeric excess)』可以應用下述所式公式計算,下述實施例中,一個組成物含有90%的一種鏡像異構物例如右型《順時針》鏡像異構物,和10%的另一種鏡像異構物例如左型《逆時針》鏡像異構物。 ee = (90-10)/100 = 80% 因此,一個組成物含有90%的一種鏡像異構物和10%的另一種鏡像異構物被稱為具有一個80%的鏡像異構物過量值。
本文所描述之化合物或組成物可以包含至少50%、75%、90%、95%、或99%的該化合物的一個型式(form)例如左型《逆時針》鏡像異構物(S‑enantiomers)的一個鏡像異構物過量值;換句話說,這種化合物或組成物包含一個左型《逆時針》鏡像異構物超過右型《順時針》鏡像異構物的鏡像異構物過量值。
本文所描述之化合物也可以在一個或多個構成此化合物的原子含有非自然比例(unnatural proportions)的原子同位素(atomic isotopes),舉例來說,該化合物可以用放射性同位素(radioactive isotopes)如氘《重氫》(2
H)、氚《三重氫》(3
H)、碳13(carbon-13;13
C)、或碳13(carbon-14;14
C),做放射性標記(radiolabel)。所有本文所描述之化合物的同位素變種(isotopic variations),無論是否有放射性,都主張包括在本發明的範圍內,此外,本文所描述之該化合物的所有互變異構型式(tautomeric forms)也主張包括在本發明的範圍內。
化合物可以游離鹼(free base)或鹽類使用,代表性的鹽類包括溴化氫、氯化氫、硫酸鹽(sulfate)、硫酸氫鹽(bisulfate)、磷酸鹽、硝酸鹽、醋酸鹽、戊酸鹽(valerate)、油酸鹽(oleate)、棕櫚酸鹽(palmitate)、硬脂酸鹽(stearate)、月桂酸鹽(laurate)、苯甲酸鹽(benzoate)、乳酸鹽(lactate)、甲苯磺酸鹽(tosylate)、檸檬酸鹽(citrate)、馬來酸鹽(maleate)、延胡索酸鹽(fumarate)、琥珀酸鹽(succinate)、酒石酸鹽(tartrate)、萘二甲酸鹽(napthylate)、甲磺酸鹽(mesylate)、葡萄糖酸鹽(glucoheptonate)、乳糖酸鹽(lactobionate)、和十二烷基硫酸鹽(laurylsulphonate),及同類物《參照,例如,Berge等人(1977) “Pharmaceutical Salts”,J. Pharm. Sci.
66:1-19 》。
如本文所描述,本發明之化合物可以含有『可選擇性地被取代(optionally substituted)』部分(moieties)。通常,名詞『被取代(substituted)』,無論有無名詞『可選擇性地(optionally)』放在前面,都表示特定部分的一個或多個氫原子被一個適當的取代基取代,除非另有說明,一個『可選擇性地被取代』基可以在該基的每一個可取代的位置具有一個適當的取代基,又,當在任何指定結構中有超過一個位置可以被超過一個選自特定族群的取代基取代時,在每個位置的該取代基可以相同,也可以不同。本發明中預見的合併取代基最好是能產生穩定的(stable)或化學上切實可行的(chemically feasible)化合物的形成之物。名詞『穩定的(stable)』,如本文所述,係指化合物,當它們在製造、檢測時,又,於某些具體模式例中,它們的復原、純化和使用於一或多個本文所述之目的時,本質上沒有改變。
對於一個可選擇性被取代的烷基、烯烴基(alkylene)、雜烷基、雜烯烴基(heteroalkylene)、環碳基、雜環碳基、芳基族群和雜芳基族群,適當的取代基包括:鹵素、=O、-CN、‑ORc
、‑NRd
Re
、‑S(O)k
Rc
、‑NRc
S(O)2
Rc
、‑S(O)2
NRd
Re
、‑C(=O)ORc
、‑OC(=O)ORc
、-OC(=O)Rc
、 -OC(=S)ORc
、‑C(=S)ORc
、‑O(C=S)Rc
、‑C(=O)NRd
Re
、‑NRc
C(=O)Rc
、‑C(=S)NRd
Re
、‑NRc
C(=S)Rc
、‑NRc
(C=O)ORc
、‑O(C=O)NRd
Re
、‑NRc
(C=S)ORc
、‑O(C=S)NRd
Re
、‑NRc
(C=O)NRd
Re
、‑NRc
(C=S)NRd
Re
、‑C(=S)Rc
、‑C(=O)Rc
、C1
-C6
烷基、 C1
-C6
鹵烷基、C1
-C6
雜烷基、環碳基、(C1
-C6
-烯烴基)-環碳基、(C1
-C6
-雜烯烴基)-環碳基、雜環(heterocyclyl)、(C1
-C6
-烯烴基)-雜環基、(C1
-C6
-雜烯烴基)-雜環基、芳基、(C1
-C6
-烯烴基)-芳基、(C1
-C6
-雜烯烴基)-芳基、雜芳基、(C1
-C6
-烯烴基)-雜芳基、或 (C1
-C6
-雜烯烴基)-雜芳基,其中所述之烷基、烯烴基、雜烷基、雜烯烴基、環碳基、雜環碳基、芳基、和雜芳基的每一者,都可選擇性地以一個或多個鹵素、ORc
、‑NO2
、‑CN、‑NRc
C(=O)Rc
、‑NRd
Re
、‑S(O)k
Rc
、‑C(=O)ORc
、‑C(=O)NRd
Re
、‑C(=O)Rc
、C1
-C6
烷基、C1
-C6
鹵烷基、或 C1
-C6
雜烷基取代; 其中Rc
是氫、羥基、C1
-C6
烷基、C1
-C6
雜烷基、環碳基、(C1
-C6
-烯烴基)-環碳基、(C1
-C6
-雜烯烴基)-環碳基、雜環(heterocyclyl)、(C1
-C6
-烯烴基)-雜環基、(C1
-C6
-雜烯烴基)-雜環基、芳基、(C1
-C6
-烯烴基)-芳基、(C1
-C6
-雜烯烴基)-芳基、雜芳基、(C1
-C6
-烯烴基)-雜芳基、或 (C1
-C6
-雜烯烴基)-雜芳基,這些的每一者,都可選擇性地以一個或多個鹵素、羥基、C1
-C6
烷基、C1
-C6
鹵烷基、C1
-C6
雜烷基、環碳基、雜環、芳基、或雜芳基取代; Rd
和Re
係各自獨立地選自氫、C1
-C6
烷基、或C1
-C6
雜烷基;且k係0、1、或2。本發明並未有意以任何方式侷限於前述表列例示之取代基。
『藥劑學上可接受的鹽類(Pharmaceutically acceptable salt)』係指本發明的一個化合物的任何鹽類,保留其生物性質且無毒性或其他不符藥劑使用期望之處。藥劑學上可接受的鹽類可以從各種本領域熟知的有機和無機的相反離子(counter-ions)衍生而來,這類鹽類包括:(1)酸加成鹽(acid addition salts),由有機和無機的酸所做成,例如氫氯酸《鹽酸》、氫溴酸、硫酸、硝酸、磷酸、胺磺酸(sulfamic acid)、醋酸、三氟醋酸(trifluoroacetic acid)、三氯醋酸、丙酸(propionic acid)、己酸(hexanoic acid)、環戊基丙酸(cyclopentylpropionic acid)、乙醇酸(glycolic acid)、戊二酸(glutaric acid)、丙酮酸(pyruvic acid)、乳酸、丙二酸(malonic acid)、琥珀酸(succinic acid)、山梨酸(sorbic acid)、抗壞血酸(ascorbic acid)、蘋果酸(malic acid)、馬來酸(maleic acid)、延胡索酸(fumaric acid)、酒石酸(tartaric acid)、檸檬酸(citric acid)、苯甲酸《安息香酸》(benzoic acid)、3-(4-羥機苯甲醯基)苯甲酸(3-(4-hydroxybenzoyl)benzoic acid)、苦味酸(picric acid)、肉桂酸(cinnamic acid)、苦杏仁酸(mandelic acid)、酞酸《苯二酸》(phthalic acid)、月桂酸(lauric acid)、甲烷磺酸(methanesulfonic acid)、乙烷磺酸(ethanesulfonic acid)、1 ,2-乙烷-二磺酸(1 ,2-ethane-disulfonic acid)、2-羥基乙烷磺酸、苯磺酸(benzenesulfonic acid)、4-氯苯磺酸、2-萘磺酸(2-naphthalenesulfonic acid)、4-甲苯磺酸(4-toluenesulfonic acid)、樟腦酸(camphoric acid)、樟腦磺酸(camphorsulfonic acid)、4-甲基二環[2.2.2]辛-2-烯-1-羧酸(4-methylbicyclo[2.2.2]-oct-2-ene -1-carboxylic acid)、葡庚糖酸(glucoheptonic acid)、3-苯基丙酸、三甲基醋酸、特-丁基醋酸、月桂醇硫酸(lauryl sulfuric acid)、葡萄糖酸(gluconic acid)、安息香酸(benzoic acid)、谷胺酸(glutamic acid)、羥基萘甲酸(hydroxynaphthoic acid)、水楊酸(salicylic acid)、硬脂酸(stearic acid)、環己基胺磺酸(cyclohexylsulfamic acid)、奎尼酸(quinic acid)、黏康酸(muconic acid)和其類似的酸; 或,(2)當一個酸性質子出現於親體化合物時,無論是(a)被一個金屬離子取代,例如一個鹼金屬離子(alkali metal ion);一個鹼土離子(alkaline earth ion)或一個鋁離子;或鹼金屬或鹼土金屬氫氧化物,例如氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂、氫氧化鋁、氫氧化鋰、氫氧化鋅、和氫氧化鋇;氨(ammonia);或(b)與一個有機鹼(organic base)相配,例如脂族胺(aliphatic amines);脂環胺(alicyclic amines);或芳香族有基氨(aromatic organic amines),例如胺(ammonia)、甲基氨(methylamine)、二甲基氨、二乙基氨、甲基吡啶《皮考啉》(picoline)、乙醇胺《氨基乙醇》(ethanolamine)、二乙醇胺(diethanolamine)、三二乙醇胺、乙二胺(ethylenediamine)、離氨酸(lysine)、精氨酸(arginine)、鳥氨酸(ornithine)、膽鹼(choline)、N,N'-二苄基乙二胺(N,N'-dibenzylethylene-diamine)、氯普魯卡因(chloroprocaine)、普魯卡因(procaine)、N -苄基苯乙胺(N-benzyl phenethylamine)、N-葡甲胺哌嗪(N- methylglucamine piperazine)、三個(羥甲基)氨基甲烷(tris(hydroxymethyl) -aminomethane)、氫氧化四甲銨(tetramethylammonium hydroxide)、和其同類物。
藥劑學上可接受的鹽類更進一步包括,只限例示,鈉、鉀、鈣、鎂、氨、四烷基氨(tetraalkylammonium)和其同類物;又當該化合物含有一個鹼性官能性(basic functionality),包括:無毒的有機或無機酸的鹽類,例如氫氯酸鹽、氫溴酸鹽、酒石酸鹽、甲磺酸鹽(mesylate)、苯磺酸鹽(besylate)、醋酸鹽、馬來酸鹽(maleate)、草酸鹽(oxalate)和其同類物。
藥劑組成物
本發明之藥劑組成物包含一或多個本發明之化合物和一或多個生理學上(physiologically)或藥劑學上(pharmaceutically)可接受的載體(carrier)。名詞『藥劑學上可接受的載體(pharmaceutically acceptable carrier)』表示一個藥劑學上可接受的材料、組成物或載具(vehicle),例如一個液體或固體填料(filler)、稀釋劑(diluent)、賦形劑(excipient)、溶劑或包封材料(encapsulating material),用於攜帶或運送任何主體組成物(subject composition)或其成分。每一個載體必須是『可接受的(acceptable)』表示必須與主體組成物和它的成份相容,且不會對病人有傷害。可做為藥劑學上可接受的載體的某些材料的實例包括:(1)醣類,例如乳糖、葡萄糖和蔗糖;(2)澱粉類,例如玉米澱粉和馬鈴薯澱粉;(3)纖維素(cellulose)和其衍生物,例如鈉羧甲基纖維素(sodium carboxymethyl cellulose)、乙基纖維素(ethyl cellulose)和醋酸纖維素(cellulose acetate);(4)西黃蓍膠粉(powdered tragacanth);(5)麥芽;(6)明膠(gelatin);(7)滑石粉;(8)賦形劑,例如可可脂(cocoa butter)和栓劑蠟(suppository waxes);(9)由類,例如花生油、棉籽油(cottonseed oil)、紅花籽油(safflower oil)、芝麻油、橄欖油、玉米油和大豆油;(10)二醇類(glycols),例如丙二醇(propylene glycol);(11) 多元醇(polyols),例如甘油、山梨糖醇(sorbitol)、甘露醇(mannitol)和聚乙二醇(polyethylene glycol);(12)酯類,例如油酸乙酯(ethyl oleate)和月桂酸乙酯(ethyl laurate);(13)瓊脂(agar);(14)緩衝劑,例如氫氧化鎂和氫氧化鋁;(15)海藻酸(alginic acid);(16)無致熱原水(pyrogen-free water);(17)等滲壓鹽溶液(isotonic saline);(18)林格氏溶液(Ringer’s solution);(19)乙醇;(20)磷酸鹽緩衝液;以及(21)其他應用於藥劑配方中的無毒性相容物質。
本發明之組成物的投與方式有口服、腸道外給藥(parenterally)、藉由吸入噴霧(by inhalation spray)、局部、經肛門、噴鼻、口腔含服(buccally)、經陰道或經過一個植入型貯藏器(implanted reservoi)。名詞『腸道外給藥(parenterally)』如本文所用,係包括皮下、靜脈內、肌肉內、關節內(intra-articular)、滑膜內(intra-synovial)、胸骨內(intrasternal)、鞘內(intrathecal)、肝內(intrahepatic)、病灶內(intralesional)和顱內(intracranial)的注射(injection)或灌注(infusion)技術。於某些具體模式例中,本發明之組成物係以口服、腹膜內(intraperitoneally)或靜脈內投與。本發明之組成物的無菌注射型式可以是水性或油性懸浮液,這些懸浮液可以依照本領域所知之技術使用適當的分散劑(dispersing agents)或潤濕劑(wetting agents)和懸浮劑(suspending agents)來配方。無菌注射製劑也可以是在一個無毒性膓道外可接受的稀釋劑或溶劑中的一個無菌注射溶液或懸浮液,例如一個在1,3-丁二醇中的溶液。在可接受的載具和溶劑中,可能使用水、林格氏液和等透壓氯化鈉溶液;此外,無菌的不揮發油(fixed oils)傳統上被用作為溶劑或懸浮介質。
為了這個目的,可以使用任何刺激性少的不揮發油包括合成的單或雙甘油脂(mono- or di-glycerides)。脂肪酸例如油酸(oleic acid)和它的甘油脂衍生物可用於注射劑的製備,就如同天然的藥劑學上可接受的油類如橄欖油或蓖麻油(castor oil),特別是它們的聚乙氧基化變體(polyoxyethylated versions),這些油溶液或懸浮液也可以含有一個長鏈醇類稀釋劑或分散劑,例如羧甲基纖維素或通常使用於藥劑學上可接受的劑型(dosage forms)包括乳劑(emulsions)和懸浮劑的配方中的相同分散劑;其他常用的介面活性劑(surfactants),例如吐溫《非離子活性劑》(Tween)、司盤類(Spans)和其他乳化劑或常用於藥劑學上可接受的固體、液體、或其他劑型的製造之生物可利用率促進劑(bioavailability enhancers),也可以使用於做成配方的目的。
本發明之藥劑學上可接受的組成物能以任何口服可接受的劑型口服投與,這些劑型包括但非侷限於此,有膠囊、錠劑、水性懸浮液或溶液。如果是口服用的錠劑,通常使用的載體包括乳糖和玉米澱粉;柔滑劑(Lubricating agents)如硬脂酸鎂(magnesium stearate)通常也會添加。對於以膠囊型式的口服投與方式,有用的稀釋劑包括乳糖和乾燥的玉米澱粉;若需要水性懸浮劑作為口服投與方式,活性成分則與乳化劑或懸浮劑併用;如果有需要,某些甜味劑、芳香劑或著色劑也可以添加。
另一方面,本發明之藥劑學上可接受的組成物能以栓劑型式投與,作為直腸給藥(rectal administration);這些栓劑的製備係將藥物與一個安定無刺激性的賦形劑混合,該賦形劑在室溫為固體而在直腸溫度為液體,因此在直腸內會融解釋出藥物,這類材料包括可可脂、蜂蠟(beeswax)和聚乙二醇(polyethylene glycols)。
本發明之藥劑學上可接受的組成物也能局部投與,特別是當治療的標靶包含局部使用時很快到達的區域或器官,如眼、皮膚或下腸道(lower intestinal tract)的疾病;用於這些區域或器官的適當的局部配方很容易製備。用於下腸道的局部配方應用可以用一個直腸栓劑配方《參照前述》或一個適當的灌腸劑(enema)配方。局部的穿皮貼劑(transdermal patches)也可使用。
