DK2193133T3 - IMIDAZOLOTHIADIAZOLES USED AS PROTEINKINASE INHIBITORS - Google Patents

Info

Publication number

DK2193133T3

DK2193133T3 DK08806437.3T DK08806437T DK2193133T3 DK 2193133 T3 DK2193133 T3 DK 2193133T3 DK 08806437 T DK08806437 T DK 08806437T DK 2193133 T3 DK2193133 T3 DK 2193133T3

Authority

DK

Denmark

Prior art keywords

imidazo

formula

compound

thiadiazol

phenyl

Prior art date

2007-09-27

Links

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• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 3
• 239000003909 protein kinase inhibitor Substances 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims description 311
• -1 4-fluoro-1-naphthyl Chemical group 0.000 claims description 137
• 125000001424 substituent group Chemical group 0.000 claims description 72
• 238000006243 chemical reaction Methods 0.000 claims description 63
• 125000000217 alkyl group Chemical group 0.000 claims description 60
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 60
• 125000005843 halogen group Chemical group 0.000 claims description 58
• 229910052739 hydrogen Inorganic materials 0.000 claims description 53
• 238000000034 method Methods 0.000 claims description 51
• 239000001257 hydrogen Substances 0.000 claims description 48
• 125000003118 aryl group Chemical group 0.000 claims description 43
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 42
• 125000001072 heteroaryl group Chemical group 0.000 claims description 41
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
• 206010028980 Neoplasm Diseases 0.000 claims description 34
• 201000011510 cancer Diseases 0.000 claims description 29
• 150000003839 salts Chemical class 0.000 claims description 29
• 125000002947 alkylene group Chemical group 0.000 claims description 28
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
• 201000010099 disease Diseases 0.000 claims description 23
• 238000011282 treatment Methods 0.000 claims description 23
• 150000002431 hydrogen Chemical class 0.000 claims description 21
• 238000002360 preparation method Methods 0.000 claims description 21
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
• 239000012453 solvate Substances 0.000 claims description 19
• 150000001408 amides Chemical class 0.000 claims description 18
• 239000003814 drug Substances 0.000 claims description 18
• 125000004122 cyclic group Chemical group 0.000 claims description 17
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims description 16
• 239000002671 adjuvant Substances 0.000 claims description 15
• 239000003085 diluting agent Substances 0.000 claims description 15
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
• 230000008569 process Effects 0.000 claims description 14
• 125000001153 fluoro group Chemical group F* 0.000 claims description 13
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
• 229940124597 therapeutic agent Drugs 0.000 claims description 12
• 230000009467 reduction Effects 0.000 claims description 11
• 238000006722 reduction reaction Methods 0.000 claims description 11
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 10
• 230000002062 proliferating effect Effects 0.000 claims description 10
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
• 125000005647 linker group Chemical group 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
• 230000004663 cell proliferation Effects 0.000 claims description 6
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
• 150000003335 secondary amines Chemical class 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
• UOFCXVBAUZFSQT-UHFFFAOYSA-N 2-(cyclopropylmethylamino)-n-phenylimidazo[2,1-b][1,3,4]thiadiazole-5-sulfonamide Chemical compound C=1N=C2SC(NCC3CC3)=NN2C=1S(=O)(=O)NC1=CC=CC=C1 UOFCXVBAUZFSQT-UHFFFAOYSA-N 0.000 claims description 4
• HEWKCLUEWLJWBV-UHFFFAOYSA-N 2-[(4-fluorophenyl)methylamino]-n-phenylimidazo[2,1-b][1,3,4]thiadiazole-5-sulfonamide Chemical compound C1=CC(F)=CC=C1CNC(S1)=NN2C1=NC=C2S(=O)(=O)NC1=CC=CC=C1 HEWKCLUEWLJWBV-UHFFFAOYSA-N 0.000 claims description 4
• YKGMCRDGQBHBRZ-UHFFFAOYSA-N 3-[2-(4-fluorophenoxy)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC(C=2N3N=C(OC=4C=CC(F)=CC=4)SC3=NC=2)=C1 YKGMCRDGQBHBRZ-UHFFFAOYSA-N 0.000 claims description 4
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• 208000009905 Neurofibromatoses Diseases 0.000 claims description 4
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• 206010003246 arthritis Diseases 0.000 claims description 4
• 239000013066 combination product Substances 0.000 claims description 4
• 229940127555 combination product Drugs 0.000 claims description 4
