US20070155724A1 - Methods of Treating Cytokine Mediated Diseases - Google Patents
Methods of Treating Cytokine Mediated Diseases Download PDFInfo
- Publication number
- US20070155724A1 US20070155724A1 US11/684,173 US68417307A US2007155724A1 US 20070155724 A1 US20070155724 A1 US 20070155724A1 US 68417307 A US68417307 A US 68417307A US 2007155724 A1 US2007155724 A1 US 2007155724A1
- Authority
- US
- United States
- Prior art keywords
- naphthalen
- pyridin
- phenyl
- alkyl
- urea
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 90
- 102000004127 Cytokines Human genes 0.000 title abstract description 46
- 108090000695 Cytokines Proteins 0.000 title abstract description 46
- 230000001404 mediated effect Effects 0.000 title abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 46
- 201000010099 disease Diseases 0.000 title description 42
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 201000011510 cancer Diseases 0.000 claims abstract description 16
- -1 pyridinonyl Chemical group 0.000 claims description 539
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 224
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 154
- 229910052736 halogen Inorganic materials 0.000 claims description 130
- 125000000217 alkyl group Chemical group 0.000 claims description 128
- 150000002825 nitriles Chemical class 0.000 claims description 125
- 125000004076 pyridyl group Chemical group 0.000 claims description 122
- 150000002367 halogens Chemical class 0.000 claims description 120
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 107
- 150000001875 compounds Chemical class 0.000 claims description 92
- 125000000623 heterocyclic group Chemical group 0.000 claims description 90
- 125000002883 imidazolyl group Chemical group 0.000 claims description 85
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 77
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 74
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 74
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 72
- 229910052760 oxygen Inorganic materials 0.000 claims description 72
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 71
- 125000001624 naphthyl group Chemical group 0.000 claims description 69
- 125000004043 oxo group Chemical group O=* 0.000 claims description 69
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 69
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 63
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 61
- 125000001072 heteroaryl group Chemical group 0.000 claims description 61
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 53
- 229910052717 sulfur Inorganic materials 0.000 claims description 53
- 125000004193 piperazinyl group Chemical group 0.000 claims description 52
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 50
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 50
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 49
- 125000003545 alkoxy group Chemical group 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 49
- 125000002541 furyl group Chemical group 0.000 claims description 48
- 239000004202 carbamide Substances 0.000 claims description 43
- 125000005843 halogen group Chemical group 0.000 claims description 42
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 40
- 125000001544 thienyl group Chemical group 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 33
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 32
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 31
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 29
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 27
- 125000003435 aroyl group Chemical group 0.000 claims description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 26
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 26
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
- 125000003386 piperidinyl group Chemical group 0.000 claims description 25
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 24
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 24
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 24
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 24
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 24
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 23
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 23
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 22
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 22
- 125000006576 di-(C1-C3-alkyl)-aminocarbonyl group Chemical group 0.000 claims description 21
- 125000001041 indolyl group Chemical group 0.000 claims description 21
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 20
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 19
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 17
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 17
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 17
- 125000003282 alkyl amino group Chemical group 0.000 claims description 16
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 16
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 16
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 16
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 15
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 15
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 13
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims description 13
- 125000005494 pyridonyl group Chemical group 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000004599 benzpyrazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 12
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- QYCGBAJADAGLLK-UHFFFAOYSA-N 1-(cyclohepten-1-yl)cycloheptene Chemical group C1CCCCC=C1C1=CCCCCC1 QYCGBAJADAGLLK-UHFFFAOYSA-N 0.000 claims description 10
- VSIYJQNFMOOGCU-UHFFFAOYSA-N 1-(cyclohexen-1-yl)cyclohexene Chemical group C1CCCC(C=2CCCCC=2)=C1 VSIYJQNFMOOGCU-UHFFFAOYSA-N 0.000 claims description 10
- 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 claims description 10
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 claims description 10
- 125000005436 dihydrobenzothiophenyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 claims description 10
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000005046 dihydronaphthyl group Chemical group 0.000 claims description 9
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 claims description 9
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 9
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 9
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 8
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 claims description 8
- GFGAVPLNMQVFHP-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(2,6-dimethylmorpholin-4-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CC(C)OC(C)C1 GFGAVPLNMQVFHP-UHFFFAOYSA-N 0.000 claims description 8
- 125000005466 alkylenyl group Chemical group 0.000 claims description 8
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 8
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 8
- 125000005940 1,4-dioxanyl group Chemical group 0.000 claims description 7
- FBPMUUXVDWZTBK-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[2-(morpholin-4-ylmethyl)pyrimidin-5-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CN=C1CN1CCOCC1 FBPMUUXVDWZTBK-UHFFFAOYSA-N 0.000 claims description 7
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 238000002560 therapeutic procedure Methods 0.000 claims description 7
- 125000001425 triazolyl group Chemical group 0.000 claims description 7
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
- HYSJPAQMILEQFY-UHFFFAOYSA-N 1-(3-methylnaphthalen-2-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC2=CC=CC=C2C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 HYSJPAQMILEQFY-UHFFFAOYSA-N 0.000 claims description 6
- BCYXSXJASCDAPJ-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCN(C)CC1 BCYXSXJASCDAPJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000005872 benzooxazolyl group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 6
- CGONTLDBLAAPSU-UHFFFAOYSA-N n-[5-tert-butyl-2-methoxy-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenyl]acetamide Chemical compound COC1=C(NC(C)=O)C=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 CGONTLDBLAAPSU-UHFFFAOYSA-N 0.000 claims description 6
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 6
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 6
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 5
- ZMQPIXAVYIDIBG-UHFFFAOYSA-N 1-(2,3-dimethyl-1h-indol-5-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C2C(C)=C(C)NC2=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ZMQPIXAVYIDIBG-UHFFFAOYSA-N 0.000 claims description 5
- XMJCSEMZSSHAPU-UHFFFAOYSA-N 1-(3-amino-5-tert-butyl-2-methoxyphenyl)-3-[4-(6-methylpyridin-3-yl)naphthalen-1-yl]urea Chemical compound COC1=C(N)C=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=C(C)N=C1 XMJCSEMZSSHAPU-UHFFFAOYSA-N 0.000 claims description 5
- PZXHLFLLNPJDJD-UHFFFAOYSA-N 1-(3-amino-5-tert-butyl-2-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=C(N)C=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 PZXHLFLLNPJDJD-UHFFFAOYSA-N 0.000 claims description 5
- ZHEMIWZWBVZODY-UHFFFAOYSA-N 1-(5-tert-butyl-2-ethoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCOC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ZHEMIWZWBVZODY-UHFFFAOYSA-N 0.000 claims description 5
- SYRCZMWWOSOYQG-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-(thiomorpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCSCC1 SYRCZMWWOSOYQG-UHFFFAOYSA-N 0.000 claims description 5
- BYPZLIPMLRPGCS-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(2-methyl-3-oxopiperazin-1-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1C(C)C(=O)NCC1 BYPZLIPMLRPGCS-UHFFFAOYSA-N 0.000 claims description 5
- QAMPLFFTYHFJJP-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxypyridin-3-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=NC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 QAMPLFFTYHFJJP-UHFFFAOYSA-N 0.000 claims description 5
- GZRSLWDGXYUDLG-UHFFFAOYSA-N 1-(5-tert-butyl-2-pyrrolidin-1-ylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1N1CCCC1 GZRSLWDGXYUDLG-UHFFFAOYSA-N 0.000 claims description 5
- ICGUENJRUODDDI-UHFFFAOYSA-N 1-[4-[6-[[bis(2-cyanoethyl)amino]methyl]pyridin-3-yl]naphthalen-1-yl]-3-(5-tert-butyl-2-methoxyphenyl)urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=C(CN(CCC#N)CCC#N)N=C1 ICGUENJRUODDDI-UHFFFAOYSA-N 0.000 claims description 5
- KVOJMIMBKVGVQO-UHFFFAOYSA-N 1-[4-[6-[[bis(2-methoxyethyl)amino]methyl]pyridin-3-yl]naphthalen-1-yl]-3-(5-tert-butyl-2-methoxyphenyl)urea Chemical compound C1=NC(CN(CCOC)CCOC)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=CC=C1OC KVOJMIMBKVGVQO-UHFFFAOYSA-N 0.000 claims description 5
- YNPXZZMQKNKUHC-UHFFFAOYSA-N 1-[5-tert-butyl-2-methoxy-3-(2,2,2-trifluoroethylsulfonylamino)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C(NS(=O)(=O)CC(F)(F)F)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 YNPXZZMQKNKUHC-UHFFFAOYSA-N 0.000 claims description 5
- KSHWQBSJRNVYMU-UHFFFAOYSA-N 1-[5-tert-butyl-3-(2,3-dihydroxypropyl)-2-hydroxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC(CC(O)CO)=C(O)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 KSHWQBSJRNVYMU-UHFFFAOYSA-N 0.000 claims description 5
- KLPFPTSVYVEKOL-UHFFFAOYSA-N 1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C(NS(C)(=O)=O)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 KLPFPTSVYVEKOL-UHFFFAOYSA-N 0.000 claims description 5
- 206010006895 Cachexia Diseases 0.000 claims description 5
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 5
- 125000004442 acylamino group Chemical group 0.000 claims description 5
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 5
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 5
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 5
- BNBBKSUHPPUOLO-UHFFFAOYSA-N (3-tert-butylphenyl) n-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamate Chemical compound CC(C)(C)C1=CC=CC(OC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 BNBBKSUHPPUOLO-UHFFFAOYSA-N 0.000 claims description 4
- 125000006594 (C1-C3) alkylsulfony group Chemical group 0.000 claims description 4
- WQEJWTVTSDKASV-UHFFFAOYSA-N 1-(1-acetyl-3,3-dimethyl-2h-indol-5-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C2N(C(=O)C)CC(C)(C)C2=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 WQEJWTVTSDKASV-UHFFFAOYSA-N 0.000 claims description 4
- JWVPCJKQLGUCRA-UHFFFAOYSA-N 1-(3,3-dimethyl-2-oxo-1h-indol-5-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C2C(C)(C)C(=O)NC2=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 JWVPCJKQLGUCRA-UHFFFAOYSA-N 0.000 claims description 4
- HPQQHGUMMVKGPO-UHFFFAOYSA-N 1-(5-cyclohexyl-2-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C2CCCCC2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 HPQQHGUMMVKGPO-UHFFFAOYSA-N 0.000 claims description 4
- CDGVKVKZQCDYCD-UHFFFAOYSA-N 1-(5-tert-butyl-1,3-benzoxazol-7-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=12OC=NC2=CC(C(C)(C)C)=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 CDGVKVKZQCDYCD-UHFFFAOYSA-N 0.000 claims description 4
- NAZWEBNDZAMONP-UHFFFAOYSA-N 1-(5-tert-butyl-2-imidazol-1-ylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C(C(C)(C)C)=CC=C(N2C=NC=C2)C=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 NAZWEBNDZAMONP-UHFFFAOYSA-N 0.000 claims description 4
- UVDHLVZENVKMSJ-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxy-3-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C([N+]([O-])=O)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 UVDHLVZENVKMSJ-UHFFFAOYSA-N 0.000 claims description 4
- VVADCVAKMLBGPC-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-(6-pyridin-3-yloxypyridin-3-yl)naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1OC1=CC=CN=C1 VVADCVAKMLBGPC-UHFFFAOYSA-N 0.000 claims description 4
- JNWZPGHDLVFOHU-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[5-(morpholin-4-ylmethyl)pyrazin-2-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(N=C1)=CN=C1CN1CCOCC1 JNWZPGHDLVFOHU-UHFFFAOYSA-N 0.000 claims description 4
- NNXDLNQHNUKICX-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-(1,3-dioxolan-2-yl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=C(C2OCCO2)N=C1 NNXDLNQHNUKICX-UHFFFAOYSA-N 0.000 claims description 4
- IMEYFHRLJNHVKB-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1C(CO2)CC2C1 IMEYFHRLJNHVKB-UHFFFAOYSA-N 0.000 claims description 4
- OLHILEWECVENBS-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-(hydroxymethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=C(CO)N=C1 OLHILEWECVENBS-UHFFFAOYSA-N 0.000 claims description 4
- VRQBVALNRMCCRQ-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-(morpholine-4-carbonyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=C(C(=O)N2CCOCC2)N=C1 VRQBVALNRMCCRQ-UHFFFAOYSA-N 0.000 claims description 4
- USPQVAWOBXKNOF-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-(oxan-4-ylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1NC1CCOCC1 USPQVAWOBXKNOF-UHFFFAOYSA-N 0.000 claims description 4
- FBHTZEIJBMNUJC-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(1-oxothian-4-yl)amino]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1NC1CCS(=O)CC1 FBHTZEIJBMNUJC-UHFFFAOYSA-N 0.000 claims description 4
- OXGNMBLVMSVAPZ-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(2,6-dimethylpiperidin-1-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1C(C)CCCC1C OXGNMBLVMSVAPZ-UHFFFAOYSA-N 0.000 claims description 4
- YFMSNBUWORKEJK-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(3-oxopiperazin-1-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CC(=O)NCC1 YFMSNBUWORKEJK-UHFFFAOYSA-N 0.000 claims description 4
- LNMOYKCXUACLIC-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(oxolan-3-ylamino)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CNC1COCC1 LNMOYKCXUACLIC-UHFFFAOYSA-N 0.000 claims description 4
- LFMQDEIBFGMGHX-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[[2-(methoxymethyl)morpholin-4-yl]methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1COC(COC)CN1CC1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3C(=CC=C(C=3)C(C)(C)C)OC)=CC=2)C=N1 LFMQDEIBFGMGHX-UHFFFAOYSA-N 0.000 claims description 4
- FPQDJMDZVOJUJL-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[[2-cyanoethyl(oxolan-2-ylmethyl)amino]methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN(CCC#N)CC1OCCC1 FPQDJMDZVOJUJL-UHFFFAOYSA-N 0.000 claims description 4
- GYIDFUYJHFDKSW-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[[2-cyanoethyl(pyridin-3-ylmethyl)amino]methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN(CCC#N)CC1=CC=CN=C1 GYIDFUYJHFDKSW-UHFFFAOYSA-N 0.000 claims description 4
- SXWHJWVLUMVFGS-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[[4-(3-methoxyphenyl)piperazin-1-yl]methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=CC(N2CCN(CC=3N=CC(=CC=3)C=3C4=CC=CC=C4C(NC(=O)NC=4C(=CC=C(C=4)C(C)(C)C)OC)=CC=3)CC2)=C1 SXWHJWVLUMVFGS-UHFFFAOYSA-N 0.000 claims description 4
- RSRIISDWBQWUPX-UHFFFAOYSA-N 1-(5-tert-butyl-2-methyl-1,3-benzoxazol-7-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=12OC(C)=NC2=CC(C(C)(C)C)=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 RSRIISDWBQWUPX-UHFFFAOYSA-N 0.000 claims description 4
- KFXVPIJOIPYPSH-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylphenyl)-3-[4-[5-(methanesulfonamido)pyrazin-2-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CN=C(NS(C)(=O)=O)C=N1 KFXVPIJOIPYPSH-UHFFFAOYSA-N 0.000 claims description 4
- BFMKWXXXLFBTMH-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylsulfanylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CSC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 BFMKWXXXLFBTMH-UHFFFAOYSA-N 0.000 claims description 4
- BRZWHPXAPTYZID-UHFFFAOYSA-N 1-(5-tert-butyl-2-oxo-3h-1,3-benzoxazol-7-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=12OC(=O)NC2=CC(C(C)(C)C)=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 BRZWHPXAPTYZID-UHFFFAOYSA-N 0.000 claims description 4
- TYBHUHOIYNNGQO-UHFFFAOYSA-N 1-(5-tert-butyl-2-propan-2-yloxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)OC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 TYBHUHOIYNNGQO-UHFFFAOYSA-N 0.000 claims description 4
- LPLXKSPOWLXYGG-UHFFFAOYSA-N 1-(5-tert-butyl-2-propoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCCOC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 LPLXKSPOWLXYGG-UHFFFAOYSA-N 0.000 claims description 4
- USGJETFWAMMMLN-UHFFFAOYSA-N 1-(5-tert-butyl-3-cyano-2-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C(C#N)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 USGJETFWAMMMLN-UHFFFAOYSA-N 0.000 claims description 4
- AHZOPOQRANAHAY-UHFFFAOYSA-N 1-(6-tert-butyl-3-oxo-4h-1,4-benzoxazin-8-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=12OCC(=O)NC2=CC(C(C)(C)C)=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 AHZOPOQRANAHAY-UHFFFAOYSA-N 0.000 claims description 4
- GZOFCRDWNOPBEB-UHFFFAOYSA-N 1-(6-tert-butyl-4-methyl-3-oxo-1,4-benzoxazin-8-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C2N(C)C(=O)COC2=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 GZOFCRDWNOPBEB-UHFFFAOYSA-N 0.000 claims description 4
- HOULHNIBVCNAGC-UHFFFAOYSA-N 1-[2,4-dimethoxy-5-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC(OC)=C(C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 HOULHNIBVCNAGC-UHFFFAOYSA-N 0.000 claims description 4
- FBVHTEUZJDFLTA-UHFFFAOYSA-N 1-[2-methoxy-5-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 FBVHTEUZJDFLTA-UHFFFAOYSA-N 0.000 claims description 4
- BUNHUXDJKLVIBC-UHFFFAOYSA-N 1-[2-methoxy-5-[(2-methylpropan-2-yl)oxy]phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(OC(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 BUNHUXDJKLVIBC-UHFFFAOYSA-N 0.000 claims description 4
- MUQPJRRMNAGMKL-UHFFFAOYSA-N 1-[2-methylsulfinyl-5-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CS(=O)C1=CC=C(C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MUQPJRRMNAGMKL-UHFFFAOYSA-N 0.000 claims description 4
- LHRSCHWQXZSVDM-UHFFFAOYSA-N 1-[3-(benzenesulfonamido)-5-tert-butyl-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C(NS(=O)(=O)C=2C=CC=CC=2)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 LHRSCHWQXZSVDM-UHFFFAOYSA-N 0.000 claims description 4
- MUNNAQCVMSTQDD-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-[3-(trifluoromethylsulfonyl)phenyl]urea Chemical compound FC(F)(F)S(=O)(=O)C1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 MUNNAQCVMSTQDD-UHFFFAOYSA-N 0.000 claims description 4
- HPNQMSKRZIBEMH-UHFFFAOYSA-N 1-[5-(1-cyanocyclopropyl)-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C2(CC2)C#N)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 HPNQMSKRZIBEMH-UHFFFAOYSA-N 0.000 claims description 4
- FQAMJOYQZKEDGX-UHFFFAOYSA-N 1-[5-(2,2-dimethylpropanoyl)-2-methylphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=C(C(=O)C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 FQAMJOYQZKEDGX-UHFFFAOYSA-N 0.000 claims description 4
- LLVFXQIIDJSAES-UHFFFAOYSA-N 1-[5-tert-butyl-2-(1-methylpyrazol-4-yl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NN(C)C=C1C1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 LLVFXQIIDJSAES-UHFFFAOYSA-N 0.000 claims description 4
- CCBYJKVGOSVVLE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(3-hydroxyprop-1-ynyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC=C(C#CCO)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 CCBYJKVGOSVVLE-UHFFFAOYSA-N 0.000 claims description 4
- ZCPTVULXWYSYNL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(dimethylamino)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CN(C)C1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ZCPTVULXWYSYNL-UHFFFAOYSA-N 0.000 claims description 4
- IGBDEMKWRDVXMC-UHFFFAOYSA-N 1-[5-tert-butyl-2-methyl-3-[3-(oxan-2-yloxy)prop-1-ynyl]phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C(C#CCOC2OCCCC2)C(C)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 IGBDEMKWRDVXMC-UHFFFAOYSA-N 0.000 claims description 4
- MRRTWVXKQWEBCG-UHFFFAOYSA-N 1-[5-tert-butyl-3-(2,3-dihydroxypropyl)-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=C(CC(O)CO)C=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MRRTWVXKQWEBCG-UHFFFAOYSA-N 0.000 claims description 4
- OXSRFMNERVPWMR-UHFFFAOYSA-N 1-[5-tert-butyl-3-(3-hydroxyprop-1-ynyl)-2-methylphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C(C#CCO)C(C)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 OXSRFMNERVPWMR-UHFFFAOYSA-N 0.000 claims description 4
- JJHSDQDGIZUPON-UHFFFAOYSA-N 1-[5-tert-butyl-3-(ethylamino)-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCNC1=CC(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1OC JJHSDQDGIZUPON-UHFFFAOYSA-N 0.000 claims description 4
- PQHOEPBLRPBZKT-UHFFFAOYSA-N 1-[5-tert-butyl-3-(ethylsulfonylamino)-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCS(=O)(=O)NC1=CC(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1OC PQHOEPBLRPBZKT-UHFFFAOYSA-N 0.000 claims description 4
- ZKKCYGKTHPYSLR-UHFFFAOYSA-N 1-[5-tert-butyl-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)C(OC)=C1CC1COC(C)(C)O1 ZKKCYGKTHPYSLR-UHFFFAOYSA-N 0.000 claims description 4
