MXPA99000483A - Biciclic heteroaromatic compounds as protein inhibitors tirosin cin - Google Patents
Biciclic heteroaromatic compounds as protein inhibitors tirosin cinInfo
- Publication number
- MXPA99000483A MXPA99000483A MXPA/A/1999/000483A MX9900483A MXPA99000483A MX PA99000483 A MXPA99000483 A MX PA99000483A MX 9900483 A MX9900483 A MX 9900483A MX PA99000483 A MXPA99000483 A MX PA99000483A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- compound
- group
- alkoxy
- methyl
- Prior art date
Links
- 150000002390 heteroarenes Chemical class 0.000 title abstract 2
- 239000012268 protein inhibitor Substances 0.000 title 1
- 229940121649 protein inhibitors Drugs 0.000 title 1
- -1 bicyclic heteroaromatic compounds Chemical class 0.000 claims abstract description 264
- 150000001875 compounds Chemical class 0.000 claims abstract description 182
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 27
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims abstract description 19
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 201000011510 cancer Diseases 0.000 claims abstract description 11
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 201000004681 psoriasis Diseases 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 166
- 229910052799 carbon Inorganic materials 0.000 claims description 112
- 125000003545 alkoxy group Chemical group 0.000 claims description 79
- 125000003282 alkyl amino group Chemical group 0.000 claims description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 44
- 239000011780 sodium chloride Substances 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 38
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 32
- 239000012453 solvate Substances 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 230000000694 effects Effects 0.000 claims description 17
- 150000002431 hydrogen Chemical group 0.000 claims description 17
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 17
- 150000002367 halogens Chemical group 0.000 claims description 16
- 125000005842 heteroatoms Chemical group 0.000 claims description 15
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 15
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000002837 carbocyclic group Chemical group 0.000 claims description 10
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 8
- 230000001404 mediated Effects 0.000 claims description 8
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 8
- 125000004429 atoms Chemical group 0.000 claims description 7
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 7
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 7
- 150000003536 tetrazoles Chemical group 0.000 claims description 7
- 150000003852 triazoles Chemical group 0.000 claims description 7
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- SNQXJPARXFUULZ-UHFFFAOYSA-N dioxolane Chemical compound C1COOC1 SNQXJPARXFUULZ-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 230000001594 aberrant Effects 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- CHXUFRRQOZZSNV-UHFFFAOYSA-N 1-methylpiperidine Chemical group [CH2]N1CCCCC1 CHXUFRRQOZZSNV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000004989 dicarbonyl group Chemical group 0.000 claims description 4
- 125000004175 fluorobenzyl group Chemical group 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 229910052721 tungsten Inorganic materials 0.000 claims description 4
- 229910052720 vanadium Inorganic materials 0.000 claims description 4
- LOOADDNERSICKU-UHFFFAOYSA-N 6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]-N-(4-phenylmethoxyphenyl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 LOOADDNERSICKU-UHFFFAOYSA-N 0.000 claims description 3
- NVWYKCCRMGMTKD-UHFFFAOYSA-N 6-[5-[(3-methylsulfonylpropylamino)methyl]furan-2-yl]-N-(4-phenylmethoxyphenyl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound O1C(CNCCCS(=O)(=O)C)=CC=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 NVWYKCCRMGMTKD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 3
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 3
- MRYASQNSJAHEQV-UHFFFAOYSA-N 1$l^{2}-azolidin-2-one Chemical group O=C1CCC[N]1 MRYASQNSJAHEQV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- OWHIHBDLHCKOAP-UHFFFAOYSA-N N-(4-phenylmethoxyphenyl)-6-[5-[(pyridin-3-ylamino)methyl]furan-2-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound C=1C=C(C=2N=CC3=NC=NC(NC=4C=CC(OCC=5C=CC=CC=5)=CC=4)=C3C=2)OC=1CNC1=CC=CN=C1 OWHIHBDLHCKOAP-UHFFFAOYSA-N 0.000 claims description 2
- WEFQNMCUXORRGW-UHFFFAOYSA-N N-[2-[[5-[4-(4-phenylmethoxyanilino)pyrido[3,4-d]pyrimidin-6-yl]furan-2-yl]methylamino]ethyl]methanesulfonamide Chemical compound O1C(CNCCNS(=O)(=O)C)=CC=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 WEFQNMCUXORRGW-UHFFFAOYSA-N 0.000 claims description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 2
- XKQOCHOBKQOARA-UHFFFAOYSA-N [5-[4-(4-phenylmethoxyanilino)pyrido[3,4-d]pyrimidin-6-yl]furan-2-yl]methanol Chemical compound O1C(CO)=CC=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 XKQOCHOBKQOARA-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 2
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 2
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 claims description 2
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- BWESROVQGZSBRX-UHFFFAOYSA-N pyrido[3,2-d]pyrimidine Chemical group C1=NC=NC2=CC=CN=C21 BWESROVQGZSBRX-UHFFFAOYSA-N 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 229960001663 sulfanilamide Drugs 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- UBBFJKUPJFYFKH-UHFFFAOYSA-N 6-[5-[[methyl(2-methylsulfonylethyl)amino]methyl]furan-2-yl]-N-(4-phenylmethoxyphenyl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound O1C(CN(CCS(C)(=O)=O)C)=CC=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 UBBFJKUPJFYFKH-UHFFFAOYSA-N 0.000 claims 1
- JJCLPGDGYPAVDE-UHFFFAOYSA-N C[N-]CC(O)=O Chemical compound C[N-]CC(O)=O JJCLPGDGYPAVDE-UHFFFAOYSA-N 0.000 claims 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 claims 1
- 235000015450 Tilia cordata Nutrition 0.000 claims 1
- 235000011941 Tilia x europaea Nutrition 0.000 claims 1
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims 1
- 239000004571 lime Substances 0.000 claims 1
- 230000001718 repressive Effects 0.000 claims 1
- IAFSUZIBZMPMPK-UHFFFAOYSA-N thiomorpholin-4-amine Chemical compound NN1CCSCC1 IAFSUZIBZMPMPK-UHFFFAOYSA-N 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 18
- 239000003112 inhibitor Substances 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 47
- 239000000203 mixture Substances 0.000 description 29
- 239000007787 solid Substances 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 230000035492 administration Effects 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cells Anatomy 0.000 description 13
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 13
- 102000027760 ERBB2 Human genes 0.000 description 12
- 108010066668 ErbB-2 Receptor Proteins 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- UPIYTHRGZLPZQS-UHFFFAOYSA-N 5-[4-(4-phenylmethoxyanilino)pyrido[3,4-d]pyrimidin-6-yl]furan-2-carbaldehyde Chemical compound O1C(C=O)=CC=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 UPIYTHRGZLPZQS-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 230000000875 corresponding Effects 0.000 description 7
- 150000002829 nitrogen Chemical class 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 101700039191 EGFR Proteins 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 229940086542 triethylamine Drugs 0.000 description 6
- 239000000969 carrier Substances 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 102000027656 receptor tyrosine kinases Human genes 0.000 description 5
- 108091007921 receptor tyrosine kinases Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 108091000081 Phosphotransferases Proteins 0.000 description 4
- 102000001253 Protein Kinases Human genes 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 150000003246 quinazolines Chemical class 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000001665 trituration Methods 0.000 description 4
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical group C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 3
- FIIDVVUUWRJXLF-UHFFFAOYSA-N 4-phenylmethoxyaniline Chemical compound C1=CC(N)=CC=C1OCC1=CC=CC=C1 FIIDVVUUWRJXLF-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 150000001448 anilines Chemical class 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reduced Effects 0.000 description 3
- 230000001603 reducing Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000001187 sodium carbonate Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 2
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1H-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 2
- XZNGFDIIMTUDLO-UHFFFAOYSA-N 2-(4-chloropyrido[3,4-d]pyrimidin-6-yl)-5-methyl-1,3,4-oxadiazole Chemical compound O1C(C)=NN=C1C1=CC2=C(Cl)N=CN=C2C=N1 XZNGFDIIMTUDLO-UHFFFAOYSA-N 0.000 description 2
- UWYFXSVAQSTQGE-UHFFFAOYSA-N 2-[methyl-[[5-[4-(4-phenylmethoxyanilino)pyrido[3,4-d]pyrimidin-6-yl]furan-2-yl]methyl]amino]acetamide Chemical compound O1C(CN(CC(N)=O)C)=CC=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 UWYFXSVAQSTQGE-UHFFFAOYSA-N 0.000 description 2
- CKPNVNAKQGYUSK-UHFFFAOYSA-N 4,6-dichloropyrido[3,4-d]pyrimidine Chemical compound N1=CN=C2C=NC(Cl)=CC2=C1Cl CKPNVNAKQGYUSK-UHFFFAOYSA-N 0.000 description 2
- LMKDKHDGVBPEKI-UHFFFAOYSA-N 4-[(3-fluorophenyl)methoxy]aniline Chemical compound C1=CC(N)=CC=C1OCC1=CC=CC(F)=C1 LMKDKHDGVBPEKI-UHFFFAOYSA-N 0.000 description 2
- CXQNZZDKYURVDK-UHFFFAOYSA-N 6-[5-[(dimethylamino)methyl]-1-methylimidazol-2-yl]-N-(4-phenylmethoxyphenyl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound CN1C(CN(C)C)=CN=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 CXQNZZDKYURVDK-UHFFFAOYSA-N 0.000 description 2
- QXOVLZVIYMRNAV-UHFFFAOYSA-N 6-chloro-N-(4-phenylmethoxyphenyl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2C=NC(Cl)=CC2=C1NC(C=C1)=CC=C1OCC1=CC=CC=C1 QXOVLZVIYMRNAV-UHFFFAOYSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate 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-N 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L Bis(triphenylphosphine)palladium(II) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 101700067048 CDC13 Proteins 0.000 description 2
- 101710042638 CILK1 Proteins 0.000 description 2
- 101700033006 EGF Proteins 0.000 description 2
- 102100010813 EGF Human genes 0.000 description 2
- 101700037202 FYN Proteins 0.000 description 2
- ZLTPDFXIESTBQG-UHFFFAOYSA-N Isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 210000004072 Lung Anatomy 0.000 description 2
- 210000003739 Neck Anatomy 0.000 description 2
- 101710018346 PDGFRB Proteins 0.000 description 2
- 101710009384 SRC Proteins 0.000 description 2
- 102000001332 SRC Human genes 0.000 description 2
- 101710037124 TEK Proteins 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N Tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 101700083482 ZAP70 Proteins 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 102000004965 antibodies Human genes 0.000 description 2
- 108090001123 antibodies Proteins 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000005418 aryl aryl group Chemical group 0.000 description 2
- 235000020127 ayran Nutrition 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 210000000038 chest Anatomy 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000000727 fraction Substances 0.000 description 2
- 101700062055 fyna Proteins 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- KLGZELKXQMTEMM-UHFFFAOYSA-N hydride Chemical compound [H-] KLGZELKXQMTEMM-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 229940113083 morpholine Drugs 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 239000001184 potassium carbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 210000001519 tissues Anatomy 0.000 description 2
- VLJNHYLEOZPXFW-SCSAIBSYSA-N (2R)-pyrrolidine-2-carboxamide Chemical compound NC(=O)[C@H]1CCCN1 VLJNHYLEOZPXFW-SCSAIBSYSA-N 0.000 description 1
- MLLMAIJXIZOSFS-LURJTMIESA-N (2S)-N,N-dimethylpyrrolidine-2-carboxamide Chemical compound CN(C)C(=O)[C@@H]1CCCN1 MLLMAIJXIZOSFS-LURJTMIESA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- DDYDBBBQYLFRJE-UHFFFAOYSA-N (diaminomethylideneamino)urea Chemical compound NC(=N)NNC(N)=O DDYDBBBQYLFRJE-UHFFFAOYSA-N 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical group C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- ACYOAZKGYRXBII-UHFFFAOYSA-N 2-(1H-pyrrol-2-yl)-3-pyrrol-2-ylidenepyrrole Chemical group N1=CC=CC1=C1C(C=2NC=CC=2)=NC=C1 ACYOAZKGYRXBII-UHFFFAOYSA-N 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- QGKGASXQTBQINX-UHFFFAOYSA-N 3,4-dihydro-1H-pyrimidin-2-one Chemical compound O=C1NCC=CN1 QGKGASXQTBQINX-UHFFFAOYSA-N 0.000 description 1
- YHPMRWZVIQTSFZ-UHFFFAOYSA-N 3,5-difluoro-2-(2-fluorophenyl)pyridine Chemical compound FC1=CC(F)=CN=C1C1=CC=CC=C1F YHPMRWZVIQTSFZ-UHFFFAOYSA-N 0.000 description 1
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-Aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 1
- XFGRSRQUIAXQNB-UHFFFAOYSA-N 3-chloro-4-[(2-fluorophenyl)methoxy]aniline Chemical compound ClC1=CC(N)=CC=C1OCC1=CC=CC=C1F XFGRSRQUIAXQNB-UHFFFAOYSA-N 0.000 description 1
- AYPFEYDGZDPAPE-UHFFFAOYSA-N 3-chloro-4-[(3-fluorophenyl)methoxy]aniline Chemical compound ClC1=CC(N)=CC=C1OCC1=CC=CC(F)=C1 AYPFEYDGZDPAPE-UHFFFAOYSA-N 0.000 description 1
- VQCZIZIHGIJMII-UHFFFAOYSA-N 3-chloro-4-[(4-fluorophenyl)methoxy]aniline Chemical compound ClC1=CC(N)=CC=C1OCC1=CC=C(F)C=C1 VQCZIZIHGIJMII-UHFFFAOYSA-N 0.000 description 1
- WOWKZTBVWKKGJV-UHFFFAOYSA-N 3-chloro-4-phenylmethoxyaniline Chemical compound ClC1=CC(N)=CC=C1OCC1=CC=CC=C1 WOWKZTBVWKKGJV-UHFFFAOYSA-N 0.000 description 1
- QUYFSHOLLKVPGX-UHFFFAOYSA-N 3-methylsulfonylpropan-1-amine Chemical compound CS(=O)(=O)CCCN QUYFSHOLLKVPGX-UHFFFAOYSA-N 0.000 description 1
- GDYFDXDATVPPDR-UHFFFAOYSA-N 4-(benzenesulfonyl)aniline Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=CC=C1 GDYFDXDATVPPDR-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-Nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- ARKQSUYCILKUKZ-UHFFFAOYSA-N 4-[(2-fluorophenyl)methoxy]aniline Chemical compound C1=CC(N)=CC=C1OCC1=CC=CC=C1F ARKQSUYCILKUKZ-UHFFFAOYSA-N 0.000 description 1
- WKJLZHPOOMPGPI-UHFFFAOYSA-N 4-[(4-fluorophenyl)methoxy]aniline Chemical compound C1=CC(N)=CC=C1OCC1=CC=C(F)C=C1 WKJLZHPOOMPGPI-UHFFFAOYSA-N 0.000 description 1
- DBPKMSBWOKAKLA-UHFFFAOYSA-N 4-chloropyrimidine Chemical group ClC1=CC=NC=N1 DBPKMSBWOKAKLA-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- JQXJBXVWVPVTOO-UHFFFAOYSA-L 4-diphenylphosphanylbutyl(diphenyl)phosphane;palladium(2+);dichloride Chemical compound Cl[Pd]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 JQXJBXVWVPVTOO-UHFFFAOYSA-L 0.000 description 1
- WDNVTYCNDLLHTL-UHFFFAOYSA-N 4-oxo-1H-pyrido[3,4-d]pyrimidine-6-carbonitrile Chemical compound N1=C(C#N)C=C2C(=O)NC=NC2=C1 WDNVTYCNDLLHTL-UHFFFAOYSA-N 0.000 description 1
- WOYZXEVUWXQVNV-UHFFFAOYSA-N 4-phenoxyaniline Chemical compound C1=CC(N)=CC=C1OC1=CC=CC=C1 WOYZXEVUWXQVNV-UHFFFAOYSA-N 0.000 description 1
- VRNHWAZLHPUTSM-UHFFFAOYSA-N 6-(2H-tetrazol-5-yl)-1H-pyrido[3,4-d]pyrimidin-4-one Chemical compound C1=C2C(=O)NC=NC2=CN=C1C1=NN=NN1 VRNHWAZLHPUTSM-UHFFFAOYSA-N 0.000 description 1
- VTDJBXQYCPBDBY-UHFFFAOYSA-N 6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-phenylmethoxyphenyl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound O1C(C)=NN=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 VTDJBXQYCPBDBY-UHFFFAOYSA-N 0.000 description 1
- FWIWNMGMJKKMMW-UHFFFAOYSA-N 6-[5-[(2-methylsulfinylethylamino)methyl]furan-2-yl]-N-(4-phenylmethoxyphenyl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound O1C(CNCCS(=O)C)=CC=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 FWIWNMGMJKKMMW-UHFFFAOYSA-N 0.000 description 1
- AKCBRJJNOLVXJF-UHFFFAOYSA-N 6-[5-[(dimethylamino)methyl]-1H-imidazol-2-yl]-N-(4-phenylmethoxyphenyl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound N1C(CN(C)C)=CN=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 AKCBRJJNOLVXJF-UHFFFAOYSA-N 0.000 description 1
- NUTUPYCNXAFILA-UHFFFAOYSA-N 6-chloro-1H-pyrido[3,4-d]pyrimidin-2-one Chemical compound C1=NC(=O)NC2=C1C=C(Cl)N=C2 NUTUPYCNXAFILA-UHFFFAOYSA-N 0.000 description 1
