TWI752026B - 一類蛋白激酶抑制劑 - Google Patents

Info

Publication number

TWI752026B

TWI752026B TW106114998A TW106114998A TWI752026B TW I752026 B TWI752026 B TW I752026B TW 106114998 A TW106114998 A TW 106114998A TW 106114998 A TW106114998 A TW 106114998A TW I752026 B TWI752026 B TW I752026B

Authority

TW

Taiwan

Prior art keywords

compound

pharmaceutically acceptable

acceptable salt

alkyl

amino

Prior art date

2016-05-07

Links

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• Global Dossier
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• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title 1
• 239000003909 protein kinase inhibitor Substances 0.000 title 1
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
• 150000001875 compounds Chemical class 0.000 claims description 154
• -1 2-piperidinyl Chemical group 0.000 claims description 142
• 150000003839 salts Chemical class 0.000 claims description 80
• 125000000217 alkyl group Chemical group 0.000 claims description 77
• 239000003814 drug Substances 0.000 claims description 40
• 229910052757 nitrogen Inorganic materials 0.000 claims description 40
• 125000000623 heterocyclic group Chemical group 0.000 claims description 37
• 125000001424 substituent group Chemical group 0.000 claims description 29
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
• 229910052739 hydrogen Inorganic materials 0.000 claims description 26
• 239000001257 hydrogen Substances 0.000 claims description 26
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 19
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 18
• NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 17
• 150000002431 hydrogen Chemical class 0.000 claims description 16
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 229940124597 therapeutic agent Drugs 0.000 claims description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 9
• 229910052736 halogen Inorganic materials 0.000 claims description 9
• 230000005764 inhibitory process Effects 0.000 claims description 9
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 150000002367 halogens Chemical class 0.000 claims description 8
• 238000002360 preparation method Methods 0.000 claims description 8
• 241000009298 Trigla lyra Species 0.000 claims description 7
• 125000004414 alkyl thio group Chemical group 0.000 claims description 7
• 239000004202 carbamide Substances 0.000 claims description 7
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 7
• 125000003386 piperidinyl group Chemical group 0.000 claims description 7
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
• 102000003903 Cyclin-dependent kinases Human genes 0.000 claims description 5
• 108090000266 Cyclin-dependent kinases Proteins 0.000 claims description 5
• 230000002159 abnormal effect Effects 0.000 claims description 5
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
• FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 claims description 3
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
• 230000004663 cell proliferation Effects 0.000 claims description 3
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 3
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 3
• MXXWOMGUGJBKIW-YPCIICBESA-N piperine Chemical compound C=1C=C2OCOC2=CC=1/C=C/C=C/C(=O)N1CCCCC1 MXXWOMGUGJBKIW-YPCIICBESA-N 0.000 claims description 3
• WVWHRXVVAYXKDE-UHFFFAOYSA-N piperine Natural products O=C(C=CC=Cc1ccc2OCOc2c1)C3CCCCN3 WVWHRXVVAYXKDE-UHFFFAOYSA-N 0.000 claims description 3
• 229940075559 piperine Drugs 0.000 claims description 3
• 235000019100 piperine Nutrition 0.000 claims description 3
• HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 claims description 3
• 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 2
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 2
• PGGPKYATZSPYKB-HPRDVNIFSA-N C1(CCCC1)C1=C(SC2=C1N=C(N=C2)NC1=NC=C(C=C1)N1CCC(CC1)N1CCN(CC1)C([2H])([2H])[2H])C(=O)N(C)C Chemical compound C1(CCCC1)C1=C(SC2=C1N=C(N=C2)NC1=NC=C(C=C1)N1CCC(CC1)N1CCN(CC1)C([2H])([2H])[2H])C(=O)N(C)C PGGPKYATZSPYKB-HPRDVNIFSA-N 0.000 claims description 2
• 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims description 2
• 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• 150000001345 alkine derivatives Chemical class 0.000 claims 1
• 229940124297 CDK 4/6 inhibitor Drugs 0.000 abstract description 5
• 235000002639 sodium chloride Nutrition 0.000 description 63
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 50
• 201000010099 disease Diseases 0.000 description 38
• 238000000034 method Methods 0.000 description 34
• 125000003118 aryl group Chemical group 0.000 description 33
• 125000004432 carbon atom Chemical group C* 0.000 description 32
• 125000001072 heteroaryl group Chemical group 0.000 description 28
• 239000000203 mixture Substances 0.000 description 27
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 25
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 25
• 239000002585 base Substances 0.000 description 25