- VUJVQDMCLKCGNP-UHFFFAOYSA-N 1-[5-tert-butyl-3-[2-(diethylamino)ethyl]-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCN(CC)CCC1=CC(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1OC VUJVQDMCLKCGNP-UHFFFAOYSA-N 0.000 claims description 4
- IUIBRMQDNNSMAC-UHFFFAOYSA-N 1-[[5-[4-[(5-tert-butyl-2-methoxyphenyl)carbamoylamino]naphthalen-1-yl]pyridin-2-yl]methyl]piperidine-3-carboxamide Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CC(C(N)=O)CCC1 IUIBRMQDNNSMAC-UHFFFAOYSA-N 0.000 claims description 4
- TWTPPEZVNRJSQU-UHFFFAOYSA-N 2-[4-tert-butyl-2-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenoxy]acetamide Chemical compound CC(C)(C)C1=CC=C(OCC(N)=O)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 TWTPPEZVNRJSQU-UHFFFAOYSA-N 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000002243 cyclohexanonyl group Chemical group *C1(*)C(=O)C(*)(*)C(*)(*)C(*)(*)C1(*)* 0.000 claims description 4
- 125000004652 decahydroisoquinolinyl group Chemical group C1(NCCC2CCCCC12)* 0.000 claims description 4
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 claims description 4
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 claims description 4
- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000000532 dioxanyl group Chemical group 0.000 claims description 4
- 125000005883 dithianyl group Chemical group 0.000 claims description 4
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- DAIAIOBTYVJHHJ-UHFFFAOYSA-N n-[1-[[5-[4-[(5-tert-butyl-2-methoxyphenyl)carbamoylamino]naphthalen-1-yl]pyridin-2-yl]methyl]pyrrolidin-3-yl]acetamide Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CC(NC(C)=O)CC1 DAIAIOBTYVJHHJ-UHFFFAOYSA-N 0.000 claims description 4
- KGJOEOIQYVJQFZ-UHFFFAOYSA-N n-[5-[4-[(5-tert-butyl-2-methoxyphenyl)carbamoylamino]naphthalen-1-yl]pyridin-2-yl]acetamide Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=C(NC(C)=O)N=C1 KGJOEOIQYVJQFZ-UHFFFAOYSA-N 0.000 claims description 4
- VZTPVFAWGLVYSE-UHFFFAOYSA-N n-[5-tert-butyl-2-methoxy-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenyl]-2,2,2-trifluoroacetamide Chemical compound C1=C(C(C)(C)C)C=C(NC(=O)C(F)(F)F)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 VZTPVFAWGLVYSE-UHFFFAOYSA-N 0.000 claims description 4
- CBBNEQNYUJVZPQ-UHFFFAOYSA-N n-[5-tert-butyl-2-methoxy-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenyl]-2-methylpropanamide Chemical compound C1=C(C(C)(C)C)C=C(NC(=O)C(C)C)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 CBBNEQNYUJVZPQ-UHFFFAOYSA-N 0.000 claims description 4
- ASKMNBKOUIHYNF-UHFFFAOYSA-N n-[5-tert-butyl-2-methoxy-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenyl]-n-methylacetamide Chemical compound C1=C(C(C)(C)C)C=C(N(C)C(C)=O)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ASKMNBKOUIHYNF-UHFFFAOYSA-N 0.000 claims description 4
- XZOIAOHMOBBSMM-UHFFFAOYSA-N n-[5-tert-butyl-2-methoxy-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenyl]propanamide Chemical compound CCC(=O)NC1=CC(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1OC XZOIAOHMOBBSMM-UHFFFAOYSA-N 0.000 claims description 4
- GMIGDYDIMXGYOL-UHFFFAOYSA-N n-acetyl-n-[5-tert-butyl-2-methoxy-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenyl]acetamide Chemical compound C1=C(C(C)(C)C)C=C(N(C(C)=O)C(C)=O)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 GMIGDYDIMXGYOL-UHFFFAOYSA-N 0.000 claims description 4
- 125000005968 oxazolinyl group Chemical group 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- 125000005545 phthalimidyl group Chemical group 0.000 claims description 4
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 4
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 claims description 4
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 4
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 4
- 125000005503 thioxanyl group Chemical group 0.000 claims description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- QNLNFLUVBSWVIG-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[4-(morpholin-4-ylmethyl)piperidin-1-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1N1CCC(CN2CCOCC2)CC1 QNLNFLUVBSWVIG-UHFFFAOYSA-N 0.000 claims description 3
- UPXGUSBHVAVLGH-UHFFFAOYSA-N 1-[2-tert-butyl-4-(methanesulfonamido)-5-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(NS(C)(=O)=O)C(OC)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1C(C)(C)C UPXGUSBHVAVLGH-UHFFFAOYSA-N 0.000 claims description 3
- POKPQQXNRDFJKE-UHFFFAOYSA-N 2-(5-tert-butyl-2-methoxyphenyl)-n-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]acetamide Chemical compound COC1=CC=C(C(C)(C)C)C=C1CC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 POKPQQXNRDFJKE-UHFFFAOYSA-N 0.000 claims description 3
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000003113 cycloheptyloxy group Chemical group C1(CCCCCC1)O* 0.000 claims description 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
- 230000035755 proliferation Effects 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 2
- RGDYCIHVZRSMAR-UHFFFAOYSA-N 1,3-bis[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 RGDYCIHVZRSMAR-UHFFFAOYSA-N 0.000 claims description 2
- CBEQVMLALWOOQZ-UHFFFAOYSA-N 1-(1-acetyl-2,3-dihydroindol-5-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C2N(C(=O)C)CCC2=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 CBEQVMLALWOOQZ-UHFFFAOYSA-N 0.000 claims description 2
- ULZLBCDVMYGAHV-UHFFFAOYSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C2OC(F)(F)OC2=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ULZLBCDVMYGAHV-UHFFFAOYSA-N 0.000 claims description 2
- YNCLMYJXNRLKIU-UHFFFAOYSA-N 1-(2,5-ditert-butylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC=C(C(C)(C)C)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 YNCLMYJXNRLKIU-UHFFFAOYSA-N 0.000 claims description 2
- NZLMNKKHXFTHNB-UHFFFAOYSA-N 1-(2-methoxy-5-phenoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)C(OC)=CC=C1OC1=CC=CC=C1 NZLMNKKHXFTHNB-UHFFFAOYSA-N 0.000 claims description 2
- JBQZUUIMGVSOBI-UHFFFAOYSA-N 1-(2-methoxydibenzofuran-3-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC(C2=CC=CC=C2O2)=C2C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 JBQZUUIMGVSOBI-UHFFFAOYSA-N 0.000 claims description 2
- DUKOBXKBDNMPMC-UHFFFAOYSA-N 1-(3,3-dimethyl-2-oxo-1h-indol-7-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1(C)C(=O)NC2=C1C=CC=C2NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 DUKOBXKBDNMPMC-UHFFFAOYSA-N 0.000 claims description 2
- TZQUDCVXRIQQNV-UHFFFAOYSA-N 1-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound OC1=CC=2CCCCC=2C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 TZQUDCVXRIQQNV-UHFFFAOYSA-N 0.000 claims description 2
- YOTMDOZVZLPFOE-UHFFFAOYSA-N 1-(3-hydroxynaphthalen-2-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound OC1=CC2=CC=CC=C2C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 YOTMDOZVZLPFOE-UHFFFAOYSA-N 0.000 claims description 2
- QWXGKJCBIRHWBX-UHFFFAOYSA-N 1-(4-amino-3,5-dibromophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(Br)C(N)=C(Br)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 QWXGKJCBIRHWBX-UHFFFAOYSA-N 0.000 claims description 2
- ITPDMJOSPFQMSH-UHFFFAOYSA-N 1-(4-anilino-2-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)C(OC)=CC=1NC1=CC=CC=C1 ITPDMJOSPFQMSH-UHFFFAOYSA-N 0.000 claims description 2
- ZRJLFXTYVMVNFT-UHFFFAOYSA-N 1-(4-tert-butylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C(C)(C)C)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ZRJLFXTYVMVNFT-UHFFFAOYSA-N 0.000 claims description 2
- GGRJYGKEBOTNHP-UHFFFAOYSA-N 1-(5-methoxy-2-methylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 GGRJYGKEBOTNHP-UHFFFAOYSA-N 0.000 claims description 2
- BKRYIJDAFCTFOD-UHFFFAOYSA-N 1-(5-tert-butyl-2-chloropyridin-3-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CN=C(Cl)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 BKRYIJDAFCTFOD-UHFFFAOYSA-N 0.000 claims description 2
- PNRCNWGZYUYWER-UHFFFAOYSA-N 1-(5-tert-butyl-2-cyclopentyloxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1OC1CCCC1 PNRCNWGZYUYWER-UHFFFAOYSA-N 0.000 claims description 2
- URXPRAJLPNCBRO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-(2-thia-5-azabicyclo[2.2.1]heptan-5-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1C(CS2)CC2C1 URXPRAJLPNCBRO-UHFFFAOYSA-N 0.000 claims description 2
- OOCWXPQLMUBOTM-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-(pyridin-3-ylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1NC1=CC=CN=C1 OOCWXPQLMUBOTM-UHFFFAOYSA-N 0.000 claims description 2
- SYEWQIACIPTFRA-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(2-methylsulfanylethylamino)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=C(CNCCSC)N=C1 SYEWQIACIPTFRA-UHFFFAOYSA-N 0.000 claims description 2
- ICSFCDJDIQYEBI-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(2-morpholin-4-ylethylamino)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CNCCN1CCOCC1 ICSFCDJDIQYEBI-UHFFFAOYSA-N 0.000 claims description 2
- DBMDOWNTQPAXHX-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(2-piperazin-1-ylethylamino)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CNCCN1CCNCC1 DBMDOWNTQPAXHX-UHFFFAOYSA-N 0.000 claims description 2
- BIZAXCQMFGBSDV-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(2-pyridin-3-ylethylamino)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CNCCC1=CC=CN=C1 BIZAXCQMFGBSDV-UHFFFAOYSA-N 0.000 claims description 2
- HGUYGZUWDGTFPX-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(3-pyridin-3-ylpyrrolidin-1-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CC(C=2C=NC=CC=2)CC1 HGUYGZUWDGTFPX-UHFFFAOYSA-N 0.000 claims description 2
- RNQGADDUAZCRFR-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(4-pyridin-2-ylpiperazin-1-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCN(C=2N=CC=CC=2)CC1 RNQGADDUAZCRFR-UHFFFAOYSA-N 0.000 claims description 2
- SLJBHZRSDHQULA-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[(4-pyrimidin-2-ylpiperazin-1-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCN(C=2N=CC=CN=2)CC1 SLJBHZRSDHQULA-UHFFFAOYSA-N 0.000 claims description 2
- ULVQEVVJODEZCC-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CC(N(C)C)CC1 ULVQEVVJODEZCC-UHFFFAOYSA-N 0.000 claims description 2
- ZEZSFDXTRYVVAM-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylphenyl)-3-[4-[4-(morpholin-4-ylmethyl)piperidin-1-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1N1CCC(CN2CCOCC2)CC1 ZEZSFDXTRYVVAM-UHFFFAOYSA-N 0.000 claims description 2
- PWENNHRVYOERJZ-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylsulfanylpyridin-3-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CSC1=NC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 PWENNHRVYOERJZ-UHFFFAOYSA-N 0.000 claims description 2
- RFSCUKVBDSZLJK-UHFFFAOYSA-N 1-(6-tert-butyl-1,3-benzodioxol-5-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC=2OCOC=2C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 RFSCUKVBDSZLJK-UHFFFAOYSA-N 0.000 claims description 2
- GMRDHDUAZOIXSA-UHFFFAOYSA-N 1-(6-tert-butyl-3-cyano-2-oxo-1h-pyridin-4-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound OC1=NC(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1C#N GMRDHDUAZOIXSA-UHFFFAOYSA-N 0.000 claims description 2
- YIBZEBREYBDTGG-UHFFFAOYSA-N 1-(6-tert-butyl-3-oxo-4h-1,4-benzoxazin-7-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC=2NC(=O)COC=2C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 YIBZEBREYBDTGG-UHFFFAOYSA-N 0.000 claims description 2
- JRUKMXCPKKAGES-UHFFFAOYSA-N 1-[2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=CC=C1OC1=CC=C(C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 JRUKMXCPKKAGES-UHFFFAOYSA-N 0.000 claims description 2
- GPGIZCCQTKUMAX-UHFFFAOYSA-N 1-[2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1OC1=CC=C(C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 GPGIZCCQTKUMAX-UHFFFAOYSA-N 0.000 claims description 2
- PRPNFLYMCIAXMC-UHFFFAOYSA-N 1-[2-ethylsulfonyl-5-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCS(=O)(=O)C1=CC=C(C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 PRPNFLYMCIAXMC-UHFFFAOYSA-N 0.000 claims description 2
- KLESEJISLAVJCW-UHFFFAOYSA-N 1-[2-methoxy-5-(2-phenylpropan-2-yl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C=2C=CC=CC=2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 KLESEJISLAVJCW-UHFFFAOYSA-N 0.000 claims description 2
- JXNJLIQCKVEDAP-UHFFFAOYSA-N 1-[3-(4-bromo-1-methylpyrazol-3-yl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CN1C=C(Br)C(C=2C=C(NC(=O)NC=3C4=CC=CC=C4C(C=4C=NC(CN5CCOCC5)=CC=4)=CC=3)C=CC=2)=N1 JXNJLIQCKVEDAP-UHFFFAOYSA-N 0.000 claims description 2
- UUAXUBVBEGLBSR-UHFFFAOYSA-N 1-[4-(difluoromethoxy)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(OC(F)F)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 UUAXUBVBEGLBSR-UHFFFAOYSA-N 0.000 claims description 2
- ZDCYCEGUVOQVHD-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-(1,3,3-trimethyl-2h-indol-5-yl)urea Chemical compound C=1C=C2N(C)CC(C)(C)C2=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ZDCYCEGUVOQVHD-UHFFFAOYSA-N 0.000 claims description 2
- DDHYJZZWEHJDGZ-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-[3-(1,3,4-oxadiazol-2-yl)phenyl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC(C=1)=CC=CC=1C1=NN=CO1 DDHYJZZWEHJDGZ-UHFFFAOYSA-N 0.000 claims description 2
- HPGCGTTYJWYWKO-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-[3-(1,3-oxazol-5-yl)phenyl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC(C=1)=CC=CC=1C1=CN=CO1 HPGCGTTYJWYWKO-UHFFFAOYSA-N 0.000 claims description 2
- MEGAZNOEWHRNPW-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-naphthalen-1-ylurea Chemical compound C=1C=CC2=CC=CC=C2C=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MEGAZNOEWHRNPW-UHFFFAOYSA-N 0.000 claims description 2
- UMURFXAIRXJCDG-UHFFFAOYSA-N 1-[4-[6-[(4-acetylpiperazin-1-yl)methyl]pyridin-3-yl]naphthalen-1-yl]-3-(5-tert-butyl-2-methoxyphenyl)urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCN(C(C)=O)CC1 UMURFXAIRXJCDG-UHFFFAOYSA-N 0.000 claims description 2
- JCRCYQYGUOZTJN-UHFFFAOYSA-N 1-[5-(2-methylbutan-2-yl)-2-phenoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)CC)=CC=C1OC1=CC=CC=C1 JCRCYQYGUOZTJN-UHFFFAOYSA-N 0.000 claims description 2
- LMXXQARHVCAHKT-UHFFFAOYSA-N 1-[5-(diethylsulfamoyl)-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCN(CC)S(=O)(=O)C1=CC=C(OC)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 LMXXQARHVCAHKT-UHFFFAOYSA-N 0.000 claims description 2
- PFEMRUFOORUDMI-UHFFFAOYSA-N 1-[5-(hydroxymethyl)-2-methylphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=C(CO)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 PFEMRUFOORUDMI-UHFFFAOYSA-N 0.000 claims description 2
- LKCURQCMUIKKBG-UHFFFAOYSA-N 1-[5-tert-butyl-1-(methanesulfonamido)-2-oxopyridin-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound O=C1N(NS(C)(=O)=O)C=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 LKCURQCMUIKKBG-UHFFFAOYSA-N 0.000 claims description 2
- BTOUXFPGALDZMQ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(1-methylpyrazol-4-yl)phenyl]-3-[4-[4-(morpholin-4-ylmethyl)piperidin-1-yl]naphthalen-1-yl]urea Chemical compound C1=NN(C)C=C1C1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1N1CCC(CN2CCOCC2)CC1 BTOUXFPGALDZMQ-UHFFFAOYSA-N 0.000 claims description 2
- GNURXJLCVXAFJJ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-pyrrolidin-1-ylethoxy)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1OCCN1CCCC1 GNURXJLCVXAFJJ-UHFFFAOYSA-N 0.000 claims description 2
- APHGTPBXJDMWPL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(methylamino)pyridin-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CNC1=NC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 APHGTPBXJDMWPL-UHFFFAOYSA-N 0.000 claims description 2
- UHGVMCQHFZBODE-UHFFFAOYSA-N 1-[5-tert-butyl-2-[3-(oxan-2-yloxy)prop-1-ynyl]phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1C#CCOC1CCCCO1 UHGVMCQHFZBODE-UHFFFAOYSA-N 0.000 claims description 2
- TUBMTBGAIWWEQK-UHFFFAOYSA-N 1-[5-tert-butyl-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-hydroxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound OC=1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=CC=1CC1COC(C)(C)O1 TUBMTBGAIWWEQK-UHFFFAOYSA-N 0.000 claims description 2
- LJJFRDKKIIEGQB-UHFFFAOYSA-N 1-[6-chloro-4-(trifluoromethyl)pyridin-2-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound FC(F)(F)C1=CC(Cl)=NC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 LJJFRDKKIIEGQB-UHFFFAOYSA-N 0.000 claims description 2
- MFSCEESLLCMMGE-UHFFFAOYSA-N 1-[6-tert-butyl-3-cyano-2-(methoxymethoxy)pyridin-4-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COCOC1=NC(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1C#N MFSCEESLLCMMGE-UHFFFAOYSA-N 0.000 claims description 2
- AWHKQZGPADWBLT-UHFFFAOYSA-N 1-[6-tert-butyl-4-(2-morpholin-4-ylethyl)-3-oxo-1,4-benzoxazin-8-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=12OCC(=O)N(CCN3CCOCC3)C2=CC(C(C)(C)C)=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 AWHKQZGPADWBLT-UHFFFAOYSA-N 0.000 claims description 2
- IDKOTTUTKZEGRW-UHFFFAOYSA-N 1-[[5-[4-[(5-tert-butyl-2-methoxyphenyl)carbamoylamino]naphthalen-1-yl]pyridin-2-yl]methyl]piperidine-4-carboxamide Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCC(C(N)=O)CC1 IDKOTTUTKZEGRW-UHFFFAOYSA-N 0.000 claims description 2
- BIZOAYKLGAULJD-UHFFFAOYSA-N 2-[5-tert-butyl-7-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]-1,3-benzoxazol-2-yl]acetamide Chemical compound C=12OC(CC(N)=O)=NC2=CC(C(C)(C)C)=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 BIZOAYKLGAULJD-UHFFFAOYSA-N 0.000 claims description 2
- UQZPGHOJMQTOHB-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)-n-ethylethanamine Chemical compound ClCCN(CC)CCCl UQZPGHOJMQTOHB-UHFFFAOYSA-N 0.000 claims description 2
- WOJATDXXHKRDIF-UHFFFAOYSA-N 3-[4-(2-methoxyphenyl)piperazin-1-yl]-1-(4-morpholin-4-ylphenyl)propan-1-one;dihydrochloride Chemical group Cl.Cl.COC1=CC=CC=C1N1CCN(CCC(=O)C=2C=CC(=CC=2)N2CCOCC2)CC1 WOJATDXXHKRDIF-UHFFFAOYSA-N 0.000 claims description 2
- NXNOYGXRCAUQKA-UHFFFAOYSA-N 3-[[5-[4-[(5-tert-butyl-2-methylphenyl)carbamoylamino]naphthalen-1-yl]pyridin-2-yl]amino]propyl n-(5-tert-butyl-2-methylphenyl)carbamate Chemical compound CC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1NCCCOC(=O)NC1=CC(C(C)(C)C)=CC=C1C NXNOYGXRCAUQKA-UHFFFAOYSA-N 0.000 claims description 2
- AYMFLFCMARIIJF-UHFFFAOYSA-N 5-tert-butyl-2-methoxy-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]benzamide Chemical compound C1=C(C(C)(C)C)C=C(C(N)=O)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 AYMFLFCMARIIJF-UHFFFAOYSA-N 0.000 claims description 2
- IPQXTPZITPPENO-UHFFFAOYSA-N 5-tert-butyl-7-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]-1,3-benzoxazole-2-carboxamide Chemical compound C=12OC(C(N)=O)=NC2=CC(C(C)(C)C)=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 IPQXTPZITPPENO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 208000005024 Castleman disease Diseases 0.000 claims description 2
- 208000002774 Paraproteinemias Diseases 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- SIBKXTHADZRLHY-UHFFFAOYSA-N ethyl 4-[[5-[4-[(5-tert-butyl-2-methoxyphenyl)carbamoylamino]naphthalen-1-yl]pyridin-2-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3C(=CC=C(C=3)C(C)(C)C)OC)=CC=2)C=N1 SIBKXTHADZRLHY-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 231100000024 genotoxic Toxicity 0.000 claims description 2
- 230000001738 genotoxic effect Effects 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- RVAVFVOISHIQLI-UHFFFAOYSA-N n-[4-tert-butyl-2-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenyl]furan-2-carboxamide Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1NC(=O)C1=CC=CO1 RVAVFVOISHIQLI-UHFFFAOYSA-N 0.000 claims description 2
- BJPLHTBTHCPUJG-UHFFFAOYSA-N propan-2-yl 2-chloro-5-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]benzoate Chemical compound C1=C(Cl)C(C(=O)OC(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 BJPLHTBTHCPUJG-UHFFFAOYSA-N 0.000 claims description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 2
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 2
- 210000004881 tumor cell Anatomy 0.000 claims description 2
- 208000038016 acute inflammation Diseases 0.000 abstract description 12
- 230000006022 acute inflammation Effects 0.000 abstract description 12
- 210000004072 lung Anatomy 0.000 abstract description 12
- 208000009137 Behcet syndrome Diseases 0.000 abstract description 11
- 206010019280 Heart failures Diseases 0.000 abstract description 11
- 208000037976 chronic inflammation Diseases 0.000 abstract description 11
- 230000006020 chronic inflammation Effects 0.000 abstract description 11
- 239000000779 smoke Substances 0.000 abstract description 11
- 206010002556 Ankylosing Spondylitis Diseases 0.000 abstract description 10
- 206010007559 Cardiac failure congestive Diseases 0.000 abstract description 10
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 10
- 201000009273 Endometriosis Diseases 0.000 abstract description 10
- 208000016604 Lyme disease Diseases 0.000 abstract description 10
- 206010033645 Pancreatitis Diseases 0.000 abstract description 10
- 206010040047 Sepsis Diseases 0.000 abstract description 10
- 206010048873 Traumatic arthritis Diseases 0.000 abstract description 10
- 206010046851 Uveitis Diseases 0.000 abstract description 10
- 238000007887 coronary angioplasty Methods 0.000 abstract description 10
- 208000037803 restenosis Diseases 0.000 abstract description 9
- 125000006615 aromatic heterocyclic group Chemical group 0.000 abstract description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 37
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 37
- 102000000589 Interleukin-1 Human genes 0.000 description 23
- 108010002352 Interleukin-1 Proteins 0.000 description 23
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 22
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 21
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 238000011282 treatment Methods 0.000 description 14
- 208000024827 Alzheimer disease Diseases 0.000 description 13
- 102000004889 Interleukin-6 Human genes 0.000 description 13
- 108090001005 Interleukin-6 Proteins 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 11
- 230000004054 inflammatory process Effects 0.000 description 11
- 230000000770 proinflammatory effect Effects 0.000 description 11
- 206010061218 Inflammation Diseases 0.000 description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 235000013877 carbamide Nutrition 0.000 description 10
- 125000002757 morpholinyl group Chemical group 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 9
- 230000006378 damage Effects 0.000 description 9
- 230000002757 inflammatory effect Effects 0.000 description 9
- 208000014674 injury Diseases 0.000 description 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 229930192474 thiophene Natural products 0.000 description 8
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 7
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 7
- 102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 description 7
- 101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 description 7
- 108090001007 Interleukin-8 Proteins 0.000 description 7
- 102000004890 Interleukin-8 Human genes 0.000 description 7