- UAWMVMPAYRWUFX-UHFFFAOYSA-N 6-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1 UAWMVMPAYRWUFX-UHFFFAOYSA-N 0.000 description 1
- 241001136782 Alca Species 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N Benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 210000000481 Breast Anatomy 0.000 description 1
- XXSVUGAPKYJTCY-UHFFFAOYSA-N C(#N)C1=CC2=C(N=CNC2=O)C=N1.N1N=NN=C1C1=CC2=C(N=CNC2=O)C=N1 Chemical compound C(#N)C1=CC2=C(N=CNC2=O)C=N1.N1N=NN=C1C1=CC2=C(N=CNC2=O)C=N1 XXSVUGAPKYJTCY-UHFFFAOYSA-N 0.000 description 1
- HIDYBUANPLOXCP-UHFFFAOYSA-N C(C)(=O)NCCN.CS(=O)(=O)NCCNC(C)=O Chemical compound C(C)(=O)NCCN.CS(=O)(=O)NCCNC(C)=O HIDYBUANPLOXCP-UHFFFAOYSA-N 0.000 description 1
- 101700063802 CSF1R Proteins 0.000 description 1
- 102100005175 CSF1R Human genes 0.000 description 1
- XEVRDFDBXJMZFG-UHFFFAOYSA-N Carbohydrazide Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 210000000170 Cell Membrane Anatomy 0.000 description 1
- 210000001072 Colon Anatomy 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M Copper(I) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- YVGGHNCTFXOJCH-UHFFFAOYSA-N DDT Chemical compound C1=CC(Cl)=CC=C1C(C(Cl)(Cl)Cl)C1=CC=C(Cl)C=C1 YVGGHNCTFXOJCH-UHFFFAOYSA-N 0.000 description 1
- NNBZCPXTIHJBJL-UHFFFAOYSA-N Decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N Diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N Diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- MUZIZEZCKKMZRT-UHFFFAOYSA-N Dithiolane Chemical compound C1CSSC1 MUZIZEZCKKMZRT-UHFFFAOYSA-N 0.000 description 1
- 102000033147 ERVK-25 Human genes 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 229940079360 Enema for Constipation Drugs 0.000 description 1
- 229940116977 Epidermal Growth Factor Drugs 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- 229940012356 Eye Drops Drugs 0.000 description 1
- HYBBIBNJHNGZAN-UHFFFAOYSA-N Furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 1
- 206010017758 Gastric cancer Diseases 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- 229960002449 Glycine Drugs 0.000 description 1
- 229960001269 Glycine Hydrochloride Drugs 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 210000003128 Head Anatomy 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Incidol Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N Indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 208000001083 Kidney Disease Diseases 0.000 description 1
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L MANGANESE CHLORIDE Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- 101710034456 MT-CO1 Proteins 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M Methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229940042115 Methylene blue Drugs 0.000 description 1
- 240000004841 Meum athamanticum Species 0.000 description 1
- 241001139947 Mida Species 0.000 description 1
- 229910021380 MnCl2 Inorganic materials 0.000 description 1
- DAKZISABEDGGSV-UHFFFAOYSA-N N-(2-aminoethyl)acetamide Chemical compound CC(=O)NCCN DAKZISABEDGGSV-UHFFFAOYSA-N 0.000 description 1
- GCDZDXVTDCMNMN-UHFFFAOYSA-N N-(2-aminoethyl)methanesulfonamide Chemical compound CS(=O)(=O)NCCN GCDZDXVTDCMNMN-UHFFFAOYSA-N 0.000 description 1
- YESJKZGCXPCJMF-UHFFFAOYSA-N N-(2-aminoethyl)methanesulfonamide;hydrochloride Chemical compound Cl.CS(=O)(=O)NCCN YESJKZGCXPCJMF-UHFFFAOYSA-N 0.000 description 1
- FXZWPZMCZNJILD-UHFFFAOYSA-N N-[(6-bromopyridin-3-yl)methyl]ethanamine;hydrochloride Chemical compound Cl.CCNCC1=CC=C(Br)N=C1 FXZWPZMCZNJILD-UHFFFAOYSA-N 0.000 description 1
- OYEVBVBJLIOIJY-UHFFFAOYSA-N N-[2-(methanesulfonamido)ethyl]acetamide Chemical compound CC(=O)NCCNS(C)(=O)=O OYEVBVBJLIOIJY-UHFFFAOYSA-N 0.000 description 1
- KEMMHCGOIOPTBO-UHFFFAOYSA-N N-[4-[(3-fluorophenyl)methoxy]phenyl]-6-(5-methyl-1,3,4-oxadiazol-2-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound O1C(C)=NN=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC(F)=C1 KEMMHCGOIOPTBO-UHFFFAOYSA-N 0.000 description 1
- PCMIWUMCWPXGNF-UHFFFAOYSA-N N-methyl-2-methylsulfinylethanamine Chemical compound CNCCS(C)=O PCMIWUMCWPXGNF-UHFFFAOYSA-N 0.000 description 1
- SJOAKYZBKUNFLA-UHFFFAOYSA-N N-methyl-3-methylsulfinylpropan-1-amine Chemical compound CNCCCS(C)=O SJOAKYZBKUNFLA-UHFFFAOYSA-N 0.000 description 1
- 102100016102 NTRK1 Human genes 0.000 description 1
- 101700043017 NTRK1 Proteins 0.000 description 1
- 229940100662 Nasal Drops Drugs 0.000 description 1
- 229940097496 Nasal Spray Drugs 0.000 description 1
- 210000001331 Nose Anatomy 0.000 description 1
- DCWXELXMIBXGTH-UHFFFAOYSA-N O(4)-phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 108091005771 Peptidases Proteins 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N Potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M Potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N Pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N Pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- RVOLLAQWKVFTGE-UHFFFAOYSA-N Pyridostigmine Chemical compound CN(C)C(=O)OC1=CC=C[N+](C)=C1 RVOLLAQWKVFTGE-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N Quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 244000097202 Rathbunia alamosensis Species 0.000 description 1
- 235000009776 Rathbunia alamosensis Nutrition 0.000 description 1
- 101700060380 SINA Proteins 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 210000003491 Skin Anatomy 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N Sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N Tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 229940100611 Topical Cream Drugs 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 210000003932 Urinary Bladder Anatomy 0.000 description 1
- NQXGXMVCHOBSJW-UHFFFAOYSA-N [5-[4-(4-phenylmethoxyanilino)pyrido[3,4-d]pyrimidin-6-yl]furan-2-yl]methanol;hydrochloride Chemical compound Cl.O1C(CO)=CC=C1C(N=CC1=NC=N2)=CC1=C2NC(C=C1)=CC=C1OCC1=CC=CC=C1 NQXGXMVCHOBSJW-UHFFFAOYSA-N 0.000 description 1
- PCTNAMGLSYHIPL-UHFFFAOYSA-N [Sn+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] Chemical compound [Sn+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] PCTNAMGLSYHIPL-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000000033 alkoxyamino group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000003705 anilinocarbonyl group Chemical group O=C([*])N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000012223 aqueous fraction Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000069 breast epithelial cell Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 201000009030 carcinoma Diseases 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- 108060002020 cyanase family Proteins 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000062 cyclohexylmethoxy group Chemical group [H]C([H])(O*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 239000011928 denatured alcohol Substances 0.000 description 1
- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- UFHFLCQGNIYNRP-JMRXTUGHSA-N ditritium Chemical group [3H][3H] UFHFLCQGNIYNRP-JMRXTUGHSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000877 morphologic Effects 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000001613 neoplastic Effects 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 159000000018 pyrido[2,3-d]pyrimidines Chemical class 0.000 description 1
- 150000008518 pyridopyrimidines Chemical class 0.000 description 1
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical group CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- KFFMWJLUQMFKOH-UHFFFAOYSA-N pyrrol-1-ide Chemical compound C=1C=C[N-]C=1 KFFMWJLUQMFKOH-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical class [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- BBUQUBATODVRRV-UHFFFAOYSA-N triacetyloxyboron(1-) Chemical compound CC(=O)O[B-](OC(C)=O)OC(C)=O BBUQUBATODVRRV-UHFFFAOYSA-N 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic Effects 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
Abstract
Substituted hetero-aromatic compounds, and in particular substituted bicyclic heteroaromatic compounds in which the ring is a pyridine or pyrimidine, are inhibitors of the protein tyrosine kinase. The compounds are described, as are methods for their preparation, pharmaceutical compositions including such compounds and their use in medicine, for example in the treatment of cancer and psoriasis
Description
,
Genesis has been associated with a number of disease states - (eg, tumor, genesis, psoriasis, rheumatic arthritis) and this is shown to be controlled by the action of a receptor tyrosine kinase number (L. Shawver, DDT). , 1997, 2 (2), 50-63).
EP0635507 discloses a class of tricyclic quinazoline derivatives of the formula:
wherein R 1 and R 2 together form optionally substituted subtituted groups containing at least one heteroatom to form a 5- or 6-membered ring, in which there is a 3-N atom at the 6-position of the quinazoline ring; R independently includes hydrogen, hydroxy, halogen, (1-4C) alkyl, coxy (1-4C) di- [(1-4C) alkyl, or (2-4C) alkanoylamino. The above citation notes that the receptor cirosine kinase in general, which are important in the transmission of biochemical signals that initiate cell replication, frequently occur at increased levels or higher activities in common human cancers such as cancer. chest - (Sainbury et al, Brit. J. Cancer, 1988, 58, 458). It is suggested that inhibitors of the tyrosine kinase receptor are of value, such as inhibitors of the growth of mammalian cancer cells (Yaish et al., Science, 1988, 242, 933). This citation therefore has the objective of providing quinazoline derivatives which inhibit the receptor tyrosine kinase -comprehended in the control of the tumorigenic phenotype.
WO 95/15758 discloses aryl and heteroaryl quinazoline derivatives of the formula
where X includes a link, 0, S, SO, S02 > S02, C = C, C = C, CH2 and NH; Ar includes phenyl, naphthyl, naphthalenyl, indolyl, pyridyl, piperidinyl, piperazinyl, dihydroquinolinyl, tetrahydro-quinolinyl, thienyl, indanyl, pyrazolyl, and 1,4-benzodioxanil; and R_, R, and R-, independently include hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, -halo, haloalkyl, carboxy or carbalkoxy; as inhibitors of the receptor tyrosine kinase activity CSF-1R and / or p56Ick.
WO 95/19774 discloses bicyclic derivatives of the formula
wherein A to E are nitrogen or carbon and at least one of A to E is nitrogen; or 2 adjacent atoms together are N, -0 or S; R- is H or alkyl and n is 0, 1 or 2; m is from 0 to 3 and R includes alkyl, alkoxy, cycloalkoxy, optionally substituted-cycloalkoxy or 2 R groups together form a carbocycle or heterocycle. The compounds are said to inhibit the epidermal growth factor of the receptor tyrosine kinase and the suggested uses include the treatment of cancer, psoriasis, kidney disease, pancreatitis and contraception.
WO 96/07657 discloses pyrimido [5, 4-d] irimidine derivatives of the formula
wherein Ra includes hydrogen or alkyl; R, D includes phenyl optionally subsituted; and R includes hydrogen, halo, alkyl, cycloalkyl, cycloalkylalkaryl, aralkyl, OH, optionally substituted alkoxy, cycloalkoxy, aryloxy, aralkoxy, mercapto, optionally substituted alkyl- or arylsulfenyl, -sylaryl, or substituted sulfonyl and alkyleneimino; as inhibitors of EGF-R.
WO 96/09294 discloses quinoline and quinazoline derivatives of formula
where X is N or CH; And it includes 0, S, CH20 and NH; R includes phenoxy, benzyloxy, benzylmercapto, benzylamino, benzyl, anilino, benzoyl, anilinocarbonyl, anilinomethyl, phenylethynyl, phenylene, phenylethyl, phenylthio, phenylsulfonyl, benzylthio, benzyl. sulfonyl, phenylthiomethyl, phenylsulfonylmethyl, phenoxymethyl, -thienylmethoxy, furanylmethoxy, cyclohexyl, and cyclohexylmethoxy; and R 1, R 2, R 3 and R 3 ', include a range of possible substituents, - predominantly do not include heterocyclic ring systems;
as inhibitors of the tyrosine cipase protein receptor, in particular as inhibitors of c-erbB-2 and / or p56Ick.
WO 96/15118 discloses derivatives of the quinoline of formula;
wherein X includes 0, S, SO, S02, CH2, 0CH2 > CH20 and CO; Q includes a phenyl or naphthyl group and several parts of 2-5 or 6-membered heteroaryl; n is 0, 1, 2 or 3 and each R is independently halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C, C, C, C, C, C, C, C, C, C, C, C, C, C,. C "_ ,; m is 1, 2 or 3 and R includes a range of substituent pj3, predominantly not including heterocyclic ring systems; as inhibitors of the ti-rosin kinase receptor, specifically as EGF-R inhidores.
WO 96/15128 discloses derivatives of pyrido [2,3-d] pyrimidine and naphthi. ridine of formula
where X is CH or N; B is halo, hydroxy or NR ~ R; Ar includes nil or substituted and unsubstituted pyridyl; and R-,, R, R, and R, independently include hydrogen, amino, alkylamino C, _ft, alkylamino di-C, ", substituted and unsubstituted heteroaromatic or aromatic groups, and C-, o-, alkenyl-C2_o alkyl groups or C2_fi alkynyl substituted and unsubstituted.
WO 96/16960 discloses quinazoline derivatives of the formula:
in d Aond, e m is il or o2; cad Aa rR > l independently include Hydrogen-2-no and C-alkoxy,; n is 1, 2 or 3; each R independently includes hydrogen, halogen, and C,,, or R alkyl is a group containing aryl- or heteroaryl-, which includes pyridylmethoxy and benzoyl; and Ar includes a portion of 5- or 9-membered substituted or unsubstituted nitrogen-linked heteroaryl containing up to 4 nitrogen atoms, namely imidazol-1-yl, imidazolin-1-yl, benzimidazol-1-yl, pyrazol-1-yl and 1,2,4-triazol-1-yl; as inhibitors of the receptor tyrosine kinase, in particular as inhibitors of EGF-R.
Therefore, a general objective of the present invention is to provide compounds suitable for the treatment of disorders mediated by the activity of the protein tyrosine kinase, and in particular for the treatment of the disorders described above.
In addition to the treatment of tumors, the present invention has the object that the disorders mediated by the tyrosine kinase protein activity can be treated effectively by inhibition, which includes preferential inhibition, of the activity of the protein tyrosine kinase. appropriate
The inhibition of the general tyrosine kinase protein spectrum does not always provide an optimal treatment of, for example, tumors, and in certain cases it is always harmful for patients since the protein tyrosine kinase provides an essential function in the normal regulation of the growth of the cells.
Another objective of the present invention is to provide compounds which preferentially inhibit the protein tyrosine kinases, such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, Ick, Zap70, and fyn. A benefit is seen in the preferential inhibition comprised in small groups of the protein tyrosine kinase, for example c-erb-2 and c-erbB-4 or -c-erbB-2, c-erbB-4 and EGF-R.
A further objective of the present invention is to provide compounds useful in the treatment of the protein tyrosine kinase related to diseases which minimize undesirable side effects in the recipient.
The present invention relates to heterocyclic compounds which can be used for the treatment of disorders mediated by protein tyrosine kinases and in particular that have anti-cancer properties. More specifically, the compounds of the present invention are potential inhibitors of the protein tyrosine kinases such as EGFr, c-erbB-2, c-erbB-4, -c-met, tie-2, PDGFr, c-src, Ick, Zap70 and fyn, that is why they allow the clinical management of particular diseased tissues.
The present invention focuses, in particular, on the treatment of human malignancies, for example tumors of non-small cells of the lung, ovary, stomach, and pancreatic, especially those carried by EGFr or erbB-2, which use the compounds of the present invention. For example, the invention includes compounds which are highly active against the protein tyrosine kinase c-erbB-2 often in preference to the cyanase receptor EGF, thus allowing the treatment of tomers carried by c-erbB-2. However, the invention also includes -compounds which are highly active against both c-erbB-2 and EGF-R kinase receptors, therefore allow tra. of a wide range of tumors.
More specifically, the present invention has the object that disorders mediated by the activity of the tyrosine kinase protease can be effectively treated by inhibiting the activity of the appropriate protein tyrosine kinase-in a relatively selective manner, that is why the minimization of potential side effects.