關於局部使用,本藥劑學上可接受的組成物可以配方在一個適當的軟膏劑(ointment)裡,其中活性成分係懸浮於或溶解於一個或多個載體中。用於本發明之化合物的局部投與的載體包括但非侷限,有礦物油(mineral oil)、液體石蠟(liquid petrolatum)、白石蠟、丙二醇、聚氧乙烯(polyoxyethylene)、聚氧乙烯化合物、乳化蠟(emulsifying wax)和水。另一方面,本藥劑學上可接受的組成物可以配方在一個適當的洗劑(lotion)或霜劑(cream)裡,其中活性成分係懸浮於或溶解於一個或多個藥劑學上可接受的載體中。適當的載體包括但非侷限,有礦物油、山梨醇酐硬脂酸酯(sorbitan monostearate)、聚山梨醇酯60(polysorbate 60)、十六烷基酯蠟(cetyl esters wax)、鯨蠟醇(cetearyl alcohol cetearyl alcohol)、辛基十二烷醇(2-octyldodecanol)、苯甲醇(benzyl alcohol)和水。
本發明之藥劑學上可接受的組成物也可以用鼻用氣化噴霧劑(nasal aerosol)或吸入劑(inhalation)方式投與,這類組成物依照已知的藥劑學配方領域之技術即可製備,且可製作為鹽水溶液,使用芐醇(benzyl alcohol)或其他適當的防腐劑、 吸收促進劑(absorption promoters)來加強生體可用率;氟碳化合物(fluorocarbons)、及/或其他傳統增溶劑(solubilizing agents)或分散劑(dispersing agents)。 本發明之化合物可合併於載體做成一個單一劑量型式,其數量會隨著治療對象、特定投與模式而改變。
劑量
本發明化合物包括藥劑學上可接受的鹽類和氘化變異物(deuterated variants)的毒性(Toxicity)和治療效果可以用細胞培養(cell cultures)或實驗動物的標準藥劑學程序(standard pharmaceutical procedures)來測定。半數致死量(LD50
)是指總體的50%致死的劑量,半數有效量 (ED50
)是總體的50%發生治療效果的劑量,在毒性和治療效果之間的劑量比率(LD50
/ ED50
)就是治療指數(therapeutic index),展現較大的治療指數的化合物是吾人所願。當可能使用呈現毒性副作用的化合物時,就必須謹慎設計一個將該化合物標靶至被影響部位的遞送系統,對未感染細胞的潛在損害減至最低,從而減少副作用。
得自細胞培養測定和動物研究的數據可以應用於劑量範圍的配方設計以供人類使用,這類化合物的劑量會落在一個包括極小或沒有毒性的半數有效量的血中濃度(circulating concentrations)的範圍內,劑量隨著使用的劑型和應用的投與途徑可以在這個範圍內改變。對於任何化合物,治療上有效劑量可以從細胞培養測定做初次估計,一個劑量可以用動物模型做配方設計以達到一個循環系統的血漿濃度範圍其中包括半數抑制濃度(IC50
)《亦即,試驗化合物的濃度達到一個症狀的半數最大抑制(half-maximal inhibition of symptoms)》,這類資訊能被應用以便更正確地決定對人類的有用劑量,例如藉由高效液相層析儀(high performance liquid chromatography)可以測量血漿中的濃度。
吾人亦應了解,對於任何一個特定病人的特定劑量和治療方法係隨著各種因素改變,包括所使用之特定化合物的活性、年齡、體重、一般健康狀況、性別、飲食、給藥的時間、排泄速率、藥物併用、和治療醫師的判斷及所治療疾病的嚴重度。在組成物中的本發明之一個化合物的數量也隨著組成物中特定化合物而變。
治療 轉染過程重排融合物(RET fusions)在數種類型癌症中都有關聯,一般而言,這些轉染過程重排融合物具有一個轉染過程重排激酶結構域(RET kinase domain),係和原生型轉染過程重排(wild-type RET)相同;因此,如同此處所用,任何轉染過程重排蛋白質帶有與原生型轉染過程重排相同的激酶結構域都被視為『原生型轉染過程重排』,轉染過程重排激酶結構域可能發生突變,導致抵抗性突變體(resistant mutant)。
本發明提供之化合物抑制原生型轉染過程重排和轉染過程重排突變體二者,亦即轉染過程重排突變體係對照護治療的現時標準具有抵抗性《『轉染過程重排抗性突變體(RET resistant mutants)』》此外,本發明之化合物可以選擇性地用於原生型轉染過程重排、超越其他激酶,因此減低由於抑制其他激酶而生的毒性。
突變可以預測,使用結構生物學(structural biology)和電腦分析,以及藉由檢查密碼子序列(codon sequences),其中一個序列改變產生一個密碼子(codon)用於一個不同的胺基酸。利用這個方法,轉染過程重排抵抗性突變體可以被預測有位點突變(point mutations)在轉染過程重排蛋白質中在804卡口殘基(gatekeeper residue)處及/或在殘基或靠近該卡口殘基。於某些具體模式例中,該突變體可能在804、806、810、865、891、和918殘基;轉染過程重排抵抗性突變體的特殊實例包括:V804L、V804M、V804E、Y806C、Y806S、Y806H、Y806N、G810S、G810S、L865V、L870F、S891A和M918T突變體。
將細胞暴露於一個突變促進劑(mutation-promoting agent)例如乙基亞硝酸基尿素(N-ethyl-N-nitrosourea;ENU),可以做實驗性測定突變係由投與一個特定抑制劑《例如,一個已知的轉染過程重排原生型抑制劑(RET wild-type inhibitor)》而發生,該細胞被清洗,然後用逐漸增加濃度《2-100倍增殖半數抑制量》的所選化合物包鍍,3-4星期後收集細胞過度生長(cellular outgrowth)的培養井(wells),接著將轉染過程重排激酶結構域(RET kinase domain)定序以辨明抵抗性突變《亦即,維持酵素活性的轉染過程重排蛋白質的改變型式》,將這些細胞暴露於所選化合物中,可以確認抵抗性,經由實驗性辨明的抵抗性突變包括V804L、V804M、和Y806H突變體。
由於它們對抗原生型轉染過程重排和突變的轉染過程重排,此處所描述之化合物可以用來治療一個帶有與變異轉染過程重排活性相關情況的病人,它們也可以用來治療各種癌症。在某些具體模式例中,癌症係選自甲狀腺乳突癌(papillary thyroid carcinoma (PTC))、甲狀腺髓質癌(medullary thyroid cancer (MTC))、嗜鉻細胞瘤(pheochromocytoma (PC))、胰腺導管腺癌(pancreatic ductal adenocarcinoma)、多發性內分泌瘤病(multiple endocrine neoplasia(MEN))《MEN2A 和MEN2B》、轉移性乳癌(metastatic breast cancer)、睪丸癌(testicular cancer)、小細胞肺癌小細胞肺癌(small cell lung cancer)、非小細胞肺癌(non-small cell lung cancer)、慢性骨髓性白血病(chronic myelomonocytic leukemia)、大腸直腸癌(colorectal cancer)、卵巢癌(ovarian cancer)、唾液腺癌(cancers of the salivary gland)。
這些化合物也可以使用於治療一個已發展出對原生型轉染過程重排有抵抗性的病人、或一個具有特定轉染過程重排突變體的病人。本方法包括投與一個對一或多個轉染過程重排抵抗性突變體有活性的本發明化合物或組成物的步驟,在一些具體模式例中,該轉染過程重排抵抗性突變體係選自V804L、V804M、V804E、 Y806C、Y806S、Y806N、Y806H、G810R、G810S、L865V、L870F、S891A 和 M918T。由於『有活性(active)』係表示一個化合物用生化學方法分析時,至少對於一個抵抗性突變體具有低於1微米(µM)、500奈米(nM)、250奈米、100奈米、75奈米、50奈米、25奈米、10奈米、或5奈米的半數抑制量。
此處所描述之化合物或組成物可以單獨給予或與其他化合物包括其他轉染過程重排調制(RET-modulating)化合物或其他治療劑併用,在某些具體模式例中,本發明化合物或組成物可以和一個或多個選自以下之化合物合併給藥:卡博替尼(Cabozantinib (COMETRIQ))、凡德他尼(Vandetanib (CALPRESA))、索拉非尼(蕾莎瓦)(Sorafenib (NEXAVAR))、舒尼替尼(舒癌特)(Sunitinib (SUTENT))、瑞格菲尼(癌瑞格)(Regorafenib (STAVARGA))、普納替尼(Ponatinib (ICLUSIG))、貝伐斯抗(癌思停)(Bevacizumab (AVASTIN))、克里替尼(Crizotinib (XALKORI))、或吉非替尼(艾瑞莎)(Gefitinib (IRESSA))的化合物併用投與;本發明化合物或組成物可以同時或順次與其他治療藥物以相同或不同投與路徑給藥。本發明之化合物可以和其他治療藥劑包括在一個單一配方中、或做成分別的配方。
實施例
以下實施例係用來說明,並且不代表任何侷限之意義。 本發明之化合物,包括其鹽類和N-氧化物,使用已知的有機合成技術即可製備且依照眾多合成途徑之任一者如下述合成計畫方案(Synthetic Protocols)和實施例中所述者即可合成,以下的圖解方案之意義係提供關連於製備本發明化合物之一般指引,一個熟習本領域之專家應了解,顯示於圖解方案的製備方法可以用有機化學的一般知識加以修改、或選擇性地使用有機化學的一般知識來製備不同的本發明化合物。
用鹵化有機鋰(organolithium halide)或鹵化有機鎂(organomagnesium halide)例如正丁基鋰(n- butyllithium,n
-BuLi)或異丙基氯化鎂(Isopropylmagnesium chloride,i
-PrMgCl)處理一個芳基二鹵化物(aryl dihalide),而芳基金屬試劑(arylmetal reagent)可以接著進行加成(addition)至一個酯類取代的環己酮cyclohexanone)《選擇商品化產品或以『酮類及硼酸酯中間產物的和成(Synthesis of Ketone and Boronate Intermediates)』所描述方法製備》,所留下的鹵化物可以在芳基錫情況(SnAr conditions)下或金屬催化耦合情況(metal-catalyzed coupling conditions)下與一個芳基胺(arylamine)進行一個耦合反應(coupling reaction),以產生一個三環酯中間產物(tricyclic ester intermediate);該酯接著在鹼性情況下被水解(hydrolyzed)而產生一個酸,後者接著與一個胺(amine)《選擇商品化產品或以『胺類中間產物和成(Synthesis of Amine Intermediates)』所描述方法製備》進行一個醯胺耦合反應(amide coupling reaction),此醯胺是此處所描述之轉染過程重排抑制劑的實施例,但也可以更進一步加以修改。舉例來說,三級醇可以用氟化試劑(fluorinating reagent)如三氟化二乙氨基硫(DAST;Diethylaminosulfur trifluoride)處理,產生一個脫氧氟化產物(deoxyfluorinated products)和脫水產物(dehydrated products)的混合物;該脫水產物可以在標準氫化情況例如鈀(Pd)和氫(H2
)、或(Pd)和甲酸銨(ammonium formate)的情況下被還原,產生一個還原產物,這也是轉染過程重排抑制劑的實施例。
在親核性芳香取代反應(nucleophilic aromatic substitution reaction)情況下,使用一個鹼例如二異丙基乙基胺(diisopropylethylamine;DIPEA)或三乙基胺(triethylamine;TEA),在一個極性溶劑中,雜芳基二鹵化物(heteroaryl dihalide)可以被耦合至一個氨基吡唑(amino pyrazole)以提供二環系統(bicyclic ring system)。該二環雜芳基鹵化物接著經由鈀催化耦合反應(Palladium-mediated coupling reaction)例如鈴木耦合反應(Suzuki coupling)、施蒂勒耦合反應(Stille coupling)、根岸耦合反應(Negishi coupling),耦合至一個烯基或烷基的硼、錫或鋅試劑,以提供一個三環系統(tricyclic ring system)。舉例來說,在和成擬定方案2中,於鈴木耦合反應情況《X = 鹵代,例如氯;而M = B(OR)2
》下,二環雜芳基鹵化物能被耦合至各種不同的酯取代環己烯基硼酸酯(cyclohexenyl boronic esters)《選擇商品化產品或『乙烯硼酸酯的和成(Synthesis of Vinyl Boronates)』條項下所描述者》,以提供三環羧酸酯(tricyclic carboxylic ester)中間產物;羧酸酯接著在酸或鹼的情況下被水解,提供一個羧酸(carboxylic acid)中間產物;羧酸中間產物接著又被耦合至各種不同的胺中間產物如實施例9所描述者,生成醯胺最終產物。
一個取代的環烷基碘化物(substituted cycloalkyl iodide)《選擇商品化產品或『碘化物中間產物的和成(Synthesis of Iodide Intermediates)』條項下所描述者》用活性鋅(activated zinc)處理,鋅以各種方法加以活性化,包括但非侷限於瑞奇方法(method of Reike)或以三甲基氯硅烷(Chlorotrimethylsilane;TMS-Cl)和1,2-二溴乙烷(1,2-dibromoethane)處理;該環烷基鋅試劑,在根岸耦合條件下,靠著鈀催化劑可以耦合至一個雜芳基鹵化物;結果產物的硫甲基(thiomethyl group)然後經由氧化為碸(sulfone)、在酸性情況下水解、和用三氯氧磷(phosphorus oxychloride;POCl3
)或草醯氯(oxalyl chloride)氯化過程,被轉化為一個氯化物;雜芳基氯化物接著在芳基錫(SnAr)情況或鈀催化耦合反應(Palladium-mediated coupling reaction)情況下,用一個芳基胺可以進行換置(displacement);然後三環羧酸酯(tricyclic carboxylic ester)在酸性或鹼性情況下可以被水解,生成一個羧酸中間產物,該羧酸中間產物接著可以耦和各種不同的胺中間產物如實施例9所描述者,生成醯胺最終產物。
一個取代的環烷基碘化物(cycloalkyl iodide))《選擇商品化產品或『碘化物中間產物的和成(Synthesis of Iodide Intermediates)』條項下所描述者》,用活性鋅處理,鋅可以用不同方法活性化,包括但非侷限於瑞奇方法(method of Reike)或以三甲基氯硅烷(Chlorotrimethylsilane;TMS-Cl)和1,2-二溴乙烷(1,2-dibromoethane)處理,該環烷基鋅試劑,在根岸耦合條件下,靠著鈀催化劑可以耦合至一個雜芳基二鹵化物;結果產物剩餘的的鹵化基(halide group)接著在芳基錫(SnAr)情況或鈀催化耦合反應(Palladium-mediated coupling reaction)情況下,與一個芳基胺進行換置(displacement),芳基胺可以是未保護或者吡唑(pyrazole)N-H以各種官能基如叔丁氧羰基(Boc)保護;然後三環羧酸酯(tricyclic carboxylic ester)在酸性或鹼性情況下可以被水解,生成一個羧酸中間產物,該羧酸中間產物也移除吡唑的保護基,接著該羧酸中間產物可以耦和各種不同的胺中間產物如『胺中間產物的和成(Synthesis of Amine Intermediates)』條項下所描述者,生成醯胺最終產物。
製備本發明化合物的化學反應可以在適當的溶劑中實施,溶劑可以由有機合成領域之具有通常技術者選用,適當的溶劑係實質地在反應實施時的溫度時,與起始物質《試劑》、中間產物、或產物沒有反應,例如溫度的範圍可以從溶劑的凝固點到溶劑的沸點。一個指定的反應可以在單一溶劑或一個以上溶劑的混合物中實施,隨著特定反應步驟,可以由具有通常技術者選用一個特定步驟的適當溶劑。
本發明化合物的製備可以包含不同化學官能基的保護(protection)和去保護(deprotection);對於保護和去保護的需求、以及合適的保護基的選用,一個本領域之具有通常技術者可以很快決定,保護基的化學可以找到,例如Wuts和 Greene著,『有機合成中的保護基(Protective Groups in Organic Synthesis)第5版』書中,《John Wiley & Sons公司出版:新澤西(New Jersey)2014年》,此書全部地於此處併入做為參考。
依照本領域所習知之的任何適當方法可以監測反應,舉例來說,產物形成可以用光譜分析方法(spectroscopic means)監測,例如核磁共振光譜分析(nuclear magnetic resonance (NMR) spectroscopy)《例如1
H或13
C》、紅外線光譜分析(infrared (IR) spectroscopy)、分光光度測定法(spectrophotometry)《例如紫外線至可見光(UV-visible)》、質譜分析儀(mass spectrometry(MS))、或色層分析方法如高效液相色層分析(high performance liquid chromatography (HPLC))或薄層色層分析(thin layer chromatography (TLC))。用於化合物特性記述的分析儀器和方法:
液相色層分析-質譜 分析
(LC-MS