- 230000001154 acute effect Effects 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- ARUKYTASOALXFG-UHFFFAOYSA-N cycloheptylcycloheptane Chemical group C1CCCCCC1C1CCCCCC1 ARUKYTASOALXFG-UHFFFAOYSA-N 0.000 description 6
- WVIIMZNLDWSIRH-UHFFFAOYSA-N cyclohexylcyclohexane Chemical group C1CCCCC1C1CCCCC1 WVIIMZNLDWSIRH-UHFFFAOYSA-N 0.000 description 6
- MAWOHFOSAIXURX-UHFFFAOYSA-N cyclopentylcyclopentane Chemical group C1CCCC1C1CCCC1 MAWOHFOSAIXURX-UHFFFAOYSA-N 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000008506 pathogenesis Effects 0.000 description 6
- 230000008733 trauma Effects 0.000 description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 5
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 201000006417 multiple sclerosis Diseases 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 208000011580 syndromic disease Diseases 0.000 description 5
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 5
- 125000006563 (C1-3) alkylaminocarbonyl group Chemical group 0.000 description 4
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 4
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 4
- BBOPRMNMLDLRKQ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[5-(morpholin-4-ylmethyl)pyridin-2-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3N=CC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 BBOPRMNMLDLRKQ-UHFFFAOYSA-N 0.000 description 4
- KAZMQKPLIPWQNO-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 KAZMQKPLIPWQNO-UHFFFAOYSA-N 0.000 description 4
- SOZBHYOHAZVOBT-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methoxypyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(OC)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 SOZBHYOHAZVOBT-UHFFFAOYSA-N 0.000 description 4
- 208000006386 Bone Resorption Diseases 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 4
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 4
- 206010040070 Septic Shock Diseases 0.000 description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 4
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000024279 bone resorption Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000002596 correlated effect Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- ITBZMXUGTUHWGK-UHFFFAOYSA-N 1-(2-methyl-5-phenylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=C(C=2C=CC=CC=2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ITBZMXUGTUHWGK-UHFFFAOYSA-N 0.000 description 3
- SEHRPXLAFSFMSI-UHFFFAOYSA-N 1-(2-methyl-5-propan-2-ylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)C1=CC=C(C)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 SEHRPXLAFSFMSI-UHFFFAOYSA-N 0.000 description 3
- OKJJYXJBKGPJLH-UHFFFAOYSA-N 1-(2-tert-butyl-5-methylpyridin-4-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CN=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 OKJJYXJBKGPJLH-UHFFFAOYSA-N 0.000 description 3
- QCYRZCANKXBEHZ-UHFFFAOYSA-N 1-(3-tert-butylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 QCYRZCANKXBEHZ-UHFFFAOYSA-N 0.000 description 3
- FFBUDLJONCUVMD-UHFFFAOYSA-N 1-(5-butan-2-yl-2-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCC(C)C1=CC=C(OC)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 FFBUDLJONCUVMD-UHFFFAOYSA-N 0.000 description 3
- GQLCRASPHLJOAW-UHFFFAOYSA-N 1-(5-chloro-2,4-dimethoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 GQLCRASPHLJOAW-UHFFFAOYSA-N 0.000 description 3
- TVJZPCWJLIDBMN-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 TVJZPCWJLIDBMN-UHFFFAOYSA-N 0.000 description 3
- DVBKZPSCTGHZHB-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 DVBKZPSCTGHZHB-UHFFFAOYSA-N 0.000 description 3
- YNOBSNNZZPAJLM-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylphenyl)-3-[4-[6-[3-methoxypropyl(methyl)amino]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(N(C)CCCOC)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=CC=C1C YNOBSNNZZPAJLM-UHFFFAOYSA-N 0.000 description 3
- HTEMUDPCVAMLEB-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 HTEMUDPCVAMLEB-UHFFFAOYSA-N 0.000 description 3
- WUGLAQLTUHTAJZ-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyridin-3-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=NC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 WUGLAQLTUHTAJZ-UHFFFAOYSA-N 0.000 description 3
- UHWHXNSOZPFADL-UHFFFAOYSA-N 1-(5-tert-butyl-2-phenylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C(C(C)(C)C)=CC=C(C=2C=CC=CC=2)C=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 UHWHXNSOZPFADL-UHFFFAOYSA-N 0.000 description 3
- MOCYVOKWTBPIGE-UHFFFAOYSA-N 1-[2-methoxy-5-(2-methylbutan-2-yl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCC(C)(C)C1=CC=C(OC)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 MOCYVOKWTBPIGE-UHFFFAOYSA-N 0.000 description 3
- KBYAIWPIVQYVDZ-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-[4-(trifluoromethoxy)phenyl]urea Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 KBYAIWPIVQYVDZ-UHFFFAOYSA-N 0.000 description 3
- ONWPLLAEIIGIGW-UHFFFAOYSA-N 1-[5-tert-butyl-2-(1-methylpyrazol-4-yl)pyrazol-3-yl]-3-[4-[2-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=NN(C)C=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C(=CC=CC=3)CN3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 ONWPLLAEIIGIGW-UHFFFAOYSA-N 0.000 description 3
- IMTTUCLAGNXNLX-UHFFFAOYSA-N 1-[5-tert-butyl-2-(1-methylpyrazol-4-yl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NN(C)C=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 IMTTUCLAGNXNLX-UHFFFAOYSA-N 0.000 description 3
- BBCMFRFQYUIZRS-UHFFFAOYSA-N 1-[5-tert-butyl-2-(1h-pyrazol-4-yl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1C=1C=NNC=1 BBCMFRFQYUIZRS-UHFFFAOYSA-N 0.000 description 3
- DEVSCWJPCSXFMM-UHFFFAOYSA-N 1-[5-tert-butyl-2-(1h-pyrazol-4-yl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NNC=C1N1N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 DEVSCWJPCSXFMM-UHFFFAOYSA-N 0.000 description 3
- YTISFTRMFXFAKS-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=NC=C1C1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 YTISFTRMFXFAKS-UHFFFAOYSA-N 0.000 description 3
- FRPYEOALLMIMQH-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=NC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 FRPYEOALLMIMQH-UHFFFAOYSA-N 0.000 description 3
- JTRWJPGNIGWPEL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methylsulfanylpyrimidin-5-yl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(SC)=NC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 JTRWJPGNIGWPEL-UHFFFAOYSA-N 0.000 description 3
- WMRRCPFERWSFEX-UHFFFAOYSA-N 1-[5-tert-butyl-2-(3-hydroxypropyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC=C(CCCO)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 WMRRCPFERWSFEX-UHFFFAOYSA-N 0.000 description 3
- WXBMMVPWYARDGV-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[2-(morpholin-4-ylmethyl)pyrimidin-5-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=NC=3)=CC=2)=CC(C(C)(C)C)=N1 WXBMMVPWYARDGV-UHFFFAOYSA-N 0.000 description 3
- HWLKVWAXMATBJX-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[6-[(1-oxo-1,4-thiazinan-4-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCS(=O)CC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 HWLKVWAXMATBJX-UHFFFAOYSA-N 0.000 description 3
- FZCFXZARDIWKGU-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-(2-pyridin-2-ylethylamino)cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCCC(C=3)NCCC=3N=CC=CC=3)=CC=2)=CC(C(C)(C)C)=N1 FZCFXZARDIWKGU-UHFFFAOYSA-N 0.000 description 3
- IRJNKEVLQRRUSA-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 IRJNKEVLQRRUSA-UHFFFAOYSA-N 0.000 description 3
- BOAGBUKUGQYVKM-UHFFFAOYSA-N 1-[5-tert-butyl-2-(methoxymethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COCC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 BOAGBUKUGQYVKM-UHFFFAOYSA-N 0.000 description 3
- XZMNYZSIMZGMEY-UHFFFAOYSA-N 1-[5-tert-butyl-2-(morpholine-4-carbonyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1C(=O)N1CCOCC1 XZMNYZSIMZGMEY-UHFFFAOYSA-N 0.000 description 3
- NEGALIADGFBSDW-UHFFFAOYSA-N 1-[5-tert-butyl-2-[1-(3-methylsulfanylpropyl)pyrazol-4-yl]pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NN(CCCSC)C=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 NEGALIADGFBSDW-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 208000011231 Crohn disease Diseases 0.000 description 3
- 208000031886 HIV Infections Diseases 0.000 description 3
- 208000037357 HIV infectious disease Diseases 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- 201000009906 Meningitis Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000016396 cytokine production Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 230000007302 negative regulation of cytokine production Effects 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 210000002997 osteoclast Anatomy 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 150000003536 tetrazoles Chemical group 0.000 description 3
- 230000006433 tumor necrosis factor production Effects 0.000 description 3
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 description 2
- KZSAABCCRZPRJK-UHFFFAOYSA-N 1-(3-tert-butylphenyl)-3-[4-[4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN4CCOCC4)=CC=3)=CC=2)=C1 KZSAABCCRZPRJK-UHFFFAOYSA-N 0.000 description 2
- CAQYVODRHABUJH-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxy-3-propylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCCC1=CC(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1OC CAQYVODRHABUJH-UHFFFAOYSA-N 0.000 description 2
- MIBYPKINMBREPE-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[2-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=CC=C1CN1CCOCC1 MIBYPKINMBREPE-UHFFFAOYSA-N 0.000 description 2
- RDBWUJDARKEUNS-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[4-(oxan-4-ylamino)phenyl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1NC1CCOCC1 RDBWUJDARKEUNS-UHFFFAOYSA-N 0.000 description 2
- SYGFXFLLYOMQKH-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[4-(thiomorpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1CN1CCSCC1 SYGFXFLLYOMQKH-UHFFFAOYSA-N 0.000 description 2
- HZMQYZHTBFZUTB-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylphenyl)-3-[4-[4-(morpholin-4-ylmethyl)imidazol-1-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1N1C=C(CN2CCOCC2)N=C1 HZMQYZHTBFZUTB-UHFFFAOYSA-N 0.000 description 2
- NMJPRGQFIVOUJR-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylphenyl)-3-[4-[4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound CC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1CN1CCOCC1 NMJPRGQFIVOUJR-UHFFFAOYSA-N 0.000 description 2
- ULCWMQOJQGXRRU-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylphenyl)-3-[4-[6-(3-methoxypropylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(NCCCOC)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=CC=C1C ULCWMQOJQGXRRU-UHFFFAOYSA-N 0.000 description 2
- VKTLDTPBPJGRIJ-UHFFFAOYSA-N 1-(5-tert-butyl-2-morpholin-4-ylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1N1CCOCC1 VKTLDTPBPJGRIJ-UHFFFAOYSA-N 0.000 description 2
- VEZUUSJWADNERS-UHFFFAOYSA-N 1-(6-tert-butyl-2-chloro-3-methylpyridin-4-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=C(Cl)N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 VEZUUSJWADNERS-UHFFFAOYSA-N 0.000 description 2
- VFPLJXGPPDYXOI-UHFFFAOYSA-N 1-(6-tert-butyl-2-chloro-3-methylpyridin-4-yl)-3-[4-[6-(thiomorpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=C(Cl)N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCSCC1 VFPLJXGPPDYXOI-UHFFFAOYSA-N 0.000 description 2
- URDGGACDWSWQMA-UHFFFAOYSA-N 1-[2-(2-aminopyrimidin-5-yl)-5-tert-butylpyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1N=C(N)N=CC=1N1N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 URDGGACDWSWQMA-UHFFFAOYSA-N 0.000 description 2
- HXTMKULUSANYTM-UHFFFAOYSA-N 1-[2-methoxy-5-(1-methylcyclopropyl)phenyl]-3-[4-[2-(morpholin-4-ylmethyl)pyrimidin-5-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C2(C)CC2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CN=C1CN1CCOCC1 HXTMKULUSANYTM-UHFFFAOYSA-N 0.000 description 2
- DIPZYLWYNOYUJR-UHFFFAOYSA-N 1-[2-methoxy-5-(2-methylbutan-2-yl)phenyl]-3-[4-[4-(thiomorpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound CCC(C)(C)C1=CC=C(OC)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN4CCSCC4)=CC=3)=CC=2)=C1 DIPZYLWYNOYUJR-UHFFFAOYSA-N 0.000 description 2
- VJMISIPCJWKEGO-UHFFFAOYSA-N 1-[4-[4-[[bis(2-methoxyethyl)amino]methyl]phenyl]naphthalen-1-yl]-3-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]urea Chemical compound C1=CC(CN(CCOC)CCOC)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)N=C1 VJMISIPCJWKEGO-UHFFFAOYSA-N 0.000 description 2
- SVGQPGDMEXQRQN-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound FC(F)(F)C1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 SVGQPGDMEXQRQN-UHFFFAOYSA-N 0.000 description 2
- XYCOYKZYTVPXSZ-UHFFFAOYSA-N 1-[5-(1-cyanocyclopropyl)-2-methoxyphenyl]-3-[4-[2-(morpholin-4-ylmethyl)pyrimidin-5-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C2(CC2)C#N)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CN=C1CN1CCOCC1 XYCOYKZYTVPXSZ-UHFFFAOYSA-N 0.000 description 2
- ZNYNPFIRXYNDQU-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-cyanoethyl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound N#CCCN1N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ZNYNPFIRXYNDQU-UHFFFAOYSA-N 0.000 description 2
- DXBVYGQYSUEISI-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methoxypyrimidin-5-yl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(OC)=NC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 DXBVYGQYSUEISI-UHFFFAOYSA-N 0.000 description 2
- NHJQQOQIJQBRRW-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)phenyl]-3-[4-[5-(pyridin-4-ylmethyl)pyridin-2-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=NC=C1C1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(N=C1)=CC=C1CC1=CC=NC=C1 NHJQQOQIJQBRRW-UHFFFAOYSA-N 0.000 description 2
- WWSGPSTYXUUGKA-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)pyrazol-3-yl]-3-[4-[2-(morpholin-4-ylmethyl)pyrimidin-5-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=NC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=NC=3)=CC=2)=CC(C(C)(C)C)=N1 WWSGPSTYXUUGKA-UHFFFAOYSA-N 0.000 description 2
- FHLQPCUMQVYGNX-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)pyrazol-3-yl]-3-[4-[6-(oxan-4-ylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=NC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(NC4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 FHLQPCUMQVYGNX-UHFFFAOYSA-N 0.000 description 2
- MCKFAVIMAYCFIH-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)pyrazol-3-yl]-3-[4-[6-[(1-oxo-1,4-thiazinan-4-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=NC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCS(=O)CC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 MCKFAVIMAYCFIH-UHFFFAOYSA-N 0.000 description 2
- XDGJCAJXCUILEZ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(3-morpholin-4-yl-3-oxopropyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1CCC(=O)N1CCOCC1 XDGJCAJXCUILEZ-UHFFFAOYSA-N 0.000 description 2
- USGPKPYWOURZEK-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[2-(morpholine-4-carbonyl)pyrimidin-5-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(=NC=3)C(=O)N3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 USGPKPYWOURZEK-UHFFFAOYSA-N 0.000 description 2
- BMXNQGASYHVGST-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[3-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(CN4CCOCC4)C=CC=3)=CC=2)=CC(C(C)(C)C)=N1 BMXNQGASYHVGST-UHFFFAOYSA-N 0.000 description 2
- KHOJCKYLSONCCN-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[4-(2-morpholin-4-ylethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CCN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 KHOJCKYLSONCCN-UHFFFAOYSA-N 0.000 description 2
- JHCPOCAZTCPCQQ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 JHCPOCAZTCPCQQ-UHFFFAOYSA-N 0.000 description 2
- DDSUPZFRUFSRID-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[4-[methylamino(pyridin-3-yl)methyl]phenyl]naphthalen-1-yl]urea Chemical compound C=1C=CN=CC=1C(NC)C(C=C1)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)C=C1 DDSUPZFRUFSRID-UHFFFAOYSA-N 0.000 description 2
- IKJJFZMMHAIPNB-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[5-(morpholin-4-ylmethyl)furan-2-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3OC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 IKJJFZMMHAIPNB-UHFFFAOYSA-N 0.000 description 2
- HWPPZXCPZJQDSK-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[6-(thiomorpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCSCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 HWPPZXCPZJQDSK-UHFFFAOYSA-N 0.000 description 2
- HZOOQEANFBKRIM-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[6-[(1-oxothian-4-yl)amino]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(NC4CCS(=O)CC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 HZOOQEANFBKRIM-UHFFFAOYSA-N 0.000 description 2
- SIOKWKLHLCPFPN-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-(morpholin-4-ylmethyl)cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCCC(CN4CCOCC4)C=3)=CC=2)=CC(C(C)(C)C)=N1 SIOKWKLHLCPFPN-UHFFFAOYSA-N 0.000 description 2
- KNAHYEJUOBRJIC-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-hydroxy-4-(oxolan-3-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(O)C(CC4COCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 KNAHYEJUOBRJIC-UHFFFAOYSA-N 0.000 description 2
- XFJUDEHDAGOXMR-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-(furan-2-ylmethyl)-3-hydroxyphenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(O)C(CC=4OC=CC=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 XFJUDEHDAGOXMR-UHFFFAOYSA-N 0.000 description 2
- OVPDTMKGYGGJNU-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 OVPDTMKGYGGJNU-UHFFFAOYSA-N 0.000 description 2
- ROGOQXDNDRXOAB-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-(thiomorpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN4CCSCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 ROGOQXDNDRXOAB-UHFFFAOYSA-N 0.000 description 2
- AITNULMUNMWYTC-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-[[2-cyanoethyl(oxolan-2-ylmethyl)amino]methyl]phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN(CCC#N)CC4OCCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 AITNULMUNMWYTC-UHFFFAOYSA-N 0.000 description 2
- OCYIIPQUEFWVOX-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-[[2-cyanoethyl(pyridin-3-ylmethyl)amino]methyl]phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN(CCC#N)CC=4C=NC=CC=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 OCYIIPQUEFWVOX-UHFFFAOYSA-N 0.000 description 2
- GUFFIMDDQASHSZ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-methoxy-6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound N=1C=C(C=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=NC(C)=CC=3)=CC=2)C(OC)=CC=1CN1CCOCC1 GUFFIMDDQASHSZ-UHFFFAOYSA-N 0.000 description 2
- CMNIBMRFKPYNHN-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[5-(thian-4-ylamino)pyrazin-2-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3N=CC(NC4CCSCC4)=NC=3)=CC=2)=CC(C(C)(C)C)=N1 CMNIBMRFKPYNHN-UHFFFAOYSA-N 0.000 description 2
- MKQIWKMKTHHOCV-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(1-morpholin-4-ylpropyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=NC(C)=CC=3)=CC=2)C=NC=1C(CC)N1CCOCC1 MKQIWKMKTHHOCV-UHFFFAOYSA-N 0.000 description 2
- MXEDNULIXVIKDP-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4C5CC(OC5)C4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 MXEDNULIXVIKDP-UHFFFAOYSA-N 0.000 description 2
- DVJVCKCZQZCEDE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(3-cyanopropoxy)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(OCCCC#N)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 DVJVCKCZQZCEDE-UHFFFAOYSA-N 0.000 description 2
- KXRIDVAKSBVUNI-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(4-hydroxybutoxy)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(OCCCCO)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 KXRIDVAKSBVUNI-UHFFFAOYSA-N 0.000 description 2
- CLADYCSYECLIBL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(4-hydroxybutylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(NCCCCO)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 CLADYCSYECLIBL-UHFFFAOYSA-N 0.000 description 2
- WLOIMSRPDWSQAE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(oxan-4-ylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(NC4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 WLOIMSRPDWSQAE-UHFFFAOYSA-N 0.000 description 2
- VNJBNRJGLBZRMN-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(pyridin-3-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CC=4C=NC=CC=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 VNJBNRJGLBZRMN-UHFFFAOYSA-N 0.000 description 2
- GIRWDEZWNFUKPS-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(thian-4-ylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(NC4CCSCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 GIRWDEZWNFUKPS-UHFFFAOYSA-N 0.000 description 2
- RZGGQVGHFLXQDL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-[(1-oxothian-4-yl)amino]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(NC4CCS(=O)CC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 RZGGQVGHFLXQDL-UHFFFAOYSA-N 0.000 description 2
- YEBURKNDXZVPML-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-[(2,6-dimethylmorpholin-4-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1C(C)OC(C)CN1CC1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=NC(C)=CC=3)=CC=2)C=N1 YEBURKNDXZVPML-UHFFFAOYSA-N 0.000 description 2
- DYHSPTUMGZFPAR-UHFFFAOYSA-N 2-[4-tert-butyl-2-[[4-[6-[(2,6-dimethylmorpholin-4-yl)methyl]pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenoxy]acetamide Chemical compound C1C(C)OC(C)CN1CC1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3C(=CC=C(C=3)C(C)(C)C)OCC(N)=O)=CC=2)C=N1 DYHSPTUMGZFPAR-UHFFFAOYSA-N 0.000 description 2
- SYPCACMBAYWOGV-UHFFFAOYSA-N 3-[4-[(5-tert-butyl-2-methoxyphenyl)carbamoylamino]naphthalen-1-yl]benzamide Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=CC(C(N)=O)=C1 SYPCACMBAYWOGV-UHFFFAOYSA-N 0.000 description 2
- ZGXFVYOWURGVSM-UHFFFAOYSA-N 4-[4-(2-morpholin-4-yl-2-thiomorpholin-4-ylthiomorpholin-4-yl)sulfinyl-2-thiomorpholin-4-ylthiomorpholin-2-yl]morpholine Chemical compound C1CSC(N2CCSCC2)(N2CCOCC2)CN1S(=O)N(C1)CCSC1(N1CCSCC1)N1CCOCC1 ZGXFVYOWURGVSM-UHFFFAOYSA-N 0.000 description 2
- RZBFJKANZHTGNJ-UHFFFAOYSA-N 4-tert-butyl-2-[[4-[2-chloro-4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]carbamoylamino]benzamide Chemical compound CC(C)(C)C1=CC=C(C(N)=O)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C(=CC(CN4CCOCC4)=CC=3)Cl)=CC=2)=C1 RZBFJKANZHTGNJ-UHFFFAOYSA-N 0.000 description 2
- BUXDDVRTTIYFHI-UHFFFAOYSA-N 5-[3-tert-butyl-5-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]pyrazol-1-yl]-2-methylbenzamide Chemical compound C1=C(C(N)=O)C(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 BUXDDVRTTIYFHI-UHFFFAOYSA-N 0.000 description 2
- 206010065040 AIDS dementia complex Diseases 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 206010048998 Acute phase reaction Diseases 0.000 description 2
- 208000000103 Anorexia Nervosa Diseases 0.000 description 2