Accordingly, the present invention provides a compound of formula (I):
(1) or a salt thereof;
where X is N or CH;
Y is a group W (CH2), (CH2) W, or W, in which W is 0, S (0) m where m is 0, 1 or 2, or NR where R is hydrogen or an alkyl group C, _ ":
R represents a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, 0 or S (0), where m is as defined above, with the condition that the ring does not contain & amp; amp; to 2 adjacent atoms 0 or S (0). m, the ring is substituted, either by (a) by one or more independent groups -me selected from carbamate, ureido, guanidine, alkyl- C-, Q-alkoxy, C- or cycloalkoxy, alkylcycloalkoxy C, ". ' alkylcarbonyl C._, alkoxycarbonyl C n) alkylcarbamoyl
N, N, N-di [C, _, alkyl] carbamoyl, hydroxyamino, alkoxyamino C ,,, C alca _ ,,alkynyloxyamino, phenyl, phenoxy, 4-pyridon-1-yl, -pyrrolidin-1-yl, imidazol-1-yl, piperidino, morpholino, thiomor folino, thiomorpholino-1-oxide, thiomorphonyl-1, 1-dioxide, pipera-zin-1-yl, 4-C, _, alkyl-piperazin-1-yl, dioxolanyl, alkylthio C, R. arylthio, alkylsulfinyl C, ,, alkylsulfonyl C, ,, arylsulphonyl, alkylsulfinyl, halogen-C,, alkyl, hydroxy-C, alkyl, C2-alkanoyloxy, C-, C ,,, alkoxy, -alkyl C, C, C, C, C, C, C, C, C, C, C, C, C, alkylcarbamoyl, alkylcarbamoyl -C, _, alkyl, N, N-di- [C,, alkyl] carbamoyl-C, -alkyl, amino-C,, alkyl, C,, alkylamino-C, _, alkyl, di- [C, , alkyl) amino-C, alkyl, di- [C, _, alkyl] amino-C,, alkyl, alkyl, amino, C,, alkylamino-C,, alkylene- (C,, alkyl) amino , hydroxy-C,. alkylene- (C,, alkyl) amino, phenyl-C, alkyl, 4-pyridon-1-yl-C, _, alkyl, pyrrolidin-1-yl-C-, _, alkyl, imidazole-1-yl- C,, alkyl, piperidino-C,, alkyl, morfo-lino-C,, alkyl, thiomorpholino-C, _, alkyl, thiomorpholino-1-oxide-C, _, alkyl, thiomorpholino-l, l-dioxide-C alkyl, piperazin-1-yl-C, alkyl, 4-C, alkyl, piperazin-1-ylC, alkyl, hydroxy-C, -C, -alkoxy, alkyl, C, alkoxy -C2_. alkoxy-C, _, alkyl, hydroxy-C2, alkylamino-C, _, alkyl, C,, alco-xi-C ~, alkylamino-C, _, alkyl, C, _, alkylthio-C, _, alkyl, -hydroxy-C "_, alkylthio-C,, alkyl, C,, C2-alkoxy, alkylthio-C, _, alkyl, phenoxy-C, _, alkyl, C-anilino, alkyl, phenyl-thio-C, , alkyl, cyano-C, alkyl, halogen-C-, _, alkoxy, hydroxy-C-. , alkoxy, C2_, C-alkanoyloxy, alkoxy, C,, C2-alkoxy, alkoxy, carboxy-C, alkoxy, formyl-C, _, alkoxy, C,, alkoxycarbonyl, C, alkoxy, carbamoyl-C , _, alkoxy, NC,. alkylcarbamo-yl-C, alkoxy, N, N-di [C,, alkyl] carbamoyl-C, _, alkoxy, amino-C-, alkoxy, C, alkylamino-C2_, alkoxy, di- [C ,, alkyl-C, alkoxy] amino-C, alkoxy, di- [C,, alkyl] amino-C2_, alkoxy, C2_ alkanoyloxy, hydroxy-Cp, alkanoyloxy, C- ^ _ ^ alkoxy-C2_ ^ alkanoyloxy, phenyl-C, _, alkoxy, phenoxy-C2, alkoxy, C2-anilino, alkoxy, phenylthio-C2_, alkoxy, 4-pyridon-l-yl-C2_, alkoxy, pipe-Ridino-Co, alkoxy, morpholino-C2, alkoxy, thiomorpholino-C2, alkoxy, thiomorpholino-l-oxide-C2, alkoxy, thiomorpholino-1,1-dioxy-do-Cn, alkoxy, piperazin-l-yl-C2_, alkoxy, 4-C,, alkylpipera zin-l-yl-C2_, alkoxy, pyrrolidin-l-yl-C2_, alkoxy, imidazol-1-yl-C2_, alkoxy, halogen-C2_, alkylamino, hydroxy-C2_, alkylamino, C2_, alkanoyloxy-C-, alkylamino , C,, C 2 alkoxy, alkylamino, carboxy-C, alkylamino, C,. alkoxycarbonyl-C,, alkyl amino, carbamoyl-C, alkylamino, N-C, _, alkylcarbamoyl-C, _, alkylamino, N, N-di [C, _, alkyl] carbamoyl-C, _, alkylamino, ami. non-C2_, alkylamino, C, _, alkylamino-C _, alkylamino, di- [C,, alkyl] amino-C, -, alkylamino, phenyl-C, alkylamino, phenoxy- C ~, alkylamino, anilino-C "_, Alkylamino, 4-pyridon-l-yl-C, alkylamino, piperidino-C-, _, alkylamino, morpholino-C _, alkyl-amino, thiomor folino-C.,, Alkylamino, thiomorpholino-l-oxide-C _, alkylamino, thiomorpholino-1, l-dioxide-C2_, alkylamino, pipera-zin-l-yl-C7_, alkylamino, 4-C, _, alkylpiperazin-l-yl-C-, alkylamino, pyrrolid'in-l-yl -C, alkylamino, imidazol-1-yl-Co, alkylamino, phenylthio-C _, alkylamino, C2_, alkanoylamino, C, _, alkoxycarbonylamino, C, alkylsulfonylamino, C,, alkylsulphonylamino, benzamido, benzenesulfonamido, 3- phenylureido, 2-oxopi-rrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halo-C2_, alkanoi lamino, hydroxy-C, alkanoylamino, hydroxy-C, alkanoyl- (C,, 2-4 2- 4 1-4 alkyl) -amino, C, _. C2_alkoxy, alkanoylamino, carboxy-C2_, alkanoylamino, C, _, alkoxycarbonyl-C _, alkanoylamino, carbamoyl-C2_, alkanoylamino, NC,, alkylcarbamoyl-C2_, alkanoylamino, -N, N-di [C, _, alkyl ] carbamoyl-C2_, alkanoylamino, amino-C2, alkanoylamino, C, _, alkylamino-C-, alkanoylamino or di- [C, _, alkyl] amino-C? , alkanoylamino; and wherein said benzamido or benzenesulfonamido substituent or any anilino, phenoxy or phenyl group in a substituent R may optionally have one or two halogen substituents, C,, or alkoxy -GI_ substituents? 5 and wherein any substituent containing a heterocyclic ring may optionally have one or two halogen substituent, C, C, or C, alkoxy, in said ring; and wherein any substituent containing a heterocyclic ring may optionally have one or 2 oxo and thioxo substituents on said ring; or (b) by one or more groups independently selected from M1-M2-M3-M4, M ^ 5 or M1-M2-M3-M6 where M represents a C,, alkyl group, wherein optionally a CH2 group is replaced by a CO group; 2 12 12 13 12 13 M represents NR or CR R, in which R and R each independently represents H or C,, alkyl; 3 M represents a C,, alkyl group; 3 'M represents a C, or alkyl group, or is absent; M4 represents CN, NR12S (0) R13, S (0) NR14R15, C0NR14R15, S (0) R13 * 'm m' '/ m
° C02R f in which R12, Rl3 and m are as defined above and
each independently represents H or C,,, or R alkyl and R together with the nitrogen atom to which they are attached represents a 5- or 6-membered ring optionally containing 1 or 2 additional heteroatoms selected from -N, 0 or S (0) in which any nitrogen atom present in the ring can be optionally substituted with an alkyl group -C, _,, and which, the ring optionally can have one or two oxo or thioxo substituents; M represents the group NR R, where R and R are as defined above, or M represents the group
represents OH, alkyl 0C1_4 or NR1 R15, and M represents a C, _ft cycloalkyl group, the group NR R, wherein R and R are as defined above, or a 5- or 6-membered heterocyclic anion system containing from 1 to 4 heteroatoms selected from N, 0 or S;
and R is then optionally substituted by one or two halogen, C, C, or C, C, alkoxy groups;
R is selected from the group consisting of hydrogen, halogen, -trifluoromethyl, C, alkyl, and C,, alkoxy;
each R is independently selected from the group consisting of hydrogen, hydroxy, halogen, C, alkyl, C, C, C, C, C, C, C, C, C, C, alkylsulfinyl C , C 1, alkylsulfonyl C 1, C 1, C 1 alkylcarbamoyl C 1, 4 - [C 2, alkyl] carbamoyl, carbamyl, C 1 4 alkoxycarbonyl, nitro and trifluoromethyl, and n is 1,2 or 3;
R is a group ZR where Z is attached to R by a group (CH _.-- ,.) p in which p is 0, 1 or 2 and Z represents a group V (CH2), V (CF2), (CH2) V, (CF2) V, V (CRR '), V (CHR) or V where R and R'are each on the C, C, and in which V is a hydrocarbyl group containing 0, 1 or 2 carbon atoms, carbonyl, dicarbonyl, CH (OH),
CH (CN), sulfonamide, amide, 0, S (0) or NR where R is hydrogen 4 or R is C,, alkyl; and R is an optionally substituted cycloalkyl or a carbocyclic or heterocyclic part of 5,6,7,8,
9 or 10 optionally substituted; or R 3 is a group ZR 4 in which Z is NRb, and NRb and R 4 together form a carbocyclic or heterocyclic part of 5, 6, 7, 8, 9 or -10 members optionally substituted;
represents a 5, 6 or 7-membered heterocyclic ring fused to containing 1 to 5 heteroatoms which may be the same or different and which are selected from N, 0 or
S (0), where m is as defined above, the heterocyclic ring containing a total of 1, 2 or 3 inclusive double bonds of the bond in the pyridine or pyrimidine ring, with the proviso that the ring The heterocyclic ring is not part of a purine and the fused heterocyclic ring does not contain 2 adjacent atoms 0 or S (0) m
The solvates of the compounds of the formula (I) are also included within the scope of the present invention.
Heterocyclic groups consist of one or more rings which may be saturated, unsaturated, or aromatic and which may independently contain one or more heterojámes in each ring.
The carbocyclic groups consist of one or more ring-which can be independently saturated, unsaturated or aromatic and which contain only carbon and hydrogen.
Suitably the heterocyclic part of 5, 6, 7, 8, 9 or 10 members is selected from the group consisting of: furan, xolane, thiophene, pyrrole, imidazole, pyrrolidine, pyran, pyridine, pyrimidine, morpholine, piperidine, oxazole, isoxazole, oxazo-lina. oxazolidine, thiazole, isothiazole, thiadiazole, benzofuran, -indol, isoindol, quinazoline, quinoline, isoquinoline and ketal.
Suitably the carbocyclic part of 5, 6, 7, 8, 9-or 10 members is selected from the group consisting of: phenyl, beyl, indene, naphthalene, tetralin, decalin, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl.
By halo means fluoro, chloro, bromo or iodo.
Alkyl groups containing three or more carbon atoms can be linear, branched or cyclized.
In an embodiment R is as above defined with the exception that any substituent containing a -heterocyclic ring carries one or two oxo or thioxo substituents on said ring; and R and R are as defined above with the exception that, together with the nitrogen atom to which they are attached, represents a 5- or 6-membered ring and the membered ring carries one or two oxo or thioxo substituents.; unless R can represent a 5- or 6-membered heterocyclic ring substituted by a 4-pyridon-1-yl group, 4-pyridon-1-yl-C 1 -4 alkyl, 4-pyridon-1-yl-C 2 -4 alkoxy, -pyridon-1-yl-C "_ alkylamino, 2-oxopyrrolidin-1-yl or 2,5-dioxopyrrolidin-1-yl.
In one modality, X is N,
In a later embodiment, Y is NR, NR (CH2), or (CH) NR; preferably Y is NR and R is preferably hydrogen or methyl.
In a later embodiment R is a 5- or 6-membered heterocyclic ring as defined above substituted by one or more groups selected from dioxolanyl, hydroxy-C, alkyl, C, _, alkylamino-C, _, alkyl or di ( C,, alkyl) amino-C,, alkyi. it, and then optionally substituted by one or more C-alkyl groups, ..
In a later embodiment R is a 5- or 6-membered heterocyclic ring as defined above with a selected group of M -M -M -M, M -M or MM -M -M as above fine
2 3 4 In a later embodiment the group M -M -M represents an alpha-, beta- or gamma-amino carboxylic acid, sulfinic or sulphonic acid or a C,, alkyl ester, an amide or a C, _, alkyl - or di- (C, _, alkyl) -amide thereof.
Preferably 1 represents CH2 > CO, CH2CH2 or CH2C0,
more preferably CH2.
Preferably M2 represents NR12 in which R12 is as defined above; more preferably R 12 represents H or methyl.
Preferably M represents CH2, CH2CH2 or propyl,
Preferably M 3 'represents CH, ethyl, propyl, isopropyl or is absent.
Preferably M represents SOR 13 S02R 13 NR12S02R 13
C02R or CONR R in which R and R are defined above and R and R each independently represent H or aluyl C,,; 1 1 * 1 / i c: more preferably R, R, R and R each independently represent H or methyl.
Preferably M represents a group NR R in which R 14 and R 15 together with the nitrogen atom to which they are attached represent a 6-membered ring optionally containing an additional heteroatom selected from N or O, in which any atom of nitrogen in the ring can optionally be substituted with a C, C, alkyl group, preferably-a methyl group; or M represents a group
wherein t represents 2 or 3 and R16 represents OH, NH2, N (C, _, alkyl) or OC,, alkyl; more preferably R 16 represents NH 2 or N (CH ") 2 <
M preferably also represents a group NR R in which R 14 and R 15 each independently represent hydrogen or C, alkyl, more preferably hydrogen, methyl, ethyl or isopropyl.
Preferably M represents a group NR R at -X 5 c to R 14 and R 15 each independently represent C 1, more preferably methyl, or R 14 and R 15 together with the nitrogen atom to which they are attached represent a ring from
• 5- or 6-membered optionally containing an additional heteroatom selected from N or 0, in which any nitrogen atom present in the ring can optionally be substituted with a C, _, preferably a methyl group; or - M represents a 5- or 6-membered heterocyclic ring system containing 1 or 2 heteroatoms selected from N or 0.
O / In a further preferred embodiment M-M represents an alpha-amino carboxylic acid or a methyl ester or amide thereof.
2 3 4 In a later preferred embodiment M -M -M represents an alpha-, beta- or gamma-amino-sulfinic or sulfonic acid, - more preferably a beta- or gamma-amino-sulfinic or sulphonic acid, more preferably an acid beta-aminosulfonic, or methyl ester thereof.
In a particularly preferred embodiment M ~ M -M represents a methylsulphonylethylamino, methylsulfinylethylamine, methylsulfonylpropylamino, methylsulfinylpropylamino, methylsulfonamidoethylamino, sarcosinamide, glycine, glycinamide, glycine methyl ester or acetylaminoethylamino group.
In a particularly preferred embodiment M-represents a piperazinyl group, methylpiperazinyl, piperidinii, prolinamido or N, N-dimethylprolinamido.
In a particularly preferred embodiment, M-M represents an isopropyl acetamido or N-morpholinoacetamido group.
In a particularly preferred embodiment, M represents a pyridylamino group, cyclopropylamino, -N- (iperidin-4-yl) -N-methylamino, N, N-dimethylaminoprop-2-ylamino, N- (2-dimethylaminoethyl) -N-ethylamino or tetrahydrofuranomethylamino, preferably a pyridylamino group.
In an R mode, it can be selected from the group consisting of phenyl, furan, thiophene, pyridine, pyrimidine, pyrazi. na, pyrrole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, triazole, tetrazole and imidazole or a hydrogenated derivative of any of the aforementioned.
In a further preferred embodiment R can be selected from the group consisting of phenyl, furan, imidazole, tetrazole, triazole, pyrrolidine, piperazine, piperidine and oxadiazole.
In a particularly preferred embodiment R can be selected from the group consisting of furan, imidazole and oxadiazole, more especially furan.
In one embodiment R is hydrogen, C, C, C, or halogen alkyl, preferably hydrogen or methyl, more preferably hydrogen.
In a further embodiment, R is hydrogen, hydroxy, -alkyl C1_4 > a? coxi CL_4, di [C1-4 alkyl] amino, halogen, nitro
or trifluoromethyl, preferably hydrogen, halogen or methyl, more preferably hydrogen.
In a preferred embodiment, R is a phenyl, dioxolanyl, thienyl, cyclohexyl or optionally substituted pyridyl group.
In a later embodiment, Z is absent or represents oxygen, CH2, NRbCH2, CH2NRb, CH (CH3), 0CH2 > CH (CN), 0CF2, CH20,
CF20, SCH2, S (0) m, carbonyl or dicarbonyl, wherein R is hydrogen or C,, alkyl.
In a preferred embodiment, Z is oxygen, dicarbonyl, -0CH2, CH (CN), S (0) or NRb, wherein Rb is hydrogen or alkyl-
1-4 '
In a further preferred embodiment, R is benzyl, halo-, dihalo- and trihalobenzyl, alpha-ethylbenzyl. phenyl. halo-, dihalo- and trihalophenyl, pyridyl, pyridylmethyl, pyridyloxy, pyridylmethoxy, thienylmethoxy, dioxolanylmethoxy, cyclohexylmethoxy, f-e noxy, halo-, dihalo- and trihalophenyloxy, phenylthio, benzyloxy, halo-, dihalo- and trihalobenzyloxy, alkoxybenzyloxy C,., phenyloxalyl or benzenesulfonyl, more preferably benzyl, fluorobenzyl, -benzyloxy, fluorobenzyloxy, pyridylmethyl, phenyl, benzenesulfonyl, phenoxy or fluorophenoxy.
In a later mode, R is in the para position with respect to Y.
In a later embodiment, (R) represents substitute (s) meta with respect to Y, and preferably n = l
In a later modality,
is selected from the group consisting of:
Preferably,
more preferably
In one embodiment, the optional substituents for the carbocyclic or heterocyclic part, which can be presented to any available position in the aforementioned part, are selected from the group consisting of:
(CH, 1) qS (0) mC, 1-4.alkyl, (CH2") qS (0) m-C3" -6, cycloalkyl, (CH2) 'qS02NR8R9,' (CH2) qNR8R9, '(CH2) 'qC02R8,' (CH2) qOR8, (CH, 2) q C0NR8R9, (CH "2) q NR8C0R9, '(CH" 2) qCOR8,' (CH ~ 2) qR8, NR8S092R9 and
where q is an integer from 0 to 4 inclusive; m is 0, 1 or 2; R 8 and R 9 are independently selected from the group consisting of hydrogen, C, C, C, cycloalkyl, aryl, a saturated and unsaturated anheterocyclic, which may be the same or different and the cells contain and which contain one or more heteroatoms which are selected from N, 0 or -S (0), with the proviso that the heterocyclic ring does not contain
2 adjacent atoms 0 or S (0) m
In a further embodiment, the optional substituents for the carbocyclic or heterocyclic part are selected from the group consisting of morpholine, piperazine, piperidine, pyrrolidine, tetrahydrofuran, dioxolane, oxothiolane and oxides thereof, dithiolane and oxides thereof, dioxane , pyridine, pyrimidine, pyrazine, pyridazine, furan, thiofuran, pyrrole, tria zina, imidazole, triazole, tetrazole, pyrazole, oxazole, oxadiazole and thiadiazole.