• 238000011282 treatment Methods 0.000 description 23
• 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 description 22
• 125000000753 cycloalkyl group Chemical group 0.000 description 21
• 229940079593 drug Drugs 0.000 description 21
• 229910052717 sulfur Inorganic materials 0.000 description 20
• 239000000243 solution Substances 0.000 description 19
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
• 239000000543 intermediate Substances 0.000 description 18
• 210000004027 cell Anatomy 0.000 description 17
• 238000006243 chemical reaction Methods 0.000 description 17
• 125000005842 heteroatom Chemical group 0.000 description 17
• 125000000304 alkynyl group Chemical group 0.000 description 16
• 229910052760 oxygen Inorganic materials 0.000 description 15
• 206010028980 Neoplasm Diseases 0.000 description 14
• 239000002253 acid Substances 0.000 description 14
• 230000000694 effects Effects 0.000 description 14
• 208000024891 symptom Diseases 0.000 description 14
• 125000006239 protecting group Chemical group 0.000 description 13
• 229920006395 saturated elastomer Polymers 0.000 description 13
• 125000004429 atom Chemical group 0.000 description 12
• 208000035475 disorder Diseases 0.000 description 12
• 239000004480 active ingredient Substances 0.000 description 11
• 230000008901 benefit Effects 0.000 description 11
• 239000003112 inhibitor Substances 0.000 description 11
• 239000011734 sodium Substances 0.000 description 11
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
• 229910052799 carbon Inorganic materials 0.000 description 9
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 9
• 238000004519 manufacturing process Methods 0.000 description 9
• 239000000126 substance Substances 0.000 description 9
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
• 125000003342 alkenyl group Chemical group 0.000 description 8
• 125000005366 cycloalkylthio group Chemical group 0.000 description 8
• 230000002401 inhibitory effect Effects 0.000 description 8
• 230000002062 proliferating effect Effects 0.000 description 8
• 150000003254 radicals Chemical class 0.000 description 8
• 239000011593 sulfur Chemical group 0.000 description 8
• 230000001225 therapeutic effect Effects 0.000 description 8
• 108091007914 CDKs Proteins 0.000 description 7
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
• 241000124008 Mammalia Species 0.000 description 7
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
• 125000004433 nitrogen atom Chemical group N* 0.000 description 7
• 239000001301 oxygen Substances 0.000 description 7
• 230000002829 reductive effect Effects 0.000 description 7
• 239000002904 solvent Substances 0.000 description 7
• 239000000725 suspension Substances 0.000 description 7
• 238000010189 synthetic method Methods 0.000 description 7
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 6
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
• 125000003282 alkyl amino group Chemical group 0.000 description 6
• 150000001721 carbon Chemical group 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 125000004122 cyclic group Chemical group 0.000 description 6
• 235000014113 dietary fatty acids Nutrition 0.000 description 6
• 239000000194 fatty acid Substances 0.000 description 6
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• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
• 238000001727 in vivo Methods 0.000 description 6
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• 229920001223 polyethylene glycol Chemical class 0.000 description 6
• 239000000047 product Substances 0.000 description 6
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
• 241001465754 Metazoa Species 0.000 description 5
• 150000001204 N-oxides Chemical class 0.000 description 5
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
• 150000001412 amines Chemical class 0.000 description 5
• 201000011510 cancer Diseases 0.000 description 5
• 239000003480 eluent Substances 0.000 description 5
• 239000007788 liquid Substances 0.000 description 5
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
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• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
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• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
• QKOJVRNBAUVMHT-UHFFFAOYSA-N 7-cyclopentyl-N,N-dimethyl-2-[[5-(4-morpholin-4-ylpiperidin-1-yl)pyridin-2-yl]amino]thieno[3,2-d]pyrimidine-6-carboxamide Chemical compound CN(C)C(=O)C1=C(C2CCCC2)C2=NC(NC3=NC=C(C=C3)N3CCC(CC3)N3CCOCC3)=NC=C2S1 QKOJVRNBAUVMHT-UHFFFAOYSA-N 0.000 description 4
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• FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
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• 125000003710 aryl alkyl group Chemical group 0.000 description 4
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• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
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