- 208000020084 Bone disease Diseases 0.000 description 2
- 208000000094 Chronic Pain Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- 206010018366 Glomerulonephritis acute Diseases 0.000 description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- 102000055008 Matrilin Proteins Human genes 0.000 description 2
- 108010072582 Matrilin Proteins Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 2
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 206010044248 Toxic shock syndrome Diseases 0.000 description 2
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- GEZNJXCFWXGUBW-UHFFFAOYSA-N [Ar].[H]N(C)C(=[W])N([H])[Ar]C[Y]C Chemical compound [Ar].[H]N(C)C(=[W])N([H])[Ar]C[Y]C GEZNJXCFWXGUBW-UHFFFAOYSA-N 0.000 description 2
- UUKMMXUHWGFVRN-UHFFFAOYSA-N [H]N([Ar]C[Y]C)C(=[W])CC Chemical compound [H]N([Ar]C[Y]C)C(=[W])CC UUKMMXUHWGFVRN-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 231100000851 acute glomerulonephritis Toxicity 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000003092 anti-cytokine Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 230000003143 atherosclerotic effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000010072 bone remodeling Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 238000001631 haemodialysis Methods 0.000 description 2
- 230000000322 hemodialysis Effects 0.000 description 2
- 102000057041 human TNF Human genes 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 208000037890 multiple organ injury Diseases 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- TVBZKMHBLROHSN-UHFFFAOYSA-N n-[5-[4-[[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]pyridin-2-yl]acetamide Chemical compound C1=NC(NC(=O)C)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)N=C1 TVBZKMHBLROHSN-UHFFFAOYSA-N 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 2
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 208000028169 periodontal disease Diseases 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000036303 septic shock Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 2
- 230000002537 thrombolytic effect Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- NQPJDJVGBDHCAD-UHFFFAOYSA-N 1,3-diazinan-2-one Chemical compound OC1=NCCCN1 NQPJDJVGBDHCAD-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- REERFUMNYQUJQG-UHFFFAOYSA-N 1-(1,3-benzothiazol-6-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C2N=CSC2=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 REERFUMNYQUJQG-UHFFFAOYSA-N 0.000 description 1
- GVSWVZOVDXUIFL-UHFFFAOYSA-N 1-(2,3-dichlorophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound ClC1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1Cl GVSWVZOVDXUIFL-UHFFFAOYSA-N 0.000 description 1
- SUAXLPQBMQNTSP-UHFFFAOYSA-N 1-(2,3-dimethylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1C SUAXLPQBMQNTSP-UHFFFAOYSA-N 0.000 description 1
- WUQGLNIDHPPBNI-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound ClC1=CC(Cl)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 WUQGLNIDHPPBNI-UHFFFAOYSA-N 0.000 description 1
- SYBGVADGOHETFE-UHFFFAOYSA-N 1-(2,4-dimethoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC(OC)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 SYBGVADGOHETFE-UHFFFAOYSA-N 0.000 description 1
- RXDWJZREJOZEGL-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC(C)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 RXDWJZREJOZEGL-UHFFFAOYSA-N 0.000 description 1
- SFPBHNAFVHSBPU-UHFFFAOYSA-N 1-(2,5-dichlorophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound ClC1=CC=C(Cl)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 SFPBHNAFVHSBPU-UHFFFAOYSA-N 0.000 description 1
- CYCLXMSCCANVDK-UHFFFAOYSA-N 1-(2,5-diethoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCOC1=CC=C(OCC)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 CYCLXMSCCANVDK-UHFFFAOYSA-N 0.000 description 1
- AWEJMFLMIIIWQH-UHFFFAOYSA-N 1-(2,5-difluorophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound FC1=CC=C(F)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 AWEJMFLMIIIWQH-UHFFFAOYSA-N 0.000 description 1
- FAZWSMQUSZIVSV-UHFFFAOYSA-N 1-(2,5-dimethoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(OC)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 FAZWSMQUSZIVSV-UHFFFAOYSA-N 0.000 description 1
- WUXVANAGFKJIES-UHFFFAOYSA-N 1-(2,6-dibromo-4-propan-2-ylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound BrC1=CC(C(C)C)=CC(Br)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 WUXVANAGFKJIES-UHFFFAOYSA-N 0.000 description 1
- GJPVQMQMDVIWJN-UHFFFAOYSA-N 1-(2-benzyl-5-tert-butylpyrazol-3-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=CC=CC=1CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 GJPVQMQMDVIWJN-UHFFFAOYSA-N 0.000 description 1
- CRTPUTWKRSDIKT-UHFFFAOYSA-N 1-(2-chloro-6-methylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=CC(Cl)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 CRTPUTWKRSDIKT-UHFFFAOYSA-N 0.000 description 1
- MCESVWQYJXZHOH-UHFFFAOYSA-N 1-(2-ethoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCOC1=CC=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MCESVWQYJXZHOH-UHFFFAOYSA-N 0.000 description 1
- VQDANEUSMXVNGY-UHFFFAOYSA-N 1-(2-fluoro-5-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound [O-][N+](=O)C1=CC=C(F)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 VQDANEUSMXVNGY-UHFFFAOYSA-N 0.000 description 1
- BKVJLRPQHGWDNH-UHFFFAOYSA-N 1-(2-methoxy-4-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC([N+]([O-])=O)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 BKVJLRPQHGWDNH-UHFFFAOYSA-N 0.000 description 1
- YRWFTPPPNBPMNF-UHFFFAOYSA-N 1-(2-methoxy-5-methylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 YRWFTPPPNBPMNF-UHFFFAOYSA-N 0.000 description 1
- NVRRPPBQBVYFJF-UHFFFAOYSA-N 1-(2-methoxy-5-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C([N+]([O-])=O)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 NVRRPPBQBVYFJF-UHFFFAOYSA-N 0.000 description 1
- NTGITDUWLJNPCG-UHFFFAOYSA-N 1-(2-methoxy-5-phenylphenyl)-3-[4-[4-(oxan-4-ylmethyl)imidazol-1-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C=2C=CC=CC=2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1N(C=1)C=NC=1CC1CCOCC1 NTGITDUWLJNPCG-UHFFFAOYSA-N 0.000 description 1
- DTMGDZVXFBDPCJ-UHFFFAOYSA-N 1-(2-methoxy-5-trimethylsilylphenyl)-3-[4-[4-(oxan-4-ylamino)phenyl]naphthalen-1-yl]urea Chemical compound COC1=CC=C([Si](C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1NC1CCOCC1 DTMGDZVXFBDPCJ-UHFFFAOYSA-N 0.000 description 1
- IZUDERUUDIJAIC-UHFFFAOYSA-N 1-(2-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 IZUDERUUDIJAIC-UHFFFAOYSA-N 0.000 description 1
- WZCAGFROEGNXOQ-UHFFFAOYSA-N 1-(2-methyl-1,3-dioxoisoindol-5-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C2C(=O)N(C)C(=O)C2=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 WZCAGFROEGNXOQ-UHFFFAOYSA-N 0.000 description 1
- SLCLHNJCNWDURK-UHFFFAOYSA-N 1-(2-methyl-3-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC=C([N+]([O-])=O)C(C)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 SLCLHNJCNWDURK-UHFFFAOYSA-N 0.000 description 1
- DNIOFXKFGFGVAV-UHFFFAOYSA-N 1-(2-methyl-4-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC([N+]([O-])=O)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 DNIOFXKFGFGVAV-UHFFFAOYSA-N 0.000 description 1
- XBWMGYBQDGAPLE-UHFFFAOYSA-N 1-(2-methyl-5-phenylphenyl)-3-[4-[4-(2-pyridin-4-ylethyl)piperazin-1-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=C(C=2C=CC=CC=2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1N(CC1)CCN1CCC1=CC=NC=C1 XBWMGYBQDGAPLE-UHFFFAOYSA-N 0.000 description 1
- VTOFXBYEZWMSIR-UHFFFAOYSA-N 1-(2-methyl-6-propan-2-ylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)C1=CC=CC(C)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 VTOFXBYEZWMSIR-UHFFFAOYSA-N 0.000 description 1
- ISWYJMDOFPGKKL-UHFFFAOYSA-N 1-(2-methylsulfanylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CSC1=CC=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ISWYJMDOFPGKKL-UHFFFAOYSA-N 0.000 description 1
- MYUPRBWNKVNHHN-UHFFFAOYSA-N 1-(3,4-dimethylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C)C(C)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MYUPRBWNKVNHHN-UHFFFAOYSA-N 0.000 description 1
- UCVHVJOQGPMCSJ-UHFFFAOYSA-N 1-(3,5-dimethoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC(OC)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 UCVHVJOQGPMCSJ-UHFFFAOYSA-N 0.000 description 1
- DELSLEWHRQVXEV-UHFFFAOYSA-N 1-(3-chloro-2-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=C(Cl)C=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 DELSLEWHRQVXEV-UHFFFAOYSA-N 0.000 description 1
- NVYYWTXAJCTIRC-UHFFFAOYSA-N 1-(3-chloro-4-methylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(Cl)C(C)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 NVYYWTXAJCTIRC-UHFFFAOYSA-N 0.000 description 1
- SKGOFDWOHKOHPM-UHFFFAOYSA-N 1-(3-chlorophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound ClC1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 SKGOFDWOHKOHPM-UHFFFAOYSA-N 0.000 description 1
- GTNFKGBUXGFUIS-UHFFFAOYSA-N 1-(3-cyanophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC=CC(C#N)=C1 GTNFKGBUXGFUIS-UHFFFAOYSA-N 0.000 description 1
- GCEWIOVJYXKEEO-UHFFFAOYSA-N 1-(3-cyclopentyloxy-4-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(OC2CCCC2)C(OC)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 GCEWIOVJYXKEEO-UHFFFAOYSA-N 0.000 description 1
- GMCBUMYNOUFINM-UHFFFAOYSA-N 1-(3-ethylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCC1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 GMCBUMYNOUFINM-UHFFFAOYSA-N 0.000 description 1
- RMRDSOFRYIUFBR-UHFFFAOYSA-N 1-(3-fluorophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound FC1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 RMRDSOFRYIUFBR-UHFFFAOYSA-N 0.000 description 1
- OSHNTNCCRAGCQP-UHFFFAOYSA-N 1-(3-iodophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound IC1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 OSHNTNCCRAGCQP-UHFFFAOYSA-N 0.000 description 1
- KGVLJKGUKCFSDO-UHFFFAOYSA-N 1-(3-methoxynaphthalen-2-yl)-3-[4-[4-(morpholin-4-ylmethyl)piperidin-1-yl]naphthalen-1-yl]urea Chemical compound COC1=CC2=CC=CC=C2C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1N(CC1)CCC1CN1CCOCC1 KGVLJKGUKCFSDO-UHFFFAOYSA-N 0.000 description 1
- QDPZFULULDYXQB-UHFFFAOYSA-N 1-(3-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 QDPZFULULDYXQB-UHFFFAOYSA-N 0.000 description 1
- XZFXEARDACDSNZ-UHFFFAOYSA-N 1-(3-methylnaphthalen-2-yl)-3-[4-[4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound CC1=CC2=CC=CC=C2C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1CN1CCOCC1 XZFXEARDACDSNZ-UHFFFAOYSA-N 0.000 description 1
- OVHYJLACXNXRRN-UHFFFAOYSA-N 1-(3-methylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 OVHYJLACXNXRRN-UHFFFAOYSA-N 0.000 description 1
- RTKWZFFSSWSSOK-UHFFFAOYSA-N 1-(3-methylsulfanylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CSC1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 RTKWZFFSSWSSOK-UHFFFAOYSA-N 0.000 description 1
- MIDPIMMHFWHYPR-UHFFFAOYSA-N 1-(3-tert-butyl-5-methylsulfinylphenyl)-3-[4-[6-[(1-methylpiperidin-4-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1CN(C)CCC1CC1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3C=C(C=C(C=3)S(C)=O)C(C)(C)C)=CC=2)C=N1 MIDPIMMHFWHYPR-UHFFFAOYSA-N 0.000 description 1
- GGENDVBBYGMGAB-UHFFFAOYSA-N 1-(3-tert-butylphenyl)-3-[4-(3-pyridin-3-ylpropoxy)naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(OCCCC=3C=NC=CC=3)=CC=2)=C1 GGENDVBBYGMGAB-UHFFFAOYSA-N 0.000 description 1
- YSQIRQHMWBJMDD-UHFFFAOYSA-N 1-(4,5-dimethyl-2-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C)C(C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1[N+]([O-])=O YSQIRQHMWBJMDD-UHFFFAOYSA-N 0.000 description 1
- WOWFGNLVWKITNL-UHFFFAOYSA-N 1-(4-butoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(OCCCC)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 WOWFGNLVWKITNL-UHFFFAOYSA-N 0.000 description 1
- UJQAWNVZBADKJV-UHFFFAOYSA-N 1-(4-butyl-2-methylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC(CCCC)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 UJQAWNVZBADKJV-UHFFFAOYSA-N 0.000 description 1
- MTKUHPDTFAQCFX-UHFFFAOYSA-N 1-(4-chloro-2-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound [O-][N+](=O)C1=CC(Cl)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MTKUHPDTFAQCFX-UHFFFAOYSA-N 0.000 description 1
- OAOJFUBUJNSPAI-UHFFFAOYSA-N 1-(4-chloro-3-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 OAOJFUBUJNSPAI-UHFFFAOYSA-N 0.000 description 1
- BOKYQOSMBRSLII-UHFFFAOYSA-N 1-(4-cyanophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC=C(C#N)C=C1 BOKYQOSMBRSLII-UHFFFAOYSA-N 0.000 description 1
- SJIPXUFJHFYJLW-UHFFFAOYSA-N 1-(4-ethoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(OCC)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 SJIPXUFJHFYJLW-UHFFFAOYSA-N 0.000 description 1
- DRWRBWVNLUABQH-UHFFFAOYSA-N 1-(4-methoxy-2-methylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC(OC)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 DRWRBWVNLUABQH-UHFFFAOYSA-N 0.000 description 1
- FJKDPIXCLCCJAW-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(OC)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 FJKDPIXCLCCJAW-UHFFFAOYSA-N 0.000 description 1
- CMADJBMFLMNTPD-UHFFFAOYSA-N 1-(4-methyl-2-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound [O-][N+](=O)C1=CC(C)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 CMADJBMFLMNTPD-UHFFFAOYSA-N 0.000 description 1
- HLZMRNBZAURXQE-UHFFFAOYSA-N 1-(4-methyl-3-nitrophenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C([N+]([O-])=O)C(C)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 HLZMRNBZAURXQE-UHFFFAOYSA-N 0.000 description 1
- MEEUJAATDOYEJC-UHFFFAOYSA-N 1-(4-methylsulfanylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(SC)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MEEUJAATDOYEJC-UHFFFAOYSA-N 0.000 description 1
- GFMFIGFHLIFYCS-UHFFFAOYSA-N 1-(5-chloro-2-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(Cl)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 GFMFIGFHLIFYCS-UHFFFAOYSA-N 0.000 description 1
- NCOSCXYSLWUWPO-UHFFFAOYSA-N 1-(5-chloro-2-methylphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC1=CC=C(Cl)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 NCOSCXYSLWUWPO-UHFFFAOYSA-N 0.000 description 1
- FEMSKAZXWCRQRB-UHFFFAOYSA-N 1-(5-ethylsulfonyl-2-methoxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCS(=O)(=O)C1=CC=C(OC)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 FEMSKAZXWCRQRB-UHFFFAOYSA-N 0.000 description 1
- LJPDYRPCIMUGJC-UHFFFAOYSA-N 1-(5-tert-butyl-2-hydroxyphenyl)-3-[4-[5-(morpholin-4-ylmethyl)pyrazin-2-yl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC=C(O)C(NC(=O)NC=2C3=CC=CC=C3C(C=3N=CC(CN4CCOCC4)=NC=3)=CC=2)=C1 LJPDYRPCIMUGJC-UHFFFAOYSA-N 0.000 description 1
- OOZAZFBOXVEMTO-UHFFFAOYSA-N 1-(5-tert-butyl-2-hydroxyphenyl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CC(C)(C)C1=CC=C(O)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 OOZAZFBOXVEMTO-UHFFFAOYSA-N 0.000 description 1
- QNKAOKYOALTOPO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxy-3-propylphenyl)-3-[4-[4-(pyrrolidine-1-carbonyl)phenyl]naphthalen-1-yl]urea Chemical compound CCCC1=CC(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(=CC=3)C(=O)N3CCCC3)=CC=2)=C1OC QNKAOKYOALTOPO-UHFFFAOYSA-N 0.000 description 1
- LPMUPSRIFUGLPK-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxyphenyl)-3-[4-[4-[(2-methyl-3-oxopiperazin-1-yl)methyl]phenyl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1CN1C(C)C(=O)NCC1 LPMUPSRIFUGLPK-UHFFFAOYSA-N 0.000 description 1
- FMTJTSXXPVFHJU-UHFFFAOYSA-N 1-(5-tert-butyl-2-methoxypyridin-3-yl)-3-[4-[6-[(4-oxopiperidin-1-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=NC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCC(=O)CC1 FMTJTSXXPVFHJU-UHFFFAOYSA-N 0.000 description 1
- MRGXNKUSWZULPT-UHFFFAOYSA-N 1-(5-tert-butyl-2-methyl-1,3-benzoxazol-7-yl)-3-[4-[6-(pyridin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=12OC(C)=NC2=CC(C(C)(C)C)=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CC1=CC=NC=C1 MRGXNKUSWZULPT-UHFFFAOYSA-N 0.000 description 1
- LCFHBRHSXCXFRU-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylphenyl)-3-[4-[6-[(2-methyl-3-oxopiperazin-1-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1CNC(=O)C(C)N1CC1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3C(=CC=C(C=3)C(C)(C)C)C)=CC=2)C=N1 LCFHBRHSXCXFRU-UHFFFAOYSA-N 0.000 description 1
- FXFWXNAYTVAMNY-UHFFFAOYSA-N 1-(5-tert-butyl-2-phenoxyphenyl)-3-[4-[6-(oxan-4-yloxy)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(OC3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1OC1=CC=CC=C1 FXFWXNAYTVAMNY-UHFFFAOYSA-N 0.000 description 1
- PJOXIJLFHGXSBL-UHFFFAOYSA-N 1-(5-tert-butyl-2-phenylpyrazol-3-yl)-3-[4-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]naphthalen-1-yl]urea Chemical compound C1CN(C)CCN1CC1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC=CC=3)=CC=2)C=C1 PJOXIJLFHGXSBL-UHFFFAOYSA-N 0.000 description 1
- WWRSVGYCZLRWQG-UHFFFAOYSA-N 1-(5-tert-butyl-2-pyrrolidin-1-ylphenyl)-3-[4-[4-methoxy-6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound N=1C=C(C=2C3=CC=CC=C3C(NC(=O)NC=3C(=CC=C(C=3)C(C)(C)C)N3CCCC3)=CC=2)C(OC)=CC=1CN1CCOCC1 WWRSVGYCZLRWQG-UHFFFAOYSA-N 0.000 description 1
- ORJSKGLMRJXJBK-UHFFFAOYSA-N 1-(5-tert-butyl-3-cyano-2-methoxyphenyl)-3-[4-[2-[(2,6-dimethylmorpholin-4-yl)methyl]pyrimidin-5-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C(C#N)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CN=C1CN1CC(C)OC(C)C1 ORJSKGLMRJXJBK-UHFFFAOYSA-N 0.000 description 1
- UBVPVRCZHPIPGW-UHFFFAOYSA-N 1-(6-methoxy-3,3-dimethyl-1,2-dihydroinden-5-yl)-3-[4-[4-(morpholine-4-carbonyl)phenyl]naphthalen-1-yl]urea Chemical compound COC1=CC=2CCC(C)(C)C=2C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1C(=O)N1CCOCC1 UBVPVRCZHPIPGW-UHFFFAOYSA-N 0.000 description 1
- KGQDSXQVTSDGLD-UHFFFAOYSA-N 1-(6-tert-butyl-1,3-benzodioxol-4-yl)-3-[4-[6-(morpholin-4-ylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C(C(C)(C)C)=CC=2OCOC=2C=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1NN1CCOCC1 KGQDSXQVTSDGLD-UHFFFAOYSA-N 0.000 description 1
- XTASSHAKXLGJIB-UHFFFAOYSA-N 1-(7-methoxy-1,4,4-trimethyl-2,3-dihydroquinolin-6-yl)-3-[4-[6-(oxan-4-yloxy)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=2N(C)CCC(C)(C)C=2C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1OC1CCOCC1 XTASSHAKXLGJIB-UHFFFAOYSA-N 0.000 description 1
- MZGLGJINJPQUKP-UHFFFAOYSA-N 1-(7-tert-butyl-2,4-dimethyl-1,3-benzoxazol-5-yl)-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C(C(C)(C)C)=C2OC(C)=NC2=C(C)C=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MZGLGJINJPQUKP-UHFFFAOYSA-N 0.000 description 1
- DXUSBDZJVDGKLG-UHFFFAOYSA-N 1-[2-(difluoromethoxy)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound FC(F)OC1=CC=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 DXUSBDZJVDGKLG-UHFFFAOYSA-N 0.000 description 1
- MHRIZTNZAKDVOM-UHFFFAOYSA-N 1-[2-(hydroxymethyl)-4-phenylcyclohexyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound OCC1CC(C=2C=CC=CC=2)CCC1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MHRIZTNZAKDVOM-UHFFFAOYSA-N 0.000 description 1
- NABBWDSOZIZSSI-UHFFFAOYSA-N 1-[2-[3-[(dimethylamino)methyl]phenyl]-5-(1-methylcyclohexyl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CN(C)CC1=CC=CC(N2C(=CC(=N2)C2(C)CCCCC2)NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 NABBWDSOZIZSSI-UHFFFAOYSA-N 0.000 description 1
- QVSLQEKXVVLVLF-UHFFFAOYSA-N 1-[2-chloro-5-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound FC(F)(F)C1=CC=C(Cl)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 QVSLQEKXVVLVLF-UHFFFAOYSA-N 0.000 description 1
- FXELSCIRQCPZSX-UHFFFAOYSA-N 1-[2-fluoro-3-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC=C(C(F)(F)F)C(F)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 FXELSCIRQCPZSX-UHFFFAOYSA-N 0.000 description 1
- QZSMGFLWRPYBMA-UHFFFAOYSA-N 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound FC1=CC=C(C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 QZSMGFLWRPYBMA-UHFFFAOYSA-N 0.000 description 1
- XIQRXBRRDXIGRH-UHFFFAOYSA-N 1-[2-fluoro-6-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound FC1=CC=CC(C(F)(F)F)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 XIQRXBRRDXIGRH-UHFFFAOYSA-N 0.000 description 1
- SDDFXDGQQJJYFY-UHFFFAOYSA-N 1-[2-methoxy-5-(1,1,2,2,2-pentafluoroethyl)phenyl]-3-[4-[4-(morpholin-4-ylmethyl)piperidin-1-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(F)(F)C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1N1CCC(CN2CCOCC2)CC1 SDDFXDGQQJJYFY-UHFFFAOYSA-N 0.000 description 1
- IZENUBLIMNLUPI-UHFFFAOYSA-N 1-[2-methoxy-5-(1-methylcyclohexyl)phenyl]-3-[4-[4-(1-methylpiperidin-4-yl)sulfanylphenyl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C2(C)CCCCC2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1SC1CCN(C)CC1 IZENUBLIMNLUPI-UHFFFAOYSA-N 0.000 description 1
- FMMUIALEYXDCFM-UHFFFAOYSA-N 1-[2-methoxy-5-(2-methyloxolan-2-yl)phenyl]-3-[4-[5-(morpholin-4-ylmethyl)pyridin-2-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C2(C)OCCC2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(N=C1)=CC=C1CN1CCOCC1 FMMUIALEYXDCFM-UHFFFAOYSA-N 0.000 description 1
- HOTFUBVPHPRIFG-UHFFFAOYSA-N 1-[2-methoxy-5-(2-phenylpropan-2-yl)phenyl]-3-[4-[6-(2-pyridin-4-ylethyl)pyridazin-3-yl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C(C)(C)C=2C=CC=CC=2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(N=N1)=CC=C1CCC1=CC=NC=C1 HOTFUBVPHPRIFG-UHFFFAOYSA-N 0.000 description 1
- IBOPGIQXLKOVRO-UHFFFAOYSA-N 1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-3-[4-[2-[(4-oxopiperidin-1-yl)methyl]pyrimidin-5-yl]naphthalen-1-yl]urea Chemical compound COC1=NC=C(C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CN=C1CN1CCC(=O)CC1 IBOPGIQXLKOVRO-UHFFFAOYSA-N 0.000 description 1
- FGYPTHNWLKARTL-UHFFFAOYSA-N 1-[2-methoxy-5-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]phenyl]-3-[4-[4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C23CC(C2)(C3)C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1CN1CCOCC1 FGYPTHNWLKARTL-UHFFFAOYSA-N 0.000 description 1
- YWSQDZYHPYLOFB-UHFFFAOYSA-N 1-[2-methylsulfanyl-5-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CSC1=CC=C(C(F)(F)F)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 YWSQDZYHPYLOFB-UHFFFAOYSA-N 0.000 description 1
- SBOIKWPUEBZGJT-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 SBOIKWPUEBZGJT-UHFFFAOYSA-N 0.000 description 1
- JZZWBYCETMHYCY-UHFFFAOYSA-N 1-[3-(2-methyl-1,3-dioxolan-2-yl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=CC=1C1(C)OCCO1 JZZWBYCETMHYCY-UHFFFAOYSA-N 0.000 description 1
- FPUUGIBFPPUPNA-UHFFFAOYSA-N 1-[3-methoxy-5-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound FC(F)(F)C1=CC(OC)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 FPUUGIBFPPUPNA-UHFFFAOYSA-N 0.000 description 1
- GQYLQHFCYCXCAS-UHFFFAOYSA-N 1-[3-tert-butyl-5-(1-methylimidazol-4-yl)phenyl]-3-[4-[5-(morpholin-4-ylmethyl)pyridin-2-yl]naphthalen-1-yl]urea Chemical compound CN1C=NC(C=2C=C(C=C(NC(=O)NC=3C4=CC=CC=C4C(C=4N=CC(CN5CCOCC5)=CC=4)=CC=3)C=2)C(C)(C)C)=C1 GQYLQHFCYCXCAS-UHFFFAOYSA-N 0.000 description 1