Other optional substituents for the carbocyclic or heterocyclic part and also for other optionally substituted groups include, but are not limited to, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, cyano, alkoxy -C, alkylthio C,, , C, _, alkylcarbon, carboxylate and C, alkoxycarboxyl.
In a later embodiment, X represents N; U represents a pyridine ring; and the R group is in the 6-position of the pyridopyrimidine ring system.
In a preferred embodiment of the present invention there is provided a compound of formula (I) or a salt or solvate thereof, wherein X represents N; U represents a pyridine ring; Y represents NR, wherein R is hydrogen or C, alkyl; R - represents furan, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, oxazole, isoxazole, oxadiazole, imidazole, tetrazole, triazole, dioxolane or a wholly or partially hydrogenated derivative - of any of these groups, preferably furan, oxadiazole or imidazole, substituted by one or more groups selected from -hydroxy-C, _, alkyl, hydroxy-C,, alkanoyl (C, _, alkyl) amino, -1, 3-dioxolan-2-yl, C, _, alkylamino-C, , alkyl or di (C, _, alkyl) amino-C,, alkyl, and then optionally substituted by one or more C, _, alkyl groups; R represents hydrogen; R re- 3 presents hydrogen or methyl; n is 1; and R represents phenyl, -benzyl, alpha-methylbenzyl, fluorobenzyl, benzenesulfonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy.
In a further preferred embodiment of the present invention there is provided a compound of formula (I), or a salt or solvate thereof, wherein X represents N; U represents a pyridine ring; Y represents NR, wherein R is hydrogen or -alkyl C,,; R represents furan, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, oxazole, isoxazole, oxadiazole, imidazole, terazole, dioxolane or a hydrogenated derivative totally or partially of any of these groups, preferably furan, -oxadiazole or imidazole, substituted by one or more groups selected from methylsulphonylethylaminomethyl, methylsulphonylethylaminocarbonyl, methylsulfinylethylamino-methyl, methylsulfinylethylammo-carbonyl, methylsulphonylimimethyl-methyl, methylsulfinylpro-phenylamino-methyl, methylsulphonylpropylcarbonyl, methylsulfonylpropylamino-carbonyl, methylsulphonylethyl- (methylamino) - methyl, methylsulfonylethyl- (methylamino) -carbonyl, methylsulfinylethyl- (methylamine) -methyl, methylsulfinylethyl- (methylamino) -carbonyl, methylsulfonylpropyl- (methylamino) -methyl, methylsulfinylpropyl- (methylamine) -methyl, methylsulfonylpropyl- (methylamino) -carbonyl, -methylsulfinylpropyl- (methylamino) -carbonyl, methylsulfonamidoe-thylamino-methyl, methylsulfonamidopropylamino- methyl, sarcosine-midomethyl, glycinylmethyl, glycinemidomethyl, glycinylmethyl-methyl. ester, acetylaminoethylaminomethyl, piperazinylmethyl, tylpiperazinylmethyl, piperidinylmethyl, N- (prolinamido) methyl, (N, N-dimethyl-prolinamido) methyl, pyridylaminomethyl, cyclopro-phenylaromethyl, N- (piperidin-4-yl) -N-methylaminomethyl, N , N-dimethylaminoprop-2-ylaminomethyl, N- (2-dimethylaminoethyl) -N-ethylamino-nomethyl, isopropylacetamido, N-morpholinyl acetamido or tetrahydrofuranmamuramomethyl, and then optionally substituted by one or more C-alkyl groups , _,; R represents hydrogen; R 3 represents hydrogen or methyl; n is 1; and R represents phenyl, -benzyl, alpha-methylbenzyl, f-luorobenzyl, benzenesulfonyl, phenoxy, p-chlorophenoxy, benzyloxy or fluo-obenzyloxy.
In a particularly preferred embodiment of the present invention there is provided a compound of the formula (I), or a salt thereof, wherein X represents N; U represents a pyridine ring; Y represents NR, where R is hydrogen or C,,; R represents furan, oxadiazole or imidazole, preferably furan, substituted by a group selected from hydroxy-C, .alkyl, 1,3-dioxolan-2-yl, C, .alkylamino-C,, alkyl or di (C,, alkyl) amino-C, .alkyl, methylsulphonylethylaminomethyl, methylsulfinylethylamino-methyl, methylsulfonylpropylamino-methyl, methylsulfonylethyl- (methylamino) -methyl, imrylsulfonamidoethylamine-methyl, sarcosinamidomethyl, glycinylmethyl, glycinylmethylmethyl ester, acetylaminoethylaminomethyl, piperazinylmethyl, tilpiperazinylmethyl, piperidinylmethyl, N- (prolylamino) methyl, 2 (N, N-dimethyl-prolylamino) methyl and pyridylaminomethyl; R represents hydrogen 3; R represents hydrogen or methyl; n is 1; and R represents fluorobenzyloxy, benzenesulfonyl or benzyloxy, preferably benzyloxy.
Preferred compounds of the present invention include: (4-Benzyloxy-phenyl) - (6- (5-piperidin-1-ylmethyl) furan-2-yl) -piLido [3,4-d] pyrimidine- 4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (5- (4-methyl-piperazin-1-ylmethyl) furan-2-yl) pyrido [3,4-d] pyrimidin-4-yl) amine; (4-Benzyloxy-phenyl) - (6- (5 - ((2-methanesulfonyl-ethylamino) methyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) amine; (5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -amino) -acetic acid methyl ester;
(4-Benzyloxy-phenyl) - (6- (5- (pyridin-3-ylaminomethyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) amine; (4-Benzyloxy-phenyl) -6- (5- (dimethylaminomethyl) -furan-2-yl) -pi-amido [3,4-d] pyrimidin-4-yl) -amine; (2S) -l- (5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidine-6-yl) -fura-2-ylmethyl) -pyrrolidine-2-carboxylic acid amide; 2 - ((5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -methylamino) -acetamide; N- (2 - ((5- (4- (4-Benzyloxy-phenylamino) -pyrimido [3,4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -amino) -ethyl) -acetamide; (4-Benzyloxy-phenyl) - (6- (5 - ((2-methanesulfinyl-ethylamino) -methyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidine-6-yl) -furan-2-ylmethyl) -amino) -acetic acid; (5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-yl) -methanol; (2R) -1- _ 5- [4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] p ± rimidin-6-yl] -f.uran-2-ylmethyl-pyrrolidine- 2-carboxylic amide; (4-Benzyloxy-phenyl) - (6- (5 - ((3-methanesulfonyl-propylamino) methyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (5 - (((2-methanesulfonyl-ethyl) -methyl-ami-no) -methyl) -furan-2-yl) -pyrido [3, 4-d] pyrimidin-4-yl) -amine; (2S) -1-, -5- [4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl] -furan-2-ylmethyl J- pyrrolidine-2-acid carboxylic acid di-methylamide;
N- (2- ((5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -amino) -ethyl) - methanesulfonamide; (4-Benzyloxyphenyl) - (6- (5- (1, 3-dioxolan-2-yl-furan-2-yl) -pyrid [3,4-d] pyrimidin-4-yl) -amine; salts or solvates thereof, particularly pharmaceutically acceptable salts thereof.
Other preferred compounds of the present invention include: (4-Benzyloxy-phenyl) - (6- (5- (4-methyl-piperazin-1-ylmethyl) -N-? Ne-tilimidazol-2-yl) -pyrido [ 3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (5- (dimethylaminomethyl) -N-methylimidazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (5- (4-methyl-piperazin-1-ylmethyl) -imido ^ zol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (5- (dimethylaminomethyl) -imidazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (1- (4-methyl-piperazin-1-ylmethyl) -N-methylimidazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (1- (diraethylaminomethyl) -N-methylimidazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; and salts or solvates thereof, particularly pharmaceutically acceptable salts thereof.
Especially preferred compounds of the present invention include: (4-Benzyloxy-phenyl) - (6- (5 - ((2-methanesulfonyl-ethylamino) methyl) -furan-2-yl) -pyrido [3,4- d] pyrimidin-4-yl) -amine; (2S) -l- (5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyro] midin-6-yl) -furan-2-ylmethyl) -pyrrolidine-2-carboxylic acid amide;
(2R) -1,5- [4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pi-rimidin-6-yl] -furan-2-ylmethyl-pyrrolidine-2-carboxylic acid amide;
(2S) -1- -5- [4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl] -furan-2-ylmethyl-pyrrolidine-2-carboxylic acid -methylamide; and salts or solvates thereof, particularly pharmaceutically acceptable salts thereof.
Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. may contain one or more asymmetric carbon atoms or many exhibit cis-trans isomerism).
Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the present invention. Likewise, it has been understood that the compounds of formula (I) exist in tautomeric forms otherwise than are shown in the formula and these are also included within the scope of the present invention.
The salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen in the compound of formula (I). The residues of the therapeutic activity in the derivative part of the compound of the invention as defined herein and the identity of the other compounds is of minor importance although for therapeutic and prophylactic purposes it is preferably pharmaceutically acceptable for the patient. Examples of pharmaceutically acceptable acid addition salts include those mineral acid derivatives, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfuric, and inorganic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and metasulphonic and arylsulfonic, for example p-toluenesulfonic.
According to a later aspect of the present invention it is to provide a process for the preparation of a compound of formula (I) as defined above which consists of 2 steps: (a) the reaction of a compound of formula (II)
where U, X and R are as defined above and L and L'are-appropriate exit groups, with a compound of formula (III)
3 where Y, R, R and n are as defined above, to prepare a compound of formula (IV)
and subsequently (b) reacting with an appropriate reagent to replace the R group on the U-ring by replacing the outlet group L '; and, if desired, (c) subsequently converting the compound of formula (I) therefor is obtained in another compound of formula (I) by means of appropriate reagents.
Alternatively, the compound of formula (II) as above is reacted with the appropriate reagent to substitute the R group on the U-ring by replacement of the leaving group L'and then the product is thereby obtained (from formula (V) below) is reacted with the compound of formula (III) as above defined, followed, if desired, by conversion of the compound of formula (I) thereby obtained in another compound of formula (I).
In a variant of this alternative the compound of formula (V)
can be prepared by the reaction of a compound of formula
(SAW)
with an appropriate reagent to replace the R group on the U ring to prepare a compound of formula (VII)
and a subsequent reaction to incorporate the leaving group L. For example, a chloro leaving group can be incorporated by reaction of a corresponding 3,4-dihydropyrimidone with tetrachloride / triphenylphosphine in an appropriate solvent.
The group R, therefore, can be replaced in the ring by replacement of a convenient output group. It is especially convenient for the preparation of compounds where -R is a substituted or unsubstituted heterocyclic ring system; such compounds, for example, can be prepared by the reaction of the corresponding hetearyl stannane derivative with the corresponding compound of formula (IV) which carries the leaving group L'in the appropriate position in the ring.
The reagent used to effect the substitution of the R group on the U-ring, in certain circumstances, may include appropriate protection group (s) well known to the person skilled in the art for specific functionalities. -This can, for example, be appropriate, where the R group contains a free amino functionality. Such protection group (s) is removed by standard methods after the substi. in the U ring has been effected. For a description of protection groups and their use see T.W. Greene and P.G.M. Wuts, - "Groups Protective Groups in Organic Synthesis", 2nd edn., John Wiley and Sons, York Mew, 1991.
According to a later aspect of the present invention, it is to provide a process for the preparation of a compound of formula (I) as defined above, which consists of the steps:
(a) reaction of a compound of formula (IV) as above is defined with appropriate reagent (s) to prepare a compound in which the group L 'is replaced with an appropriately functionalized group Z; and (b) subsequently converting the group Z into the group R by means of appropriate reagent (s); and, if desired, (c) subsequently converting the compound of formula (I) therefor is obtained in another compound of formula (I) by means of appropriate reagents.
Such processes are particularly suitable for the preparation of compounds of formula (I) in which R has a substituent selected from M-M -M, M-M or M-1. -M -M 2 12 as defined above in which M represents NR In such cases, preferably group Z carries a terminal formyl group
(CHO)
where Z carries a formyl group, the compound can be appropriately prepared by reaction of a compound of formula (IV) - with an appropriate heteroaryl stannane derivative. Each derivative is readily available or can easily be synthesized by those skilled in the art using conventional methods of organic synthesis. Suitable possibilities include the following schematic examples:
The resulting compounds, for example, are then converted to the respective stannamin derivative.
Analogous methods can be used for other heterocyclic ring systems.
Therefore a convenient process may consist of the reaction of the compound in which the group Z bears a terminal methyl group (eg a group -CHO or - (C, alkylene) -CH0) with-2 3 4 a compound of formula HM -M -M, a compound of formula - n or-- _ • r, HM -M -MO a compound of formula HM, wherein M represents
12 NR. The reaction preferably comprises a reductive amination by means of an appropriate reducing agent, for example sodium triacetoxyborohydride.
A similar process is involved where, in M a group 2 12 CH2 was replaced with a group CO and M was replaced with NR. If -in certain circumstances, the ketone is protected by standard methods to ensure that the reductive amination comprises the functionality of the aldehyde.
For the preparation of these compounds in which, in M 2, the CH ~ group adjacent to M is replaced with a CO group, a convenient tpto_ ceso consists of the reaction of a compound in which the Z group carries a group - (Cn "Alkylene" -C0? H with a copolymer of formula HM -M, a compound of formula HM -M -M 5 2 12 or a compound of formula HM, wherein M represents NR
Alternatively, a scheme analogous to those above-described is used, wherein the substitution of the R group on the U-ring preempts preference to the coupling reaction with the compound of the formula (III).
According to a subsequent alternative process, the group Z is converted into the R group by a de novo synthesis of the substituted or unsubstituted heterocyclic ring system using appropriate reagents. Such a process comprises a standard synthetic methodology known to the person skilled in the -technique for the construction of the heterocyclic ring system.For example, Z appropriately represents an alkyl group which when reacted with a nitrile oxide - appropriate as - result in "the formation of an isoxazole ring system The group Z appropriately also represents a group - amidoxime (derivative of a cyano group) which when done-reacts with an activated carboxylic acid derivative (such as an acid chloride or an acid imidazolide) as a result --in the formation of a 1, 2, 4-oxadiazole ring system The group Z appropriately also represents a bromomethylene carbonyl group which is reacted with an imidate as a result of formation in the formation of a ring-oxazole system, with a guanidinc group resulting in the formation of a system of the N-imidazole ring The Z group appropriately - also represents a group of activated carboxylic acid which is reacted to form a hydrazinoketone which subsequently it is reacted with another derivative of the activated carboxylic acid as a result in the preparation of a system of the 1,3,4-oxadiazole ring. Thus the reaction of a compound carrying a relevant Z group with appropriate reagents that carry some of -C = N = 0, -NH-C (NH2) = NH, -COX, -C (NH2) = N0H, - C (0Me) = NH, or -C (NH2) = NH, as a terminal group results in the formation of the ring systems indicated above.
Alternatively, an analogous scheme for those above-described are used, wherein the substitution of the R group on the U-ring presents preference to the coupling reaction with the compound of the formula (III).
The lines of the following scheme, for example, the synthesis of derivatives bearing a substituted 1, 3, 4-oxadiazole ring as a substituent R:
idinor.a
or another equivalent or.
Such processes are particularly convenient for the preparation of the compounds of formula (I) wherein the substituted compounds bear a substituent selected from M -M -M, -
M -M or M -M -M -M as above are defined in which M represents- 12 13 1 CR R, including those in which in M some group
CH 2 is replaced by a CO group
Suitable leaving groups for L and L'will be well known to those skilled in the art and include, for example, halo such as chlorine and bromine; sulfonyloxy groups such as methanesulfonyloxy and toluene-p-sulfonyloxy; alkoxy groups; and triple.
The coupling reaction referred to above with the compound of formula (III) is conveniently carried in the presence of a suitable inert solvent, for example an alkanol C,, such as isopropanol, a halogenated hydrocarbon, an ether, a Aromatic hydrocarbon or a dipolar aprotic solvent such as acetone or acetonitrile at a non-extreme temperature, for example from 0 to 150 °, conveniently from 10 to 100 ° C, preferably from 50 to 100 ° C.
Optionally, the reaction is carried out in the presence of a base when Y = NH. Examples of suitable bases include an organic amine such as triethylamine, or a metal carbonate of alkaline earth, hydride or hydroxide, such as sodium or potassium carbonate, hydride or hydroxide. When YH = OH or SH it is necessary to carry out the reaction in the presence of a base, and in such case the product is not obtained as the salt.
The compound of formula (I) in the case where Y = NR can be obtained from this process in the form of a salt - with the acid HL, where L is as defined above, or as the free base by the salt treatment with a base as described above.
The compounds of formula (II) and (III) as above are defined, the reagent to replace the group R and the reagent - (s) to convert the group Z to the group R are either of the two readily available or they can easily be synthesized by those skilled in the art using conventional methods of organic synthesis.
As indicated above, the compound of formula (I) prepared can be converted to another compound of formula (I) by chemical transformation of the substitute or suitable substitutes using chemical methods (see for example, J. March - "Advanced Organic Chemistry" , Edition III, Wiley Interscience, 1985).
For example, a compound containing an alkyl or aryl mercapto group can be oxidized to the corresponding sulfinyl or sulfonyl compound by the use of an organic peroxide (e.g., benzoyl peroxide) or an appropriate inorganic oxidant (e.g., OXONE).
A compound containing a nitro substituent can be reduced to the corresponding amino compound, e.g. by - the use of hydrogen and an appropriate catalyst (if there are no other 10 susceptible groups) or by the use of Raney Nickel and ^ - ^ hydrazine hydrate.