):除非另有說明,所有液相色層分析-質譜分析(liquid chromatography-mass spectrometry (LC-MS))數據《分析樣本純度和確認樣本》係得自於在22.4℃時,一個使用一個安捷倫型號6120質譜分析儀的安捷倫型號-1260液相色層分析系統(Agilent model-1260 LC system),該質譜分析儀利用安裝於一個安捷倫Poroshell 120《EC-C18,粒子大小2.7微米,直徑3.0x50毫米》反相管柱(Agilent Poroshell 120 reverse-phase column)的電噴霧離子化-大氣壓離子化(ES-API ionization;electrospray ionization- atmospheric pressure ionization)。移動相包含一個0.1%甲酸(formic acid)於水之溶液和0.1%甲酸於乙腈(acetonitrile)之溶液的溶劑混合物,利用一個固定梯度(constant gradient)從95%水性∕5%有機到5%水性∕95%有機的移動相經過流動路程4分鐘,流速為固定的每分鐘1毫升(1mL/min)。
製備型液相色層分析-質譜 分析
(Prep LC-MS
):製備型高效液相色層分析係在22.4℃時,於一個安裝一個Luna 5u C18(2) 100A、AXIA 封裝、250x21.2毫米之反相管柱的島津發現製備系統(Shimadzu Discovery VP® Preparative system)上實施;移動相包含一個0.1%甲酸(formic acid)於水之溶液和0.1%甲酸於乙腈之溶液的溶劑混合物,利用一個固定梯度(constant gradient)從95%水性∕5%有機到5%水性∕95%有機的移動相經過流動路程25分鐘,流速為固定的每分鐘20毫升(20mL/min),化學反應係在微波爐實施,在一個Biotage公司的微波合成儀(Biotage Initiator microwave)單元中也是如此。矽膠色層分析法
:矽膠色層分析法可以在一個Teledyne Isco CombiFlash® Rf 單元或一個Biotage® Isolera Four單元中實施。
質子核磁共振光譜分析
:除非另有說明,所有質子核磁共振波譜(1
H NMR spectra)係得自於瓦里安400百萬赫茲高磁場核磁共振儀(Varian 400MHz Unity Inova 400 MHz NMR instrument)《擷取時間(acquisition time)=3.5秒帶有1秒遲延;16至64掃描》,其特徵為:對於殘渣二甲基亞碸(residual Dimethyl sulfoxide;DMSO)《2.50百萬分率》,所有在氘代二甲基亞碸(Deuterated DMSO;dimethyl sulfoxide-d6
)溶劑中的質子係以百萬分率(parts-per million (ppm))報告。
實施例1 化合物109和110的合成
步驟1:(1R,4S)-N-((S)-1-(6-(4- 氟-1H- 吡唑 -1- 基 )
吡啶-3- 基)乙基)-4-(4-甲基-6-(5-甲基-1H- 吡唑 -3- 基 氨 基 )
吡啶-2- 基)環己基 羧 醯胺
((1R,4S)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide
)《 化合物 109 》 和 (1S,4R)-N-((S)-1-(6-(4- 氟-1H- 吡唑 -1- 基 )
吡啶-3- 基)乙基)-4-(4-甲基-6-(5-甲基-1H- 吡唑 -3- 基 氨 基 )
吡啶-2- 基)環己基 羧 醯胺
((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide
)《 化合物110 》 的合成
在環境溫度於一個氫氣氣層《1大氣壓》下,攪拌N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)吡啶-2-基)環己-3-烯羧醯胺(N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl -6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)cyclohex-3-enecarboxamide)《50毫克(mg),0.10毫莫耳(mmol)》和10%鈀碳催化劑(Pd/C;Palladium on carbon)《20毫克》於甲醇中之溶液《5毫升》1小時,然後將混合物通過一個矽藻土(celite)厚墊(pad)過濾,用製備型高效液相色層分析將過濾的溶液濃縮並純化,生成標題化合物二者(1R,4S)-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡啶-2-基)環己基羧醯胺((1R,4S)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl -6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide)《化合物 109;10.0毫克,19.9%》和(1S,4R)-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡啶-2-基)環己基羧醯胺((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl -6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide)《化合物110;24.8毫克,49.5%》,為白色固體。質譜分析《正離子峰》(MS (ES+))C27
H31
FN8
O要求:502,結果:503 [M+H]+
。
(1R,4S)-N-((S)-1-(6-(4- 氟-1H- 吡唑 -1- 基 )
吡啶-3- 基)乙基)-4-(4-甲基-6-(5-甲基-1H- 吡唑 -3- 基 氨 基 )
吡啶-2- 基)環己基 羧 醯胺
((1R,4S)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide
)《 化合物 109 》 : 1
H-NMR (400 MHz, DMSO-d6
)δ
ppm 11.66 (s, 1H)、8.82 (s, 1H)、8.68 (d, 1H,J
= 4.4 Hz)、8.39 (s, 1H)、8.35 (d, 1H,J
= 6.8 Hz)、7.92-7.86 (m, 3H)、6.89 (s, 1H)、6.37 (s, 1H)、6.12 (s, 1H)、5.00-4.97 (m, 1H)、2.50-2.44 (m, 1H)、2.40-2.15 (m, 7H)、1.90-1.85 (m, 4H)、1.55-1.45 (m, 4H)、1.40 (d, 3H,J
= 6.4 Hz)。(1S,4R)-N-((S)-1-(6-(4- 氟-1H- 吡唑 -1- 基 )
吡啶-3- 基)乙基)-4-(4-甲基-6-(5-甲基-1H- 吡唑 -3- 基 氨 基 )
吡啶-2- 基)環己基 羧 醯胺
((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide
)《 化合物110 》 : 1
H-NMR (400 MHz, DMSO-d6
)δ
ppm 11.62 (s, 1H)、8.78 (s, 1H)、8.66 (d, 1H,J
= 4.4 Hz)、8.38 (d, 1H,J
= 1.6 Hz)、8.23 (d, 1H,J
= 7.6 Hz)、7.93-7.84 (m, 3H)、6.83 (s, 1H)、6.35 (s, 1H)、6.15 (s, 1H)、5.03-5.00 (m, 1H)、2.59-2.50 (m, 1H)、2.50-2.46 (m, 1H)、2.14-2.02 (m, 6H)、2.02-1.84 (m, 4H)、1.63-1.55 (m, 4H)、1.40 (d, 3H,J
= 7.6 Hz)。
實施例2 化合物112之合成 步驟1:合成2- 氯 -6- 甲基 -N-(5- 甲基 -1H- 吡唑 -3- 基 ) 嘧 啶 -4- 胺(2-chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine) 一個2,4-二氯-6-甲基-嘧啶(2,4-dichloro-6-methyl-pyrimidine)《120.00公克,736.2毫莫耳,1.00當量》、5-甲基-1H-吡唑-3-胺(5-methyl-1H-pyrazol-3-amine)《78.65公克,0.81莫耳,1.10當量》和二異丙基乙基胺(DIPEA;N,N-Diisopropylethylamine)《142.72公克,1.10莫耳,1.50當量》於二甲基亞碸(Dimethyl sulfoxide;DMSO)之溶液的懸浮液在60℃加熱16小時,於該處,在薄層色層分析《聚乙烯/乙酸乙酯(PE;Polyethylene /EA;ethyl acetate),5:1、1:1》顯示反應已完成。反應混合物冷卻至30℃,倒進冰水《800毫升》中,然後將形成的混合物用甲基特-丁基醚(MTBE;methyl tert-butyl ether)萃取《800毫升,10次》,合併的有機層再用水洗《400毫升,3次》、鹽水(brine)洗《400毫升,3次》,然後用硫酸鈉乾燥;過濾後,於減壓下濃縮濾液,將賸餘物從二氯甲烷(DCM;dichloromethane)《10毫升/公克》結晶,生成一個黃色固體之2-氯-6-甲基-N-(5-甲基-1H-吡唑-3-基) 嘧啶-4-胺(2-chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine)《105.60公克,472.14毫莫耳,64%》,其結構以液相色層分析-質譜分析和核磁共振光譜分析確認。
步驟2:合成4-(4- 甲基 -6-((5- 甲基 -1H- 吡唑 -3- 基 ) 氨基 ) 嘧 啶 -2- 基 ) 環己 -3- 烯 -1- 羧酸 鹽 ( 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohex -3-ene-1-carboxylate ) 一個混合物含有2-氯-6-甲基-N
-(5-甲基-1H
-吡唑-3-基) -4-胺(2-chloro-6-methyl-N
-(5-methyl-1H
-pyrazol-3-yl)pyrimidin-4-amine)《0.530公克,2.37毫莫耳》、乙基4-(4,4,5,5-四甲基-1,3,2-二氧雜硼環戊烷-2-基)環己-3-烯羧酸鹽(ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate)《0.530公克,2.37毫莫耳》、以及碳酸鉀《0.819公克,5.92毫莫耳》在二噁烷(dioxane)《8.89毫升》和水《2.96毫升》的溶液,用氮氣噴霧10分鐘,然後加入四(三苯基膦)鈀(Pd(PPh3
)4
;Tetrakis(triphenylphosphine)palladium(0))《0.137公克,0.118毫莫耳》,將反應容器密封;反應混合物在一個微波反應器中於125℃加熱80分鐘,然後冷卻至環境溫度,再用5:1二氯甲烷/異丙酮(DCM/IPA;Dichloromethane/Isopropyl alcohol)和水做分割(partition),水層再進一步用5:1二氯甲烷/異丙酮提取,將有機層合併,用硫酸鈉乾燥,過濾、濃縮乾燥過的溶液,用矽凝膠色層分析法(silica gel chromatography)純化《梯度淘析(gradient elution):0至10%甲醇-二氯甲烷》,得到一個黃色固體的乙基 4-(4-甲基-6-((5-甲基-1H
-吡唑-3-基)氨基)嘧啶-2-基)環己-3-烯羧酸鹽(ethyl 4-(4-methyl-6-((5-methyl-1H
-pyrazol-3-yl) amino) pyrimidin-2-yl)cyclohex-3-ene-1-carboxylate)。MS (ES+) C18
H23
N5
O2
要求:341,結果:342 [M+H]+
。
步驟3:合成 乙基 4-(4- 甲基 -6-((5- 甲基 -1H- 吡唑 -3- 基 ) 氨基 ) 嘧 啶 -2- 基 ) 環己 烷 -1- 羧酸 鹽 ( ethyl 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxylate ) 乙基 4-(4-甲基-6-((5-甲基-1H
-吡唑-3-基)氨基)嘧啶-2-基)環己-3-烯羧酸鹽《0.40公克,1.2毫莫耳》的乙醇《11.7毫升》溶液中,加入鈀碳催化劑(Pd/C;Palladium on carbon)《10%重量比,0.125公克,0.117毫莫耳》和甲酸銨(ammonium formate)《0.296公克,4.69毫莫耳》,將生成的混合物加熱至70℃維持30分鐘;反應混合物冷卻至環境溫度,經過一個矽藻土(celite)厚墊(pad)過濾,用甲醇沖洗矽藻土,然後將過濾的溶液在矽凝膠上濃縮並用矽凝膠色層分析法純化《梯度淘析(gradient elution):0至10%甲醇-二氯甲烷》,得到一個3:1的順式:反式的乙基 4-(4-甲基-6-((5-甲基-1H
-吡唑-3-基)氨基)嘧啶-2-基)環己烷-1-羧酸鹽(ethyl 4-(4-methyl-6-((5-methyl-1H
-pyrazol-3-yl)amino)pyrimidin-2-yl) cyclohexane-1-carboxylate)之混合物。MS (ES+) C18
H25
N5
O2
要求:343,結果:344 [M+H]+
。
步驟4:合成4-(4- 甲基 -6-((5- 甲基 -1H- 吡唑 -3- 基 ) 氨基 ) 嘧 啶 -2- 基 ) 環己 烷 -1- 羧酸 ( 4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxylic acid ) 在環境溫度裡將氫氧化鋰單水合物(Lithium hydroxide monohydrate)《0.029公克,0.70毫莫耳》加入一個乙基 4-(4-甲基-6-((5-甲基-1H
-吡唑-3-基)氨基)嘧啶-2-基)環己烷-1-羧酸鹽《0.12公克,0.35毫莫耳》的四氫呋喃(tetrahydrofuran;THF)《2.8毫升》、乙醇《2.8毫升》和水的溶液,攪拌反應混合物6小時,然後加入濃縮的水性鹽酸《37%,0.072毫升,0.87毫莫耳》,濃縮反應混合物然後進行下一個步驟。
步驟5:合成(1R,4S)-N-((S)-1-(6-(4- 氟 -1H- 吡唑 -1- 基 )
吡啶-3- 基 ) 乙基 )-4-(4- 甲基 -6-((5- 甲基 -1H- 吡唑 -3- 基 ) 氨基 ) 嘧 啶 -2- 基 ) 環己 烷 -1- 羧 醯胺 ( (1R,4S)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide ) 《化合物 112 》 在環境溫度裡,將2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU;O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)《162毫克,0.427毫莫耳》加入一個含未精製4-(4-甲基-6-((5-甲基-1H
-吡唑-3-基)氨基)嘧啶-2-基)環己烷羧酸《72毫克,0.23毫莫耳》、(S
)-1-(6-(4-氟-1H-吡唑-1-基)嘧啶-3-基)乙胺 鹽酸鹽((S
)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride salt)《97毫克,0.40毫莫耳》、和二異丙基乙胺(DIEA;diisopropylethylamine)《0.34毫升,1.9毫莫耳》的二甲基甲醯胺(DMF ;Dimethylformamide)《3.8毫升》的溶液中,將反應混合物攪拌10分鐘,然後用乙酸乙酯(EtOAc;ethyl acetate)和水做分割,將有機層用飽和食鹽水溶液清洗,在硫酸鈉上乾燥、過濾及濃縮。將殘渣用矽凝膠色層分析法純化《梯度淘析(gradient elution):0至10%甲醇-二氯甲烷並加入2%三乙基胺(triethylamine)》,得到一個白色固體的(1R,4S)-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)環己烷-1-羧醯胺((1R,4S)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxamide)《化合物112;26毫克,生成率13%》。MS (ES+) C26
H30
FN9
O 要求:503, 結果:504 [M+H]+
。1
H NMR (500 MHz, DMSO-d6
) δ 11.88 (s, 1H)、9.48 (s, 1H)、8.66 (d,J
= 4.5 Hz, 1H)、8.38 (d,J
= 2.2 Hz, 1H)、8.30 (d,J
= 7.7 Hz, 1H)、7.94 – 7.81 (m, 3H)、6.83 (s, 1H)、6.16 (s, 1H) 5.02 – 4.93 (m, 1H)、2-57-2.49 (m, 1H)、2.26-2.16 (m, 7H)、1.99-1.92 (m, 2H)、1.88-1.80 (m, 2H)、1.58-1.36 (m, 7H)。
實施例3 化合物120的合成 步驟1:合成(1S,4S)-乙基 4-(6-溴-4-甲基吡
啶-2- 基)-4-羥 基 環己 烷 - 羧酸鹽 ( 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexane-carboxylate )及 (1R,4R)- 乙基 4-(6-溴-4-甲基吡
啶-2- 基)-4-羥 基 環己 烷 - 羧酸鹽 ( (1R,4R)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexane-carboxylate ) 一個2,6-二溴-4-甲基吡啶(2,6-dibromo-4-methylpyridine)《1.00公克,3.98毫莫耳》的二氯甲烷《30毫升》的溶液,冷卻至 -78o