- IWAXQMNUTMZNDW-UHFFFAOYSA-N 1-[3-tert-butyl-5-(2-pyrrolidin-1-ylethyl)phenyl]-3-[4-[6-(1-methylpiperidin-4-yl)oxypyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1CN(C)CCC1OC1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3C=C(C=C(CCN4CCCC4)C=3)C(C)(C)C)=CC=2)C=N1 IWAXQMNUTMZNDW-UHFFFAOYSA-N 0.000 description 1
- YWTHBRKLKCHYBH-UHFFFAOYSA-N 1-[3-tert-butyl-5-(3-pyrrolidin-1-ylprop-1-ynyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C(C#CCN2CCCC2)=CC(C(C)(C)C)=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 YWTHBRKLKCHYBH-UHFFFAOYSA-N 0.000 description 1
- GKBQVCYHOMWCQT-UHFFFAOYSA-N 1-[3-tert-butyl-5-[4-(dimethylamino)phenyl]phenyl]-3-[4-[2-(morpholin-4-ylmethyl)pyrimidin-5-yl]naphthalen-1-yl]urea Chemical compound C1=CC(N(C)C)=CC=C1C1=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=NC=3)=CC=2)=CC(C(C)(C)C)=C1 GKBQVCYHOMWCQT-UHFFFAOYSA-N 0.000 description 1
- PZTDOGVERGXERN-UHFFFAOYSA-N 1-[4-(3-benzylimidazo[4,5-b]pyridin-6-yl)naphthalen-1-yl]-3-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C4N=CN(CC=5C=CC=CC=5)C4=NC=3)=CC=2)=CC(C(C)(C)C)=N1 PZTDOGVERGXERN-UHFFFAOYSA-N 0.000 description 1
- TUGCSOSVVFTZIJ-UHFFFAOYSA-N 1-[4-(6-aminopyridin-3-yl)naphthalen-1-yl]-3-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(N)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 TUGCSOSVVFTZIJ-UHFFFAOYSA-N 0.000 description 1
- DZMINIWMQATNMZ-UHFFFAOYSA-N 1-[4-[3,4-bis(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]-3-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(CN4CCOCC4)C(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 DZMINIWMQATNMZ-UHFFFAOYSA-N 0.000 description 1
- NUDHSTZFJXZRRH-UHFFFAOYSA-N 1-[4-[4-[[bis(2-cyanoethyl)amino]methyl]phenyl]naphthalen-1-yl]-3-(5-tert-butyl-2-methoxyphenyl)urea Chemical compound COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=C(CN(CCC#N)CCC#N)C=C1 NUDHSTZFJXZRRH-UHFFFAOYSA-N 0.000 description 1
- GSQKKUDSQVZUJV-UHFFFAOYSA-N 1-[4-[4-[[bis(2-cyanoethyl)amino]methyl]phenyl]naphthalen-1-yl]-3-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN(CCC#N)CCC#N)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 GSQKKUDSQVZUJV-UHFFFAOYSA-N 0.000 description 1
- IUIIKMAXKVASOZ-UHFFFAOYSA-N 1-[4-[6-(imidazol-1-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-[2-methoxy-5-(1-phenylcyclopropyl)phenyl]urea Chemical compound COC1=CC=C(C2(CC2)C=2C=CC=CC=2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1C=CN=C1 IUIIKMAXKVASOZ-UHFFFAOYSA-N 0.000 description 1
- YYVVBVYHDUPJNZ-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-(2,4,5-trimethylphenyl)urea Chemical compound C1=C(C)C(C)=CC(C)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 YYVVBVYHDUPJNZ-UHFFFAOYSA-N 0.000 description 1
- DZTYZESAZHRWEL-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-(2,4,6-trichlorophenyl)urea Chemical compound ClC1=CC(Cl)=CC(Cl)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 DZTYZESAZHRWEL-UHFFFAOYSA-N 0.000 description 1
- OKTQQECLESQZMT-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-(2-pentoxy-5-phenylphenyl)urea Chemical compound CCCCCOC1=CC=C(C=2C=CC=CC=2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 OKTQQECLESQZMT-UHFFFAOYSA-N 0.000 description 1
- QOVMEGLQDPRYJR-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-(2-phenoxyphenyl)urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC=CC=C1OC1=CC=CC=C1 QOVMEGLQDPRYJR-UHFFFAOYSA-N 0.000 description 1
- JZQIYUOWHSFMHD-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-(3,4,5-trimethoxyphenyl)urea Chemical compound COC1=C(OC)C(OC)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 JZQIYUOWHSFMHD-UHFFFAOYSA-N 0.000 description 1
- RVNIHSVMRBJWGV-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-(3-phenoxyphenyl)urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC(C=1)=CC=CC=1OC1=CC=CC=C1 RVNIHSVMRBJWGV-UHFFFAOYSA-N 0.000 description 1
- VGYHEUSLDXFJCX-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-(4-phenylmethoxyphenyl)urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC(C=C1)=CC=C1OCC1=CC=CC=C1 VGYHEUSLDXFJCX-UHFFFAOYSA-N 0.000 description 1
- XTRFOLYPDHICQA-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-(4-phenylphenyl)urea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC(C=C1)=CC=C1C1=CC=CC=C1 XTRFOLYPDHICQA-UHFFFAOYSA-N 0.000 description 1
- XUSKDFHOLIZMPZ-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-(4-propan-2-ylphenyl)urea Chemical compound C1=CC(C(C)C)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 XUSKDFHOLIZMPZ-UHFFFAOYSA-N 0.000 description 1
- HCSXXHQZLIWWCF-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-[3-(trifluoromethylsulfanyl)phenyl]urea Chemical compound FC(F)(F)SC1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 HCSXXHQZLIWWCF-UHFFFAOYSA-N 0.000 description 1
- MSYXLPKGQJTTIR-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-[4-(trifluoromethyl)phenyl]urea Chemical compound C1=CC(C(F)(F)F)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MSYXLPKGQJTTIR-UHFFFAOYSA-N 0.000 description 1
- LEEKRWMUGPKUQK-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-[4-(trifluoromethylsulfanyl)phenyl]urea Chemical compound C1=CC(SC(F)(F)F)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 LEEKRWMUGPKUQK-UHFFFAOYSA-N 0.000 description 1
- ITLMWHYFKHLGOI-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-naphthalen-2-ylurea Chemical compound C=1C=C2C=CC=CC2=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 ITLMWHYFKHLGOI-UHFFFAOYSA-N 0.000 description 1
- ZDXNVBXXPNTCDV-UHFFFAOYSA-N 1-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]-3-phenylurea Chemical compound C=1C=C(C=2C=NC(CN3CCOCC3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC=CC=C1 ZDXNVBXXPNTCDV-UHFFFAOYSA-N 0.000 description 1
- VXJNZEAJZPMRMU-UHFFFAOYSA-N 1-[4-[6-[[bis(2-methoxyethyl)amino]methyl]pyridin-3-yl]naphthalen-1-yl]-3-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)pyrazol-3-yl]urea Chemical compound C1=NC(CN(CCOC)CCOC)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CN=C(C)N=C1 VXJNZEAJZPMRMU-UHFFFAOYSA-N 0.000 description 1
- VMIXRXULLUDLCC-UHFFFAOYSA-N 1-[4-chloro-2-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound FC(F)(F)C1=CC(Cl)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 VMIXRXULLUDLCC-UHFFFAOYSA-N 0.000 description 1
- LUMDRDSNLWYIAJ-UHFFFAOYSA-N 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(Cl)C(C(F)(F)F)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 LUMDRDSNLWYIAJ-UHFFFAOYSA-N 0.000 description 1
- BDCNTBMKZQYZPK-UHFFFAOYSA-N 1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(F)(F)F)C(F)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 BDCNTBMKZQYZPK-UHFFFAOYSA-N 0.000 description 1
- VAZOYARPRLVOKK-UHFFFAOYSA-N 1-[5-(butylsulfamoyl)-2-methoxyphenyl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound CCCCNS(=O)(=O)C1=CC=C(OC)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 VAZOYARPRLVOKK-UHFFFAOYSA-N 0.000 description 1
- FYRMGVWDFQZNGA-UHFFFAOYSA-N 1-[5-[1-(hydroxymethyl)cyclopropyl]-2-methoxyphenyl]-3-[4-[4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound COC1=CC=C(C2(CO)CC2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1CN1CCOCC1 FYRMGVWDFQZNGA-UHFFFAOYSA-N 0.000 description 1
- NSAQAZKZZFADBN-UHFFFAOYSA-N 1-[5-tert-butyl-1-[2-(diethylamino)ethyl]-2-oxopyridin-3-yl]-3-[4-[6-(1-methylpiperidin-4-yl)oxypyridin-3-yl]naphthalen-1-yl]urea Chemical compound O=C1N(CCN(CC)CC)C=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1OC1CCN(C)CC1 NSAQAZKZZFADBN-UHFFFAOYSA-N 0.000 description 1
- HXNARSOBTYIVTI-UHFFFAOYSA-N 1-[5-tert-butyl-2-(1h-pyrazol-4-yl)phenyl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea Chemical compound C=1C=C(OCCN2CCOCC2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1C=1C=NNC=1 HXNARSOBTYIVTI-UHFFFAOYSA-N 0.000 description 1
- BHISVUBAXRMUGR-UHFFFAOYSA-N 1-[5-tert-butyl-2-(1h-pyrazol-4-yl)phenyl]-3-[4-[4-(4-methylpiperazine-1-carbonyl)phenyl]naphthalen-1-yl]urea Chemical compound C1CN(C)CCN1C(=O)C1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3C(=CC=C(C=3)C(C)(C)C)C3=CNN=C3)=CC=2)C=C1 BHISVUBAXRMUGR-UHFFFAOYSA-N 0.000 description 1
- ZCYGWBHGEFNHAC-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2,5-dioxopyrrolidin-1-yl)phenyl]-3-[4-[6-(1h-imidazol-2-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2C=NC(CC=3NC=CN=3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1N1C(=O)CCC1=O ZCYGWBHGEFNHAC-UHFFFAOYSA-N 0.000 description 1
- MOJPDKUUTRIKNP-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-cyclopropylpyrimidin-5-yl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C=1N=C(C2CC2)N=CC=1N1N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 MOJPDKUUTRIKNP-UHFFFAOYSA-N 0.000 description 1
- MVUKHCMSUFRDNK-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)pyrazol-3-yl]-3-[4-[4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=NC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 MVUKHCMSUFRDNK-UHFFFAOYSA-N 0.000 description 1
- OVBWFOWXZMICRG-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)pyrazol-3-yl]-3-[4-[5-(morpholin-4-ylmethyl)pyrazin-2-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=NC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3N=CC(CN4CCOCC4)=NC=3)=CC=2)=CC(C(C)(C)C)=N1 OVBWFOWXZMICRG-UHFFFAOYSA-N 0.000 description 1
- ZVTAQYKESHSLHQ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)pyrazol-3-yl]-3-[4-[6-(morpholine-4-carbonyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=NC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(=CC=3)C(=O)N3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 ZVTAQYKESHSLHQ-UHFFFAOYSA-N 0.000 description 1
- UVKLKCLMBHRNBS-UHFFFAOYSA-N 1-[5-tert-butyl-2-(2-morpholin-4-yl-2-oxoethoxy)phenyl]-3-[4-[6-(2-pyridin-4-ylethyl)pyridazin-3-yl]naphthalen-1-yl]urea Chemical compound C=1C=C(C=2N=NC(CCC=3C=CN=CC=3)=CC=2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1OCC(=O)N1CCOCC1 UVKLKCLMBHRNBS-UHFFFAOYSA-N 0.000 description 1
- UEQRWQVJAQYPAI-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[3-(2-methyl-4-morpholin-4-ylphenyl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C=C(C=2)C=2C(=CC(=CC=2)N2CCOCC2)C)=CC(C(C)(C)C)=N1 UEQRWQVJAQYPAI-UHFFFAOYSA-N 0.000 description 1
- SMJMNVALWCFSQR-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(1-morpholin-4-yl-2,3-dihydro-1h-inden-5-yl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C4CCC(C4=CC=3)N3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 SMJMNVALWCFSQR-UHFFFAOYSA-N 0.000 description 1
- IHQYQTOVSWVUSK-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(2-methyl-4-morpholin-4-ylphenyl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C(=CC(=CC=3)N3CCOCC3)C)=CC=2)=CC(C(C)(C)C)=N1 IHQYQTOVSWVUSK-UHFFFAOYSA-N 0.000 description 1
- UFNMQOJNVUDGDG-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(3-methyl-5-morpholin-4-ylfuran-2-yl)naphthalen-1-yl]urea Chemical compound CC=1C=C(N2CCOCC2)OC=1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)C=C1 UFNMQOJNVUDGDG-UHFFFAOYSA-N 0.000 description 1
- ALGANHBCSBPFLJ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(3-methylsulfinylphenyl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(C=CC=3)S(C)=O)=CC=2)=CC(C(C)(C)C)=N1 ALGANHBCSBPFLJ-UHFFFAOYSA-N 0.000 description 1
- JKLFIEZXJIVSJZ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(3-methylsulfonylphenyl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(C=CC=3)S(C)(=O)=O)=CC=2)=CC(C(C)(C)C)=N1 JKLFIEZXJIVSJZ-UHFFFAOYSA-N 0.000 description 1
- ASJFQKWXDUOSDG-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(3-morpholin-4-ylcyclohepten-1-yl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCCCC(C=3)N3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 ASJFQKWXDUOSDG-UHFFFAOYSA-N 0.000 description 1
- HZCMATDIMJCKIP-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(3-morpholin-4-ylcyclohexen-1-yl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCCC(C=3)N3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 HZCMATDIMJCKIP-UHFFFAOYSA-N 0.000 description 1
- SKTLTPXXGDRZGT-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(3-morpholin-4-ylphenyl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(C=CC=3)N3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 SKTLTPXXGDRZGT-UHFFFAOYSA-N 0.000 description 1
- VGXFLFBXAFHANE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(4-morpholin-4-ylphenyl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(=CC=3)N3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 VGXFLFBXAFHANE-UHFFFAOYSA-N 0.000 description 1
- CARWVQWRYKBXLE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(6-oxo-1-pyridin-4-yl-2,3-dihydropyridin-4-yl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCN(C(=O)C=3)C=3C=CN=CC=3)=CC=2)=CC(C(C)(C)C)=N1 CARWVQWRYKBXLE-UHFFFAOYSA-N 0.000 description 1
- JFSGGTPFIBPXBL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(6-oxo-1h-pyridin-3-yl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C3=CNC(=O)C=C3)=CC=2)=CC(C(C)(C)C)=N1 JFSGGTPFIBPXBL-UHFFFAOYSA-N 0.000 description 1
- JIIKGDUUABJJLU-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-(6-pyridin-3-yloxypyridin-3-yl)naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(OC=4C=NC=CC=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 JIIKGDUUABJJLU-UHFFFAOYSA-N 0.000 description 1
- OSNKQXUAVYDKAG-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[2-(pyridin-3-ylamino)pyrimidin-5-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(NC=4C=NC=CC=4)=NC=3)=CC=2)=CC(C(C)(C)C)=N1 OSNKQXUAVYDKAG-UHFFFAOYSA-N 0.000 description 1
- NAQVMJURUKMKMV-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[3-(2-morpholin-4-ylethylamino)cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCCC(C=3)NCCN3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 NAQVMJURUKMKMV-UHFFFAOYSA-N 0.000 description 1
- RLXSICBLXUVGCB-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[3-(morpholin-4-ylmethyl)cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCCC(CN4CCOCC4)C=3)=CC=2)=CC(C(C)(C)C)=N1 RLXSICBLXUVGCB-UHFFFAOYSA-N 0.000 description 1
- PEYFPLYHYJCFLS-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[3-(morpholine-4-carbonyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(C=CC=3)C(=O)N3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 PEYFPLYHYJCFLS-UHFFFAOYSA-N 0.000 description 1
- YMTLTNAESUCGOE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[3-oxo-4-[(1-oxo-1,4-thiazinan-4-yl)methyl]cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCC(CN4CCS(=O)CC4)C(=O)C=3)=CC=2)=CC(C(C)(C)C)=N1 YMTLTNAESUCGOE-UHFFFAOYSA-N 0.000 description 1
- VVULTIQZIBDJBN-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[3-oxo-4-[(1-oxothiolan-3-yl)methyl]cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCC(CC4CS(=O)CC4)C(=O)C=3)=CC=2)=CC(C(C)(C)C)=N1 VVULTIQZIBDJBN-UHFFFAOYSA-N 0.000 description 1
- CECNUIGWRRXUBK-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[4-(dimethylamino)phenyl]naphthalen-1-yl]urea Chemical compound C1=CC(N(C)C)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)C=C1 CECNUIGWRRXUBK-UHFFFAOYSA-N 0.000 description 1
- KUQLITRTIJXKBL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[4-(morpholin-4-ylmethyl)-3-oxocyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCC(CN4CCOCC4)C(=O)C=3)=CC=2)=CC(C(C)(C)C)=N1 KUQLITRTIJXKBL-UHFFFAOYSA-N 0.000 description 1
- SXEMQWFLKYPVSF-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[4-(morpholin-4-ylmethyl)imidazol-1-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(N3C=C(CN4CCOCC4)N=C3)=CC=2)=CC(C(C)(C)C)=N1 SXEMQWFLKYPVSF-UHFFFAOYSA-N 0.000 description 1
- UBFIQFLZFCCWTQ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[4-[(2-pyridin-4-ylethylamino)methyl]phenyl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CNCCC=4C=CN=CC=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 UBFIQFLZFCCWTQ-UHFFFAOYSA-N 0.000 description 1
- BSQWOONHGXKYPN-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[4-[(dimethylamino)methyl]phenyl]naphthalen-1-yl]urea Chemical compound C1=CC(CN(C)C)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)C=C1 BSQWOONHGXKYPN-UHFFFAOYSA-N 0.000 description 1
- DHUMLLIDHZANKX-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[5-(morpholine-4-carbonyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(C=NC=3)C(=O)N3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 DHUMLLIDHZANKX-UHFFFAOYSA-N 0.000 description 1
- GNLOYKZLDCXBOL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[6-(pyridin-3-ylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(NC=4C=NC=CC=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 GNLOYKZLDCXBOL-UHFFFAOYSA-N 0.000 description 1
- XPWOVMIMHCRKTK-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[6-(pyridin-3-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CC=4C=NC=CC=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 XPWOVMIMHCRKTK-UHFFFAOYSA-N 0.000 description 1
- HZMRKDCJYRCOBI-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[6-[hydroxy(pyridin-3-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(=CC=3)C(O)C=3C=NC=CC=3)=CC=2)=CC(C(C)(C)C)=N1 HZMRKDCJYRCOBI-UHFFFAOYSA-N 0.000 description 1
- VBDOTBNNWICDRE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)phenyl]-3-[4-[5-(2-pyrrolidin-1-ylethyl)pyridin-2-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1C1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(N=C1)=CC=C1CCN1CCCC1 VBDOTBNNWICDRE-UHFFFAOYSA-N 0.000 description 1
- BCRSNFJKYNVRJZ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-(6-oxo-1-pyridin-4-yl-2,3-dihydropyridin-4-yl)naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCN(C(=O)C=3)C=3C=CN=CC=3)=CC=2)=CC(C(C)(C)C)=N1 BCRSNFJKYNVRJZ-UHFFFAOYSA-N 0.000 description 1
- WIAANKLDUHBKIL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[1-(oxan-4-ylmethyl)-6-oxo-2,3-dihydropyridin-4-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCN(CC4CCOCC4)C(=O)C=3)=CC=2)=CC(C(C)(C)C)=N1 WIAANKLDUHBKIL-UHFFFAOYSA-N 0.000 description 1
- PHJNXMRZUNXTNX-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-(2-morpholin-4-ylethoxy)phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(OCCN4CCOCC4)C=CC=3)=CC=2)=CC(C(C)(C)C)=N1 PHJNXMRZUNXTNX-UHFFFAOYSA-N 0.000 description 1
- RMICFSBYAKHHJW-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-(2-morpholin-4-ylethylamino)cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCCC(C=3)NCCN3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 RMICFSBYAKHHJW-UHFFFAOYSA-N 0.000 description 1
- HSFLKMGQEKZVJB-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-(2-phenylethylamino)cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCCC(C=3)NCCC=3C=CC=CC=3)=CC=2)=CC(C(C)(C)C)=N1 HSFLKMGQEKZVJB-UHFFFAOYSA-N 0.000 description 1
- BZACDDLNKGCJIT-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-(n-methylanilino)cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C=1C=CC=CC=1N(C)C(C=1)CCCC=1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)N=C1 BZACDDLNKGCJIT-UHFFFAOYSA-N 0.000 description 1
- GLBJVRFLTJXPFP-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-[2-(1h-imidazol-5-yl)ethylamino]cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3CCCC(C=3)NCCC=3N=CNC=3)=CC=2)=CC(C(C)(C)C)=N1 GLBJVRFLTJXPFP-UHFFFAOYSA-N 0.000 description 1
- QHNFIMMYAMKZGG-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-[2-(4-methoxyphenyl)ethylamino]cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C1=CC(OC)=CC=C1CCNC1C=C(C=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=NC(C)=CC=3)=CC=2)CCC1 QHNFIMMYAMKZGG-UHFFFAOYSA-N 0.000 description 1
- CCXAOUGARNDNOE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-[2-(dimethylamino)ethylamino]cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound CN(C)CCNC1CCCC(C=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=NC(C)=CC=3)=CC=2)=C1 CCXAOUGARNDNOE-UHFFFAOYSA-N 0.000 description 1
- NQSMYWBOMXTRMP-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-[furan-2-yl(methyl)amino]cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C=1C=COC=1N(C)C(C=1)CCCC=1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)N=C1 NQSMYWBOMXTRMP-UHFFFAOYSA-N 0.000 description 1
- YQLZMQZEURCIBM-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-[methyl(pyridin-2-yl)amino]cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C=1C=CC=NC=1N(C)C(C=1)CCCC=1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)N=C1 YQLZMQZEURCIBM-UHFFFAOYSA-N 0.000 description 1
- YEHSVFFUGWPDHS-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-[methyl(pyridin-3-yl)amino]cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C=1C=CN=CC=1N(C)C(C=1)CCCC=1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)N=C1 YEHSVFFUGWPDHS-UHFFFAOYSA-N 0.000 description 1
- JCQJTMOQWQNIRR-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-[methyl(pyridin-4-yl)amino]cyclohexen-1-yl]naphthalen-1-yl]urea Chemical compound C=1C=NC=CC=1N(C)C(C=1)CCCC=1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)N=C1 JCQJTMOQWQNIRR-UHFFFAOYSA-N 0.000 description 1
- FIUPTBDERXQHNT-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-hydroxy-4-(1h-imidazol-2-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(O)C(CC=4NC=CN=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 FIUPTBDERXQHNT-UHFFFAOYSA-N 0.000 description 1
- GIAVPYIFVUYJDJ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-hydroxy-4-(pyridin-3-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(O)C(CC=4C=NC=CC=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 GIAVPYIFVUYJDJ-UHFFFAOYSA-N 0.000 description 1
- JAYHQWUBYOMJDE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[3-methoxy-5-(2-morpholin-4-ylethoxy)phenyl]naphthalen-1-yl]urea Chemical compound C=1C(C=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=NC(C)=CC=3)=CC=2)=CC(OC)=CC=1OCCN1CCOCC1 JAYHQWUBYOMJDE-UHFFFAOYSA-N 0.000 description 1
- LYXKKQJAFLTMSN-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-(furan-2-ylmethyl)-3-methoxyphenyl]naphthalen-1-yl]urea Chemical compound COC1=CC(C=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=NC(C)=CC=3)=CC=2)=CC=C1CC1=CC=CO1 LYXKKQJAFLTMSN-UHFFFAOYSA-N 0.000 description 1
- SGUUMAQWHXLAAC-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-(furan-3-ylmethyl)-3-hydroxyphenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(O)C(CC4=COC=C4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 SGUUMAQWHXLAAC-UHFFFAOYSA-N 0.000 description 1
- IXTITMXEHYGGCM-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-(morpholin-4-ylmethyl)imidazol-1-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(N3C=C(CN4CCOCC4)N=C3)=CC=2)=CC(C(C)(C)C)=N1 IXTITMXEHYGGCM-UHFFFAOYSA-N 0.000 description 1
- ICQKLSHONDDLAY-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-[(3,4-dimethoxyphenyl)methyl]-3-hydroxyphenyl]naphthalen-1-yl]urea Chemical compound C1=C(OC)C(OC)=CC=C1CC1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=NC(C)=CC=3)=CC=2)C=C1O ICQKLSHONDDLAY-UHFFFAOYSA-N 0.000 description 1
- XVKNHTBDLNKRBD-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-[(3-hydroxymorpholin-4-yl)methyl]phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN4C(COCC4)O)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 XVKNHTBDLNKRBD-UHFFFAOYSA-N 0.000 description 1