The amino or hydroxy substituents can be acylated or the use of an anhydride acid chloride under appropriate conditions. Likewise, an acetate or amide group can be split for the amine or hydroxy compound respectively by the treatment with, for example, a dilute aqueous base.
In addition, the reaction of an amino substituent with thiphosphate and any amine (e.g., aqueous ammonia, dimethylamine) yields the product of the substituted urea.
An amino substituent can also be converted to a dimethylamino substituent by reaction with formic acid and sodium cyanoborohydride.
A formyl substituent can be converted to a hydroxymethyl or a carboxy substituent by standard reduction or oxidation methods respectively. •
All of the chemical transformations mentioned above can also be used to convert a compound of formula - (II) to a subsequent compound of formula (II) preferred for - any subsequent reaction; or to convert a compound - of formula (III) to a later compound of formula (III) pre¬
for any subsequent reaction.
. Various intermediates used in the processes mentioned above include, but are not limited to, certain compounds of formula (II), (III), (IV), (V), (VI) and (VII) as
above is illustrated, are new and thus represent a later aspect of the present invention.
The compounds of formula (I) and salts thereof have anticancer activity as demonstrated below by their in.
The inhibition of the enzymes of the protein tyrosine kinase c-erbB-2, c-erbB-4 and / or EGFr and its effect on cell lines selected from the growth is': "dependent on the activity of the tirc > sina kinase from c-erbB-2 or EGF-r.
The present invention also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof for use in medical therapy, and in particular in the treatment of disorders mediated by the aberrant activity of the protein tyrosine kinase such as malignancies. human and the other disorders mentioned above, The compounds of the present invention are especially useful for the treatment of disorders caused by the aberrant activity of c-erbB-2 and / or EGF-r such as breast, ovarian, gastric cancers , pancreatic, non-small cells of the lung, bladder, head and neck, and psoriasis.
A further aspect of the invention is to provide a method for the treatment of a human or animal subject suffering from a disorder mediated by the aberrant activity of the protein tyrosine kinase, which includes susceptible malignancies, which consists of administration to the subject before mentioned of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
A further aspect of the present invention is to provide the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in therapy.
A further aspect of the present invention is to provide the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of malignant tumors and cancers.
A further aspect of the present invention is to provide the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of psoriais.
While it is possible for the compounds, salts or solvates of the present invention to be administered as new quimi
< ~ "s, is preferred for those present in the form of a pharmaceutical formulation.
According to a later feature of the present invention is to provide a pharmaceutical formulation comprising at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients. .
The pharmaceutical formulations may be presented in dosage forms per unit containing a predetermined amount of the active ingredient per dose of unit. Such a unit contains for example 0.5 mg to 1 g, preferably 70 mg to 700 mg, more specifically 5 mg to 100 mg of a compound of the formula (I) which depends on the condition to be treated, the route of administration and the age, weight and condition of the patient.
The pharmaceutical formulations can be adapted for administration by any appropriate route, for example the oral (which includes the buccal or sublingual), rectal, nasal, topical (which includes the buccal, sublingual or transdermal), vaginal or parenteral (which includes subcutaneous, intramuscular, intravenous or -intradermal). Such formulations can be prepared by any method known in the pharmacy art, for example by compromising the association of the active ingredient with the carrier (s) or excipient (s).
Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or - suspensions in aqueous and non-aqueous liquids; edible or whipped foams; or liquid emulsions of oil in water and liquid emulsions of water in oil.
Pharmaceutical formulations adapted for transdermal administration can be presented as described parts which are intended to remain in intimate contact with the epidermis-of the recipient for a prolonged period of time. For example, the active ingredient can be formulated by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
Pharmaceutical formulations adapted for topical administration can be formulated as ointments, creams, their pensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For treatments of the o or other external tissues, for example mouth and skin, the formulations are preferably applied as an ointment or topical cream. When formulated in an ointment, the active ingredient can be used with each - a water-miscible or paraffin-based ointment. Alternatively, the active ingredient can be formulated in a cream - with an oil-in-water-based cream or a water-in-oil base.
Pharmaceutical formulations for administrations -topics for the eye include eye drops wherein the active ingredient is dissolved or suspended in an appropriate carrier, especially an aqueous solvent.
Formulations adapted for topical administration in the mouth include tablets, lozenges and mouth rinses.
Pharmaceutical formulations adapted for rectal administration can be presented as suppositories or as enemas.
Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid includes a coarse powder having a particle size for example in the
I »range of 20 to 500 microns which is administered in a manner in which by inhalation it is taken, e.g. Rapid inhalation through the nasal passage of an inhalation container helps close up the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include oil or aqueous solutions of the active ingredient.
Pharmaceutical formulations adapted for administration by inhalation include powders or mists of fine particles which can be generated by means of various types of doses mediated in pressurized aerosols, nebulizers or insufflators.
Pharmaceutical formulations adapted for vaginal administration may be presented as heavy formulations, buffers, creams, gels, pastes, foams or spray.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, 5-buffers, bacteriostats 7 solutes which give the formulation isotonic with the blood from which it has to receive; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations can be presented in containers per dose unit or multi-dose, for example sealed vials and flasks, and can be stored with the condition of freeze-drying (freeze-dried) which requires only the addition of a sterile liquid carrier, for example water for injections, immediately preferable to use. Extemporaneous injection solutions and suspensions can be prepared from powders, granules, and sterile tablets.
Preferred unit dosage formulations are those containing a daily dose or sub-dose, as hereinabove set forth, or an appropriate fraction thereof, of an active ingredient.
It is understood that in addition to the ingredients particularly mentioned above, the formulations may include other conventional agents in the art taking into account the type of formulation in question, for example, that suitable for oral administration may include flavoring agents.
The animal that requires treatment with a compound, salt or solvate of the present invention is usually a mammal, such as the human.
A therapeutically effective amount of a compound, salt or solvate of the present invention will depend on a number of factors including, for example, the age and weight of the animal, the precise condition that the treatment requires and this severity, the nature of the formulation, and the route of administration, and finally will be at the discretion of the attending physician or veterinarian. However, an effective amount of a compound of the present invention for the treatment of neoplastic growth, for example carcinoma of the colon and chest - will generally be in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and more usually in the range of 1 to 10 mg / kg of body weight per day. Thus, for a 70k adult mammal, the current amount per day is usually 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as 2, 3, 4, 5 or 6) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt or solvate of the present invention can be determined as a proportion of the effective amount of the compound per se.
The compounds of the present invention and their salts and -solvates can be used alone or in combination with other therapeutic agents for the treatment of conditions.
mentioned above. Specifically, in an anti-cancer therapy, the combination with other chemotherapeutic agents, hormones or antibodies are focused. The combination of therapies according to the present invention thus accounts for the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least some other pharmaceutically active agent. The compound (s) of formula - (I) and the other pharmaceutically active agent (s) can be administered together or separately and, when administered separately, this can occur simultaneously or sequentially in any order. The amounts of the compound (s) of formula (I) and the other pharmaceutically active agent (s) and the relative regulations of administration will be selected in order to carry out the desirable combination of the therapeutic effect.
Certain embodiments of the present invention will now be illustrated by the example route only. The physical data given for the exemplified compounds is consistent with the assigned structure of those compounds.
The H NMR spectrum was obtained at 250MHz in a Bruker AC250 or Bruker AM250 spectrophotometer. The J-values are given in Hz. The mass spectrum was obtained in one of the following machines: VG Micromass Platform (positive or negative electroatomization) or HP5989A Engine (positive thermoatomizer). Analytical thin-layer chromatography (tlc) was used to verify the purity of some intermediates which can not be isolated or which were also unstable for the full characterization, and to follow the progress of the reactions-Unless otherwise stated , this is done using silica gel (Merck Silice Gel 60 F254). except for the opposite approach, column chromatography for the purification of some compounds use Silica Gel Merck 60 (Art. 1.09385, mesh 230-240), and the system of the given solvent under pressure. Pretol refers to diethyl ether. DMAP refers to 4-dimethylaminopyridine DMF refers to dimethylformamide. DMSO refers to dimethylsulfoxide. IMS refers to the industrial methylated spirit. THF refers to tetrahydrofuran. TMEDA refers to N, N, N ^ N'-tetramethylethylenediamine. HPLC refers to a high pressure liquid chromatography. RT refers to the retention time.
Useful preparative techniques are described in W096 / 09294, W097 / 03069 and W097 / 13771; Also described in these applications are appropriate intermediate compounds other than those detailed below.
General procedure
A / The reaction of an amine with a bicyclic species - which contains a 4-chloro-pyrimidine ring. The optionally substituted bicyclic species and the specific aryne were mixed in an appropriate solvent and refluxed. When the reaction was complete '(as estimated by tic), the reaction mixture was allowed to cool. The suspension that resulted was diluted e.g. with acetone and the solid was collected by filtration, washed e.g. with an excess of acetone, and dried at 60 ° C under vacuum.
B / The reaction of the product of A / with a heteroaryl ester reagent. A stirred mixture of the product of A /, e.g. a chloropiolidopyrimide, a heteroaryl stannamine and a suitable palladium catalyst, such as bis- (triphenylphosphine) palladium (II) chloride or 1,4-bis (diphenylphosphino) -butane-palladium (II) chloride ( prepared as described in C. E. Housecraft et-al., Inorg. Chem. (1991), 30 (1), 125-30), together with other suitable additives, were heated to reflux in dry dioxane or other solvent convenient under nitrogen until the reaction was complete. The dark mixture was purified by silica chromatography eluting with the ethyl acetate / methanol mixture.
Preparation of intermediaries
4-Benzyloxyaniline is commercially available as the hydrochloride salt; this is treated with an aqueous sodium carbonate solution, and the mixture is extracted with ethyl acetate; the organic solution is dried (MgSO4) and concentrated to give the free base as a tan solid, used without further purification.
Other substituted anilines are generally prepared - by methods analogous to those summarized in W096 / 09294 and / or as if:
Step 1: Preparation of the nitro precursor compounds 4-nitrophenol (or an appropriate substituted analog, such as 3-co ro-4-nitrophenol) was treated with a base such as potassium carbonate or sodium hydroxide in an appropriate solvent, such as - acetone or acetonitrile. The appropriate aryl halide or heteroaryl was added and the reaction mixture was heated or stirred at room temperature overnight.
Purification A: More than acetonitrile was removed in vacuo, and the residue was partitioned between water and dichloromethane. The aqueous layer was then extracted with dichloromethane (x2), and the combined -5 dichloromethane layers were concentrated in vacuo.
Purification B: remove the insoluble material by filtration, followed by the concentration of the reaction mixture - in vacuo, and chromatography on silica.
Step 2: Reduction for the corresponding aniline The nitro precursor compound was reduced by catalytic hydrogenation at atmospheric pressure using 5% Pt / carbon, in a convenient solvent (eg ethanol, THF, or mixtures thereof to cause solubility ). When the reduction was complete, the mixture was filtered through Harborlite, washed with an excess of solvent, and the resulting solution is concentrated in vacuo to give the desired aniline. In some cases, the anilines were acidified with HCl (e.g. in a dioxane solution) to give the corresponding hydrochloride salt.
Anilines prepared by such methods include: 4-La 4- (2-fluorobenzyloxy) aniline; m / z (M + 1) 218 4- (3-fluorobenzyloxy) aniline; m / z (M + 1) 218 4- (4-fluorobenzyloxy) aniline; m / z (M + 1) 218 3-Chloro-4- (2-fluorobenzyloxy) aniline; m / z (M + 1) 252 3-Chloro-4- (3-fluorobenzyloxy) aniline; m / z (M + 1) 252 3-Chloro-4- (4-fluorobenzyloxy) aniline; m / z (M + 1) 252 4- (Pyridyl-2-methoxy) aniline; m / z (M + 1) 201 4- (pyridin-4-methoxy) aniline; m / z (M + 1) 201 4- (pyridyl-3-methoxy) aniline; m / z (M + 1) 201 4-Benzyloxy-3-chloroaniline; m / z (M + 1) 234 and, in appropriate cases, its hydrochloride salts.
4 Bencensulfopylaniline was prepared by the published method (Helv. Chim. Acta., 1983, 66 (4), p 1064.
N-5- [N-tert-butoxycarbonyl) amino] -2-chloropyridine A stirred solution of 6-chloronicotinic acid (47.3 g), diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in t-butanol (240 ml) ) were heated to reflux under nitrogen for 2.5 hours. The solution was cooled and concentrated in vacuo. The impasto residue was poured into 3 liters of a rapidly stirred solution-aqueous 0.33N sodium carbonate. The precipitate was stirred for one hour and filtered. The solid was washed with water and dried in vacuo at 70 ° C to give the title compound (62g) as a pale brown tan solid, m.p. 144-146 ° C: deltaH [2H6] -DMS0 8.25 (lH, d), 7.95 (lH, bd), 7.25 (1H, d), 6.65 (1H, bs), 1.51 (9H, s); m / z - (M + 1) + 229.
This material can subsequently be brought to the appropriately substituted pyridopyrimidine intermediate in accordance with the procedures as described in WO95 / 19774, J. Med. Chem., 1996, 39, pp. 1823-1835, and J. Chem. Soc, Perkin
Trans. 1, 1996, pp 2221-2226. Specific compounds made by such methods include 6-chloro-pyrido [3,4-d] pyrimidin-one and 4,6-dichloro-pyrido [3,4-d] pyrimidine,
(4-Benzyloxy-phenyl) - (6-chloro-pyrido [3,4-d] pyrimidin-4-yl) -amine
It is prepared according to process A of 4-benzyloxyaniline and 4,6-dichloropyrido [3,4-d] pyrimidine; deltaH (CDC13) 9.11 (1H, s), 8.78 (1H, s), 7.75 (1H, d), 7.56 (2H, dd), 7.40 (5H, m), 7.15 - (2H, d), 5.10 (2H , s); m / z (M + 1) 409.
- (- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde
(4-Benzyloxyphenyl) - (6-chloro-pyrido [3,4-d] pyrimidin-4-yl) -nane (4.0g, 11.0 mmol), 5- (1,3-dioxolan-2-) il) -2- (tributylstanil) furan (J. Chem. Soc., Chem Commun., (1988), 560) (6.0g, 14.0 mmoles) were reacted together in a procedure -analog to procedure B above by 20 hours. The reaction mixture was allowed to cool, IN HCl (50 mL) was added and stirred at room temperature for 15 minutes. The reaction was filtered and the residue was washed with dioxane (20 ml) and 2N HCl (20 ml). The combined filtrate and washings were stirred at room temperature after one hour. The dioxane was removed under vacuum, the reaction was diluted with water and the solid which precipitated was collected by filtration, and washed with water, isohexane and acetone. This -precipitate was converted to the free base by dividing-dividing a mixture of triethylamine, ethyl acetate and water. The organic phase was washed with water, dried (magnesium sulfate) and the solvent was removed under vacuum. The residue was triturated with ethyl acetate / iso-hexane to give the product (2.41g, 52%) -2 as a yellow solid; deltaH [H6] -DMS0 10.60 (1H, b, NH), -
9. 83 (1H, s, CHO), 9.30 (1H, s, 2-H), 9.08 (1H, s, 5-H or 8-H), - 8.76 (1H, s, 5-H or 8-H) 7.89 (1H, d, furan-H), 7.82 (2H, d,
2'-H, 6'-H), 7.65-7.42 (6H, m, 5x Ph-H, furan-H), 7.21 (2H, d, -3'-H, 5'-H), 5.26 (2H , s, 0CH2); m / z (M + 1) + 423.
N-methyl-N- (2-methanesulfonyl) amine hydrochloride
Methylvinyl sulfone (2.1g, 19.78 mmol) and methylamine - (33% solution in IMS, 40 ml, excess) are mixed and heated under reflux under a nitrogen atmosphere for 6 hours. After-staying overnight at room temperature, the mixture was concentrated in vacuo to give a yellow oil, which was treated with etheric HCl to give a wet solid. Trituration with absolute ethanol gives the title compound as a white solid which was collected by filtration and dried at 60 ° C in vacuo (1.Olg, 5.82 mmol, 29%); delta [2H6] D S0 9.27 (2H, br s), 3.59 (2H, dd), 3.31 (2H, dd), 2.57 (3H, s).
N- [2- (Methanesulfonamido) ethyl] acetamide
N-Acetylethylenediamine (10.2 g, 100 mmol) and triethylamine (15 ml, 10.9 g, 108 mmol) were dissolved in dichloromethane (300 ml) and the solution was cooled to 0 ° C. The methanesulfonyl chloride (8 ml, 11.8 g, 103 mmol) was dissolved in dichloromethane (10 ml) and added by dripping, and stirring was continued at 0 ° C for 3 hours. The dichloromethane was removed in vacuo, and the residue was suspended in a mixture of ether and acetone, the insoluble material was removed by filtration. The filtrate was concentrated in vacuo to give the title compound as a pale brown gum (14.5 g, -88.3 mmol, 88%); deltaH [2H6] DMSO 7.93 (1H, br t), 7.05 (1H, t), 3.11 (2H, t), 2.97 (2H, t), 2.89 (3H, s), 2.09 (3H, s).
2- (methanesulfonamido) ethylamine hydrochloride
The N- [2- (methanesulfonamido) ethyl] acetamide (14.5 g, 88.3 mmol) and concentrated hydrochloric acid (100 ml) were dissolved in water - (100 ml) and heated to reflux for a total of 3 hours. After cooling down, the water was removed in vacuo, and the residue was left for several days at room temperature until the crystallization was complete.
Trituration with a mixture of ethanol and ether gives the title compound as a white solid which was dried under vacuum at 60 ° C (7.5 g, 42.9 mmol, 49%); deltaH [2H &] DMSO 8.22 (2H, br s), 7.42 (1H, t), 3.23 (2H, q), 2.87 (3H, s), 2.85-2.95 (2H, m).
The following preparations, although the compounds of the present invention do not result in the synthesis procedures used to prepare compounds having a substituted 1,3,4-oxadiazole ring; Analogous procedures are used to prepare compounds of the present invention.