C,然後將正丁基鋰(n
-BuLi;n-
Butyllithium)《2.5莫耳濃度(M),1.74毫升,4.37毫莫耳》逐滴加入前述溶液中,在-78o
C攪拌該溶液15分鐘,再加入4-氧代環己烷羧酸乙酯(ethyl 4-oxocyclohexanecarboxylate)《811毫克,4.77毫莫耳》,生成的混合物在-78o
C攪拌30分鐘,然後加入飽和的氯化銨水溶液將混合物淬熄(quench)並用二氯甲烷抽提。合併有機層,通過硫酸鈉乾燥、過濾及濃縮,用矽凝膠管柱純化《PE:EA = 2:1》,得到一個白色固體的(1R,4R)-乙基 4-(6-溴-4-甲基吡啶-2-基)-4-羥基環己烷-酸鹽((1R,4R)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexane carboxylate)《在薄層色層分析法極性較低(less polar),500毫克,36.7%生成率》,MS (ES+) C15
H20
BrNO3
要求:341,結果:342 [M+H]+
;以及一個白色固體的(1S,4S)-乙基 4-(6-溴-4-甲基吡啶-2-基)-4-羥基環己烷羧酸鹽((1S,4S)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexane carboxylate)《在薄層色層分析法極性較高(more polar),500毫克,36.7%生成率》,MS (ES+) C15
H20
BrNO3
要求:341,結果:342 [M+H]+
。
步驟2:合成(1S,4S)-乙基 4- 羥 基-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡
啶-2- 基)環己 烷 羧酸鹽 ( (1S,4S)-ethyl 4-hydroxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxylate ) 一個(1S,4S)-乙基 4-(6-溴-4-甲基吡啶-2-基)-4-羥基環己烷羧酸鹽((1S,4S)-ethyl 4-(6-bromo-4-methylpyridin-2-yl)-4-hydroxycyclohexane carboxylate)《283毫克,2.92毫莫耳》、5-甲基-1H-吡唑-3-胺(5-methyl-1H-pyrazol-3-amine)《283毫克,2.92毫莫耳》、特丁基膦(t-BuXPhos)《185毫克,0.438毫莫耳》、三個(二亞苄基丙酮)二鈀(Pd2
(dba)3
;Tris(dibenzylideneacetone) dipalladium(0))《200毫克,0.219毫莫耳》和醋酸鉀(KOAc)《429毫克,4.38毫莫耳》在二甲基甲醯胺(DMF;Dimethylformamide)《2毫升》和甲苯(toluene)《10毫升》中的混合物,在微波刺激下加熱至140℃持續2小時;等到冷卻至環境溫度後,將混合物用矽凝膠管柱《PE:EA = 2:1》濃縮及純化,得到一個白色固體的(1s,4s)-乙基 4-羥基-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡啶-2-基)環己烷羧酸鹽((1s,4s)-ethyl 4-hydroxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxylate)《80毫克,生成率15%》,MS (ES+) C19
H26
N4
O3
要求:358,結果:359 [M+H]+
。
步驟3:合成(1S,4S)-4- 羥 基-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡
啶-2- 基)環己 烷 羧酸 ( (1S,4S)-4-hydroxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxylic acid ) 於25o
C,在一個(1S,4S)-乙基 4-羥基-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)吡啶-2-基)環己烷羧酸鹽((1s,4s)-ethyl 4-hydroxy-4-(4-methyl-6-((5-methyl -1H-pyrazol-3-yl)amino)pyridin-2-yl)cyclohexanecarboxylate)《80毫克,0.2231毫莫耳》的甲醇(MeOH)《3毫升》溶液中,加入2莫爾濃度的氫氧化鈉水溶液《0.5毫升,1毫莫耳》;在25o
C 攪拌該溶液15小時,然後濃縮,移除甲醇,用2莫爾濃度的氯化氫將水溶液酸化,使酸鹼值濃度(pH)達到6,可以產生沉澱;收集沉澱的固體並乾燥之,得到一個黃色固體的(1S,4S)-4-羥基-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡啶-2-基)環己烷羧酸((1S,4S)-4-hydroxy -4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl) cyclohexanecarboxylic acid)《60 毫克,生成率81%》。MS (ES+) C17
H22
N4
O3
要求:330,結果:331 [M+H]+
。
步驟4:合成(1s,4R)-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡
啶-3- 基)乙基)-4- 羥 基-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡
啶-2- 基)環己 烷 羧 醯胺((1s,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-hydroxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide)
《化合物120
》一個含有(1S,4S)-4-羥基-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基) -2-基)環己烷羧酸((1S,4S)-4-hydroxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino) pyridin-2-yl) cyclohexanecarboxylic acid)《60 毫克,0.18毫莫耳》、(S)-1-(6-(4-氟-1H
-吡唑-1-基)吡啶-3-基)乙胺 鹽酸鹽((S)-1-(6-(4-fluoro-1H
-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride)《44.0 毫克,0.1816毫莫耳》、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU;O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)《69.0毫克,0.1816毫莫耳》和二異丙基乙胺(DIEA;diisopropylethylamine)《70.4毫升,0.545毫莫耳》的二甲基甲醯胺(DMF;Dimethylformamide)《2毫升》的溶液,在25℃攪拌2小時,濃縮該溶液,用製備高效液相色層分析法(preparative HPLC)純化,得到一個白色固體的產物《40 毫克,生成率43%》。MS (ES+) C27
H31
FN8
O2
要求:518,結果:519 [M + H]+
。1
H-NMR (400 MHz,DMSO-d6
)δ
ppm 11.71 (br. s.,1H), 8.92 (br. s.,1H), 8.69 (d,1H,J
= 4.4 Hz)、8.39 (d,1H,J
= 2.0 Hz)、8.31 (d,1H,J
= 7.6 Hz)、7.95-7.87 (m,3H)、6.83 (br. s.,1H)、6.79 (s,1H)、6.09 (br. s.,1H)、5.01-4.98 (m,1H)、4.89 (s,1H)、2.50-2.48 (m, 1H)、2.21 (s,3H)、2.20 (s,3H)、2.00-1.75(m,4H)、1.65-1.50 (m,4H)、1.41 (d,3H,J
= 7.2 Hz)。
實施例 4 化合物121和122的合成 步驟1:合成 (1s,4R)-4- 氟 -N-((S)-1-(6-(4- 氟 -1H- 吡唑 -1- 基)吡
啶-3- 基)乙基) -4-(4- 甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡
啶-2- 基)環己 烷 羧 醯胺( (1s,4R)-4-fluoro-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide )
《化合物121
》、(1R,4S)-4- 氟 -N-((S)-1-(6-(4- 氟 -1H- 吡唑 -1- 基)吡
啶-3- 基)乙基) -4-(4- 甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡
啶-2- 基)環己 烷 羧 醯胺( (1R,4S)-4-fluoro-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide )
《化合物122
》、和 N-((S)-1-(6-(4- 氟 -1H- 吡唑 -1- 基)吡
啶-3- 基)乙基) -4-(4- 甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡
啶-2- 基)環己-3-烯羧醯胺( N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide ) 二氯甲烷《6毫升》中含(1R,4S)-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-羥基-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)吡啶-
2-基)環己烷羧醯胺((1R,4S)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-hydroxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)cyclohexanecarboxamide)《120毫克,0.23毫莫耳》的混合物,冷卻至0℃,在0℃時加入三氟化二乙氨基硫(DAST;Diethylaminosulfur trifluoride)《111毫克,0.69毫莫耳》,將產生的混合物在25℃攪拌2小時,濃縮該混合物,用製備高效液相色層分析法(preparative HPLC)純化,得到白色固體的標題化合物(1S,4R)-4-氟-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡啶-2-基)環己烷羧醯胺((1s,4R)-4-fluoro-N-((S)-1-(6-(4-fluoro -1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide)《化合物121;6.1毫克,生成率5.08%》和(1R,4S)-4-氟-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡啶-2-基)環己烷羧醯胺((1R,4S)-4-fluoro-N-((S)-1-(6- (4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl- 1H-pyrazol-3-ylamino) pyridin-2-yl)cyclohexanecarboxamide)《化合物122;13.2毫克,生成率11.0%》。MS (ES+) C27
H30
F2
N8
O 要求:520,結果:521 [M+H]+
。也得到一個白色固體的N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-4-(4-甲基-6-(5-甲基-1H-吡唑-3-基氨基)吡啶-2-基)環己-3-烯羧醯胺(N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl -6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide)《50毫克,生成率43.4%》MS (ES+) C27
H29
FN8
O 要求:500,結果:501 [M+H]+
。(1S,4R)-4- 氟 -N-((S)-1-(6-(4- 氟 -1H- 吡唑 -1- 基 )
吡啶-3- 基 ) 乙基 )-4-(4- 甲基 -6-(5- 甲基 -1H- 吡唑 -3- 基氨基 )
吡啶-2- 基 ) 環己 烷 羧 醯胺 ( (1S,4R)-4-fluoro-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide )
《化合物 121
》:1
H-NMR (400 MHz, DMSO-d6
)δ
ppm 11.73 (s, 1H)、9.01 (d, 1H,J
= 2.8 Hz)、8.69 (d, 1H,J
= 4.4 Hz)、8.41-8.38 (m, 2H)、7.95-7.87 (m, 3H)、6.92 (s, 1H)、6.66 (s, 1H)、6.14 (s, 1H)、5.00 (q, 1H,J
= 7.2 Hz)、2.50-2.31 (m, 1H)、2.21-2.21 (m, 6H)、2.21-1.74 (m, 8H)、1.41 (d, 3H,J
= 7.2 Hz)。(1R,4S)-4- 氟 -N-((S)-1-(6-(4- 氟 -1H- 吡唑 -1- 基 )
吡啶-3- 基 ) 乙基 )-4-(4- 甲基 -6-(5- 甲基 -1H- 吡唑 -3- 基氨基 )
吡啶-2- 基 ) 環己 烷 羧 醯胺 ( (1R,4S)-4-fluoro-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-yl)cyclohexanecarboxamide )
《化合物 122
》:1
H-NMR (400 MHz, DMSO-d6
)δ
ppm 11.65 (s, 1H)、9.01 (s, 1H)、8.65 (d, 1H,J
= 4.4 Hz)、8.38-8.33 (m, 2H)、7.92-7.84 (m, 3H)、6.83 (s, 1H)、6.67 (s, 1H)、6.30 (s, 1H)、5.04 (q, 1H,J
= 7.2 Hz)、2.70-2.50 (m, 3H)、2.20 (s, 3H)、2.15 (s, 3H)、2.21-1.70 (m, 6H)、1.40 (d, 3H,J
= 7.2 Hz)。
實施例 5 化合物 129 和 130 的合成 步驟 1 : 合成 2- 氯 -4- 甲基 -6-( 甲硫 基 ) 嘧 啶 ( 2-chloro-4-methyl-6-(methylthio)pyrimidine ) 將2,4-二氯-6-甲基嘧啶(2,4-Dichloro-6-methylpyrimidine)《20公克,0.123莫耳》溶解於四氫呋喃(THF;tetrahydrofuran)《200毫升》中,於 -5 °C時逐滴加入甲基磺酸鈉(Methanesulfonic acid sodium salt)《20%水溶液,43公克,0.129莫耳》,形成的混合物在室溫攪拌整夜;加入水《100毫升》和醋酸乙酯(EtOAc)《100毫升》,分成不同液體層,有機層用鹽水洗《2次》,通過硫酸鈉乾燥並濃縮,生成一個黃色固體,該固體用聚乙烯《100毫升》洗滌,得到目標化合物《9.1公克》。MS (ES+) C6
H7
ClN2
S 要求:174,結果:175 [M+H]+
。
步驟 2 : 合成甲基 1- 甲氧基-4-(4- 甲基 -6-( 甲硫 基 ) 嘧 啶 -2- 基) 環己 烷 -1- 羧酸鹽 ( Methyl 1-methoxy-4-(4-methyl-6-(methylthio)pyrimidin-2-yl) cyclohexane-1-carboxylate ) 於一個氮氣氣流下,在一個壓力容器中將甲基 4-碘-1-甲氧基環己烷羧酸鹽(Methyl 4-iodo-1-methoxycyclohexanecarboxylate)《1.35公克,4.53毫莫耳》溶解於二甲基乙醯胺(dimethylacetamide)《10毫升》,用注射器快速將芮克鋅(Rieke Zinc)《5.7毫升的一個50毫克/毫升的四氫呋喃懸浮液,4.34毫莫耳》加入,然後將容器蓋上並在環境溫度下攪拌15分鐘,在一個氮氣氣流下開啟容器,並加入2-氯-4-甲基-6-(甲硫基)嘧啶(2-chloro-4-methyl-6-(methylthio)pyrimidine)《659毫克,3.8毫莫耳》,接著加入1,1'-二個(二苯基膦)二茂鐵二氯化鈀(PdCl2
dppf;1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride)《138毫克,0.19毫莫耳》;將容器蓋上並加熱至80 °C持續1小時,然後冷卻至室溫。反應混合物用醋酸乙酯稀釋,經過矽藻土(celite)過濾,然後將濾液用水《3次》、鹽水洗滌,在硫酸鈉上乾燥,過濾及濃縮,生成的賸餘物藉由矽凝膠上的快速管柱色層分析(flash-column chromatography)《梯度淘析(gradient elution):0至30%醋酸乙酯-己烷》純化,得到一個無色油狀的甲基 1-甲氧基-4-(4-甲基-6-(甲硫基)嘧啶-2-基)環己烷羧酸鹽(methyl 1-methoxy-4-(4-methyl-6-(methylthio)pyrimidin-2-yl) cyclohexanecarboxylate)《828毫克,生成率70%》;在液相色層分析-質譜(LC/MS)分析中的紫外線峰綜合和核磁共振(NMR)綜合結果,確定生成物係3:2的異構物的混合物。MS (ES+) C15