- FPPJHMYVKAPSSO-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-[(3-hydroxypiperidin-1-yl)methyl]phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN4CC(O)CCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 FPPJHMYVKAPSSO-UHFFFAOYSA-N 0.000 description 1
- XQYVRZQMNKTDKE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[4-[[2-cyanoethyl(pyridin-2-ylmethyl)amino]methyl]phenyl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN(CCC#N)CC=4N=CC=CC=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 XQYVRZQMNKTDKE-UHFFFAOYSA-N 0.000 description 1
- WUXJTRGACDOALB-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[5-(morpholin-4-ylmethyl)pyrazin-2-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3N=CC(CN4CCOCC4)=NC=3)=CC=2)=CC(C(C)(C)C)=N1 WUXJTRGACDOALB-UHFFFAOYSA-N 0.000 description 1
- JWSABMNLFXDLGN-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[5-(morpholine-4-carbonyl)pyrazin-2-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3N=CC(=NC=3)C(=O)N3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 JWSABMNLFXDLGN-UHFFFAOYSA-N 0.000 description 1
- WZOBNENWIXYHIE-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(3-methoxypropylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(NCCCOC)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)N=C1 WZOBNENWIXYHIE-UHFFFAOYSA-N 0.000 description 1
- QIPOFOVHSNDLFR-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(imidazol-1-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4C=NC=C4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 QIPOFOVHSNDLFR-UHFFFAOYSA-N 0.000 description 1
- VGAXCJBQWVVJCD-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(oxan-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CC4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 VGAXCJBQWVVJCD-UHFFFAOYSA-N 0.000 description 1
- BHMXRCWXMHPUGV-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(pyridin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CC=4C=CN=CC=4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 BHMXRCWXMHPUGV-UHFFFAOYSA-N 0.000 description 1
- QBSZKIFIVMHWAA-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-[(1-oxo-1,4-thiazinan-4-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCS(=O)CC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 QBSZKIFIVMHWAA-UHFFFAOYSA-N 0.000 description 1
- QQWQPWRNNKDCIT-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-[(1-oxothiolan-3-yl)methyl]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CC4CS(=O)CC4)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 QQWQPWRNNKDCIT-UHFFFAOYSA-N 0.000 description 1
- ILSAXKWINSZDNL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-[6-[3-methoxypropyl(methyl)amino]pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NC(N(C)CCCOC)=CC=C1C(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)N=C1 ILSAXKWINSZDNL-UHFFFAOYSA-N 0.000 description 1
- YFZUZDQLWRZHGS-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-oxo-1h-pyridin-3-yl)pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=CC(=O)NC=C1N1N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 YFZUZDQLWRZHGS-UHFFFAOYSA-N 0.000 description 1
- UNDVURHDGHOUDK-UHFFFAOYSA-N 1-[5-tert-butyl-2-[(2-morpholin-4-yl-2-oxoethyl)amino]phenyl]-3-[4-[4-[(1-methylpiperidin-4-yl)amino]piperidin-1-yl]naphthalen-1-yl]urea Chemical compound C1CN(C)CCC1NC1CCN(C=2C3=CC=CC=C3C(NC(=O)NC=3C(=CC=C(C=3)C(C)(C)C)NCC(=O)N3CCOCC3)=CC=2)CC1 UNDVURHDGHOUDK-UHFFFAOYSA-N 0.000 description 1
- LCEPJQBTBGKBJN-UHFFFAOYSA-N 1-[5-tert-butyl-2-[1-(3-cyanopropyl)pyrazol-4-yl]pyrazol-3-yl]-3-[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=NN(CCCC#N)C=C1N1N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 LCEPJQBTBGKBJN-UHFFFAOYSA-N 0.000 description 1
- OSMSESONFQKFKK-UHFFFAOYSA-N 1-[5-tert-butyl-2-methoxy-3-(3-morpholin-4-yl-3-oxoprop-1-enyl)phenyl]-3-[4-[6-(pyrrolidin-1-ylmethyl)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C(C=CC(=O)N2CCOCC2)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCCC1 OSMSESONFQKFKK-UHFFFAOYSA-N 0.000 description 1
- CYVXEELQBNKAGM-UHFFFAOYSA-N 1-[5-tert-butyl-2-methoxy-3-[2-(1-methylpiperidin-4-yl)oxyethyl]phenyl]-3-[4-[4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(CN4CCOCC4)=CC=3)=CC=2)C(OC)=C1CCOC1CCN(C)CC1 CYVXEELQBNKAGM-UHFFFAOYSA-N 0.000 description 1
- IKFHTYOQSYCKEX-UHFFFAOYSA-N 1-[5-tert-butyl-3-(2-pyrrolidin-1-ylethyl)-1-benzofuran-7-yl]-3-[4-[4-(morpholin-4-ylmethyl)phenyl]naphthalen-1-yl]urea Chemical compound C=12OC=C(CCN3CCCC3)C2=CC(C(C)(C)C)=CC=1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=C1)=CC=C1CN1CCOCC1 IKFHTYOQSYCKEX-UHFFFAOYSA-N 0.000 description 1
- YIQUOKDSEJAVTB-UHFFFAOYSA-N 1-[5-tert-butyl-3-[2-(diethylamino)ethoxy]-2-methoxyphenyl]-3-[4-[4-(oxan-4-yloxy)phenyl]naphthalen-1-yl]urea Chemical compound CCN(CC)CCOC1=CC(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=CC(OC4CCOCC4)=CC=3)=CC=2)=C1OC YIQUOKDSEJAVTB-UHFFFAOYSA-N 0.000 description 1
- BJVKHYJDQWVCMI-UHFFFAOYSA-N 1-[6-tert-butyl-4-[2-(dimethylamino)ethyl]-3-oxo-1,4-benzoxazin-8-yl]-3-[4-[6-(thiomorpholin-4-ylamino)pyridin-3-yl]naphthalen-1-yl]urea Chemical compound C1=C(C(C)(C)C)C=C2N(CCN(C)C)C(=O)COC2=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1NN1CCSCC1 BJVKHYJDQWVCMI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HKNYPYATWZNINL-UHFFFAOYSA-N 2-[4-tert-butyl-2-[[4-[5-(pyrrolidin-1-ylmethyl)pyridin-2-yl]naphthalen-1-yl]carbamoylamino]phenoxy]-n-methylacetamide Chemical compound CNC(=O)COC1=CC=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(N=C1)=CC=C1CN1CCCC1 HKNYPYATWZNINL-UHFFFAOYSA-N 0.000 description 1
- NEOQJMIGRQDLOB-UHFFFAOYSA-N 2-amino-4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]benzamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(N)C(C(N)=O)=CC=3)=CC=2)=CC(C(C)(C)C)=N1 NEOQJMIGRQDLOB-UHFFFAOYSA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical group C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- HLSAQRWCIRURAK-UHFFFAOYSA-N 3-[5-tert-butyl-2-methoxy-3-[[4-[6-(pyrrolidin-1-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenyl]prop-2-enamide Chemical compound C1=C(C(C)(C)C)C=C(C=CC(N)=O)C(OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCCC1 HLSAQRWCIRURAK-UHFFFAOYSA-N 0.000 description 1
- OGPJKXOXSPAMGV-UHFFFAOYSA-N 4-methoxy-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]-n-phenylbenzamide Chemical compound COC1=CC=C(C(=O)NC=2C=CC=CC=2)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 OGPJKXOXSPAMGV-UHFFFAOYSA-N 0.000 description 1
- VIUDNHJNUDJCMW-UHFFFAOYSA-N 5-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]pyridine-3-carboxamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=C(C=NC=3)C(N)=O)=CC=2)=CC(C(C)(C)C)=N1 VIUDNHJNUDJCMW-UHFFFAOYSA-N 0.000 description 1
- AYQWJGOJDRFTDG-UHFFFAOYSA-N 5-tert-butyl-n,1-dimethyl-3-[[4-(3-morpholin-4-ylcyclohexen-1-yl)naphthalen-1-yl]carbamoylamino]pyrrole-2-carboxamide Chemical compound C1=C(C(C)(C)C)N(C)C(C(=O)NC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC(N2CCOCC2)CCC1 AYQWJGOJDRFTDG-UHFFFAOYSA-N 0.000 description 1
- DGTAPLGGJIUJGF-UHFFFAOYSA-N 5-tert-butyl-n,1-dimethyl-3-[[4-(6-oxo-1-pyridin-4-yl-2,3-dihydropyridin-4-yl)naphthalen-1-yl]carbamoylamino]pyrrole-2-carboxamide Chemical compound C1=C(C(C)(C)C)N(C)C(C(=O)NC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC(=O)N(C=2C=CN=CC=2)CC1 DGTAPLGGJIUJGF-UHFFFAOYSA-N 0.000 description 1
- PFYNGCWTZMCBRP-UHFFFAOYSA-N 5-tert-butyl-n,1-dimethyl-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]pyrrole-2-carboxamide Chemical compound C1=C(C(C)(C)C)N(C)C(C(=O)NC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 PFYNGCWTZMCBRP-UHFFFAOYSA-N 0.000 description 1
- WAIRRLYHTBPAQI-UHFFFAOYSA-N 5-tert-butyl-n-methyl-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]thiophene-2-carboxamide Chemical compound S1C(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1C(=O)NC WAIRRLYHTBPAQI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010001939 Aminoaciduria Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000012657 Atopic disease Diseases 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000589969 Borreliella burgdorferi Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 229940124638 COX inhibitor Drugs 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010063094 Cerebral malaria Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 241000709661 Enterovirus Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 102100033495 Glycine dehydrogenase (decarboxylating), mitochondrial Human genes 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000032087 Hereditary Leber Optic Atrophy Diseases 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000033892 Hyperhomocysteinemia Diseases 0.000 description 1
- 206010020674 Hypermetabolism Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 1
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 1
- 102000010781 Interleukin-6 Receptors Human genes 0.000 description 1
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 1
- 208000021342 Isolated sulfite oxidase deficiency Diseases 0.000 description 1
- 201000003533 Leber congenital amaurosis Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000009564 MELAS Syndrome Diseases 0.000 description 1
- 201000009035 MERRF syndrome Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 208000005903 Manganese Poisoning Diseases 0.000 description 1
- 206010027202 Meningitis bacterial Diseases 0.000 description 1
- 206010027260 Meningitis viral Diseases 0.000 description 1
- 206010027439 Metal poisoning Diseases 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 208000034486 Multi-organ failure Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 206010069825 Myoclonic epilepsy and ragged-red fibres Diseases 0.000 description 1
- 229910003844 NSO2 Inorganic materials 0.000 description 1
- 206010051606 Necrotising colitis Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 208000035544 Nonketotic hyperglycinaemia Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000003435 Optic Neuritis Diseases 0.000 description 1
- 206010061323 Optic neuropathy Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 239000012826 P38 inhibitor Substances 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- 208000006289 Rett Syndrome Diseases 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 108700036932 Sulfite oxidase deficiency Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 241000256838 Vespula Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- AAVCYMAOKKTDIE-UHFFFAOYSA-N [H]N(C)C(=[W])N([H])[Ar]C[Y]C Chemical compound [H]N(C)C(=[W])N([H])[Ar]C[Y]C AAVCYMAOKKTDIE-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 206010069351 acute lung injury Diseases 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 201000009904 bacterial meningitis Diseases 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 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
- 210000004556 brain Anatomy 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 208000029039 cyanide poisoning Diseases 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- KCSIVKUACGHGPH-UHFFFAOYSA-N dimethyl 5-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]benzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC(C(=O)OC)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 KCSIVKUACGHGPH-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- VZFRNCSOCOPNDB-AJKFJWDBSA-N domoic acid Chemical compound OC(=O)[C@@H](C)\C=C\C=C(/C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VZFRNCSOCOPNDB-AJKFJWDBSA-N 0.000 description 1
- VZFRNCSOCOPNDB-UHFFFAOYSA-N domoic acid Natural products OC(=O)C(C)C=CC=C(C)C1CNC(C(O)=O)C1CC(O)=O VZFRNCSOCOPNDB-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- GNHWYXRSHRJMDP-UHFFFAOYSA-N ethyl 3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]benzoate Chemical compound CCOC(=O)C1=CC=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 GNHWYXRSHRJMDP-UHFFFAOYSA-N 0.000 description 1
- JGENQXRHGVLQOK-UHFFFAOYSA-N ethyl 4-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 JGENQXRHGVLQOK-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 201000011205 glycine encephalopathy Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 230000003118 histopathologic effect Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003225 hyperhomocysteinemia Effects 0.000 description 1
- 208000023399 hyperprolinemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 239000003407 interleukin 1 receptor blocking agent Substances 0.000 description 1
- 230000021995 interleukin-8 production Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 208000001875 irritant dermatitis Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- VZFRNCSOCOPNDB-OXYNIABMSA-N isodomoic acid D Natural products CC(C=C/C=C(/C)C1CNC(C1CC(=O)O)C(=O)O)C(=O)O VZFRNCSOCOPNDB-OXYNIABMSA-N 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 238000012332 laboratory investigation Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- NXAHPYBSEXEXPT-UHFFFAOYSA-N methyl 4-methoxy-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]benzoate Chemical compound COC(=O)C1=CC=C(OC)C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1 NXAHPYBSEXEXPT-UHFFFAOYSA-N 0.000 description 1
- XRRWPONERREOCZ-UHFFFAOYSA-N methyl 5-tert-butyl-1-methyl-3-[[4-(3-morpholin-4-ylcyclohexen-1-yl)naphthalen-1-yl]carbamoylamino]pyrrole-2-carboxylate Chemical compound C1=C(C(C)(C)C)N(C)C(C(=O)OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC(N2CCOCC2)CCC1 XRRWPONERREOCZ-UHFFFAOYSA-N 0.000 description 1
- VAJGUMSBKIWZPH-UHFFFAOYSA-N methyl 5-tert-butyl-1-methyl-3-[[4-(6-oxo-1-pyridin-4-yl-2,3-dihydropyridin-4-yl)naphthalen-1-yl]carbamoylamino]pyrrole-2-carboxylate Chemical compound C1=C(C(C)(C)C)N(C)C(C(=O)OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC(=O)N(C=2C=CN=CC=2)CC1 VAJGUMSBKIWZPH-UHFFFAOYSA-N 0.000 description 1
- RBOHWTKXOJGTSC-UHFFFAOYSA-N methyl 5-tert-butyl-1-methyl-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]pyrrole-2-carboxylate Chemical compound C1=C(C(C)(C)C)N(C)C(C(=O)OC)=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1C(C=N1)=CC=C1CN1CCOCC1 RBOHWTKXOJGTSC-UHFFFAOYSA-N 0.000 description 1
- ARUDGTVSHPBRDS-UHFFFAOYSA-N methyl 5-tert-butyl-3-[[4-(3-morpholin-4-ylcyclohexen-1-yl)naphthalen-1-yl]carbamoylamino]thiophene-2-carboxylate Chemical compound S1C(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3CCCC(C=3)N3CCOCC3)=CC=2)=C1C(=O)OC ARUDGTVSHPBRDS-UHFFFAOYSA-N 0.000 description 1
- UWYKWAAIAXCYMM-UHFFFAOYSA-N methyl 5-tert-butyl-3-[[4-(6-oxo-1-pyridin-4-yl-2,3-dihydropyridin-4-yl)naphthalen-1-yl]carbamoylamino]thiophene-2-carboxylate Chemical compound S1C(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3CCN(C(=O)C=3)C=3C=CN=CC=3)=CC=2)=C1C(=O)OC UWYKWAAIAXCYMM-UHFFFAOYSA-N 0.000 description 1
- LNWNPOYSVSKRRD-UHFFFAOYSA-N methyl 5-tert-butyl-3-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]thiophene-2-carboxylate Chemical compound S1C(C(C)(C)C)=CC(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)=C1C(=O)OC LNWNPOYSVSKRRD-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- GPSIHAPGAMCMDF-UHFFFAOYSA-N n-[2,5-diethoxy-4-[[4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalen-1-yl]carbamoylamino]phenyl]benzamide Chemical compound CCOC=1C=C(NC(=O)NC=2C3=CC=CC=C3C(C=3C=NC(CN4CCOCC4)=CC=3)=CC=2)C(OCC)=CC=1NC(=O)C1=CC=CC=C1 GPSIHAPGAMCMDF-UHFFFAOYSA-N 0.000 description 1
- HIJNVNMNKCAXFS-UHFFFAOYSA-N n-[3-tert-butyl-5-[[4-[5-(oxan-4-ylamino)pyridin-2-yl]naphthalen-1-yl]carbamoylamino]phenyl]-2-morpholin-4-ylacetamide Chemical compound C=1C(NC(=O)NC=2C3=CC=CC=C3C(C=3N=CC(NC4CCOCC4)=CC=3)=CC=2)=CC(C(C)(C)C)=CC=1NC(=O)CN1CCOCC1 HIJNVNMNKCAXFS-UHFFFAOYSA-N 0.000 description 1
- AFASVBQWMUSSDY-UHFFFAOYSA-N n-[4-tert-butyl-2-[[4-(6-oxo-1h-pyridin-3-yl)naphthalen-1-yl]carbamoylamino]phenyl]-2-morpholin-4-ylacetamide Chemical compound C=1C=C(C2=CNC(=O)C=C2)C2=CC=CC=C2C=1NC(=O)NC1=CC(C(C)(C)C)=CC=C1NC(=O)CN1CCOCC1 AFASVBQWMUSSDY-UHFFFAOYSA-N 0.000 description 1
- XRDBSOVLPQXHKU-UHFFFAOYSA-N n-[4-tert-butyl-2-[[4-[4-(1-methylpiperidin-4-yl)oxyphenyl]naphthalen-1-yl]carbamoylamino]phenyl]acetamide Chemical compound C1CN(C)CCC1OC1=CC=C(C=2C3=CC=CC=C3C(NC(=O)NC=3C(=CC=C(C=3)C(C)(C)C)NC(C)=O)=CC=2)C=C1 XRDBSOVLPQXHKU-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 230000002956 necrotizing effect Effects 0.000 description 1
- 208000004995 necrotizing enterocolitis Diseases 0.000 description 1
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 208000031237 olivopontocerebellar atrophy Diseases 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 208000020911 optic nerve disease Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003349 osteoarthritic effect Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 230000002177 osteoclastogenic effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000006513 pyridinyl methyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000032253 retinal ischemia Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical compound O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 description 1
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 description 1
- NNLBRYQGMOYARS-UHFFFAOYSA-N thiane 1-oxide Chemical compound O=S1CCCCC1 NNLBRYQGMOYARS-UHFFFAOYSA-N 0.000 description 1
- 150000003595 thromboxanes Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- QQJLHRRUATVHED-UHFFFAOYSA-N tramazoline Chemical compound N1CCN=C1NC1=CC=CC2=C1CCCC2 QQJLHRRUATVHED-UHFFFAOYSA-N 0.000 description 1
- 229960001262 tramazoline Drugs 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical compound O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 230000006648 viral gene expression Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 201000010044 viral meningitis Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/547—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This invention relates to methods of treating acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure indicated to be cytokine mediated diseases using aromatic heterocyclic compounds disclosed in PCT publication WO 00/55139.
- TNF Tumor necrosis factor
- IL-1 interleukin-1
- Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C. A., et al., 1984, Rev. Infect. Disease 6:51). In these diseases, chronic elevation of inflammation exacerbates or causes much of the pathophysiology observed. For example, rheumatoid synovial tissue becomes invaded with inflammatory cells that result in destruction to cartilage and bone (Koch, A. E., et al., 1995, J. Invest. Med. 43: 28-38).
- cytokines may be involved in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H., et al., 2001 Mar, Coron Artery Dis 12(2):107-13).
- PTCA percutaneous transluminal coronary angioplasty
- An important and accepted therapeutic approach for potential drug intervention in these diseases is the reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell-free form as TNF ⁇ ) and IL-1 ⁇ .
- TNF also referred to in its secreted cell-free form as TNF ⁇
- IL-1 ⁇ IL-1 ⁇
- Efficacy has been demonstrated with a monoclonal antibody directed against TNF ⁇ in a number of autoimmune diseases (Heath, P., “CDP571: An Engineered Human IgG4 Anti-TNF ⁇ Antibody” IBC Meeting on Cytokine Antagonists, Philadelphia, Pa., Apr. 24-5, 1997). These include the treatment of rheumatoid arthritis, Crohn's disease and ulcerative colitis (Rankin, E. C. C., et al., 1997, British J. Rheum. 35: 334-342 and Stack, W. A., et al., 1997, Lancet 349: 521-524).
- the monoclonal antibody is thought to function by binding to both soluble TNF ⁇ and to membrane bound TNF.
- a soluble TNF ⁇ receptor has been engineered that interacts with TNF ⁇ . The approach is similar to that described above for the monoclonal antibodies directed against TNF ⁇ ; both agents bind to soluble TNF ⁇ , thus reducing its concentration.
- Enbrel Immunex, Seattle, Wash.
- Another version of the TNF ⁇ receptor, Ro 45-2081 has demonstrated efficacy in various animal models of allergic lung inflammation and acute lung injury.
- Ro 45-2081 is a recombinant chimeric molecule constructed from the soluble 55 kDa human TNF receptor fused to the hinge region of the heavy chain IgG1 gene and expressed in eukaryotic cells (Renzetti, et al., 1997 , Inflamm. Res. 46: S143).
- IL-1 has been implicated as an immunological effector molecule in a large number of disease processes.
- IL-1 receptor antagonist (IL-1ra) had been examined in human clinical trials. Efficacy has been demonstrated for the treatment of rheumatoid arthritis (Antril, Amgen). In a phase III human clinical trial IL-1ra reduced the mortality rate in patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492). Osteoarthritis is a slow progressive disease characterized by destruction of the articular cartilage. IL-1 is detected in synovial fluid and in the cartilage matrix of osteoarthritic joints.
- Antagonists of IL-1 have been shown to diminish the degradation of cartilage matrix components in a variety of experimental models of arthritis (Chevalier, 1997 , Biomed Pharmacother. 51, 58).
- Nitric oxide (NO) is a mediator of cardiovascular homeostasis, neurotransmission and immune function; recently it has been shown to have important effects in the modulation of bone remodeling.
- Cytokines such as IL-1 and TNF are potent stimulators of NO production.
- NO is an important regulatory molecule in bone with effects on cells of the osteoblast and osteoclast lineage (Evans, et al, 1996 , J Bone Miner Res. 11, 300). The promotion of beta-cell destruction leading to insulin dependent diabetes mellitus shows dependence on IL-1.
- IL-1 can effect this process by controlling the level of both cyclooxygenase II and inducible nitric oxide synthetase expression (McDaniel et al., 1996 , Proc Soc Exp Biol Med. 211, 24).
- Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-2) expression.
- COX-2 expression has been shown to be increased by cytokines and it is believed to be the isoform of cyclooxygenase responsible for inflammation (M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.)
- inhibitors of cytokines such as IL-1 would be expected to exhibit efficacy against those disorders currently treated with COX inhibitors such as the familiar NSAIDs. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.
- IBD active inflammatory bowel disease
- Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region.
- the structural and metabolic damage found in Alzheimer disease is possibly due to a sustained elevation of IL-1 (Holden, et al., 1995 , Med Hypotheses, 45, 559).
- a role for IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified.
- HIV human immunodeficiency virus
- IL-1ra showed a clear relationship to acute inflammatory events as well as to the different disease stages in the pathophysiology of HIV infection (Kreuzer, et al., 1997 , Clin Exp Immunol. 109, 54).
- IL-1 and TNF are both involved in periodontal disease. The destructive process associated with periodontal disease may be due to a disregulation of both IL-1 and TNF (Howells, 1995 , Oral Dis. 1, 266).
- TNF ⁇ and IL-1 ⁇ are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure.
- ARDS acute respiratory distress syndrome
- TNF ⁇ and IL-6 levels have also been implicated in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al., 1988 , Amer. J. Med., 85, 289). Obesity is associated with an increase incidence of infection, diabetes and cardiovascular disease.