6-Cyano-pyrido [3,4-d] pyrimidin-4-one
The 6-chloro-pyrido [3,4-d] irimidin-4-one (lOg) in l-methyl-2-pyrro lidone (100 ml) was treated with copper (I) iodide (10.52 g) and cyanide. Potassium nuride (7.10g) at 215 ° C for 72 hours under 2. Potassium cyanide (3.58g) was then added and continued heating at 230 ° C for 70 hours. The l-methyl-2-pyrrolidone was removed by distillation under reduced pressure and the residue was received in silica.
Chromatography gives the title compound (2.4g) as a beige solid; deltaH [2H DMS0 13.0 (1H, bs), 9.25 (1H, s), 8.55
(1H, s); m / z (M- • 1) + a71
6- (1, 2,3,4-tetrazol-5-yl) -pyrido [3,4-d] pyrimidin-4-one
6-Cyano-pyrido [3,4-d] pyrimidin-4-one (0.3g) in diglyme (2 ml) was treated with tibutyl tin azide (0.49g) under reflux under N2 for 15 hours. The cooled mixture was divided between ethyl acetate and
ethyl acetate and water and the aqueous phase was then extracted with ethyl acetate. The aqueous phase was concentrated in vacuo, the residue obtained from methanol and inorganics were removed by filtration. Subsequently the concentration gives the title compound (1.4g) as a beige solid; delta H [2H6] DMS0 8.96 (1H, s), 8.50 (1H, -s), 8. 27 (1H, s); m / z (M + l +) 216.
6- (5-Methyl-l, 3,4-oxadiazol-2-yl) -? Irido [3,4-d] pyrimidin-4-one
The 6- (1, 2,3,4-tetrazol-5-yl) pyrido [3,4-d] pyrimidin-4-one (1.4 g) -in acetic anhydride (10 ml) was heated to reflux under N2 by - 2.5 hours. The cooled mixture was received in silica and purified
IOG chromatography to give the title compound (0.14g) as a beige solid; deltaH [2Hft] DMSO 13.0 (1H, bs), 99..3300 ((l1iH, s), - 8.66 (1H, s), 8.47 (1H, s), 2.75 (3H, s); m / z (M + l +) 230.
4-Chloro-6- (5-methyl-l, 3,4-oxadiazol-2-yl) -pyrido [3,4-d] pyrimine
6- (5-Methyl-l, 3,4-oxadiazol-2-yl) -pyrido [3,4-d] pyrimidin-4-one (0.5g) was treated with phosphorous oxychloride in the usual manner-for give the title compound (0.17g) as an orange solid; deltaH CDC13 9 68 (1Hf s) j 9.30 (1H, s), 8.96 (1H, s), 2.75 (3H, s); m / z (M + l +) 248.
(4-Pef Oxy-F-enyl) - (6- (5-methyl-1,3,4-oxadiazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine
The title compound was prepared according to process A of 4-phenoxyaniline and 4-chloro-6- (5-methyl-1,3, -oxadiazol-2-yl) -pyrido [3,4-d] pyrimidine; deltaH [2H6] DMSO 11.15 (1H, s), 9.43 (1H, s), 9.34 (1H, s), 8.89 (1H, s), 7.86 (2H, d), 7.45 (2H, dd), 7.12 (5H , m), 2.75 (3H, s); m / z (M + l +) 397.
(4- (3-Fluoro-benzyloxy) -phenyl) - (6- (5-methyl-1,3,4-oxadiazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine
The title compound was prepared according to the procedure A-of 4- (3-fluorobenzyloxy) aniline and 4-chloro-6- (5-methyl-1,3,4-oxa-diazol-2-yl) -pyrido [3 , 4-d] pyrimidine; deltaH [2H6] DMS0 11.30
(1H, s), 9.47 (1H, s), 9.38 (1H, s), 8.93 (1H, s), 7.80 (2H, d), 7.53 (1H, m), 7.38 (2H, d), 7.22 ( 3H, m), 5.25 (2H, s), 2.74 - (3H, s); ra / z (M + l +) 429.
(4-Benzyloxy-phenyl) - (6- (5-methyl-1,3,4-oxadiazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine
The title compound was prepared according to procedure A-of 4-benzyloxyaniline and 4-chloro-6- (5-methyl-1,3,4-oxadiazol-2-yl) -pyrido [3,4-d] pyrimidane; deltaH [2H IX] DMS0 11.33 (1H, s), 9.49 - (1H, s), 9.39 (1H, s), 8.93 (1H, s), 7.80 (2H, d), 7.53 (2H, - dd), 7.45 (3H, m), 7.20 (2H, d), 5.25 (2H, s), 2.75 (3H, s); - m / z (M + l) 411 •
(4-Benzenesulfonyl-phenyl) - (6- (5-methyl-l, 3,4-oxadiazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine
The title compound was prepared according to process A of 4-benzenesulfonylaniline and 4-chloro-6- (5-methyl-1,3,4-oxadiazol-2-yl) -pyrido [3,4-d] pyrimidine; m / z (M + l) 411. •
Eg emplos
Example 1 (4-Benzyloxy-phenyl) - (6- (5-piperidin-1-ylmethyl) -furan-2-yl) pyrido [3,4-d] pyrimidin-4-yl) -amine hydrochloride
The 5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -20 furan-2-carbaldehyde (0.2 g) and piperidine (0.2 g) were mixed in dichloromethane ( 2ml) and stirred at room temperature for 5 minutes. The mixture was cooled to 0 ° C and the triacetoxyborohydride of sodium (0.5 g) added in portions with stirring. The reaction was stirred at 0 ° C for 15 minutes and then at room temperature for 1 minute.
hours The reaction was quenched with water and diluted - with dichloromethane. The organic phase was separated and the aqueous extracted with dichloromethane. The combined aqueous fractions were dried (MgSO 4) and the solvent was removed under vacuum. The resulting yellow crystals were dissolved in acetone, filtered and the filtrate was adidified with 2N HCl. The solid produced was filtered, washed with acetone and dried at 60 ° C under vacuum - to give the product as a yellow solid (0.192g); deltaH - [2H6] -DMSO 11.90 (1H, bs), 10.79 (1H, bs), 9.70 (1H, s), 9.34 (1H, s), 8.92 (1H, s), 7.91 (2H, d), 7.60 -7.40 (6H, m), 7.20 - (2H, d), 7.02 (1H, d), 5.23 (2H, s), 4.58 (2H), 3.50 (2H, d), - 3.04 (2H, b), 2.02-1.70 (5H, m), 1.47 (1H, m); m / z 492 (M + l) +.
Example 2
(4-Benzyloxy-phenyl) - (6- (5- (4-methyl-piperazin-1-ylmethyl) -fu-ran-2-yl) irido [3,4-d] irimidin-4-yl) - amine
In a manner analogous to the example, 1, .5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde and 1-methylpiperazine they became the title compound; deltaH [2H6] -DMS0 10.29 (1H, b), 9.11 (1H, s), 8.66 (1H, s), 8.60 (1H, s), 7.72 (2H, d), 7.52-7.33 (5H, m), 7.15-7.06 (3H, m), -
6. 55 (1H, d), 5.15 (2H, s), 3.62 (2H, s), 2.61-2.28 (8H, m),
2. 15 (3H, s); m / z 507 (M + l) +.
Example 3
(4-Benzyloxy-phenyl) - (6- (5- ((2-methanesulfonyl-ethylamino) methyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) - hydrochloride amine
In a manner analogous to example 1, 5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde and 2-me tansulfonyl) -ethylamine was converted to the title compound [2H-DMS0 11.73 (1H, b), 10.00 (1H, b), 9.62 (1H, s), 9.21 6 (1H, s), 8.81 (1H, s), 7.80 (2H, d), 7.49-7.24 (6H, ra), 7.09 (2H, d), 6.84 (1H, d), 5.11 (2H, s), 4.41 (2H, s), 3.69 (2H, t), 3.53
(2H, b); m / z 530 (M + l) +.
Example 4
The hydrochloride of (5- (4- (4-benzyloxy-phenylamino) -pyrido (3,4-d) pyrimidin-6-yl) -furan-2-ylmethyl) -amino) -acetic acid methyl ester .
In a manner analogous to Example 1, 5- (4- (4-benzyloxy-f-enylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde and methyl ester glycine hydrochloride were converted in the title compound; deltaH [2H6] -DMS0 9.26 (1H, s), 9.19 (1H, s), 8.77 (1H, s), - 7.90 (2H, d), 7.64-7.42 (5H, m), 7.36 (1H, d) , 7.20 (2H, d), 6.98 (1H, d), 5.25 (2H, s), 4.51 (2H, s), 4.20 (2H, s), 3.86 (3H, s); m / z 496 (M + l) +.
Example 5
(4-benzyl i-phenyl) - (6- (5- (pyridin-3-ylaminomethyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine
In a manner analogous to Example 1, 5- (4- (4-benzyloxy-phenylalani) -pyrant [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde and the 3-ami nopyridine were they became the title compound; deltaH - [2H6] -DMS0 10.42 (1H, b), 9.08 (1H, s), 8.69 (1H, s), 8.55 (1H, s), 8.09 (1H, d), 7.79 (1H, d), 7.70 (2H, d), 7.52-7.27 (5H, m), 7.16-6.99 (5H, m), 6.52 (2H, m), 5.11 (2H, s), 4.42 (2H, d); m / z 501 (M + l) +.
Example 6
(4-Benzyloxy-phenyl) -6- (5- (dimethylaminomethyl) • furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine hydrochloride
In a manner analogous to Example 1, 5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde and dimethylamine hydrochloride they became the title compound; deltaH [2H6] -DMS0 9.50 (1H, s), 9.26 (1H, s), 8.84 (1H, s), 7.87
(2H, d), 7.57-7.32 (6H, m), 7.17 (2H, d), 6.99 (1H, d), 5.20
(2H, s), 4.57 (2H, s), 2.88 (6H, s); m / z 452 (M + l) +.
Example 7 (2S) -! - (5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] irimidin-6-yl) -furan-2-ylmethyl) -pyrrolidin- hydrochloride 2-carboxylic amide
In a manner analogous to Example 1, 5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde and L-prolinamide were converted in the title compound; deltaH [2H6] -DMS0 9.92 (1H, b), 9.52 (1H, s), 9.28 (1H, s), 8.83 (1H, -s), 8.49 (1H, s), 7.81 (2H, d), 7.71 (1H, s), 7.58-7.28 (6H, m), 7.14 (2H, d), 6.91 (1H, d), 5.19 (2H, s), 4.80 (1H, b), 4.60 (2H, s), 3.67 (1H, b), 3.40 (1H, b), 2.17-2.74 (4H, m); m / z 521 (M + l) +,
Example
2- ((5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -methylamino) -acetamide.
In a manner analogous to Example 1, 5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde and the -sacosaminide were converted to the title compound; deltaH [2H6] -DMS0 10.21 (1H, b), 9.11 (1H, s), 8.65 (1H, s), 8.60 (1H, -s), 7.72 (2H, d), 7.54-7.33 (5H, m) , 7.28 (1H, b), 7.15-7.05 - (3H, m), 6.51 (1H, d), 5.15 (2H, s), 3.79 (2H, s), 3.02 (2H, s), 2.32 (3H, s); m / z 495 (M + l) +.
Example 9
N- (2 - ((5- (4- (4-benzyloxy-phenylamino) -pyrimido [3,4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -amino) -ethyl) -acet measure
In a manner analogous to Example 1, 5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde and N-acetylethylenediamine were converted in the title compound; deltaH [2H6] -DMS0 10.25 (1H, b), 9.10 (1H, s), 8.65 (1H, s), - 8.59 (1H, s), 7.86 (1H, b), 7.72 (2H, d), 7.52 -7.31 (5H, m), ~ 7.15-7.05 (3H, m), 6.50 (1H, d), 5.14 (2H, s), 3.83 (2H, s), - 3.18 (2H, q), 2.64 (2H , t), 2.20 (1H, bs), 1.79 (3H, s); m / z - 509 (M + l) +.
Example 10
(4-Benzyloxy-phenyl) - (6- (5 - ((2-me-ansulfinyl-ethylamino) -methyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) - amine
In a manner analogous to Example 1, 5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde and [2- (methansulfinyl) ethyl] amine were converted to the title compound; deltaH [2H6] -DMS0 10.20 (1H, b), 9.11 (1H, s), 8.67 (1H, s), 8.59 (1H, s), 7.72 (2H, d), 7.53-7.30 (5H, m), 7.17-7.04 (3H, m), 6.52 (1H, d), 5.15 (2H, s), 3.87 (2H, s), 3.08-2.75
(4H, m), 2.55 (3H, s); m / z 514 (M + l) +.
Example 11
(5- (4- (4-Benzyloxy-phenylamino) -α-irido [3,4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -amino) -acetic acid hydrochloride.
(5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -amino) -acetic acid hydrochloride methyl ester (0.04g) ) was suspended in acetone (5 ml) and a solution of sodium hydroxide "N (5 ml) was added.The resulting solution was stirred at room temperature for 30 minutes.The acetone was removed under vacuum and the solution was stirred. acidified with 2N HCl The mixture was chilled in an ice bath and the free precipitate was filtered and washed with a little cold water and then with acetone.The residue was dried at 60 ° C under vacuum to give the product as a solid - orange (0.03g), deltaH [2H6] -DMSO 10.30 (1H, b), 9.10 (1H, s),
8. 71 (1H, s), 8.59 (1H, s), 7.75 (2H, d), 7.53-7.28 (5H, m),
7. 15-7.00 (3H, m), 6.62 (1H, d), 5.12 (2H, s), 4.07 (2H, s); m / z 482 (M + l) +.
Example 12
(5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-yl) -methanol hydrochloride
(5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde (0.2 g) was suspended in methanol (5 ml) and bo-hydride Sodium (0.026g) was added, the reaction was stirred at room temperature for 1 hour, then acidified with 2N HCl, the methanol was removed under vacuum, the residue was diluted with acetone and the orange solid that resulted free was filtered and washed-with water and acetone.The solid was suspended in ethyl acetate / iso-hexane 1: 1 and neutralized with triethylamine, the solution-formed columnized in a flash column of silica gel eluting with a solvent index. ethyl acetate / iso-hexa_ no (50-100% ethyl acetate) and finally with acetone.The product fractions were concentrated under vacuum and the oil, which was dissolved in acetone and acidified with real HCl. ÍN) which was then dried at 60 ° C under vacuum to give the product as an orange solid (0.8 g), deltaH [H,] - DMS0 11.80
(1H, b), 9.30 (1H, s), 9.05 (1H, s), 8.90 (1H, s), 7.79 (2H, d), 7.60-7.38 (5H, m), 7.31 (1H, d), 7.21 (2H, d), 6.65 (1H, d), -5.23 (2H, s), 4.63 (2H, s); m / z 425 (M + l) +. On another occasion, the purification of the oil by column chromatography, which is eluted with 3% MeOH 3 / cHCl, gives the free base of the product as a yellow solid; deltaH [2H6] -DMS0 10.33 (1H, s), 9.74 (1H, s), 8.68 (1H, s), 8.60 (1H, s), 7.71 (2H, d), 7.33-7.51 (5H, m), 7.05-7.13 (3H, m), 6.54 (1H, d), 5.14 (2H, s).
Example 13
Amide acid hydrochloride (2R) -l- (5- (4- (4-benzyloxy-phenylamino) = pyrido [3,4-d] pyrimidin-6-yl] -furan-2-ylmethyl-pyrrolidin-2 -car-boxílico
In a manner analogous to Example 7, 5- (4- (4-benzyloxy-phenylamino) -? Irido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde (0.200g, 0.47 mmoles) was reacted with D-prolinamide (0.270 g, -2.37 mmol). Purification by silica gel chromatography, which is eluted with 3-5% MeOH / CHC1, gives an orange oil. This was treated with ethereal HCl, followed by trituration with ethyl acetate / i-hexane, to give the product as an orange solid-which was dried at 60 ° C under vacuum (0.150g, 0.253 mmol, 54%); of the. taH [2H6] -DMS0 12.35 (1H, s), 9.51 (1H, s), 9.27 (1H, s), 8.86 - (1H, s), 8.45 (1H, s), 7.80 (2H, d), 7.70 (1H, s), 7.30-7.52 (6H, m), 7.13 (2H, d), 6.92 (1H, d), 5.17 (2H, s), 4.42 (1H, t), 3. SO3.50 (2H, m, obscured by water), 1.80-2.10 (4H, m); m / z (M + l) 521.
Example 14
(4-Benzyloxy-phenyl) - (6- (5- ((3-methanesulfonyl-propylamino) methyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine
In a manner analogous to Example 1, 5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde and 3-methanesulfonyl- propylamine became the product of the title; deltaH [2H [6,] -DMS0 10. 35 (1H, s), 9. 23 (1H, s), 9 .02 (1H, s), 8.72 (1H, s), 7.90 (2H, d), 7.63-7.40 (5H, m), 7.27 (1H, d),
7. 20 (2H, d), 6.80 (1H, d), 5.25 (2H, s), 4.22 (2H, s), 3.40 -
(2H, m), 3.09 (3H, s), 3.04 (2H, m), 2.12 (2H, m); m / z (M + l) + -544.