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• SFOYFWHJOQHZRH-UHFFFAOYSA-N n-[4-[2-(4-fluorophenoxy)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1C1=CN=C2N1N=C(OC=1C=CC(F)=CC=1)S2 SFOYFWHJOQHZRH-UHFFFAOYSA-N 0.000 claims description 4
• WWKUJMBUCXUERB-UHFFFAOYSA-N n-benzyl-2-(dimethylamino)-n-methylimidazo[2,1-b][1,3,4]thiadiazole-5-carboxamide Chemical compound C=1N=C2SC(N(C)C)=NN2C=1C(=O)N(C)CC1=CC=CC=C1 WWKUJMBUCXUERB-UHFFFAOYSA-N 0.000 claims description 4
• CVFQBICVTJEPDF-UHFFFAOYSA-N n-ethyl-2-(ethylamino)imidazo[2,1-b][1,3,4]thiadiazole-5-sulfonamide Chemical compound CCNS(=O)(=O)C1=CN=C2SC(NCC)=NN21 CVFQBICVTJEPDF-UHFFFAOYSA-N 0.000 claims description 4
• 201000004931 neurofibromatosis Diseases 0.000 claims description 4
• 208000015768 polyposis Diseases 0.000 claims description 4
• 208000005069 pulmonary fibrosis Diseases 0.000 claims description 4
• 238000006268 reductive amination reaction Methods 0.000 claims description 4
• 208000037803 restenosis Diseases 0.000 claims description 4
• 230000036262 stenosis Effects 0.000 claims description 4
• 208000037804 stenosis Diseases 0.000 claims description 4
• 150000003512 tertiary amines Chemical class 0.000 claims description 4
• 230000002792 vascular Effects 0.000 claims description 4
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
• PJGLCBCBNJMVCD-UHFFFAOYSA-N 1-[3-[2-(cyclopropylmethylamino)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(C=2N3N=C(NCC4CC4)SC3=NC=2)=C1 PJGLCBCBNJMVCD-UHFFFAOYSA-N 0.000 claims description 3
• NYRUEMXFVPUIIS-UHFFFAOYSA-N 1-[3-[2-[(3,4-dichlorophenyl)methylamino]imidazo[2,1-b][1,3,4]thiadiazol-5-yl]phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(C=2N3N=C(NCC=4C=C(Cl)C(Cl)=CC=4)SC3=NC=2)=C1 NYRUEMXFVPUIIS-UHFFFAOYSA-N 0.000 claims description 3
• ISRPTTSIDVGQRW-UHFFFAOYSA-N 1-[3-[6-chloro-2-(2-methylpropylamino)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]phenyl]ethanone Chemical compound ClC=1N=C2SC(NCC(C)C)=NN2C=1C1=CC=CC(C(C)=O)=C1 ISRPTTSIDVGQRW-UHFFFAOYSA-N 0.000 claims description 3
• QORVTJMUYZLSGU-UHFFFAOYSA-N 1-[3-[[2-(2-methoxyethylamino)-7,7a-dihydroimidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylamino]phenyl]ethanone Chemical compound S1C(NCCOC)=NN2C1NC=C2CNC1=CC=CC(C(C)=O)=C1 QORVTJMUYZLSGU-UHFFFAOYSA-N 0.000 claims description 3
• QVDNROXSSNIRTQ-UHFFFAOYSA-N 1-[3-[[2-(dimethylamino)-7,7a-dihydroimidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylamino]phenyl]ethanone Chemical compound S1C(N(C)C)=NN2C1NC=C2CNC1=CC=CC(C(C)=O)=C1 QVDNROXSSNIRTQ-UHFFFAOYSA-N 0.000 claims description 3
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
• GGRZTZVOZQAFCY-UHFFFAOYSA-N 6-chloro-5-(3,4-dimethoxyphenyl)-n-(2-methoxyethyl)imidazo[2,1-b][1,3,4]thiadiazol-2-amine Chemical compound ClC=1N=C2SC(NCCOC)=NN2C=1C1=CC=C(OC)C(OC)=C1 GGRZTZVOZQAFCY-UHFFFAOYSA-N 0.000 claims description 3
• XDZAUUQMNKFTAJ-UHFFFAOYSA-N 6-chloro-n-(cyclopropylmethyl)-5-[3-(dimethylamino)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-2-amine Chemical compound CN(C)C1=CC=CC(C=2N3N=C(NCC4CC4)SC3=NC=2Cl)=C1 XDZAUUQMNKFTAJ-UHFFFAOYSA-N 0.000 claims description 3
• UXJOPIADSJBWJO-UHFFFAOYSA-N 6-chloro-n-[(4-fluorophenyl)methyl]-5-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-amine Chemical compound C1=CC(OC)=CC=C1C1=C(Cl)N=C2N1N=C(NCC=1C=CC(F)=CC=1)S2 UXJOPIADSJBWJO-UHFFFAOYSA-N 0.000 claims description 3
• 206010062016 Immunosuppression Diseases 0.000 claims description 3
• DJIOHRPAVFWMHE-UHFFFAOYSA-N [4-(2-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)phenyl]methanol Chemical compound C1=CC(CO)=CC=C1C1=CN=C2N1N=C(C=1C=CC=CC=1)S2 DJIOHRPAVFWMHE-UHFFFAOYSA-N 0.000 claims description 3
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• JAMJUPRNDQABOV-UHFFFAOYSA-N n-[4-[2-(4-fluoroanilino)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1C1=CN=C2N1N=C(NC=1C=CC(F)=CC=1)S2 JAMJUPRNDQABOV-UHFFFAOYSA-N 0.000 claims description 3
• BDFZYAAZZOPRMG-UHFFFAOYSA-N n-ethyl-2-[(4-fluorophenyl)methylamino]imidazo[2,1-b][1,3,4]thiadiazole-5-sulfonamide Chemical compound N=1N2C(S(=O)(=O)NCC)=CN=C2SC=1NCC1=CC=C(F)C=C1 BDFZYAAZZOPRMG-UHFFFAOYSA-N 0.000 claims description 3
• 244000045947 parasite Species 0.000 claims description 3
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 230000003612 virological effect Effects 0.000 claims description 3
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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• DDDUOINJEICOML-UHFFFAOYSA-N n-(cyclopropylmethyl)-5-(morpholin-4-ylmethyl)imidazo[2,1-b][1,3,4]thiadiazol-2-amine Chemical compound C1CC1CNC(SC1=NC=2)=NN1C=2CN1CCOCC1 DDDUOINJEICOML-UHFFFAOYSA-N 0.000 claims description 2
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