H22
N2
O3
S 要求:310,結果:311 [M+H]+
。
步驟 3 : 合成甲基 1- 甲氧基-4-(4- 甲基 -6-( 甲磺醯 基 ) 嘧 啶 -2- 基) 環己 烷 -1- 羧酸鹽 ( Methyl 1-methoxy-4-(4-methyl-6-(methylsulfonyl)pyrimidin-2-yl)cyclohexane-1-carboxylate ) 將甲基 1-甲氧基-4-(4-甲基-6-(甲硫基)嘧啶-2-基)環己烷羧酸鹽(methyl 1-methoxy-4-(4-methyl-6-(methylthio)pyrimidin-2-yl) cyclohexanecarboxylate)《825毫克,2.66毫莫耳》溶解於二氯甲烷《12毫升》中,然後在環境溫度加入間氯過氧苯甲酸(mCPBA;meta-Chloroperoxybenzoic acid)《1.10公克,6.38毫莫耳》,將反應混合物攪拌16小時,然後再加入更多部分的間氯過氧苯甲酸《200毫克》;再繼續攪拌4小時以後,將反應混合物用二氯甲烷稀釋,然後用飽和碳酸氫鈉溶液洗滌,洗過的溶液經硫酸鈉乾燥、過濾、濃縮,生成的賸餘物藉由矽凝膠上的快速管柱色層分析(flash-column chromatography)《梯度淘析(gradient elution):0至60%醋酸乙酯-己烷》純化,得到一個無色油狀的甲基 1-甲氧基-4-(4-甲基-6-(甲磺醯基)嘧啶-2-基)環己烷羧酸鹽(methyl 1-methoxy-4-(4-methyl-6-(methylsulfonyl)pyrimidin-2-yl) cyclohexanecarboxylate)《808毫克,生成率89%》;MS (ES+) C15
H22
N2
O5
S 要求:342,結果:343 [M+H]+
。
步驟 4 : 合成甲基 4-(4- 羥 基 -6- 甲基 嘧 啶 -2- 基)-1-甲氧基 環己 烷 -1- 羧酸鹽 ( Methyl 4-(4-hydroxy-6-methylpyrimidin-2-yl)-1-methoxycyclohexane-1-carboxylate ) 將甲基 1-甲氧基-4-(4-甲基-6-(甲磺醯基)嘧啶-2-基)環己烷羧酸鹽(methyl 1-methoxy-4-(4-methyl-6-(methylsulfonyl)pyrimidin-2-yl) cyclohexanecarboxylate)《600毫克,1.75毫莫耳》溶解於醋酸《5毫升》中並加熱至80 °C維持1小時;然後將反應混合物冷卻至環境溫度,減壓下濃縮,用水研磨並過濾;用額外的水洗滌固體,接著減壓下乾燥,得到標題化合物,係淡黃色固體的甲基4-(4-羥基-6-甲基嘧啶-2-基)-1-甲氧基環己烷羧酸鹽(methyl 4-(4-hydroxy-6-methylpyrimidin-2-yl)-1-methoxycyclohexanecarboxylate)《390毫克,生成率79%》。MS (ES+) C14
H20
N2
O4
要求:280,結果:281 [M+H]+
。
步驟 5 : 合成甲基 4-(4- 氯 -6- 甲基嘧 啶 -2- 基)-1-甲氧基 環己 烷 -1- 羧酸鹽 ( Methyl 4-(4-chloro-6-methylpyrimidin-2-yl)-1-methoxycyclohexane-1-carboxylate ) 將甲基4-(4-羥基-6-甲基嘧啶-2-基)-1-甲氧基環己烷羧酸鹽(methyl 4-(4-hydroxy-6-methylpyrimidin-2-yl)-1-methoxycyclohexanecarboxylate)《380毫克,1.36毫莫耳》懸浮在三氯氧磷(POCl3
;phosphorus oxychloride)《3.2毫升,33.9毫莫耳》中,並加熱至100℃維持2小時;反應混合物然後冷卻至環境溫度,濃縮,賸餘物用碎冰塊處理;生成的懸浮液用二氯甲烷分離,有機層已飽和碳酸氫鈉萃取並在硫酸鈉上乾燥;過濾乾燥過的溶液,濃縮,生成的賸餘物藉由矽凝膠上的快速管柱色層分析(flash-column chromatography)《梯度淘析(gradient elution):0至30%醋酸乙酯-己烷》純化,得到淡橘色油狀的甲基 4-(4-氯-6-甲基嘧啶-2-基)-1-甲氧基環己烷-1-羧酸鹽(Methyl 4-(4-chloro-6-methylpyrimidin-2-yl)-1-methoxycyclohexane-1-carboxylate)《344毫克,生成率85%》,靜置後固化。MS (ES+) C14
H19
ClN2
O3
要求:298,結果:299 [M+H]+
。
步驟 6 : 合成甲基 1- 甲氧基-4-(4-甲基-6-((5- 甲基 -1H- 吡唑 -3- 基 ) 氨 基 ) 嘧 啶 -2- 基) 環己 烷 -1- 羧酸鹽 ( Methyl 1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxylate ) 將甲基 4-(4-氯-6-甲基嘧啶-2-基)-1-甲氧基環己烷-1-羧酸鹽(Methyl 4-(4-chloro-6-methylpyrimidin-2-yl)-1-methoxycyclohexane-1-carboxylate)《300毫克,1.00毫莫耳》、3-甲基-1-吡唑-5-胺(3-methyl-1-pyrazol-5-amine)《146毫克,1.51毫莫耳》、二-特-丁基(2',4',6'-三異丙-[1,1'-二苯基]-2-基)膦(di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine)《85毫克,0.2當量(equiv.)》、三個(二亞苄基丙酮)二鈀(Pd2
(dba)3
;Tris(dibenzylidene acetone) dipalladium(0))《92毫克,0.1當量(equiv.)》、和醋酸鉀(potassium acetate)《394毫克,4.02毫莫耳》在氮氣下合併在一個瓶子裡,然後加入4毫升二噁烷(dioxane),反應混合物加熱至100°C維持1小時,然後冷卻至環境溫度。將反應混合物用醋酸乙酯稀釋,通過矽藻土過濾、濃縮,生成的賸餘物藉由矽凝膠上的快速管柱色層分析(flash-column chromatography)《梯度淘析(gradient elution):0至10%甲醇-二氯乙烷》純化,得到深棕色泡棉狀的甲基 1-甲氧基-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)環己烷-1-羧酸鹽(Methyl 1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-1-carboxylate)《192毫克,生成率53%》。MS (ES+) C18
H25
N5
O3
要求:359,結果: 360 [M+H]+
。
步驟 7 : 合成 (1R,4S)-N-((S)-1-(6-(4- 氟-1H- 吡唑 -1- 基) 吡 啶 -3- 基)乙基)-1-甲氧基-4-(4-甲基-6-((5- 甲基 -1H- 吡唑 -3- 基 ) 氨 基 ) 嘧 啶 -2- 基) 環己 烷 - 羧 醯胺 ( (1R,4S)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide ) 《化合物 129 》 和 (1S,4R)-N-((S)-1-(6-(4- 氟-1H- 吡唑 -1- 基) 吡 啶 -3- 基)乙基)-1-甲氧基-4-(4-甲基-6-((5- 甲基 -1H- 吡唑 -3- 基 ) 氨 基 ) 嘧 啶 -2- 基) 環己 烷 - 羧 醯胺 ( (1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide ) 《化合物 130 》 標題化合物係由甲基 1-甲氧基-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)環己烷羧酸鹽(Methyl1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate)《192毫克,0.53毫莫耳》製備而得,採用合成方案1和2所敘述之相同的兩步驟程序《水解(hydrolysis)和醯胺耦合(amide coupling)》,用苯并三唑-1-基-氧基三吡咯烷基磷六氟磷酸鹽(PyBOP;Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate)作為醯胺耦合劑代替2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU;O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)。生成產物最初分離出來為一個非鏡像異構物(Diastereomers)的混合物《190毫克》,然後將其溶解於6毫升甲醇中並用超臨界流體色層分析(SFC;supercritical fluid chromatography)《ChiralPak公司,AD-H 21 x 250 毫米;40%甲醇含有0.25% 二乙醇胺(DEA;diethanolamine)於CO2
中;2.5 毫升注射,70 毫升/分鐘》純化;波峰1濃縮後得到一個白色固體的(1R,4S)-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-1-甲氧基-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)環己烷-1-羧醯胺((1R,4S)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl) -1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide)《29毫克,生成率10%》;波峰2濃縮後得到一個白色固體的(1S,4R)-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-1-甲氧基-4-(4-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)環己烷-羧醯胺((1S,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide)《130毫克,生成率46%》。
實施例 6 合成化合物149 步驟 1 : 合成甲基 4-(2- 氯 -6- 甲基嘧 啶 -4 - 基 )-1- 甲氧基 環己 烷 -1- 羧酸鹽 ( Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate ) 於一個氮氣氣流下,在一個壓力容器中將甲基 4-碘-1-甲氧基環己烷羧酸鹽(Methyl 4-iodo-1-methoxycyclohexanecarboxylate)《3.37公克,11.3毫莫耳》溶解於二甲基乙醯胺(dimethylacetamide)《38毫升》,用注射器快速將芮克鋅(Rieke Zinc)《17.7毫升的一個50毫克/毫升的四氫呋喃懸浮液,13.6毫莫耳》加入,然後將容器蓋上並在環境溫度下攪拌15分鐘,在一個氮氣氣流下開啟容器,並加入2,4-二氯-6-甲基嘧啶(2,4-dichloro-6-methylpyrimidine)《1.84公克,11.3毫莫耳》,接著加入1,1'-二個(二苯基膦)二茂鐵二氯化鈀(PdCl2
dppf;1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride)《826毫克,1.13毫莫耳》;將容器蓋上並加熱至80 °C持續1小時,然後冷卻至室溫。反應混合物用醋酸乙酯稀釋,經過矽藻土(celite)過濾,然後將濾液用水《3次》、鹽水洗滌,在硫酸鈉上乾燥,過濾及濃縮,生成的賸餘物藉由矽凝膠上的快速管柱色層分析(flash-column chromatography)《梯度淘析(gradient elution):0至50%醋酸乙酯-己烷》純化,得到一個無色油狀的甲基 4-(2-氯-6-甲基嘧啶-4-基)-1-甲氧基環己烷-羧酸鹽(methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate)《74毫克,生成率2.2%》; MS (ES+) C14
H19
ClN2
O3
要求:298,結果:299 [M+H]+
。
步驟 2 : 合成 特-丁 基 3-((4-(4- 甲氧基 -4-( 甲氧基 羰基 ) 環己基)-6- 甲基 嘧 啶 -2- 基 ) 氨基)-5-甲基-1H- 吡唑 -1- 羧酸鹽 ( tert-Butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate ) 在氮氣環境下,將甲基 4-(2-氯-6-甲基嘧啶-4-基)-1-甲氧基環己烷-1-羧酸鹽(Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate)《70.5毫克,0.236毫莫耳》、特-丁基 3-氨基-5-甲基-1H
-吡唑-1-羧酸鹽(tert-butyl 3-amino-5-methyl-1H
-pyrazole-1-carboxylate)《69.8毫克,0.354毫莫耳》、二-特-丁基(2',4',6'-三異丙基-[1,1'-二苯基]-2-基)膦(di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine)《20.0毫克,0.2當量》、三個(二亞苄基丙酮)二鈀(Pd2
(dba)3
;Tris(dibenzylidene acetone) dipalladium(0))《21.6毫克,0.1當量(equiv.)》、和醋酸鉀《70毫克,0.71毫莫耳》合併在一個瓶子裡,然後加入0.98毫升二噁烷(dioxane),反應混合物加熱至115°C維持2小時,然後冷卻至環境溫度。將反應混合物用醋酸乙酯稀釋,通過矽藻土過濾,濃縮在矽凝膠上,生成的賸餘物藉由矽凝膠上的快速管柱色層分析(flash-column chromatography)《梯度淘析(gradient elution):0至100%醋酸乙酯-己烷》純化,得到黃色油狀的特-丁基 3-((4-(4-甲氧基-4-(甲氧基羰基)環己基)-6-甲基嘧啶-2-基)氨基)-5-甲基-1H-吡唑-1-羧酸鹽(tert-Butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate)《48毫克,生成率44%》。MS (ES+) C23
H33
N5
O5
要求:459,結果:460 [M+H]+
。
步驟 3 : 合成 1- 甲氧基 -4-(6- 甲基-2-((5-甲基-1H- 吡唑 -3- 基)氨基) 嘧啶 -4 - 基 ) 環己 烷 -1- 羧酸 ( 1-Methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid ) 特-丁基 3-((4-(4-甲氧基-4-(甲氧基羰基)環己基)-6-甲基嘧啶-2-基)氨基)-5-甲基-1H-吡唑-1-羧酸鹽(tert-Butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate)《47.7毫克,0.104毫莫耳》的四氫呋喃/甲醇/水(THF/MeOH/H2
O)《17:1:1,1.8毫升》溶液中,加入氫氧化鋰一水合物(Lithium hydroxide monohydrate)《13毫克,0.31毫莫耳》,反應混合物加熱至60℃,並攪拌16小時,然後將反應混合物冷卻至環境溫度並濃縮,得到粗產物的1-甲氧基-4-(6-甲基-2-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4 -基)環己烷-1-羧酸(1-Methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid)《57毫克,粗產物》,並不做更進一步的純化,將其應用於接下來的醯胺耦合。MS (ES+) C17
H23
N5
O3
要求:345,結果:346 [M+H]+
。
步驟 4 : 合成 (1s,4R)-N-((S)-1-(6-(4- 氟-1H- 吡唑 -1- 基) 吡 啶 -3- 基)乙基)-1-甲氧基-4-(6-甲基-2-((5- 甲基 -1H- 吡唑 -3- 基 ) 氨 基 ) 嘧 啶 -4- 基) 環己 烷 -1- 羧 醯胺 ( (1s,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide )《化合物149》 標題化合物係由1-甲氧基-4-(6-甲基-2-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)環己烷-1-羧酸(1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino) pyrimidin-4-yl)cyclohexane-1-carboxylic acid)《57毫克,0.104毫莫耳》製備而得,採用合成方案1和2所敘述之相同程序《醯胺耦合(amide coupling)》,用苯并三唑-1-基-氧基三吡咯烷基磷六氟磷酸鹽(PyBOP;Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate)作為醯胺耦合劑代替2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU;O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)。生成產物最初分離出來為一個非鏡像異構物(Diastereomers)的混合物《36毫克》,然後將其溶解於6毫升甲醇-二氯甲烷(methanol-DCM (1:1))中並用超臨界流體色層分析(SFC;supercritical fluid chromatography)《ChiralPak公司,AD-H 21 x 250 毫米;40%甲醇含有0.25% 二乙醇胺(DEA;diethanolamine)於CO2