Example 15
(4-Benzyloxy-phenyl) - (6- (5 - (((2-methanesulfonyl-ethyl) -methyl-amino) -methyl) -furan-2-yl) -pirodo [3,4-d] pyrimidine- 4-yl) -amine
In a manner analogous to Example 1, 5- (4- (4-benzyloxy-phenylamino) -porido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde (0.217 g, 0.473 mmole) is react with N-methyl-N- (2-methanesulfonylethyl) amine (0.411g, 3.00 mmol). Purification by silica gel chromatography, which is eluted with 2-5% MeOH / CHCl, followed by trituration with ether gives the product as a pale yellow solid (0.030 g, 0.055 mmol, 12%); deltaH [2H &] - DMS0 -10.20 (1H, s), 9.11 (1H, s), 8.63 (1H, s), 8.59 (1H, s), 7.71 ~
(2H, d), 7.33-7.52 (5H, m), 7.06-7.14 (3H, m), 6.59 (1H, d),
. 14 (2H, s), 3.72 (2H, s), 3.20-3.40 (2H, m, obscured by -water), 3.04 (3H, s), 2.85 (2H, t), 2.29 (3H, s); m / z (M + l +) 544.
Example 16
(2R) -1 - (- 5 (4- (4-benzyloxy-phenylamino) -pyrido (3,4-d) pyrimidin-6-yl) -furan-2-ylmethyl) -pyrrolidin-2-dimethylamide -carboxylic.
In a manner analogous to Example 7, 5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-carbaldehyde (0.217 g,
• 0.472 mmol) was reacted with L-N, N-dimethylprolinamide - (0.240 g, 2.10 mmol). Purification by silica gel chromatography, elutes with 2-4% MeOH / CHCl, followed by ether / i-hexane concentration gives the product as a yellow-pale solid (0.127g, 0.231 mmol, 49%); deltaH [2H6] -DMS0 10.25 (1H, s), 9.10 (1H, s), 8.62 (1H, s), 8.58 (1H, s), 7.71 (2H, d), - 7.32-7.52 (5H, m) , 7.05-7.12 (3H, m), 6.46 (1H, d), 5.14 (2H, s), 3.83 (2H, fourth), 3.51-3.63 (1H, m), 3.32 (2H, m, obscured - • by water), 2.96 (3H, s), 2.77 (3H, s), 1.63-1.82 (4H, m); m / z - (M + l +) 549.
Example 17 15 N- (2- ((5- (4- (4-benzyloxy-phenylamino) -pyrido hydrochloride [3,
4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -amino) -ethyl) -methanesulfone- • mida
In a manner analogous to Example 1, 5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -fur.an-2-carbaldehyde (0.200g, 0.435) mmoles) is reacted with 2- (methanesulfonamido) -ethylamine (0.350g, 2.53 mr., ies) and triethyl amine (10 drops). The reaction mixture is rapidly cooled with water, acidified to
pH 1 with dilute HCl, and diluted with acetone to give the product as a yellow solid which was dried at 60 ° C under vacuum (0.200g, 0.324 mmol, 74%); deltaH [2H6] -DMS0 11.40 (1H, s), -9.63 (2H, br s), 9.50 (1H, s), 9.22 (1H, s), 8.82 (1H, s), 7.85 (2H, d), 7.12-7.32 (5H, m), 7.11 (1H, d), 7.13 (2H, d), 6.88 - (1H, d), 5.17 (2H, s), 4.42 (2H, s), 3.35-3.43 (2H , m), 3.13- -3.21 (2H, m) 2.98 (3H, s); m / z (M + l +) 545.
Example 18
(4-Benzyloxyphenyl) - (6- (5- (1, 3-dioxolan-2-yl-furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine
The reaction of (4-benzyloxyphenyl) - (6-chloro-pyrido [3,4-d] pyrimidin-4-yl) -amine (5.44g, 15.0 mmol), 5- (1,3-dioxolan-2) -yl) -2- (tributylstannyl) -furan (10.4g, 24.2 mmoles) and bis- (triphenylphosphine) palladium (II) chloride (catalyticity) in dioxane - (150 ml) according to process B, which is followed by purification by silica gel chromatography (eluted with EtOAc-50-100% / i-hexane), isolation of the dioxolane product was allowed (3.54g, 7.40 mmol, 49%); deltaH [2H6] -DMS0 10.28 (1H, s), 9.13 (1H, s), 8.69 (1H, s), 8.61 (1H, s), 7.71 (2H, d), 7.31-7.52 (5H, m), 7.14 (1H, d), 7.09 (2H, d), 6.77 (1H, d), 6.03 (1H, s), 5.15 (2H, s), 3.95-4.19 (4H, m).
Examples 19 to 24 The following compounds and their hydrochloride salts, if appropriate, are prepared by analogous techniques using the appropriate starting materials: (4-benzyloxy-phenyl) - (6- (5- (4-methyl- piperazin-l-ylmethyl-N-ine-thymimidazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (5- (dimethylaminomethyl) -N-methylimidazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (5- (4-methyl-piperazin-1-ylmethyl) -imido-zol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) - amine; (4-Benzyloxy-phenyl) - (6- (5- (dimethylaminornetyl) -imidazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (-Benzyloxy-phenyl) - (6- (l- (4-methyl-piperazin-1-ylmethyl) -N-? Ne-tilimidazol-2-yl) -pyrido [3,4-d] pyrimidine- 4- il) -amine; (4-Benzyloxy-phenyl) - (6- (1- (dimethylamin-orne-butyl) -N-methylimidazol-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine.
Biological Data
The compounds of the present invention are tested for inhibitory activity of the protein tyrosine kinase in assays of substrate phosphorylation and proliferation assays of cells.
The substrate proliferation assays use recombinant, baculovirus-expressed constructs of the intracellular domains of c-erbB-2 and c-erbB-4 that are constitutively active and isolated the EGFr from solubilized A431 cell membranes. The method of measuring the ability of isolated enzymes to catalyze the transfer of gamma-phosphate from ATP to tyrosine residues in a biotinylated synthetic peptide (Bioin-GluGluGluGluTryPheGluLeuVal). The enzyme was incubated for 30.
minutes, at room temperature, with lOmM MnCl2, ATP and the peptide at Km concentrations, and the test compound (diluted by - a stock of 5mM in DMSO, the final concentration of DMSO is 2%) - in a HEPES buffer of 40mM , pH 7.4. The reaction is stopped by the addition of EDTA (final concentration of 0.15 mM) and a master is transferred to a 96-well plate with dirty Streptavidin. The plate is washed and the phosphotyrosine level in the peptide is determined using an antiphosphotyrosine-Europium-labelled antibody and quantified with a resolution time fluorescence technique. The results are shown in table 1, as the IC values in nM.
The assay of the proliferation of cells using p-a line of immortalized human breast epithelial cells - (HB4a) which have been transformed by overexpression of -c-erbB-2. The growth of these cells under serum depends on the activity of the tyrosine kinase activity c-erbB-2. The specificity of the effect of test compounds on tyrosine kinase-dependent growth on general toxicity is assessed by comparison to a cell line HB4a which are transfected with ras. The cells were placed in 3000-well plates in 96-well plates in a 0.1 ml medium and allowed to bind overnight. The test compound is added in a 0.1 ml medium, with a 0.5% DMSO concentration, and the plates are incubated for 4 days at 37 ° C. The cells were then examined microscopically, -for the evidence of morphological detransformation and cell mass are estimated by staining with methylene blue and the absorbance at 620 nm is measured. The results are shown in table 1 below as the IC50 values in nM. -The activity against a range of human tumor lines of overexpression - EGFr or c-erbB-2 that exists naturally (BT -474-chest, HN5-head and neck, -N87-gastric and Calu-3-lung) they are valued with compounds selected by the same methodology. The results are also shown in table 1 below as the IC50 values in nM.
PG3118C
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.
Claims (34)
- A compound of formula (I): or a salt or solvate thereof; characterized in that X is N or CH; And it is a group W (CH2), (CH2) W, or W, at = 1 which W is 0, S (0) m where m is 0, 1, or 2, or NR where R is hydrogen or a C 1-8 alkyl group R represents a 5- or 6-membered heterocyclic ring containing - from 1 to 4 heteroatoms selected from N, 0 or S (0) m, - where m is as defined above, with the proviso that the - ring does not contain 2 adjacent 0 or S (0) atoms, the ring is substituted, either of the two (a) by one or more groups independently selected from carbamoyl, ureido, guanidino, -alkyl C-. ", Alkoxy C -._ fi, cycloalkoxy C, fi, alkylcycloalco-xi C _8, alkylcarbonyl C5_g, alkoxycarbonyl C5_g) alkylcarbamoyl] carbamoyl, hydroxyamino, -alkoxyamino C, ,, C2_alkynyloxyamino, phenyl, phenoxy, 4-pi Ridon-1-yl, pyrrolidin-1-yl, imidazol-1-yl, piperidino, morpholino, thiomorpholino, thiomorpholin-1-oxide, thiomorpholin-1, l-dij > xido, piperazin-1-yl, 4-C, alkyl-piperazin-1-yl, dioxolanyl, alkylthio C, or, arylthio, alkylsulfinyl C, _,, alkylsulfo-nyl C-_,, arylsulfonyl, arylsulfinyl, halogen-C- , alkyl, -hydroxy-C,, alkyl, C ~, C-alkanoyloxy, alkyl, C,, alkoxy-C, alkyl, carboxy-C, alkyl, formyl-Ci, alkyl, C, _, alkoxycarbonyl-C, _, alkyl, carbamoyl-C, _, alkyl, NC, alkylcarbamoyl-C, alkyl, N, N-di [C, _, alkyl] carbamoyl-C,, alkyl, amino-C, _, alkyl, C,, alkylamino-C, _, al ^ chyl, di- [C,, alkyl] amino-C,, alkyl, di- [C,, alkyl] ami-no-C,, alkylene- (C., alkyl) amino, C,, alkylamino-C, , alkyl- (C, _, alkyl) amino, hydroxy-C,, alkylene- (C, _, alkyl) amino, phenyl-C,. alkyl, 4-pyridon-l-yl-C, _, alkyl, pyrrolidin-1-yl-C, _, alkyl, imidazol-1-yl-C, _, alkyl, piperidin-C, _, alkyl, morpholin-C, _, alkyl, thiomorpholine-C, _, alkyl, -thiomorpholin-1-oxide-C, _, alkyl, thiomorpholin-1, 1-dioxide-C, _, -alkyl, piperazin-1-yl- C, _, alkyl, 4-C ,. , alkylpiperazin-1-yl-C,, alkyl, hydroxy-C2_, alkoxy-C, alkyl, C,, C2-alkoxy, C-alkoxy,. alkyl, hydroxy-C "_, alkylamino-C, alkyl, C, _, alkoxy-C-, alkylamino-C,. alkyl, C, alkylthio-C, _, -alkyl, hydroxy-C-, alkylthio-C,, alkyl, C,, C 2 -alkoxy, -alkoxy-C _, alkylthio-C,, alkyl, phenoxy-C, , alkyl, aniline-C ^ _, alkyl, phenylthio-C, alkyl, cyano-C,. alkyl, halogen-C, alkoxy, hydroxy-C2_, alkoxy, C2_, C-alkanoyloxy, alkoxy, C, _, C-alkoxy, alkoxy, carboxy-C, alkoxy, formyl-C, 1-4, alkoxy , C, 1-4. alkoxycarbonyl-C, 1-4, alkoxy, carbamoyl-C1, -4, alkoxy, NC, _, alkylcarbamoyl-C, alkoxy, N, N-di [C,, alkyl] carbamoyl-C, 1-4, alkoxy , amino-C2-4, alkoxy, C1, -4, alkylamino-C20-4, alkoxy, di [C, _, alkyl-C2, alkoxy] amino-C2_, alkoxy, di- [C, _, alkyl] amino -C7_, alkoxy, C2_, alkanoyloxy, hydroxy-C2_, alkanoyloxy, C1, -4, alkoxy-C2 -, - 4. alkanoyloxy, phenyl-C, 1-4, alkoxy, phenoxy-C2_, alkoxy, C-anilino, alkoxy, phenylthio-C2, alkoxy, 4-pyridon-l-yl-C, -_, alkoxy, piperidine-C2_ , alkoxy, morpholin-C2, -alkoxy, thiomorpholine-C, alkoxy, thiomorpholin-l-oxide-C2, alkoxy, thiomorpholin-1, l-dioxide-C2_, alkoxy, piperazin-l-yl-C2_, coyl, -C,, alkylpiperazin-1-yl-C2_, alkoxy, pyrrolidin-1-yl-C ~ _, alkoxy, imidazol-1-yl-C ~ _, alkoxy, halogen-C2, alkylamino, hydroxy-C, alkylamino, C _, C2-alkanoyloxy, alkylamino, Ci _ / C2_ alkoxy, alkylamino, carboxy-C,, alkylamino, C,, alkoxycarbonyl-C, _, alkylamino, carbamoyl-C, _, alkylamino, NC,, alkylcarbamoyl-C ,, alkylamino, N, N-di- [C, _, alkyl] -car bamoyl-C, _, alkylaraino, amino-C ,,, alkylamino, C,, alkylamino-C, - .alkylamino, di- [ C,, alkyl] amino-C2_, alkylamino, phenyl-C.1-4. alkylamino, phenoxy-C2 -, - 4. alkylamino, anilino-C2"-4. alkylamino, 4-pyridon-l-yl-C2, alkylamino, piperidin-C-, -lakylamino, morpholin-C _, alkylamino, thiomorpholin-C2_, to the quilamino, thiomorpholin-l-oxide-C2_4 a? qui? amino, thiomorpholine -1, 1-l-dioxide-C2_, alkylamino, piperazin-1-yl-C2_, alkylamino, -4-C, alkylpiperazin-1-yl-C, alkylamino, pyrrolidin-1-yl-C9_, alkylamino, imidazole-1 -il-C2, alkylamino, pentthio-C _ , alkylamino, C ~, alkanolamino, alkoxycarbonylamino C, ,, alkylsulphonylamino C, ,, alkylsulfinylamino C, ,, benzamido, -benzenesulfonamido, 3-phenylureido, 2-oxopirrolidin-l-yl, 2,5-dioxopirrolidin-1-yl , halogen-C2_, alkanoylamine, hydroxy-C2_, alacanoylamino, hydroxy-C2, alkanoyl- (C, _, alkyl) -amino, C, _, C2_ alkoxy, alacnoylamino, carboxy-C2, alkanoylamino, - C, 1-4, alkoxycarbonyl-C 2 -, - 4-alkanolamino, carbamoyl-C 2-4, alkanoylamino, NC, _, alkylcarbamoyl-C 2_, alkanoylamino, N, N-di- [C, _, -alkyl ] carbamoyl-C "_, alkanoylamino, amino-C2_, alkanoylamino, -C, alkylamino-C2_, alkanoylamino or di- [C _, alkyl] amino-C2_, alkanoylamino; and wherein said benzamido or benzenesulfonamido substituent or any anilino, phenoxy or phenyl group in a substituent R may optionally have one or more halogen substituents, C, C, or C, C, alkoxy; and wherein any substituent containing a heterocyclic ring may optionally have one or two substituents which contain halogen, C.sub.1 alkyl, or C.sub.2 alkoxy, in said ring; and wherein any substituent containing a heterocyclic ring may optionally have one or two oxo or thioxo substituents on said ring; or (b) by one or more groups independently selected from M1-M2-M3-M4, M1-M5 or M1-M2-M3 -M6 wherein M represents a C, alkyl group, wherein optionally a CH2 group is replaced by a CO group; 2 12 12 13 12 13 M represents NR or CR R, in which R and R each independently represent H or C,, alkyl; M 'represents a C, alkyl group; M "represents a C-alkyl group, or is absent M4 represents CN, 'NR12S (0) m R13, S (0) m NR R15, C0NR14R15, S (0) m R13 13 12 13 or C02R, in which R, R and m are as defined above and - 14 15 R and R each independently represent H or C 14 alkyl, or R and R together with the nitrogen atom at which are fused represent a 5- or 6-membered ring optionally containing 1 or 2 additional heteroatoms selected from N, 0 or S (0) in which any nitrogen atom present in the ani. lio can optionally be substituted with a C,,, alkyl group and the ring which may optionally have one or 2 oxo or thioxo substituents; M represents the group NR R, where R and R are as defined above, or M represents the group -CHa) t 16 in which t represents 2 to 4 and R represents OH, alkyl OC,. or NR14 l5 1, and M represents a C-cycloalkyl group, the group NR R, where R and R are as defined above, or a 5- or 6-membered heterocyclic ring system containing 1 to 4 hete rosatoms selected from N, 0 or S; and R is optionally substituted later by one or two halogen, C, C, or C alkoxy groups, <; R is selected from the group consisting of hydrogen, halogen, trifluoromethyl, C, _, and C,, alkoxy; each R is independently selected from the group consisting of hydrogen, hydroxy, halogen, C, C, alkoxy, C, C, alkylamino, di- [C, _, alkyl] amino, alkylthio C, _,, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, C, CHL is 1, 2 or 3; 3 4 4 R is a group ZR where Z is linked to R by a group (CH?) In which p is 0, 1 or 2 and Z represents a group V (CH), V (CF), (CH2) V, (CF2) V, V (CRR '), V (CHR) or V where R and R'are each C,, and in which V is a hydrocarbyl group containing 0, 1 or 2 carbon atoms, carbonyl, dicarbonyl, CH (OH), -CH (CN), sulfonamide, amide, 0, S (0) m or NRb wherein Rb is hydrogen 4 or R is C, alkyl; and R is a C-cycloalkyl, optionally substituted or a carbocyclic or heterocyclic part of 5, 6, 7, 8, 9, or 10 members optionally substituted; 3 4 b b 4 or R is a group ZR in which Z is NR, and NR and R together form a carbocyclic or heterocyclic part of 5, 6, 7, 8, 9, or -10 members optionally substituted; represents a fused 5, 6 or 7 membered heterocyclic ring containing 1 to 5 heteroatoms which may be the same or different and which are selected from N, 0 or S (0) m, where m is as above defines, the heterocyclic ring containing a total of 1, 2 or 3 double bonds inclusive of the bond in the pyridine or pyrimidine ring, provided that the heterocyclic ring is not part of a purine and that the fused heterocyclic ring does not contain 2 atoms 0 or S (0) m -adjacent.