- TNF ⁇ expression Abnormalities in TNF ⁇ expression have been noted for each of the above conditions (Lommeda, et al., 1998 , FASEB J. 12, 57). It has been proposed that elevated levels of TNF ⁇ are involved in other eating related disorders such as anorexia and bulimia nervosa. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia (Holden, et al., 1996 , Med Hypotheses 47, 423). An inhibitor of TNF ⁇ production, HU-211, was shown to improve the outcome of closed brain injury in an experimental model (Shohami, et al., 1997 , J Neuroimmunol. 72, 169).
- Atherosclerosis is known to have an inflammatory component and cytokines such as IL-1 and TNF have been suggested to promote the disease.
- cytokines such as IL-1 and TNF have been suggested to promote the disease.
- an IL-1 receptor antagonist was shown to inhibit fatty streak formation (Elhage et al., 1998 , Circulation, 97, 242).
- TNF ⁇ levels are elevated in airways of patients with chronic obstructive pulmonary disease and it may contribute to the pathogenesis of this disease (M. A. Higham et al, 2000 , Eur. Respiratory J., 15, 281). Circulating TNF ⁇ may also contribute to weight loss associated with this disease (N. Takabatake et al., 2000 , Amer. J. Resp. & Crit. Care Med., 161 (4 Pt 1), 1179). Elevated TNF ⁇ levels have also been found to be associated with congestive heart failure and the level has been correlated with severity of the disease (A. M. Feldman et al, 2000 , J. Amer. College of Cardiology, 35, 537).
- TNF ⁇ has been implicated in reperfusion injury in lung (Borjesson et al., 2000 , Amer. J. Physiol., 278, L3-12), kidney (Lemay et al., 2000 , Transplantation, 69, 959), and the nervous system (Mitsui et al., 1999 , Brain Res., 844, 192).
- TNF ⁇ is also a potent osteoclastogenic agent and is involved in bone resorption and diseases involving bone resorption (Abu-Amer et al., 2000 , J. Biol. Chem., 275, 27307). It has also been found highly expressed in chondrocytes of patients with traumatic arthritis (Melchiorri et al., 2000 , Arthritis and Rheumatism, 41, 2165). TNF ⁇ has also been shown to play a key role in the development of glomerulonephritis (Le Hir et al., 1998 , Laboratory Investigation, 78, 1625).
- iNOS inducible nitric oxide synthetase
- IL-1 has also been shown to induce uveitis in rats which could be inhibited with IL-1 blockers.
- Cytokines including IL-1, TNF and GM-CSF have been shown to stimulate proliferation of acute myelogenous leukemia blasts (Bruserud, 1996 , Leukemia Res. 20, 65).
- IL-1 was shown to be essential for the development of both irritant and allergic contact dermatitis. Epicutaneous sensitization can be prevented by the administration of an anti-IL-1 monoclonal antibody before epicutaneous application of an allergen (Muller, et al., 1996 , Am J Contact Dermat. 7, 177).
- IL-1 knock out mice Data obtained from IL-1 knock out mice indicates the critical involvement in fever for this cytokine (Kluger et al., 1998 , Clin Exp Pharmacol Physiol. 25, 141).
- a variety of cytokines including TNF, IL-1, IL-6 and IL-8 initiate the acute-phase reaction which is stereotyped in fever, malaise, myalgia, headaches, cellular hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995 , Am J Clin Nutr. 62, 813).
- the production of these inflammatory cytokines rapidly follows trauma or pathogenic organism invasion.
- IL-8 correlates with influx of neutrophils into sites of inflammation or injury. Blocking antibodies against IL-8 have demonstrated a role for IL-8 in the neutrophil associated tissue injury in acute inflammation (Harada et al, 1996 , Molecular Medicine Today 2, 482).
- an inhibitor of IL-8 production may be useful in the treatment of diseases mediated predominantly by neutrophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing enterocolitis.
- Rhinovirus triggers the production of various proinflammatory cytokines, predominantly IL-8, which results in symptomatic illnesses such as acute rhinitis (Winther et al., 1998 , Am J Rhinol. 12, 17).
- IL-8 diseases that are effected by IL-8 include myocardial ischemia and reperfusion, inflammatory bowel disease and many others.
- IL-6 The proinflammatory cytokine IL-6 has been implicated with the acute phase response.
- IL-6 is a growth factor in a number in oncological diseases including multiple myeloma and related plasma cell dyscrasias (Treon, et al., 1998 , Current Opinion in Hematology 5: 42). It has also been shown to be an important mediator of inflammation within the central nervous system. Elevated levels of IL-6 are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et al., 1997 , Molecular Neurobiology 15: 307).
- IL-6 also plays a significant role in osteoporosis. In murine models it has been shown to effect bone resorption and to induce osteoclast activity (Ershler et al., 1997 , Development and Comparative Immunol. 21: 487). Marked cytokine differences, such as IL-6 levels, exist in vivo between osteoclasts of normal bone and bone from patients with Paget's disease (Mills, et al., 1997 , Calcif Tissue Int. 61, 16). A number of cytokines have been shown to be involved in cancer cachexia.
- IL-6 and IFN alpha as key factors in both symptom formation and in host defense.
- Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997 , Protein Sci.
- GM-CSF is another proinflammatory cytokine with relevance to a number of therapeutic diseases. It influences not only proliferation and differentiation of stem cells but also regulates several other cells involved in acute and chronic inflammation. Treatment with GM-CSF has been attempted in a number of disease states including bum-wound healing, skin-graft resolution as well as cytostatic and radiotherapy induced mucositis (Masucci, 1996 , Medical Oncology 13: 149). GM-CSF also appears to play a role in the replication of human immunodeficiency virus (HIV) in cells of macrophage lineage with relevance to AIDS therapy (Crowe et al., 1997 , Journal of Leukocyte Biology 62, 41). Bronchial asthma is characterised by an inflammatory process in lungs. Involved cytokines include GM-CSF amongst others (Lee, 1998 , J R Coll Physicians Lond 32, 56).
- HIV human immunodeficiency virus
- Interferon ⁇ has been implicated in a number of diseases. It has been associated with increased collagen deposition that is a central histopathological feature of graft-versus-host disease (Parkman, 1998 , Curr Opin Hematol. 5, 22). Following kidney transplantation, a patient was diagnosed with acute myelogenous leukemia. Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF and IFN ⁇ . These elevated levels coincided with a rise in peripheral blood white cell count (Burke, et al., 1995 , Leuk Lymphoma. 19, 173).
- Type 1 insulin-dependent diabetes
- T-cells producing IFN ⁇
- IFN ⁇ along with TNF, IL-2 and IL-6 lead to the activation of most peripheral T-cells prior to the development of lesions in the central nervous system for diseases such as multiple sclerosis (MS) and AIDS dementia complex (Martino et al., 1998 , Ann Neurol. 43, 340).
- MS multiple sclerosis
- AIDS dementia complex Piro et al., 1998 , Ann Neurol. 43, 340
- Atherosclerotic lesions result in arterial disease that can lead to cardiac and cerebral infarction.
- Many activated immune cells are present in these lesions, mainly T-cells and macrophages.
- cytokines such as TNF, IL-1 and IFN ⁇ . These cytokines are thought to be involved in promoting apoptosis or programmed cell death of the surrounding vascular smooth muscle cells resulting in the atherosclerotic lesions (Geng, 1997 , Heart Vessels Suppl 12, 76). Allergic subjects produce mRNA specific for IFN ⁇ following challenge with Vespula venom (Bonay, et al., 1997 , Clin Exp Immunol. 109, 342).
- cytokines including IFN ⁇ has been shown to increase following a delayed type hypersensitivity reaction thus indicating a role for IFN ⁇ in atopic dermatitis (Szepietowski, et al., 1997 , Br J Dermatol. 137, 195). Histopathologic and immunohistologic studies were performed in cases of fatal cerebral malaria. Evidence for elevated IFN ⁇ amongst other cytokines was observed indicating a role in this disease (Udomsangpetch et al., 1997 , Am J Trop Med Hyg. 57, 501). The importance of free radical species in the pathogenesis of various infectious diseases has been established.
- the nitric oxide synthesis pathway is activated in response to infection with certain viruses via the induction of proinflammatory cytokines such as IFN ⁇ (Akaike, et al., 1998 , Proc Soc Exp Biol Med. 217, 64).
- proinflammatory cytokines such as IFN ⁇
- Patients, chronically infected with hepatitis B virus (HBV) can develop cirrhosis and hepatocellular carcinoma.
- Viral gene expression and replication in HBV transgenic mice can be suppressed by a post-transcriptional mechanism mediated by IFN ⁇ , TNF and IL-2 (Chisari, et al., 1995 , Springer Semin Immunopathol 17, 261).
- IFN ⁇ can selectively inhibit cytokine induced bone resorption.
- NO nitric oxide
- rheumatoid arthritis a mediator of bone disease for such diseases as: the rheumatoid arthritis, tumor associated osteolysis and postmenopausal osteoporosis (Evans, et al, 1996 , J Bone Miner Res. 11, 300).
- IL-12 dependent production of IFN ⁇ is critical in the control of early parasitic growth. Although this process is independent of nitric oxide the control of chronic infection does appear to be NO dependent (Alexander et al., 1997 , Philos Trans R Soc Lond B Biol Sci 352, 1355).
- NO is an important vasodilator and convincing evidence exists for its role in cardiovascular shock (Kilboum, et al., 1997 , Dis Mon. 43, 277).
- IFN ⁇ is required for progression of chronic intestinal inflammation in such diseases as Crohn's disease and inflammatory bowel disease (IBD) presumably through the intermediacy of CD4+lymphocytes probably of the TH1 phenotype (Sartor 1996 , Aliment Pharmacol Ther. 10 Suppl 2, 43).
- An elevated level of serum IgE is associated with various atopic diseases such as bronchial asthma and atopic dermatitis.
- the level of IFN ⁇ was negatively correlated with serum IgE suggesting a role for IFN ⁇ in atopic patients (Teramoto et al., 1998 , Clin Exp Allergy 28, 74).
- WO 01/01986 discloses particular compounds alleged to having the ability to inhibit TNF-alpha.
- the specific inhibitors disclosed are structurally distinct from the novel compounds disclosed in the present application disclosed hereinbelow.
- Certain compounds disclosed in WO 01/01986 are indicated to be effective in treating the following diseases: dementia associated with HIV infection, glaucoma, optic-neuropathy, optic neuritis, retinal ischemia, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, cerebral ischemia, hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbon monoxide or manganese or cyanide poisoning, Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosis and other demyelinating diseases, amyotrophic lateral sclerosis, head and spinal cord trauma, seizures, convulsions, olivopontocerebellar atrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-
- WO 02/32862 discloses that inhibitors of pro-inflammatory cytokines including TNF ⁇ are allegedly useful for treating acute and chronic inflammation in the lung caused by inhalation of smoke such as cigarette smoke.
- TNF ⁇ anatagonists are apparently also useful for the treatment of endometriosis, see EP 1022027 A1.
- Infliximab in clinical trials for RA, has also been indicated to be useful for treating various inflammatory diseases including Behcet's disease, uveitis and ankylosing spondylitis. Pancreatitis may also be regulated by inflammatory mediator production, see J Surg Res 2000 May 15 90(2)95-101; Shock 1998 September. 10(3):160-75.
- p38MAPkinase pathway plays an role in B.burgdorferi-elicited infammation and may be useful in treating inflammation induced by the Lyme disease agent.
- Anti-cytokine drugs may also have therapeutic utility in treating tumor cells.
- WO 02/38143 discloses the use of p38 inhibitors to enhance the efficacy and safety of genotoxic therapy for treating, for example, aging, cancer and certain types of heart failure.
- WO 98/52558 discloses heteroaryl urea compounds which are indicated to be useful in treating cytokine mediated diseases.
- WO 99/23091 discloses another class of urea compounds which are useful as anti-inflammatory agents.
- WO 99/32463 relates to aryl ureas amd their use in treating cytokine diseases and proteolytic enzyme mediated disease.
- WO 00/41698 discloses aryl ureas said to be useful in treating p38 MAP kinase diseases.
- U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N′-heterocyclic substituted urea compounds which are described as being useful for treating hypercholesterolemia and atheroclerosis.
- the present invention is directed a method of treating a cytokine mediated disease or condition chosen from: acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme Disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of compounds disclosed in in WO 00/55139.
- a cytokine mediated disease or condition chosen from: acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme Disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease
- the present invention is directed a method of treating a cytokine mediated disease or condition chosen from: acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula (I) disclosed in WO 00/55139 which is the PCT case of U.S. application Ser. No. 09/505,582 (both of which are incorporated by reference herein in it their entirety):
- a preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I) as provided above and wherein:
- a more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I) as provided above and wherein:
- a yet more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I), as described in the immediate previous paragraph, wherein:
- a yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I), as described in the immediate previous paragraph, and wherein:
- a further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I), as described in the immediate previous paragraph, and wherein:
- a still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I), as described in the immediate previous paragraph, and wherein:
- X is pyridinyl
- a still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I), as described in the immediate previous paragraph, and wherein:
- the pyridinyl is attached to Ar 1 via the 3-pyridinyl position.
- a preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia) as provided above and wherein:
- a more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia) as provided above and wherein:
- a yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia), as described in the immediate previous paragraph, and wherein:
- a further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia), as described in the immediate previous paragraph, and wherein:
- a still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia), as described in the immediate previous paragraph, and wherein X is pyridinyl.
- a still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia), as described in the immediate previous paragraph, and wherein:
- the pyridinyl is attached to Ar 1 via the 3-pyridinyl position.
- a preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II) as provided above and wherein:
- oxetanyl pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl;
- G is substituted by one or more R 1 , R 2 or R 3 ;
- a more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II) as provided above and wherein:
- G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indenyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more R 1 , R 2 or R 3 ;
- a yet more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II), as described in the immediate previous paragraph, wherein:
- G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more R 1 , R 2 or R 3 ;
- a yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II), as described in the immediate previous paragraph, and wherein:
- G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, indolinyl, indolonyl, or indolinonyl, wherein G is substituted by one or more R 1 , R 2 or R 3 ;
- a further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II), as described in the immediate previous paragraph, and wherein:
- a still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II), as described in the immediate previous paragraph, and wherein X is pyridinyl.
- a still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II), as described immediately above, and wherein the pyridinyl is attached to Ar via the 3-pyridinyl position.
- a preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III) as provided above and wherein:
- a more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III) as provided above and wherein:
- a yet more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III), as described in the immediate previous paragraph, wherein:
- G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is optionally substituted by one or more R 1 , R 2 or R 3 ;
- a yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III), as described in the immediate previous paragraph, and wherein:
- G is phenyl, pyridinyl, pyridonyl, 2-naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl, indolinyl, indolonyl, or indolinonyl, wherein G is optionally substituted by one or more R 1 , R 2 or R 3 ;
- a further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III), as described in the immediate previous paragraph, and wherein:
- a still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III), as described in the immediate previous paragraph, and wherein:
- a still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III), as described immediately above, and wherein
- the invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.
- Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
- Some of the compounds of formulas (I), (Ia), (II) and (III) can exist in more than one tautomeric form.
- the invention includes methods using all such tautomers.
- C 1-4 alkoxy is a C 1-4 alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy.
- alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
- Carbocycle shall be understood to mean an aliphatic hydrocarbon radical containing from three to twelve carbon atoms. Carbocycles include hydrocarbon rings containing from three to ten carbon atoms. These carbocycles may be either aromatic and non-aromatic ring systems. The non-aromatic ring systems may be mono- or polyunsaturated.
- Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be used inerchangeably.
- heterocycle refers to a stable nonaromatic 4-8 membered (but preferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated.
- Each heterocycle consists of carbon atoms and one or more, preferably from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.
- the heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure.
- heterocycles include but are not limited to, for example oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxany
- heteroaryl shall be understood to mean an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring containing 1-4 heteroatoms such as N,O and S. Unless otherwise stated, such heteroaryls include: pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol
- the invention includes methods of using pharmaceutically acceptable derivatives of compounds of formula (I), (Ia), (II) and (III).
- a “pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt or ester, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a pharmacologically active metabolite or pharmacologically active residue thereof.
- a pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the formulas (I), (Ia), (II) or (III).
- Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
- suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids.
- Other acids such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts.
- Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N—(C 1 -C 4 alkyl) 4 + salts.
- Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.
- the compounds disclosed therein effectively block inflammatory cytokine production from cells.
- the inhibition of cytokine production is an attractive means for preventing and treating a variety of cytokine mediated diseases or conditions associated with excess cytokine production, e.g., diseases and pathological conditions involving inflammation.
- the compounds are described in WO 00/55139 as being useful for the treatment of the following conditions and diseases: osteoarthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus and insulin-dependent diabetes mellitus, rheumatoid arthritis, Alzheimer's disease, toxic shock syndrome, diabetes, inflammatory bowel diseases, acute and chronic pain as well as symptoms of inflammation and cardiovascular disease, stroke, myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing entrerocolitis.
- osteoarthritis multiple sclerosis
- the compounds disclosed in WO 00/55139 are useful in methods for treating: acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure.
- the compounds may be administered in any conventional dosage form in any conventional manner.
- Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, topically or by inhalation.
- the preferred modes of administration are oral and intravenous.
- the compounds may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutic compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients.
- combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies.
- the above described compounds may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Reference is this regard may be made to Cappola et al.: U.S. patent application Ser. No. 09/902,822 and PCT/US 01/21860 each incorporated by reference herein in their entirety.
- the compounds may then be administered together in a single dosage form.
- the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formulas (I), (Ia), (II) and (III) (w/w) or a combination thereof.
- the optimum percentage (w/w) of a compound of the invention may vary and is within the purview of those skilled in the art.
- the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
- dosage forms of the compounds described herein include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art.
- carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances.
- Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H. C. Ansel and N. G.
- Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition thereto, and the judgment of the treating physician.
- the inhibition of cytokine production can be observed by measuring inhibition of TNF ⁇ in lipopolysaccharide stimulated THP cells (for example, see W. Prichett et al., 1995 , J Inflammation, 45, 97). All cells and reagents were diluted in RPMI 1640 with phenol red and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and streptomycin (50 units/ml each) and fetal bovine serum (FBS, 3%) (GIBCO, all conc. final). Assay was performed under sterile conditions; only test compound preparation was nonsterile.
- IC50 value is the concentration of the test compound that caused a 50% decrease in the maximal TNF ⁇ production.
- Preferred compounds including those from the synthetic examples above were evaluated and had IC 50 ⁇ 10 uM in this assay.
- peripheral blood monocytic cells By similar methods using peripheral blood monocytic cells, appropriate stimuli, and commercially available ELISA kits (or other method of detection such as radioimmunoassay), for a particular cytokine, inhibition of IL-1beta, GM-CSF, IL-6 and IL-8 can be demonstrated for preferred compounds (for example, see J. C. Lee et al., 1988 , Int. J. Immunopharmacol., 10,835).
Abstract
Disclosed are methods of treating acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, sepsis, chronic obstructive pulmonary disease, traumatic arthritis, congestive heart failure and restenosis following percutaneous transluminal coronary angioplasty, known to be cytokine mediated, using aromatic heterocyclic compounds described in WO 00/55139.
Description
- This application is a divisional application of U.S. Ser. No. 10/237,306 filed Sep. 9, 2002 which claims benefit to U.S. provisional application Ser. No. 60/318,958 filed Sep. 13, 2001, the entirety of each is incorporated herein by reference.
- This invention relates to methods of treating acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure indicated to be cytokine mediated diseases using aromatic heterocyclic compounds disclosed in PCT publication WO 00/55139.
- In WO 00/55139 there are described aromatic heterocyclic compounds useful in treating certain cytokine mediated diseases. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important biological entities collectively referred to as proinflammatory cytokines. These, along with several other related molecules, mediate the inflammatory response associated with the immunological recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pathogenic infections.
- Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C. A., et al., 1984, Rev. Infect. Disease 6:51). In these diseases, chronic elevation of inflammation exacerbates or causes much of the pathophysiology observed. For example, rheumatoid synovial tissue becomes invaded with inflammatory cells that result in destruction to cartilage and bone (Koch, A. E., et al., 1995, J. Invest. Med. 43: 28-38). Studies suggest that inflammatory changes mediated by cytokines may be involved in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H., et al., 2001 Mar, Coron Artery Dis 12(2):107-13). An important and accepted therapeutic approach for potential drug intervention in these diseases is the reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell-free form as TNFα) and IL-1β. A number of anti-cytokine therapies are currently in clinical trials. Efficacy has been demonstrated with a monoclonal antibody directed against TNFα in a number of autoimmune diseases (Heath, P., “CDP571: An Engineered Human IgG4 Anti-TNFα Antibody” IBC Meeting on Cytokine Antagonists, Philadelphia, Pa., Apr. 24-5, 1997). These include the treatment of rheumatoid arthritis, Crohn's disease and ulcerative colitis (Rankin, E. C. C., et al., 1997, British J. Rheum. 35: 334-342 and Stack, W. A., et al., 1997, Lancet 349: 521-524). The monoclonal antibody is thought to function by binding to both soluble TNFα and to membrane bound TNF.
- A soluble TNFα receptor has been engineered that interacts with TNFα. The approach is similar to that described above for the monoclonal antibodies directed against TNFα; both agents bind to soluble TNFα, thus reducing its concentration. One version of this construct, called Enbrel (Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase III clinical trial for the treatment of rheumatoid arthritis (Brower et al., 1997, Nature Biotechnology 15: 1240). Another version of the TNFα receptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) has demonstrated efficacy in various animal models of allergic lung inflammation and acute lung injury. Ro 45-2081 is a recombinant chimeric molecule constructed from the soluble 55 kDa human TNF receptor fused to the hinge region of the heavy chain IgG1 gene and expressed in eukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143).
- IL-1 has been implicated as an immunological effector molecule in a large number of disease processes. IL-1 receptor antagonist (IL-1ra) had been examined in human clinical trials. Efficacy has been demonstrated for the treatment of rheumatoid arthritis (Antril, Amgen). In a phase III human clinical trial IL-1ra reduced the mortality rate in patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492). Osteoarthritis is a slow progressive disease characterized by destruction of the articular cartilage. IL-1 is detected in synovial fluid and in the cartilage matrix of osteoarthritic joints. Antagonists of IL-1 have been shown to diminish the degradation of cartilage matrix components in a variety of experimental models of arthritis (Chevalier, 1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator of cardiovascular homeostasis, neurotransmission and immune function; recently it has been shown to have important effects in the modulation of bone remodeling. Cytokines such as IL-1 and TNF are potent stimulators of NO production. NO is an important regulatory molecule in bone with effects on cells of the osteoblast and osteoclast lineage (Evans, et al, 1996, J Bone Miner Res. 11, 300). The promotion of beta-cell destruction leading to insulin dependent diabetes mellitus shows dependence on IL-1. Some of this damage may be mediated through other effectors such as prostaglandins and thromboxanes. IL-1 can effect this process by controlling the level of both cyclooxygenase II and inducible nitric oxide synthetase expression (McDaniel et al., 1996, Proc Soc Exp Biol Med. 211, 24).
- Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX-2) expression. COX-2 expression has been shown to be increased by cytokines and it is believed to be the isoform of cyclooxygenase responsible for inflammation (M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.) Accordingly, inhibitors of cytokines such as IL-1 would be expected to exhibit efficacy against those disorders currently treated with COX inhibitors such as the familiar NSAIDs. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.
- Elevation of several cytokines have been demonstrated during active inflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1 and IL-1ra is present in patients with IBD. Insufficient production of endogenous IL-1ra may contribute to the pathogenesis of IBD (Cominelli, et al., 1996, Aliment Pharmacol Ther. 10, 49).
- Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region. The structural and metabolic damage found in Alzheimer disease is possibly due to a sustained elevation of IL-1 (Holden, et al., 1995, Med Hypotheses, 45, 559). A role for IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified. IL-1ra showed a clear relationship to acute inflammatory events as well as to the different disease stages in the pathophysiology of HIV infection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54). IL-1 and TNF are both involved in periodontal disease. The destructive process associated with periodontal disease may be due to a disregulation of both IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).