中;1.0 毫升注射,70 毫升/分鐘》純化;波峰1是一個不想要的異構物,而波峰2濃縮後得到一個白色固體的(1s,4R)-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-1-甲氧基-4-(6-甲基-2-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)環己烷-1-羧醯胺((1s,4R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide)《13.4毫克,生成率24%》。
中間產物的合成 實施例 7 合成酮類(Ketone)和硼酸鹽(Boronate) A. 甲基 1-甲氧基-4-氧代環己烷-1-羧酸鹽
( Methyl 1-methoxy-4-oxocyclohexane-1-carboxylate
)標題化合物之製備係如WO 2014/130810 A1第86頁所述。
B. 乙基 1-乙氧基-4-氧代環己烷-1- 羧 酸鹽
( Ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate
) 步驟 1 : 合成乙基 8- 乙氧基 -1,4- 二氧雜螺 [4.5] 癸烷 -8- 羧酸鹽 (ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate)
一個1,4-二氧雜螺[4.5]癸-8-酮(1,4-dioxaspiro[4.5]decan-8-one)《20.0公克,128毫莫耳》的三氯甲烷(CHBr3
)《3234公克,1280毫莫耳》溶液,冷卻至0℃,然後以2.5小時以上時間逐滴加入氫氧化鉀《57.5毫克,1024毫莫耳》的乙醇溶液《300毫升》;攪拌混合物23小時後,將混合物濃縮,賸餘物用醋酸乙酯和水做分離,有機層用鹽水洗滌,通過硫酸鈉乾燥,過濾,並在減壓下濃縮,得到粗產物,藉由矽凝膠上的快速管柱色層分析(flash-column chromatography)《梯度淘析(gradient elution),聚乙烯(PE):乙酸乙酯(EA =15:1至10:1》純化,得到標題化合物《18.0公克》。
步驟 2 : 合成乙基 1- 乙氧基 -4- 氧代環己烷 -1- 羧酸鹽 (ethyl 1-ethoxy-4-oxocyclohexane -1-carboxylate)
一個乙基 8-乙氧基-1,4-二氧雜螺[4.5]癸烷-8-羧酸鹽(ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate)《10公克,43毫莫耳》的1,4-二噁烷(1,4-dioxane)《250毫升》溶液中,加入鹽酸水溶液《6當量濃度(M),92.5毫升》,然後在環境溫度將混合物攪拌23小時,接著用水稀釋該混合物並用醋酸乙酯萃取;有機層用鹽水洗滌,通過硫酸鈉乾燥、過濾,減壓下濃縮,得到粗產物,再用矽凝膠上的快速管柱色層分析《聚乙烯(PE):乙酸乙酯(EA) =15:1》純化,得到生成物《8.0公克》。1
H NMR (400 MHz, DMSO)δ
4.20 – 4.13 (m, 2H)、3.43 (q,J
= 6.9 Hz, 1H)、2.48 – 2.39 (m, 1H)、2.24 – 2.12 (m, 2H)、2.10 – 2.01 (m, 1H)、1.22 (t,J
= 7.1 Hz, 2H)、1.17 (t,J
= 7.0 Hz, 2H)。
C. 乙基 6,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼 環戊 -2- 基 ) 環己 -3- 烯-1- 羧 酸鹽(Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate) 步驟 1 : 合成乙基 2,2- 二甲基 -4- 氧代環己烷 -1- 羧 酸鹽 (ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate )
一個甲基溴化鎂《3當量濃度,109.8毫升,329.4毫莫耳》溶液,在0℃逐滴加入一個氰化銅(CuCN;copper cyanide)《14.75毫克,164.7毫莫耳》在二乙基醚(diethyl ether)《50毫升》的懸浮液,將混合物在0℃攪拌30分鐘,然後冷卻至-78 °C。接著逐滴加入乙基 2-甲基-4-氧代環己-2-烯-1-羧酸鹽(ethyl 2-methyl-4-oxocyclohex-2-ene-1-carboxylate)《10公克,54.9毫莫耳》在二乙基醚《10毫升》的溶液,將混合物在-40 ℃ 至 -20 ℃之間的溫度攪拌2小時,然後加熱至環境溫度,維持16小時;將反應混合物小心地加到一個飽和氯化銨(ammonium chloride)溶液中,將水層用二乙基醚萃取二次,,並與有機層合併,合併的有機層用鹽水洗滌,通過硫酸鈉乾燥、過濾及濃縮,賸餘物用矽凝膠上的快速管柱色層分析《聚乙烯(PE):乙酸乙酯(EA) =10:1》純化,得到2,2-二甲基-4-氧代環己烷-1-羧酸鹽(ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate)《1.16公克》。
步驟 2 : 合成乙基 6,6- 二甲基-4-(((三氟甲基)磺醯基)氧基)環己-3-烯-1 - 羧 酸鹽 (ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate )
將乙基 2,2-二甲基-4-氧代環己烷-1-羧酸鹽《1.16公克,5.85毫莫耳》和二異丙基乙基胺(diisopropylethylamine;DIPEA)《3.03公克,23.4毫莫耳》溶解於無水甲苯(dry toluene)《2毫升》,並在45 °C加熱10分鐘;乙10分鐘乙上時間逐滴加入三氟甲烷磺酸酐(Trifluoromethanesulfonic anhydride)《6.61公克,23.4毫莫耳》在二氯甲烷(DCM;dichloromethane)《20毫升》溶液,在45 °C加熱混合物2小時;讓混合物冷卻至室溫,濃縮,用水《60毫升》稀釋並用二氯甲烷抽提《2 x 40毫升》;有機層用飽和碳酸氫鈉溶液《20毫升》和鹽水《20毫升》洗滌,通過硫酸鈉乾燥、過濾、和濃縮,粗產物用矽凝膠上的快速管柱色層分析《梯度淘析,0至100%醋酸乙酯-石油醚(ethyl acetate-petroleum ether)》純化,得到乙基 6,6-二甲基-4-(((三氟甲基)磺醯基)氧基)環己-3-烯-1-羧酸鹽(ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate)《1公克》。
步驟 3 : 合成乙基 6,6- 二甲基 -4-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼環戊 -2- 基 ) 環己 -3- 烯 -1- 羧 酸鹽 (ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate)
乙基 6,6-二甲基-4-(((三氟甲基)磺醯基)氧基)環己-3-烯-1-羧酸鹽(ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate)《1公克,3.03毫莫耳》、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-l,3,2-二氧雜硼環戊-2-基)-l,3,2-二氧雜硼環戊烷(4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane)《1.15公克,4.54毫莫耳》、二個(二苯基膦基)二茂鐵]二氯化鈀(Pd(dppf)Cl2
;Bis(diphenylphosphino)ferrocene-palladium(II)dichloride)《73.5豪克,0.09毫莫耳》和醋酸鉀《891毫克,9.08毫莫耳》懸浮於1,4-二噁烷(1,4-dioxane)《20毫升》中,反應混合物用氮氣溢流,然後加熱至100℃維持2小時,將混合物冷卻至室溫,過濾,並濃縮,生成的褐色油狀物用矽凝膠上的快速管柱色層分析《梯度淘析,0至100%醋酸乙酯-石油醚(ethyl acetate-petroleum ether)》純化,得到乙基 6,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼環戊-2-基)環己-3-烯-1-羧酸鹽(ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate)《618毫克》。
D. 乙基 6- 甲基 -4-(4,4,5,5- 四甲基 -1,3,2- 二氧雜硼環戊 -2- 基 ) 環己 -3- 烯 -1- 羧 酸鹽 (Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate ) 乙基 6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼環戊-2-基)環己-3-烯-1-羧酸鹽(Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene -1-carboxylate)的製備係使用相同合成方案如前述,使用乙基 2-甲基-4-氧代環己烷-1-羧酸鹽(ethyl 2-methyl-4-oxocyclohexane-1-carboxylate)作為起始原料。
步驟 1 : 合成甲基 2-甲基-3,4-二氫-2H- 吡 喃-2- 羧 酸鹽 ( methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate )
一個丙烯醛(acrylaldehyde)《120公克,2.14莫耳》、甲基丙烯酸甲酯(methyl methacrylate)《200公克,2.00莫耳》和對苯二酚(hydroquinone)《2.2公克,20毫莫耳》的混合物,在一個密封的鋼製容器中,於180℃加熱1小時,然後將混合物冷卻至環境溫度並濃縮;賸餘物用凝膠管柱色層分析《梯度淘析,石油醚:醋酸乙酯=100:1至80:1》純化,得到淡黃色油狀物的甲基 2-甲基-3,4-二氫-2H-吡喃-2-羧酸鹽(methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate)《70公克,生成率22%》。1
H-NMR (400 MHz, CDCl3):δ 6.38 (d, J = 6.4 Hz, 1H)、4.73-4.70 (m, 1H)、3.76 (s, 3H)、2.25-2.22 (m, 1H)、1.99-1.96 (m, 2H)、1.79-1.77 (m, 1H)、1.49 (s, 3H)。
步驟 2 : 合成甲基 5- 羥 基-2-甲基四氫-2H- 吡 喃-2- 羧 酸鹽 ( methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxyla )
一個甲基 2-甲基-3,4-二氫-2H-吡喃-2-羧酸鹽(methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate)《20.0公克,128毫莫耳》在無水四氫呋喃(anhydrous tetrahydrofuran)《200毫升》的溶液,在-5 °C逐滴加入硼烷(borane)《67毫升,1當量濃度於四氫呋喃中》,反應混合物在0 °C攪拌3小時,此反應用薄層色層分析監測;該混合物用醋酸鈉《10.5公克,128毫莫耳》在水《15毫升》中的溶液淬熄(quench),然後在0 °C用30%的過氧化氫溶液(hydrogen peroxide solution)《23.6公克,208.2毫莫耳》慢慢處理並在30℃攪拌3小時;混合物接著用飽和亞硫酸氫鈉(sodium sulfite)溶液和四氫呋喃做分離,水性層則再進一步用四氫呋喃抽提《2次》,合併的有機層用飽和鹽水洗滌,通過硫酸鈉乾燥並在真空內濃縮,賸餘物用一個凝膠管柱色層分析《梯度淘析,石油醚:醋酸乙酯=10:1至1:1》純化,得到一個淡黃色油狀粗產物的甲基 5-羥基-2-甲基四氫-2H-吡喃-2-羧酸鹽(methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxyla)《18公克,粗產物》,將直接使用於下一個步驟。
步驟 3 : 合成甲基 2- 甲基 -5- 氧代四氫 -2H- 吡 喃 -2- 羧 酸鹽 (methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate)
一個甲基 5-羥基-2-甲基四氫-2H-吡喃-2-羧酸鹽(methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxyla)《18.0公克,103毫莫耳》在無水二氯甲烷《200毫升》的溶液中,分次加入沉澱碳酸鈣(PCC;Precipitated Calcium Carbonate)《45.0公克,209毫莫耳》,反應混合物在環境溫度下攪拌,直到薄層色層分析顯示反應已完全;然後加入石油醚《500毫升》並過濾混合物,濾渣(filter cake)用石油醚《100毫升》洗滌,將濾液在真空中濃縮,得到一個淡黃色油狀的甲基 2-甲基-5-氧代四氫-2H-吡喃-2-羧酸鹽(methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate)《15公克,生成率84%》。1
H-NMR (400 MHz, CDCl3
):δ 4.25 (d,J
= 17.6 Hz, 1H)、4.07 (d,J
= 17.6 Hz, 1H)、3.81 (s, 3H)、2.52-2.44 (m, 3H)、2.11-2.04 (m, 1H)、1.53 (s, 3H)。
步驟 1 : 合成甲基 1-甲氧基-4- 羥 基 環己烷 -1- 羧 酸鹽 ( methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate )
甲基 1-甲氧基-4-氧代環己烷羧酸鹽(Methyl 1-methoxy-4-oxocyclohexanecarboxylate)《4.00公克,21.5毫莫耳》溶解於甲醇《100毫升》中,並將溶液冷卻至0℃,接著以20分鐘乙上時間分次加入氫硼化鈉(Sodium borohydride)《2.03公克,53.7毫莫耳》,然後加入飽和氯化銨水溶液淬熄,蒸發淬熄的反應混合物以移除甲醇,再用二氯甲烷抽提水性懸浮液《3次》;合併的有機層通過硫酸鈉乾燥、過濾及濃縮,生成一個賸餘物,再用矽凝膠上的快速管柱色層分析《梯度淘析,5%至100%醋酸乙酯-己烷》純化,得到一個無色油狀的甲基 1-甲氧基-4-羥基環己烷-1-羧酸鹽(methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate)《2.00公克,生成率49.5%》。MS (ES+) C9
H16
O4
要求:188,結果:211 [M+Na]+
。
步驟 2 : 合成甲基 1- 甲氧基 -4- 碘代 環己烷 -1- 羧 酸鹽 (methyl 1-methoxy-4-iodo cyclohexane-1-carboxylate)
甲基 1-甲氧基-4-羥基環己烷-1-羧酸鹽(methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate)《2.00公克,10.6毫莫耳》溶解於四氫呋喃《20毫升》中,並加入咪唑(imidazole)《723毫克,10.6毫莫耳》和三苯基膦(triphenylphosphine)《3.34毫克,12.8毫莫耳》,將混合物冷卻至0℃,然後以15分鐘以上時間逐滴加入一個碘《3.24毫克,12.8毫莫耳》在四氫呋喃《10毫升》的溶液;讓反應混合物加溫至環境溫度並攪拌2天,之後將其倒入飽和硫代硫酸鈉溶液(saturated sodium thiosulfate solution)並用醋酸乙酯抽提;有機層通過硫酸鈉乾燥、過濾、濃縮,而賸餘物則用己烷《40毫升,攪拌20分鐘》磨碎,過濾混合物,將濾液蒸發後之賸餘物,用矽凝膠上的快速管柱色層分析《梯度淘析,0至30%醋酸乙酯-己烷》純化,得到一個淡黃色油狀的標題化合物《2.37公克,生成率75%》。MS (ES+) C9
H15
IO3
要求:298,結果:299 [M+H]+
。
B. 乙基 1- 乙氧基 -4- 碘代環己烷 -1- 羧 酸鹽 (Ethyl 1-ethoxy-4-iodocyclohexane-1-carboxylate) 標題化合物之製備如前述,使用乙基 1-乙氧基-4-氧代環己烷-1-羧酸鹽(ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate)作為起始原料,C11
H19
IO3
要求:326,結果:327 [M+H]+
。
實施例
9.