- 2. A compound as claimed in claim 1 characterized in that R is as above defined with the exception that in which any substituent containing a heterocyclic anion has one or 2 oxo or thioxo substituents in said ring; and R and R are as defined above with the exception that together with the nitrogen atom to which they are attached represents a 5- or 6-membered ring and said ring has one or two oxo or thioxo substituents; unless R can represent a substituted 5- or 6-membered heterocyclic ring. by a 4-pyridon-1-yl group, 4-pyridon-1-yl alkyl, 4-pyridon-l-yl-C2_, alkoxy, 4-pyridon-l-yl-C2_, alkylamino, 2-oxopyrrolidin-1-yl or 2,5-dioxopyrrolidin-1-yl.
- 3. A compound as claimed in claim 1 or claim 2, characterized in that X is N.
- 4. A compound as claimed in any of the rei indications 1 to 3, characterized in that Y is NR, NR (CH2), or (CH2) NR, preferably Y is NR and R is preferably hydrogen or methyl.
- 5. A compound as claimed in any of Claims 1 to 4, characterized in that R is a 5- or 6-membered heterocyclic ring as above is defined by one or more groups selected from dioxolanyl, hydroxy-C, alkyl, -C,, alkylamino-C, _, alkyl or di (C,, alkyl) amino-C, _, alkyl, and optionally substituted later by one or more groups C,. I rent. i-4
- A compound as claimed in any of claims 1 to 4, characterized in that R is a 5- or 6-membered heterocyclic ring as defined in claim 1 2 3 4 1 substituted with a selected group of M-M -M -M, - M -M or M -M -M -M as defined in claim 1 or -the claim 2.
- 7. A compound as claimed in any of claims 1 to 4 or 6, characterized in that M represents -CH2, CO, CH2CH2 or CH2C0; M2 represents NR12 in which R12 is -3 as defined in claim 1; M represents CH2, CH "CH2 3 'or propyl; M represents CH ", ethyl, propyl, isopropyl or is absent; M4 reprsenta SOR13, S02R13, NR12S02R13, C02R13 or CONR14 15 12 13 R in which R and R are defined in claim 1 and R and R each independently represent H or C-alkyl,,; M represents a group NR R in which R and R together with the nitrogen atom to which they are attached represents a ring of 6 members optionally containing an additional heteroatom selected from N or 0, in which any nitrogen atom present in the ring can optionally be substituted with a C,, alkyl group; or R - represents a group 16 in which t represents 2 or 3 and R represents OH, NH ~, N (alkyl C, _,) or alkyl OC,,; more preferably R represented NH- or N (CH) 2; or M represents a group NR R in which -R and R each independently represents hydrogen or C1-C2,, more preferably hydrogen, methyl, ethyl or iso- • i * .6 ._ ..-, 14015,, -.14 n15 propyl; and M represents a group NR K in which R and R each independently represent alkyl C,, more preferably methyl, or R and R together with the nitrogen atom not to which they are attached represents a ring of 5 or 6 members optionally containing an additional heteroatom selected from -N or O, in which any nitrogen atom present in the ring can be optionally substituted with an alkyl group -C,,, preferably a methyl group; or M represents a 5- or 6-membered heterocyclic ring system containing 1 or 2 heteroatoms selected from N or 0.
- 8. A compound as claimed in any of the claims 2 to 4, 6 or 7, characterized in that M-M-M re presents an alpha-amino carboxylic acid or a methyl ester or amide thereof.
- 9. A compound as claimed in any of the 1 to 4 or 6 to 8 ratios, characterized in that M 2 -M 3 -M 4 -represents a methylsulphonylethylamino, methylsulphonylethylamino group, methylsulfonylpropylamino, methylsulfinylamino, methylsulfonamidoethylamino, sarcosinamide, glycine, glycinamide, or glycine methyl ester.
- 10. A compound as claimed in any one of claims 1 to 4, 6 or 7, characterized in that M-M represents a piperazinyl-methyl, methylpiperazinyl-methyl, p-peridinyl-methyl, proline-methyl-methyl, N, N-dimethyl-prolylamido-methyl group. - lime, isopropyl acetamido or N-morpholinacetamido.
- A compound as claimed in claim 1 - 4 to 6, 6 or 7, characterized in that M-M represents a pyridylamino group
- 12. A compound as claimed in any of claims 1 to 11, characterized in that R is selected from the group consisting of phenyl, furan, imidazole, tetrazole, triazole, pyrrolidine, piperazine, piperidine and oxadiazole.
- 13. A compound as claimed in claim 12, characterized in that R is selected from furan, imidazole and oxadiazole, preferably furan.
- 14. A compound as claimed in any of claims 1 to 13, characterized in that R is benzyl, > fluorobenzyl, benzyloxy, fluorobenzyloxy, pyridylmethyl, phenyl, benzenesulfonyl, phenoxy or fluorophenoxy.
- 15. A compound as claimed in any of claims 1 to 14, characterized in that U represents
- 16. A compound as claimed in any of claims 1 to 15, characterized in that the optional substituents for the carbocyclic or heterocyclic part and also for other optionally substituted groups include hydroxy, -halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, cyano, alkoxy C, _,, alkylthio C, ,, C,. alkylcarbon, carboxylate and C., alkoxycarbonyl.
- 17. A compound as claimed in any of claims 1 to 4, characterized in that X represents N; U -represents a pyridine ring; and the R group is in the 6-position of the pyridopyrimidine ring system.
- 18. A compound of the formula (I) or salt or solvate thereof as claimed in any of claims 1 to 5 or 17, characterized in that X represents N; U represents furan, -thiophene, pyrrole, pyridine, pyrimidine, pyrazine, oxazole, isoxazole, oxadiazole, imidazole, tetrazole, triazole, dioxolane or a hydrogenated derivative partially or completely of any of these groups, preferably furan, oxadiazole or imidazole, substituted by one or more groups selected from hydroxy-C, alkyl, -hydroxy-C, alkanoyl (C., alkyl) amino, 1,3-dioxolan-2-yl, C,, alkylamino-C,, alkyl or di (C, _, alkyl) amino-C, alkyl, and optionally substituted later by one or more C-alkyl groups,; R 2 represents hydrogen; R5 represents hydrogen or -3 methyl; n is 1; and R represents phenyl, benzyl, alpha-methylbenzyl, fluorobenzyl, benzenesulfonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy.
- 19. A compound of formula (I) or a salt or solvate thereof as claimed in any of claims 1 to 4 or 17, characterized in that X represents N; U represents a pyridine ring; Y represents NR, wherein R is hydrogen or C, alkyl; R represents furan, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, oxazole, isoxazole, oxadiazole, imidazole, tetrazole, triazole, dioxolane or a derivative hydrogenated partially or wholly of any of these groups, preferably -furan, oxadiazole or imidazole, substituted by one or more groups -selected from methylsulfonylethylaminomethyl, methylsulfonylethyl aminocarbonyl, Methylsufinylethylamino-methyl, Methylsulfinyethylaminocarbonyl, Methylsulfonylpropylamino-methyl, Methylsulfinyl-propylamino-methyl.methylsulfonylpropylaminocarbonyl, Methylsulfinylpropylaminocarbonyl, Methylsulphonylethyl- (methylamino) -methyl, Methylsulfonylethyl- (methylamino) -carbonyl, Methylsulfinile-- Tyr- (methylamino) -methyl, methylsulfinylethyl- (methylamino) -carbonyl, methylsulfonylpropyl- (methylamino) -methyl, methylsulfinyl-1-propyl- (γ-thylamino) -methyl, methylsulfonylpropyl- (methylamino) -carbonyl, methylsulfinylpropyl- (methylamino) - carbonyl, methylsulfonamidoethylamino-methyl, methylsulfonamidopropylamino-methyl, sarcosaminomethyl, glycinylmethyl, glycinemidomethyl, glycinylmethyl methyl ester, acetylaminoethylaminomethyl, piperazinylmethyl, methylpiperazinylmethyl, piperidinylmethyl, N- (prolinamido) methyl, (N, N-dimethyl-prolinemide) ) methyl, pyridylaminomethyl, cyclopropylamminomethyl, N- (piperidin-4-yl) -N-methylaminomethyl, N, N-dimethylaminoprop-2-ylaminomethyl, N- (2-dimethyl) t; _: ilaminoethyl) -N-ethylaminomethyl, iso-propylacetamido, N-morpholinyl acetamido or tetrahydrofuranmethylamide. Nomethyl, and optionally substituted later by one or more groups with alkyl C,,; R hydrogen repressor; R represents hydrogen or methyl; n is 1; and R represents phenyl, benzyl, alpha-methyl-benzyl, f-luorobenzyl, benzenesulfonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy.
- 20. A compound of formula (I) or a salt or solvate thereof as claimed in claim 11 or claim 19, characterized in that X represents N; U represents a pyridine ring; Y represents NR, where R is hydrogen or C, _, alkyl; R represents furan, oxadiazole or imidazole, preferably furan, substituted by a group selected from hydroxy-C, alkyl, 1,3-dioxolan-2-yl, C, alkylamino-C, alkyl. or di (C,, alkyl) amino-C, _, alkyl, methylsulfonylethylaminomethyl, methylsulfinylethylamino-methyl, methylsulfonylpropylamino-methyl, methylsulfonylethyl- (methylamino) -methyl, methylsulfonamidoethylamino-methyl, sarcosinamidomethyl, glycinylmethyl, glycinylmethylmethyl ester, acetylaminoethylaminomethyl, piperazinylmethyl, methylpipe-razinylmethyl, piperidinylmethyl, N- (prolinamido) methyl, (N, N-di-2-methyl-prolinamido) methyl and pyridylaminomethyl; R represents hi-5 3 drógeno; R represents hydrogen or methyl; n is 1; and R represents n-fluorobenzyloxy, benzenesulfonyl or benzyloxy, preferably benzyloxy.
- 21. A compound as claimed in claim 1 or claim 2 selected from: La (4-benzyloxy-phenyl) - (6- (5-piperidin-1-ylmethyl) -furan-2-yl) -pyrido [3, 4-d] pyrimidin-4-yl) -amine; (4-benzyloxy-phenyl) - (6- (5- (4-methyl-piperazin-1-ylmethyl) -fu-ran-2-yl) pyrido [3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (5 - ((2-methanesulfonyl-ethylamino) methyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d]? Irimidin-6-yl) -furan-2-ylmethyl) -amino) -acetic acid methyl ester; (4-Benzyloxy-phenyl) - (6- (5- (pyridin-3-ylaminomethyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) -6- (5- (dimethylaminomethyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (2S) -l- (5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pi-rimidin-6-yl) -furan-2-ylmethyl) -pyrrolidin-2-acid carboxylic amide; 2- ((5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] irimidin-6-yl) -furan-2-ylmethyl) -methylamino) -acetamide; N- (2- ((5- (4- (4-benzyloxy-phenylamino) -pyrimido [3,4- d] irimidin-6-yl) -furan-2-ylmethyl) -amino) -e yl) - acetamima; (4-Benzyloxy-phenyl) - (6- (5- ((2-methanesulfini1-ethylamino) -methyl) -furan-2-yl) -pyrido [3,4-d] -pyrimidin-4-yl) - amine; (5- (4- (4-Benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -amino) -acetic acid; (5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-yl) -methanol; (2R) -1- (5- [4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pi-rimidin-6-yl] -furan-2-ylmethyl) -pyrrolidin-2-acid carboxylic amide; (4-Benzyloxy-phenyl) - (6- (5 - ((3-methanesulfonyl-propylamino) methyl) -furan-2-yl) -pyrido [3,4-d] pyrimidin-4-yl) -amine; (4-Benzyloxy-phenyl) - (6- (5- (((2-methanesulfonyl-ethyl) -methyl-amino) -methyl) -furan-2-yl) -pyrido [3,4-d] pyrimidine-4 -yl) -amine; (2S) -l - (- 5- [4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pi-rimidin-6-yl] -furan-2-ylmethyl) -pxrrolidin-2 acid carboxyl dimethyl amide; N- (2 - ((5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl) -furan-2-ylmethyl) -amino) -ethyl) -methanesulfonamide; (4-Benzyloxyphenyl) - (6- (5- (1, 3-dioxolan-2-yl-furan-2-yl) -pyr-do [3,4-d]? Irimidin-4-yl) -amine; and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof.
- 22. A compound as claimed in claim 21 selected from: La (4-benzyloxy-phenyl) - (6- (5- ((2-methanesulfonyl-ethylamino) methyl) -furan-2-yl) -pyrido [3, 4 -d] pyrimidin-4-yl) -amine; (2S) -l- (5- (4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyridin-6-yl) -furan-2-ylmethyl) -pyrrolidine-2-carboxylic acid amide; Acid (2R) -l- (5- [4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyrimidin-6-yl] -furan-2-ylmethyl) -pyrrolidin-2-carboxylic acid; (2S) -l - (- 5 [4- (4-benzyloxy-phenylamino) -pyrido [3,4-d] pyridin-6-yl] -furan-2-ylmethyl) -pyrrolidine-2-carboxylic acid dimethylamine; and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof.
- 23. A pharmaceutical formulation, characterized in that it comprises at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
- 24. A pharmaceutical formulation as claimed in claim 23, characterized in that it is in the form of. unit dose and containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of 70 to 700 mg.
- 25. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, characterized in that it is used in therapy.
- 26. The use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, characterized in that it is used in the treatment of disorders measured by the aberrant activity of the protein tyrosine kinase.
- 27. The use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, characterized in that it is used in the treatment of malignant tumors and cancer
- 28. The use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used in the treatment of psoriasis.
- 29. A method of treatment of a human or animal subject - suffering from a disorder mediated by the aberrant activity of the protein tyrosine kinase, characterized in that it comprises the administration to a human or animal subject of an effective amount of a compound of formula (I) ) or a pharmaceutically acceptable salt or solvate thereof.
- 30. A process for the preparation of a compound of formula (I) as defined in claim 1 or claim 2, characterized by the steps: (a) the reaction of a compound of formula (II) wherein U, X and R are as defined in claim 1 and L and L 'are appropriate leaving groups, with a compound of formula (III) 3 wherein Y, R, R and n are as defined in claim 1, to prepare a compound of formula (IV) (IV) and subsequently (b) Reaction with an appropriate reagent pa. to replace the group R in the ring U by replacement of the output group L; and, if desired, (c) subsequently converting the compound of the formula (I) is thereby obtained in another compound of the formula (I) by means of appropriate reagents.
- 31. A process for the preparation of a compound of form (I) as defined in claim 1 or claim 2, characterized in that the compound of formula (II) as 10 is defined in claim 30 is reacted with the appropriate reagent to replace the group R in the ring U - by replacement of the outlet group L 'and then the product is therefore obtained from the formula (V) it is reacted with the cor- > of formula (III) as it was 20 fine in claim 30, followed, if desired, by conversion of the compound of formula (I) thereby obtained in another - compound of formula (I). 25
- 32. A compound as claimed in claim 31, characterized in that the compound of formula (V) can be prepared by the reaction of a compound of formula (VI) HX U (VI) N L " with appropriate reactive uri to replace the group R in the U ring to prepare the compound of formula (VII) and a reaction subsequently to incorporate the output group L.
- 33. A process for the preparation of a compound of formula (I) as defined in claim 1 or claim 2, characterized in that it comprises the steps: (a) reaction of a compound of formula (IV) as defined in claim 30 with a suitable reagent (s) for preparing a compound, wherein the group L'is replaced with an appropriately functionalized Z group; and (b) subsequently converting the group Z into the group R by means of appropriate reagent (s); and, if desired, (c) subsequently converting the compound of formula (I), that is why it is obtained in another compound of formula - (I) by means of appropriate reagents.
- 34. A process for the preparation of a form-mule compound (I) as defined in claim 1 or claim 2, characterized in that it comprises the steps: (a) reacting a compound of formula (II) as defined in claim 30 with an appropriate reagent (s) to prepare a compound, wherein the group L 'is replaced with an appropriately functionalized Z group; and (b) subsequently converting the group Z into the group R by means of appropriate reagent (s); (c) reaction of the product obtained with the compound of formula (III) as defined in claim 30; and, if desired (d) subsequently converting the compound of formula (I), that is why it is obtained in another compound of formula (I) by means of appropriate reagents. The compounds of formula (II), (III), (IV), (V) (VI) and (VII) are defined in any of claims 30 to 32, characterized in that X, Y, U, R 1, R 2, R 3, R 5 and n are as defined in any of claims 1 to 20.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9614756.6 | 1996-07-13 | ||
GB9625495.8 | 1996-12-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99000483A true MXPA99000483A (en) | 1999-06-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6207669B1 (en) | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors | |
US6723726B1 (en) | Protein tyrosine kinase inhibitors | |
US6169091B1 (en) | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors | |
US9771362B2 (en) | [1,2,4]triazolo[1,5-a]pyridine and [1,2,4]triazolo[1,5-c]pyrimidine compounds and their use | |
US6391874B1 (en) | Fused heterocyclic compounds as protein tyrosine kinase inhibitors | |
EP0843671A1 (en) | Heterocyclic compounds and pharmaceutical compositions containing them | |
EP1047694B1 (en) | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors | |
RU2487875C2 (en) | IMIDAZO[1,2-b]PYRIDAZINE AND PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES AND USE THEREOF AS PROTEIN KINASE INHIBITOR | |
DE60024854T2 (en) | 4,5-DISUBSTITUTED 2-AMINOPYRIMIDINE | |
US20110160185A9 (en) | Pyrrolopyrimidine derivatives as jak3 inhibitors | |
TW200914443A (en) | Process for preparing substituted quinazolinyl furanaldehyde | |
WO1997013760A1 (en) | Tricyclic fused compounds and pharmaceutical compositions containing them | |
BG65566B1 (en) | Imidazo[1,2-a]pyridine and pyrazolo[2,3-a]pyridine derivatives | |
MXPA99000483A (en) | Biciclic heteroaromatic compounds as protein inhibitors tirosin cin |