合成胺中間產物
(Amine Intermediates)
A.(S)-1-(6-(4-
氟
-1H-
吡
唑
-1-
基
)
吡
啶
-3-
基
)
乙基
-1-
胺
(
(S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine
)
步驟1: 合成 1-(6-(4- 氟 -1H- 吡唑 -1- 基 )
吡啶-3- 基 ) 乙 -1- 酮 ( 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one )
將4-氟-1H-吡唑(4-Fluoro-1H-pyrazole)《4.73公克,55毫莫耳》和碳酸鉀(potassium carbonate)《17.27公克,125毫莫耳》合併,並且在加入2-溴-5-乙醯基吡啶(2-bromo-5-acetylpyridine)《10公克,50毫莫耳》之前,在一個打開密封的管子中攪拌於N,N-二甲基甲醯胺(N,N-dimethylformamide)《41.7毫升》中10分鐘,將反應管密封並於100℃攪拌20小時;然後將反應混合物冷卻至室溫,將其倒入水《~700毫升》中;該混合物用超音波處理和攪拌20分鐘,然後過濾,分離出一個淺褐色固體,用小量的水洗滌,乾燥後得到1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙-1-酮(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one)《9.81公克,生成率96%》。MS:M+1 = 206.0。
步驟2: 合成 (R)-N-((S)-1-(6-(4- 氟 -1H- 吡唑 -1- 基 )
吡啶-3- 基 ) 乙基 )-2- 甲基丙 烷 -2- 亞磺醯胺 ( (R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide )
一個被攪拌的室溫的1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙-1-酮(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one)《9.806公克,47.8毫莫耳》在四氫呋喃《96毫升》中的溶液,加入(R)-(+)-特-丁基亞磺醯胺((R)-(+)-t-Butylsulfinamide)《5.79公克,47.8毫莫耳》,接著加入鈦酸乙酯(titanium (IV)ethoxide)《21.8公克,96毫莫耳》;於75℃,在一個油浴上攪拌該溶液15小時,讓反應溶液冷卻至室溫,在下個步驟前冷卻至-78°C《外部溫度》;對該-78°C溶液,接近55分鐘時間逐滴加入三仲丁基硼氫化鋰(L-Selectride;Lithium tri-sec-butylborohydride;Lithium triisobutylhydroborate)《143毫升的1當量濃度(N)在四氫呋喃中,143毫莫耳》,在加入時可以看到有些泡沫;在完全加入後,於-78°C攪拌反應溶液15分鐘,然後加熱至室溫。在從冰浴移除時取樣樣本的液相色層分析-質譜分析(LC-MS)顯示反應已完全,反應溶液冷卻至-50°C並用甲醇《~ 10毫升》慢慢淬熄,然後倒入水《600毫升》中並攪拌;過濾移除一個灰白色沉澱,用醋酸乙酯洗滌,濾液再用醋酸乙酯《800毫升》稀釋,分離不同的液層,有機層通過硫酸鈉乾燥,過濾,及濃縮,粗產物藉由矽凝膠色層分析加以純化,得到一個淡黃色固體的(R)-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-2-甲基丙烷-2-亞磺醯胺((R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide)《10.5公克,純度99%,生成率70.3%》。MS:M+1 = 311.1。
步驟3: 合成(S)- 1-(6-(4- 氟 -1H- 吡唑 -1- 基 )
吡啶-3- 基 ) 乙基 -1- 胺 ( (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine )
一個(R)-N-((S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-2-甲基丙烷-2-亞磺醯胺((R)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane -2-sulfinamide)《10.53公克,33.9毫莫耳》在甲醇《79毫升》和4當量濃度鹽酸/二噁烷(4N HCl/dioxane)《85毫升,339毫莫耳》中的溶液,攪拌2.5小時,於此時液相色層分析-質譜分析(LC-MS)顯示反應已完全;將反應溶液倒入二乙基醚《300毫升》中形成一個黏性固體,將混合物用醋酸乙酯《200毫升》和超音波處理,輕輕倒出溶劑,該黏性固體再用更多的醋酸乙酯《~200毫升》和超音波處理並攪拌,黏性固體的塊頭轉化成一個懸浮液;過濾分離出一個淺黃色固體,用更少量的醋酸乙酯洗滌,乾燥,生成(S)-1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基-1-胺((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine)《7.419公克,生成率78%》。液相色層分析-質譜分析(LC-MS)確認係高純度的所要產物。MS:M+1 = 207.1。
B.
(S)-1-(5-(4-
氟
-1H-
吡
唑
-1-
基)吡嗪-2-基)乙基-1-胺
(
(S)-1-(5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)ethan-1-amine
)
步驟1: 合成 1-( 5 -(4- 氟 -1H- 吡唑 -1- 基 )
吡嗪 - 2 - 基 ) 乙 -1- 酮 ( 1-(5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)ethan-1-one )
一個1-(5-氯吡嗪-2-基)乙酮(1-(5-chloropyrazin-2-yl)ethanone)《800毫克,5.11毫莫耳》和4-氟-1H-吡唑(4-fluoro-1H-pyrazole)《484毫克,5.62毫莫耳》在N,N-二甲基甲醯胺(N,N-dimethylformamide)《6.0毫升》中的混合物,在環境溫度下,已10分鐘時間,加入氫化鈉(Sodium hydride)《60%重量比,276毫克,6.90毫莫耳》,然後將反應混合物倒入水《70毫升》中,並超音波處理及攪拌20分鐘,過濾,分離出一個暗紅色固體,用少量的水洗滌,乾燥,得到1-(5-(4-氟-1H-吡唑-1-基)吡嗪-2-基)乙-1-酮(1-(5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl) ethan-1-one)《919公克,生成率95%》。MS:M+1 = 207。
步驟2: 合成(R)-N-((S)-1-(5-(4-氟 -1H- 吡唑 -1- 基 )
吡嗪 - 2 - 基 ) 乙基)-2-甲基丙 烷 -2- 亞磺醯胺 ( (R)-N-((S)-1-(5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)ethyl)-2-methylpropane-2-sulfinamide )
一個被攪拌的室溫的1-(5-(4-氟-1H-吡唑-1-基)吡嗪-2-基)乙-1-酮(1-(5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl) ethan-1-one)《4.67公克,22.7毫莫耳》在四氫呋喃《45毫升》中的溶液,加入(R)-(+)-特-丁基亞磺醯胺((R)-(+)-t-Butylsulfinamide)《2.75公克,22.7毫莫耳》,接著加入鈦酸乙酯(titanium (IV)ethoxide)《10.3公克,45.3毫莫耳》;於75℃,在一個油浴上攪拌該溶液20小時,讓反應溶液冷卻至室溫,在下個步驟前冷卻至-78°C;對該-78°C溶液,以50分鐘以上時間逐滴加入三仲丁基硼氫化鋰(L-Selectride;Lithium tri-sec-butylborohydride;Lithium triisobutylhydroborate)《50.1毫升的1當量濃度(N)在四氫呋喃中,50.1毫莫耳》,在加入時可以看到有些泡沫;在完全加入後,於-78°C攪拌反應溶液15分鐘,然後加熱至室溫。在從冰浴移除時取樣樣本的液相色層分析-質譜分析(LC-MS)顯示反應已完全,反應溶液冷卻至-60°C並用甲醇《 1毫升》慢慢淬熄,然後倒入水《100毫升》中並攪拌;過濾混合物,用醋酸乙酯再進一步洗滌固體,濾液用醋酸乙酯稀釋,有機層通過硫酸鈉乾燥,過濾,及濃縮,生成的賸餘物藉由矽凝膠上的快速管柱色層分析《梯度淘析,0至100%醋酸乙酯-二氯甲烷》純化,得到一個褐色固體的(R)-N-((S)-1-(5-(4-氟-1H-吡唑-1-基)吡嗪-2-基)乙基)-2-甲基丙烷-2-亞磺醯胺((R)-N-((S)-1-(5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)ethyl)-2-methylpropane-2-sulfinamide)《1.04公克,生成率14%》。MS:M+1 = 312。1
H NMR (400 MHz, DMSO-d6
) δ 9.12 (d,J
= 1.4 Hz, 1H)、8.73 (d,J
= 4.5 Hz, 1H)、8.59 (d,J
= 1.4 Hz, 1H)、8.03 (d,J
= 4.1 Hz, 1H)、5.69 (d,J
= 5.7 Hz, 1H)、4.62 (p,J
= 6.8 Hz, 3H)、1.57 (d,J
= 6.9 Hz, 3H)、1.12 (s, 9H)。
步驟3: 合成(S)-1-(5-(4-氟 -1H- 吡唑 -1- 基 )
吡嗪 - 2 - 基 ) 乙基-1-胺 ( (S)-1-(5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)ethan-1-amine )
一個(R)-N-((S)-1-(5-(4-氟-1H-吡唑-1-基)吡嗪-2-基)乙基)-2-甲基丙烷-2-亞磺醯胺((R)-N-((S)-1-(5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)ethyl) -2-methylpropane-2-sulfinamide)《1.04公克,3.34毫莫耳》在甲醇《7.8毫升》和4當量濃度鹽酸/二噁烷(4N HCl/dioxane)《8.34毫升,33.4毫莫耳》中的溶液,在環境溫度下攪拌1.5小時,將反應混合物倒入二乙基醚《100毫升》中,過濾分離出一個淺米色固體,係(S)-1-(5-(4-氟-1H-吡唑-1-基)吡嗪-2-基)乙基-1-胺((S)-1-(5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)ethan-1-amine)《689毫克,生成率85%》。MS:M+1 = 208。
C. (5-(4- 氟 -1H- 吡唑 -1- 基 ) 吡 嗪 -2- 基 ) 甲烷胺 ( (5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)methanamine ) 步驟1: 合成 5-(4- 氟 -1H- 吡唑 -1- 基 )
吡嗪 -2- 腈( 5-(4-fluoro-1H-pyrazol-1-yl)pyrazine-2-carbonitrile )
一個5-氯吡嗪-2-腈(5-chloropyrazine-2-carbonitrile)《280毫克,2.0毫莫耳》在二甲基甲醯胺(DMF)中的溶液,加入4-氟-1H-吡唑(4-fluoro-1H-pyrazole)《170毫克,2.0毫莫耳》和醋酸鉀《395毫克,4.0毫莫耳》,反應混合物在100℃攪拌4小時,然後冷卻至20℃,倒進鹽水《25毫升》中,並用醋酸乙酯萃取;有機層用硫酸鈉乾燥、濃縮,並以管柱色層分析《己烷:醋酸乙酯=5:1》純化,得到5-(4-氟-1H-吡唑-1-基)吡嗪-2-腈(5-(4-fluoro-1H-pyrazol-1-yl)pyrazine-2-carbonitrile)《310毫克,生成率82%》。其結構以液相色層分析-質譜分析(LC-MS)確認。
步驟2: 合成 5-(4- 氟 -1H- 吡唑 -1- 基 ) 甲 烷
胺( (5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)methanamine )
一個5-(4-氟-1H-吡唑-1-基)吡嗪-2-腈(5-(4-fluoro-1H-pyrazol-1-yl)pyrazine-2-carbonitrile)《190毫克,1.0毫莫耳》和氯化鎳(NiCl2
;Nickel(II) chloride)《12毫克,0.1毫莫耳》在甲醇《5毫升》中的混合物,在0℃加入硼氫化鈉(NaBH4
;sodium borohydride)《380毫克, 10毫莫耳》,並在0℃攪拌混合物2小時,用氯化銨水溶液淬熄,再以高效液相色層分析(HPLC)純化,得到5-(4-氟-1H-吡唑-1-基)甲烷胺((5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)methanamine)《160毫克,生成率82%》。其結構以液相色層分析-質譜分析(LC-MS)確認。
D.
(6-(3,5-
二甲基
-1H-
吡唑
-1-
基
)
吡
啶
-3-
基
)
甲烷
胺(
(6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methanamine
)
步驟1: 合成6-(3,5-二甲基-1H- 吡唑 -1- 基 ) 菸鹼甲 腈 ( 6-(3,5-dimethyl-1H-pyrazol-1-yl)nicotinonitrile )
一個6-氯菸鹼甲腈(6-chloronicotinonitrile)《300毫克,2.2毫莫耳》在二甲基甲醯胺(DMF)《10毫升》中的溶液,加入3,5-二甲基-1H-吡唑(3,5-dimethyl-1H-pyrazole)《210毫克,2.2毫莫耳》和碳酸銫(Cs2
CO3
)《1.4公克,4.4毫莫耳》,混合物在90℃攪拌16小時,然後用水《25毫升》稀釋混合物並過濾,所的固體用水洗滌並在真空下乾燥,得到6-(3,5-二甲基-1H-吡唑-1-基)菸鹼甲腈(6-(3,5-dimethyl-1H-pyrazol-1-yl)nicotinonitrile)《320毫克,生成率74.6%》。
步驟2: 合成特-丁基 ((6-(3,5-二甲基- 1H- 吡唑 -1- 基 )
吡啶-3- 基 ) 甲基)胺甲酸鹽 ( tert-Butyl ((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)carbamate )
一個6-(3,5-二甲基-1H-吡唑-1-基)菸鹼甲腈(6-(3,5-dimethyl-1H-pyrazol-1-yl) nicotinonitrile)《300毫克,1.5毫莫耳》在甲醇《10毫升》中的溶液,加入氯化鎳(NiCl2
)《19毫克,0.15毫莫耳》、二碳酸二叔丁酯((Boc)2
O;Di-t-butyl dicarbonate)《654毫克,3.0毫莫耳》、和硼氫化鈉(NaBH4
)《142毫克,3.8毫莫耳》,在環境溫度攪拌混合物3小時;然後加入飽和氯化銨水溶液,並在真空下移除甲醇;水性懸浮液用醋酸乙酯分離,有機層用飽和碳酸氫鈉溶液洗滌《2 x 50毫升》,再用無水硫酸鈉乾燥、過濾,在真空下濃縮,得到450毫克的目標化合物,不再進一步純化,直接使用於下一個步驟。
步驟3: 合成 (6-(3,5- 二甲基 -1H- 吡唑 -1- 基 )
吡啶-3- 基 ) 甲 烷胺( (6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methanamine
) 一個氯化氫在二噁烷的溶液《4.0莫耳濃度,10毫升》加入化合物特-丁基 ((6-(3,5-二甲基-1H-吡唑-1-基)吡啶-3-基)甲基)胺甲酸鹽《450毫克》,攪拌混合物2小時,然後在減壓下濃縮混合物,生成一個淡褐色固體的標題化合物《350毫克》即可,不再進一步純化。1
H NMR (400 MHz, DMSO-d6
) δ 8.51 (d,J
=2.1 Hz, 1H)、8.34 (s, 3H)、8.03 (dd,J
= 8.5, 2.4 Hz, 1H)、7.87 (d,J
= 8.5 Hz, 1H)、6.14 (s, 1H)、4.12 (q,J
= 5.7 Hz, 2H)、2.59 (s, 3H)、2.21 (s, 3H)。
步驟1: 合成6-(4-氯-1H- 吡唑 -1- 基 ) 菸鹼甲 腈 ( 6-(4-Chloro-1H-pyrazol-1-yl)nicotinonitrile )
一個6-氯菸鹼甲腈(6-chloronicotinonitrile)《300毫克,2.2毫莫耳》在二甲基甲醯胺(DMF)《10毫升》中的溶液,加入4-氯-1H-吡唑(4-chloro-1H-pyrazole)《227毫克,2.2毫莫耳》和碳酸銫(Cs2
CO3
)《1.4公克,4.4毫莫耳》,混合物在90℃攪拌16小時,然後用水《25毫升》稀釋混合物並過濾,所的固體用水洗滌並在真空下乾燥,得到6-(4-氯-1H-吡唑-1-基)菸鹼甲腈(6-(4-chloro-1H-pyrazol-1-yl) nicotinonitrile)《380毫克,生成率84%》,不再進一步純化,使用於下一個步驟。
步驟2: 合成特-丁基 ((6-(4-氯- 1H- 吡唑 -1- 基 )
吡啶-3- 基 ) 甲基)胺甲酸鹽 ( tert-Butyl ((6-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)carbamate )
一個6-(4-氯-1H-吡唑-1-基)菸鹼甲腈(6-(4- chloro-1H-pyrazol-1-yl) nicotinonitrile)《350毫克,1.7毫莫耳》在甲醇《10毫升》中的溶液,加入氯化鎳(NiCl2
)《19毫克,0.17毫莫耳》、二碳酸二叔丁酯((Boc)2
O7)《741毫克,3.4毫莫耳》、和硼氫化鈉(NaBH4
)《163毫克,4.3毫莫耳》,在環境溫度攪拌混合物3小時;然後加入飽和氯化銨水溶液,並在真空下移除甲醇;水性懸浮液用醋酸乙酯分離,有機層用飽和碳酸氫鈉溶液洗滌《2 x 50毫升》,再用無水硫酸鈉乾燥、過濾,在真空下濃縮,得到480毫克的標題化合物,不再進一步純化,直接使用於下一個步驟。
步驟3: 合成 (6-( 4 - 氯 -1H- 吡唑 -1- 基 )
吡啶-3- 基 ) 甲 烷胺( (6-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine
) 一個氯化氫在二噁烷的溶液《4.0莫耳濃度,10毫升》,在環境溫度下加入化合物特-丁基 ((6-(4-氯-1H-吡唑-1-基)吡啶-3-基)甲基)胺甲酸鹽《450毫克,1.5毫莫耳》,攪拌混合物2小時,然後在減壓下濃縮混合物,生成一個淡褐色固體的標題化合物《290毫克》即可,不再進一步純化。MS:M+1 = 209。
F.
(R)-1-(6-(4-
氟
-1H-
吡
唑
-1-
基)吡
啶
-3-
基)乙基-1-胺
(
(R)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine
)
步驟1-3:(R)-1-(6-(4- 氟 -1H- 吡 唑 -1- 基)吡 啶 -3- 基)乙基-1-胺 ( (R)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine )
本化合物係使用與製備本化合物的S鏡像異構物(Enantiomers)所描述之相同程序,由1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙-1-酮(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one)製備而得,除了以(S)-(-)-特-丁基亞磺醯胺((S)-(-)-t-Butylsulfinamide)取代(R)-(+)-特-丁基亞磺醯胺((R)-(+)-t-Butylsulfinamide)作為手性助劑(chiral auxiliary)。MS (ES+) C10
H11
FN4
要求:206,結果:207 [M+H]+
。 用來製備此處揭示的化合物的合成方案顯示於下,此處揭示的化合物的核磁共振(NMR)及液相色層分析-質譜分析(LC-MS)數據也顯示於下。
實施例10: 化合物的生物活性之量測
為了評估化學化合物對抗有嫌疑的相關聯激酶的活性,使用卡尺生命科學公司(Caliper LifeSciences)電泳遷移率技術平台(electrophoretic mobility shift technology platform),在激酶和腺嘌呤核苷三磷酸(ATP;adenosine triphosphate)的存在下,培養螢光標示的受質胜肽(substrate peptide),因此胜肽的一個反應部分被磷酸化(phosphorylated),在反應終點,磷酸化《生成物》和未磷酸化《受質》胜肽的混合物於一個施加電位差(potential difference)下通過卡尺公司便利閱讀器(Caliper EZ Reader 2)微流道系統(microfluidic system),在生成物胜肽上的磷酸根基團在質量和電荷方面呈現與受質胜肽的差異,結果在樣本中產生受質和生成物池的分離;當這些池(pools)通過儀器內的LEDS,這些池受到檢測而解析為不同波峰(peaks),因此這些波峰間的比率反映出於那些情況下在該試驗井(well)中於該濃度之化學物質的活性。
A. 在 昆明小鼠
的轉染過程重排原生型試驗(RET wild type assay at KM
) 一個384試驗井(384-well)的試驗盤的每一個試驗井中,在處於存在或缺乏一個劑量濃度系列的化合物《1%二甲基亞碸(DMSO;Dimethyl sulfoxide)》的情形下,於25℃,將7.5 奈米(nM)- 10奈米的原生型轉染過程重排(ProQinase 1090-0000-1)培養於一個含1微米(µM)CSKtide《FITC-AHA-KKKKD DIYFFFG-NH2》和25微米腺嘌呤核苷三磷酸(ATP)總計有12.5微升(µL)緩衝液《100毫米的4-羥乙基哌嗪乙磺酸(HEPES;4-(2-Hydroxyethyl) -1-piperazineethanesulfonic acid)、酸鹼值7.5;0.015%布里杰35《十二烷基聚乙二醇醚》(BriJ
35;Polyoxyethylene Lauryl Ether);10毫米的氯化鎂;1毫米的二硫蘇糖醇(DTT;Dithiothreitol)》中120分鐘,反應結束係藉由加入70微升的停止緩衝液(Stop buffer)《100毫米的4-羥乙基哌嗪乙磺酸、酸鹼值7.5;0.015%布里杰35;35毫米的乙二胺四乙酸(EDTA; Ethylene diamine tetraacetic acid);和0.2%的塗覆試劑3(Coating Reagent 3)(卡尺生命科學公司)》;然後在一個卡尺公司便利閱讀器2(Caliper EZReader 2)《協議設定:-1.7帕(psi);上行電壓:-500;下行電壓:-3000;提交樣本量:35s》上讀取試驗盤,將數據正常化為0%至100%抑制控制,並用一個切合在CORE LIMS 中的4-參數計算半數抑制濃度(IC50
)。
B. 在 昆明小鼠
的轉染過程重排V804L守門人突變體試驗(RET V804L Gatekeeper mutant assay at KM
) 一個384試驗井(384-well)的試驗盤的每一個試驗井中,在處於存在或缺乏一個劑量濃度系列的化合物《1%二甲基亞碸(DMSO;Dimethyl sulfoxide)》的情形下,於25℃,將7.5 奈米(nM)-10奈米的突變體轉染過程重排(ProQinase 1096-0000-1)培養於一個含1微米(µM)CSKtide《FITC-AHA-KKKKD DIYFFFG-NH2》和10微莫耳腺嘌呤核苷三磷酸(ATP)總計有12.5微升(µL)緩衝液《100毫米的4-羥乙基哌嗪乙磺酸(HEPES)、酸鹼值7.5;0.015%布里杰35《十二烷基聚乙二醇醚》(BriJ
35;Polyoxyethylene Lauryl Ether);10毫米的氯化鎂;1毫米的二硫蘇糖醇(DTT)》中120分鐘;反應結束係藉由加入70微升的停止緩衝液(Stop buffer)《100毫米的4-羥乙基哌嗪乙磺酸、酸鹼值7.5;0.015%布里杰35;35毫米的乙二胺四乙酸(EDTA);和0.2%的塗覆試劑3(Coating Reagent 3)(卡尺生命科學公司)》;然後在一個卡尺公司便利閱讀器2(Caliper EZReader 2)《協議設定:-1.7帕(psi);上行電壓:-500;下行電壓:-3000;提交樣本量:35s》上讀取試驗盤,將數據正常化為0%至100%抑制控制,並用一個切合在CORE LIMS 中的4-參數計算半數抑制濃度(IC50
)。
參引合併
此處所述之所有出版發表和專利其全部於此併入做為參考,猶如每一個出版發表或專利係獨特地和個別地被指示併入做為參考。
等效物
本領域所屬技術人員,至多使用常規實驗,可以認知、或能夠確知此處所描述之本發明的特殊具體模式例的許多等效物(equivalents),這些等效物也將被包含在以下申請專利範圍。
Claims (31)
- 一種化合物或其藥劑學上可接受的鹽類,該化合物具有式(A):
- 如請求項1或2之化合物或其藥劑學上可接受的鹽類,其中:m係1;R1係位於5-位置;及R1係以0-3個Ra取代的C1-C4烷基。
- 如請求項1或2之化合物或其藥劑學上可接受的鹽類,其中R2係選自氫、羥基、鹵代和C1-C4烷氧基。
- 如請求項1或2之化合物或其藥劑學上可接受的鹽類,其中每一者的R3a,R3b,R8a和R8b係各自獨立地選自氫和以0-3個Ra取代的C1-C4烷基。
- 如請求項1或2之化合物或其藥劑學上可接受的鹽類,其中至少一對R3a和R3b或R8a和R8b係同時為氫。
- 如請求項1或2之化合物或其藥劑學上可接受的鹽類,其中R4係選自氫、C1-C4烷基和C1-C4烷氧基,其中每一個R4的烷基部分係以0-3個Ra取代。
- 如請求項1或2之化合物或其藥劑學上可接受的鹽類,其中R5係選自氫、以0-3個Ra取代的C1-C4烷基。
- 如請求項1或2之化合物或其藥劑學上可接受的鹽類,其中R6係各自獨立地選自氫、鹵代、和以0-3個Ra取代的C1-C4烷基。
- 如請求項1或2之化合物或其藥劑學上可接受的鹽類,其中環A係6員單環型雜芳基,環原子包含至少一個氮的環原子。
- 如請求項1或2之化合物或其藥劑學上可接受的鹽類,其中:n是1;及R7係吡唑-1-基,以0-3個Ra取代。
- 如請求項1或2之化合物或其藥劑學上可接受的鹽類,其中R9是氫。
- 如請求項14之化合物或其藥劑學上可接受的鹽類,其中:X1係選自N、CH和C(Cl);R12係選自氫、羥基、氟代和-O-CH3;R13a、R13b、R18a和R18b的每一者係獨立地選自氫、甲基和乙基,其中至少一對的R13a和R13b、或R18a和R18b係同時為氫;R14係選自氫、-CH3、-CH2CH3、-OCH3和-OCH2CH3;R15係選自氫和-CH3; R16係選自氫和-CH3;R17b係選自氫、氯代和氟代;R17a和R17c係同時為氫或-CH3,其中當R17a和R17c同時為-CH3時,R17b是氫。
- 一種藥劑組成物,包含如請求項1至18中任一項之化合物或其藥劑學上可接受的鹽類;以及藥劑學上可接受的載體。
- 一種如請求項1至18中任一項之化合物或其藥劑學上可接受的鹽類用於製造藥物之用途,該藥物係用於治療患有非小細胞肺癌(non-small cell lung cancer)之個體。
- 一種如請求項1至18中任一項之化合物或其藥劑學上可接受的鹽類用於製造藥物之用途,該藥物係用於治療患有甲狀腺乳突癌(papillary thyroid carcinoma)之個體。
- 一種如請求項1至18中任一項之化合物或其藥劑學上可接受的鹽類用於製造藥物之用途,該藥物係用於治療患有甲狀腺髓質癌(medullary thyroid cancer)之個體。
- 一種如請求項1至18中任一項之化合物或其藥劑學上可接受的鹽類用於製造藥物之用途,該藥物係用於治療大腸直腸癌(colorectal cancer)之個體。
- 一種如請求項1至18中任一項之化合物或其藥劑學上可接受的鹽類用於製造藥物之用途,該藥物係用於治療患有多發性內分泌瘤病(multiple endocrine neoplasia)之個體。
- 一種如請求項1至18中任一項之化合物或其藥劑學上可接受的鹽類用於製造藥物之用途,該藥物係用於在有其需要的個體中治療以轉染過程重排(RET)融合物或RET突變介導之癌症。
- 一種如請求項19之藥劑組成物用於製造藥物之用途,該藥物係用於治療患有非小細胞肺癌(non-small cell lung cancer)之個體。
- 一種如請求項19之藥劑組成物用於製造藥物之用途,該藥物係用於治療患有甲狀腺乳突癌(papillary thyroid carcinoma)之個體。
- 一種如請求項19之藥劑組成物用於製造藥物之用途,該藥物係用於治療患有甲狀腺髓質癌(medullary thyroid cancer)之個體。
- 一種如請求項19之藥劑組成物用於製造藥物之用途,該藥物係用於治療大腸直腸癌(colorectal cancer)之個體。
- 一種如請求項19之藥劑組成物用於製造藥物之用途,該藥物係用於治療患有多發性內分泌瘤病(multiple endocrine neoplasia)之個體。
- 一種如請求項19之藥劑組成物用於製造藥物之用途,該藥物係用於在有其需要的個體中治療以轉染過程重排(RET)融合物或RET突變介導之癌症。
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