- Proinflammatory cytokines such as TNFα and IL-1β are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure. In a study of patients presenting at a hospital with sepsis, a correlation was found between TNFα and IL-6 levels and septic complications (Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNFα has also been implicated in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289). Obesity is associated with an increase incidence of infection, diabetes and cardiovascular disease. Abnormalities in TNFα expression have been noted for each of the above conditions (Loffreda, et al., 1998, FASEB J. 12, 57). It has been proposed that elevated levels of TNFα are involved in other eating related disorders such as anorexia and bulimia nervosa. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). An inhibitor of TNFα production, HU-211, was shown to improve the outcome of closed brain injury in an experimental model (Shohami, et al., 1997, J Neuroimmunol. 72, 169). Atherosclerosis is known to have an inflammatory component and cytokines such as IL-1 and TNF have been suggested to promote the disease. In an animal model an IL-1 receptor antagonist was shown to inhibit fatty streak formation (Elhage et al., 1998, Circulation, 97, 242).
- TNFα levels are elevated in airways of patients with chronic obstructive pulmonary disease and it may contribute to the pathogenesis of this disease (M. A. Higham et al, 2000, Eur. Respiratory J., 15, 281). Circulating TNFα may also contribute to weight loss associated with this disease (N. Takabatake et al., 2000, Amer. J. Resp. & Crit. Care Med., 161 (4 Pt 1), 1179). Elevated TNFα levels have also been found to be associated with congestive heart failure and the level has been correlated with severity of the disease (A. M. Feldman et al, 2000, J. Amer. College of Cardiology, 35, 537). In addition, TNFα has been implicated in reperfusion injury in lung (Borjesson et al., 2000, Amer. J. Physiol., 278, L3-12), kidney (Lemay et al., 2000, Transplantation, 69, 959), and the nervous system (Mitsui et al., 1999, Brain Res., 844, 192).
- TNFα is also a potent osteoclastogenic agent and is involved in bone resorption and diseases involving bone resorption (Abu-Amer et al., 2000, J. Biol. Chem., 275, 27307). It has also been found highly expressed in chondrocytes of patients with traumatic arthritis (Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNFα has also been shown to play a key role in the development of glomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78, 1625).
- The abnormal expression of inducible nitric oxide synthetase (iNOS) has been associated with hypertension in the spontaneously hypertensive rat (Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in the expression of iNOS and therefore may also have a role in the pathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension, 9, 867).
- IL-1 has also been shown to induce uveitis in rats which could be inhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol. and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have been shown to stimulate proliferation of acute myelogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essential for the development of both irritant and allergic contact dermatitis. Epicutaneous sensitization can be prevented by the administration of an anti-IL-1 monoclonal antibody before epicutaneous application of an allergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Data obtained from IL-1 knock out mice indicates the critical involvement in fever for this cytokine (Kluger et al., 1998, Clin Exp Pharmacol Physiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 and IL-8 initiate the acute-phase reaction which is stereotyped in fever, malaise, myalgia, headaches, cellular hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813). The production of these inflammatory cytokines rapidly follows trauma or pathogenic organism invasion.
- Other proinflammatory cytokines have been correlated with a variety of disease states. IL-8 correlates with influx of neutrophils into sites of inflammation or injury. Blocking antibodies against IL-8 have demonstrated a role for IL-8 in the neutrophil associated tissue injury in acute inflammation (Harada et al, 1996, Molecular Medicine Today 2, 482). Therefore, an inhibitor of IL-8 production may be useful in the treatment of diseases mediated predominantly by neutrophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing enterocolitis. Rhinovirus triggers the production of various proinflammatory cytokines, predominantly IL-8, which results in symptomatic illnesses such as acute rhinitis (Winther et al., 1998, Am J Rhinol. 12, 17).
- Other diseases that are effected by IL-8 include myocardial ischemia and reperfusion, inflammatory bowel disease and many others.
- The proinflammatory cytokine IL-6 has been implicated with the acute phase response. IL-6 is a growth factor in a number in oncological diseases including multiple myeloma and related plasma cell dyscrasias (Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has also been shown to be an important mediator of inflammation within the central nervous system. Elevated levels of IL-6 are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et al., 1997, Molecular Neurobiology 15: 307). IL-6 also plays a significant role in osteoporosis. In murine models it has been shown to effect bone resorption and to induce osteoclast activity (Ershler et al., 1997, Development and Comparative Immunol. 21: 487). Marked cytokine differences, such as IL-6 levels, exist in vivo between osteoclasts of normal bone and bone from patients with Paget's disease (Mills, et al., 1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shown to be involved in cancer cachexia. The severity of key parameters of cachexia can be reduced by treatment with anti IL-6 antibodies or with IL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther. 1, 107). Several infectious diseases, such as influenza, indicate IL-6 and IFN alpha as key factors in both symptom formation and in host defense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997, Protein Sci. 6, 929). Compounds that interfered with the production of cytokines including IL-6, and TNF were effective in blocking a passive cutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41, 1050).
- GM-CSF is another proinflammatory cytokine with relevance to a number of therapeutic diseases. It influences not only proliferation and differentiation of stem cells but also regulates several other cells involved in acute and chronic inflammation. Treatment with GM-CSF has been attempted in a number of disease states including bum-wound healing, skin-graft resolution as well as cytostatic and radiotherapy induced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF also appears to play a role in the replication of human immunodeficiency virus (HIV) in cells of macrophage lineage with relevance to AIDS therapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41). Bronchial asthma is characterised by an inflammatory process in lungs. Involved cytokines include GM-CSF amongst others (Lee, 1998, J R Coll Physicians Lond 32, 56).
- Interferon γ (IFNγ) has been implicated in a number of diseases. It has been associated with increased collagen deposition that is a central histopathological feature of graft-versus-host disease (Parkman, 1998, Curr Opin Hematol. 5, 22). Following kidney transplantation, a patient was diagnosed with acute myelogenous leukemia. Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF and IFNγ. These elevated levels coincided with a rise in peripheral blood white cell count (Burke, et al., 1995, Leuk Lymphoma. 19, 173). The development of insulin-dependent diabetes (Type 1) can be correlated with the accumulation in pancreatic islet cells of T-cells producing IFNγ (Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFNγ along with TNF, IL-2 and IL-6 lead to the activation of most peripheral T-cells prior to the development of lesions in the central nervous system for diseases such as multiple sclerosis (MS) and AIDS dementia complex (Martino et al., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result in arterial disease that can lead to cardiac and cerebral infarction. Many activated immune cells are present in these lesions, mainly T-cells and macrophages. These cells produce large amounts of proinflammatory cytokines such as TNF, IL-1 and IFNγ. These cytokines are thought to be involved in promoting apoptosis or programmed cell death of the surrounding vascular smooth muscle cells resulting in the atherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76). Allergic subjects produce mRNA specific for IFNγ following challenge with Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342). The expression of a number of cytokines, including IFNγ has been shown to increase following a delayed type hypersensitivity reaction thus indicating a role for IFNγ in atopic dermatitis (Szepietowski, et al., 1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologic studies were performed in cases of fatal cerebral malaria. Evidence for elevated IFNγ amongst other cytokines was observed indicating a role in this disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501). The importance of free radical species in the pathogenesis of various infectious diseases has been established. The nitric oxide synthesis pathway is activated in response to infection with certain viruses via the induction of proinflammatory cytokines such as IFNγ (Akaike, et al., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronically infected with hepatitis B virus (HBV) can develop cirrhosis and hepatocellular carcinoma. Viral gene expression and replication in HBV transgenic mice can be suppressed by a post-transcriptional mechanism mediated by IFN γ, TNF and IL-2 (Chisari, et al., 1995, Springer Semin Immunopathol 17, 261). IFNγ can selectively inhibit cytokine induced bone resorption. It appears to do this via the intermediacy of nitric oxide (NO) which is an important regulatory molecule in bone remodeling. NO may be involved as a mediator of bone disease for such diseases as: the rheumatoid arthritis, tumor associated osteolysis and postmenopausal osteoporosis (Evans, et al, 1996, J Bone Miner Res. 11, 300). Studies with gene deficient mice have demonstrated that the IL-12 dependent production of IFNγ is critical in the control of early parasitic growth. Although this process is independent of nitric oxide the control of chronic infection does appear to be NO dependent (Alexander et al., 1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an important vasodilator and convincing evidence exists for its role in cardiovascular shock (Kilboum, et al., 1997, Dis Mon. 43, 277). IFNγ is required for progression of chronic intestinal inflammation in such diseases as Crohn's disease and inflammatory bowel disease (IBD) presumably through the intermediacy of CD4+lymphocytes probably of the TH1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). An elevated level of serum IgE is associated with various atopic diseases such as bronchial asthma and atopic dermatitis. The level of IFNγ was negatively correlated with serum IgE suggesting a role for IFNγ in atopic patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).
- WO 01/01986 discloses particular compounds alleged to having the ability to inhibit TNF-alpha. The specific inhibitors disclosed are structurally distinct from the novel compounds disclosed in the present application disclosed hereinbelow. Certain compounds disclosed in WO 01/01986 are indicated to be effective in treating the following diseases: dementia associated with HIV infection, glaucoma, optic-neuropathy, optic neuritis, retinal ischemia, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, cerebral ischemia, hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbon monoxide or manganese or cyanide poisoning, Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosis and other demyelinating diseases, amyotrophic lateral sclerosis, head and spinal cord trauma, seizures, convulsions, olivopontocerebellar atrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-related neuropathy, MERRF and MELAS syndromes, Leber's disease, Wemicke's encephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety and schizophrenia. WO 02/32862 discloses that inhibitors of pro-inflammatory cytokines including TNFα are allegedly useful for treating acute and chronic inflammation in the lung caused by inhalation of smoke such as cigarette smoke. TNFα anatagonists are apparently also useful for the treatment of endometriosis, see EP 1022027 A1. Infliximab, in clinical trials for RA, has also been indicated to be useful for treating various inflammatory diseases including Behcet's disease, uveitis and ankylosing spondylitis. Pancreatitis may also be regulated by inflammatory mediator production, see J Surg Res 2000 May 15 90(2)95-101; Shock 1998 September. 10(3):160-75. p38MAPkinase pathway plays an role in B.burgdorferi-elicited infammation and may be useful in treating inflammation induced by the Lyme disease agent. Anguita, J. et. al., The Journal of Immunology, 2002, 168:6352-6357.
- Anti-cytokine drugs may also have therapeutic utility in treating tumor cells. Drug Resistance Updates 4(4):253-267, 2001 August. WO 02/38143 discloses the use of p38 inhibitors to enhance the efficacy and safety of genotoxic therapy for treating, for example, aging, cancer and certain types of heart failure.
- Compounds which modulate release of one or more of the aforementioned inflammatory cytokines can be useful in treating diseases associated with release of these cytokines. For example, WO 98/52558 discloses heteroaryl urea compounds which are indicated to be useful in treating cytokine mediated diseases. WO 99/23091 discloses another class of urea compounds which are useful as anti-inflammatory agents. WO 99/32463 relates to aryl ureas amd their use in treating cytokine diseases and proteolytic enzyme mediated disease. WO 00/41698 discloses aryl ureas said to be useful in treating p38 MAP kinase diseases.
- U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N′-heterocyclic substituted urea compounds which are described as being useful for treating hypercholesterolemia and atheroclerosis.
- The work cited above supports the principle that inhibition of cytokine production will be beneficial in the treatment acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure. None of these specific diseases have been taught or described in WO 00/55139 as being possible indications for the compounds taught therein. Therefore a need exists for small molecule inhibitors for treating these diseases with optimized efficacy, pharmacokinetic and safety profiles.
- The present invention is directed a method of treating a cytokine mediated disease or condition chosen from: acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme Disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of compounds disclosed in in WO 00/55139.
- In a first broad generic aspect, the present invention is directed a method of treating a cytokine mediated disease or condition chosen from: acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula (I) disclosed in WO 00/55139 which is the PCT case of U.S. application Ser. No. 09/505,582 (both of which are incorporated by reference herein in it their entirety):
-
- wherein:
- Ar1 is selected from the group consisting of:
pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ar1 may be substituted by one or more R1, R2 or R3; - Ar2 is:
phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with zero to three R2 groups; - X is:
- a) a C5-8 cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C1-4 branched or unbranched alkyl, C1-4 alkoxy or C1-4 alkylamino chains;
- b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each being optionally independently substituted with 0-3 C1-4 branched or unbranched alkyl, C1-4alkoxy, hydroxy, nitrile, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, or halogen;
- Y is:
a bond or a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O), S(O)2 or S and wherein Y is optionally independently substituted with 0-2 oxo groups and one or more C1-4 branched or unbranched alkyl which may be substituted by one or more halogen atoms; - Z is:
- Y is:
- a) phenyl, pyridine, pyrimidine, pyridazine, imidazole, furan, thiophene, pyran, which are optionally substituted with one to three groups consisting of halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, COOH and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C1-6 alkyl and C1-6 alkoxy;
- b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, piperidinone, piperazine, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone which are optionally substituted with one to three groups consisting of nitrile, C1-6 alkyl, C1-6 alkoxy, hydroxy, mono- or di-(C1-3 alkyl)amino-C1-3 alkyl, phenylamino-C1-3 alkyl and C1-3 alkoxy-C1-3 alkyl;
- c) C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C1-3 alkyl, C1-5 alkoxyalkyl, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, phenylamino, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
- R1 is:
- (a) C3-10 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described in this paragraph, and being substituted with 0 to 5 groups selected from the group consisting of halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(C1-3)alkylaminocarbonyl;
- (b) C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S, CHOH, >C═O, >C═S and NH;
- (c) C3-10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C1-5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated, NH2C(O) and mono- or di(C1-3)alkylaminocarbonyl;
- (d) a C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups;
- (e) nitrile; or
- (f) C1-6 branched or unbranched alkoxycarbonyl, C1-6 branched or unbranched alkylaminocarbonyl, C1-6 branched or unbranched alkylcarbonylamino-C1-3-alkyl;
- R2 is:
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl; - R3 is:
- R2 is:
- a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of phenyl, naphthyl, heterocycle selected from the group hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, nitrile, C1-3 alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, amino-S(O)2, di-(C1-3)alkylamino-S(O)2, R4—C1-5 alkyl, R5—C1-5 alkoxy, R6—C(O)—C1-5 alkyl and R7—C1-5 alkyl(R8)N, carboxy-mono- or di-(C1-5)-alkyl-amino;
- b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1-4 alkyl-OC(O), C1-5 alkyl-C(O)-C1-4 branched or unbranched alkyl, an amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, R9—C1-5 alkyl, R10—C1-5 alkoxy, R11—C(O)—C1-5 alkyl, and R12—C1-5 alkyl(R13)N;
- c) cycloalkyl selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
- d) C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups;
- e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; or
- f) C1-6 branched or unbranched alkyl optionally partially or fully halogenated;
or R1 and R2 taken together may optionally form a fused phenyl or pyridinyl ring;- each R8 and R13 is independently selected from the group consisting of: hydrogen and C1-4 branched or unbranched alkyl optionally be partially or fully halogenated;
- each R4, R5, R6, R7, R9, R10, R11 and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
- m is 0, 1 or 2;
- W is O or S and
the pharmaceutically acceptable derivatives thereof. - A preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I) as provided above and wherein:
-
- Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and
- W is O.
- A more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I) as provided above and wherein:
-
- Ar1 is selected from thiophene and pyrazole;
- X is C5-7 cycloalkyl or C5-7cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C1-4 branched or unbranched alkyl, C1-4 alkoxy or C1-4 alkylamino; or X is phenyl, pyridine, tetrahydropyridine, pyrimidine, furan or thiophene each being optionally independently substituted with 0-3 C1-4 branched or unbranched alkyl, C1-4alkoxy, hydroxy, nitrile, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m or halogen;
- R1 is C1-4alkyl branched or unbranched, cyclopropyl or cyclohexyl optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
- R3 is C1-4alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl or pyridinyl each being optionally substituted as described hereinabove in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally substituted as described hereinabove in the broadest generic aspect.
- A yet more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I), as described in the immediate previous paragraph, wherein:
-
- Ar1 is pyrazole;
- X is cyclopentenyl, cyclohexenyl or cycloheptenyl, optionally substituted with an oxo group or 0-3 C1-4 branched or unbranched alkyl, C1-4alkoxy or C1-4alkylamino; or X is phenyl, pyridine, furan or thiophene each being optionally independently substituted with 0-3 C1-4 branched or unbranched alkyl, C1-4alkoxy, hydroxy, nitrile, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m or halogen.
- A yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I), as described in the immediate previous paragraph, and wherein:
-
- Y is —CH2—, —CH2CH2—, —CH2NH—, —CH2CH2NH— or a bond; and
- Z is
phenyl, imidazole, furan, piperazine, tetrahydropyran, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, pyridine, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C1-3 alkyl and C1-5 alkoxyalkyl, phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m and phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino.
- A further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I), as described in the immediate previous paragraph, and wherein:
-
- Ar1 is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring may be substituted by R3;
- R3 is C1-4alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl, pyridinyl each being optionally substituted as described hereinabove in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally substituted as described hereinabove in the broadest generic aspect.
- A still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I), as described in the immediate previous paragraph, and wherein:
- X is pyridinyl.
- A still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (I), as described in the immediate previous paragraph, and wherein:
- the pyridinyl is attached to Ar1 via the 3-pyridinyl position.
- The following compounds are representative of the compounds of formula (I) which may be useful in the novel methods described herein:
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminophenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-fur-2-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-piperdin-1-ylmethyl-phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-(4-methylpiperazin-1-yl)methylphenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3,4-di(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-pyridin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo- thiomorpholin-4-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-tetrahydropyran-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiophen-3-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(imidazol-1-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[2-(3-dimethylaminomethylphenyl)-5-(1-methyl-cyclohexyl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[2-(5-(1-methyl-cyclohexyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-methoxy-5-(2-morpholin-4-yl-ethoxy)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-morpholin-4-yl-ethoxy)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3-(dimethylamino)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3-(methylsulfonyl)phenyl)naphthalen-1-yl]urea;
- 5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureido}thiophene-2-carboxylic acid methyl ester;
- 5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureido}thiophene-2-carboxylic acid methylamide;
- 5-tert-butyl-1-methyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureido}-1H-pyrrole-2-carboxylic acid methyl ester;
- 5-tert-butyl-1-methyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureido}-1H-pyrrole-2-carboxylic acid methylamide;
- 2-acetylamino N-(5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]ureido}thiophen-2-ylmethyl)acetamide;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cylohept-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-morpholin-4-yl-ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohept-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-4-yl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(dimethylaminoethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-3-yl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(phenyl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-phenylethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(furan-2-yl-methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-pyridin-2-yl-ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-piperdin-1-yl-ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-imidazol-4-yl-ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-2-yl- methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(4-methoxyphenyl)ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-ylmethyl-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(1-oxo-tetrahydrothiophen-3-ylmethyl)-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(1-oxo-thiomorpholin-4-ylmethyl)-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-methylpiperazin-1-ylmethyl)-3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-{6-oxo-1-(tetrahydro-pyran-4-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl}naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-oxo-1-pyridin-4-ylmethyl-piperdin-4-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]urea;
- 5-tert-butyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]ureido}thiophene-2-carboxylic acid methyl ester;
- 5-tert-butyl-1-methyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]ureido}pyrrole-2-carboxylic acid methyl ester;
- 5-tert-butyl-1-methyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]ureido}pyrrole-2-carboxylic acid methyl amide;
- 5-tert-butyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-1-yl]ureido}thiophene-2-carboxylic acid methyl ester;
- 5-tert-butyl-1-methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-1-yl]ureido}pyrrole-2-carboxylic acid methyl ester; and
- 5-tert-butyl-1-methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-1-yl]ureido}pyrrole-2-carboxylic acid methyl amide and
the pharmaceutically acceptable derivatives thereof. - In another embodiment of the invention there are provided the following compounds of formula (I) which may be useful in the novel methods described herein:
- 1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methoxypyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′-methyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′-(3-methylsulfanylpropyl)-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′-methyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-fur-2-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
- 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea and
the pharmaceutically acceptable derivatives thereof. - In a second broad generic aspect, there is provided a method of treating a cytokine mediated disease or condition chosen from: acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula (Ia) disclosed in WO 00/55139 which is the PCT case of U.S. application Ser. No. 09/505,582:
-
- wherein:
- Ar1 is:
pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ar1 is optionally substituted by one or more R1, R2 or R3; - Ar2 is:
phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzo furan, indanyl, indenyl and indole each being optionally substituted with zero to three R2 groups; - X is:
a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched; phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen; - Y is:
a bond or a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; - Z is:
aryl, indanyl, heteroaryl selected from benzimidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl,
each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, heteroaroyl, heterocycleC1-3acyl wherein the heteroaryl and heterocycle are as defined hereinabove in this paragraph, C1-3acyl, oxo, hydroxy, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, amino-S(O)m, C1-6 alkyl-S(O)m or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino;
or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6alkyl, C1-3alkyl, arylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)m— or arylC0-3alkyl-S(O)m— each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is hydroxy, hydroxyC1-3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-6alkyl, aminoC1-6alkyl, arylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)m—, arylC0-3alkyl-S(O)m—, nitrileC1-4alkyl or C1-3alkoxyC1-3alkyl, each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkoxyheteroarylC0-3alkyl, heteroarylC0-3alkyl or heterocycyleC0-3alkyl wherein the heteroaryl and heterocycle is hereinabove described in this paragraph,
or Z is C1-6alkyl branched or unbranched, C1-6alkoxy, C1-3acylamino, nitrileC1-4alkyl, C1-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino; - R1 is:
- a) C1-10 branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle, selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(C1-3)alkylaminocarbonyl;
- b) C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, each optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S, CHOH, >C═O, >C═S and NH;
- c) C3-10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C1-5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated, NH2C(O) and mono- or di(C1-3)alkylaminocarbonyl;
- d) a C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups;
- e) nitrile; or
- f) C1-6 branched or unbranched alkoxycarbonyl, C1-6 branched or unbranched alkylaminocarbonyl, C1-6 branched or unbranched alkylcarbonylamino-C1-3-alkyl;
- R2 is:
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile,
or R2 is acetyl, aroyl, C1-4 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl; - R3 is:
- R2 is:
- a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, naphthyl, heterocycle selected from the group hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, C1-3 alkoxyC1-5alkyl, C1-3thioalkyl, C1-3thioalkylC1-5alkyl, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, amino-S(O)2, di-(C1-3)alkylamino-S(O)2, R4—C1-5 alkyl, R5—C1-5 alkoxy, R6—C(O)—C1-5 alkyl and R7—C1-5 alkyl(R8)N, carboxy-mono- or di-(C1-5)-alkyl-amino;
- b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1-4 alkyl-OC(O), C1-5 alkyl-C(O)—C1-4 branched or unbranched alkyl, an amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, R9—C1-5 alkyl, R10—C1-5 alkoxy, R11—C(O)—C1-5 alkyl and R12—C1-5 alkyl(R13)N;
- c) cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
- d) C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups;
- e) acetyl, aroyl, C1-6alkoxycarbonylC1-6alkyl or phenylsulfonyl; or
- f) C1-6 branched or unbranched alkyl optionally partially or fully halogenated;
or R1 and R2 taken together optionally form a fused phenyl or pyridinyl ring;- each R8 and R13 is independently selected from the group consisting of: hydrogen and C1-4 branched or unbranched alkyl optionally partially or fully halogenated;
- each R4, R5, R6, R7, R9, R10, R11 and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
- m is 0, 1 or 2;
- W is O or S;
wherein X is directly attached to one or two —Y-Z, and the pharmaceutically acceptable derivatives thereof. - A preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia) as provided above and wherein:
-
- Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and
- W is O.
- A more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia) as provided above and wherein:
-
- Ar1 is thiophene or pyrazole each substituted independently by one to three R1, R2 or R3;
- X is:
a C5-7 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched;
phenyl, indanyl, furanyl, thienyl, imidazolyl, pyridinyl, pyrazinyl, tetrahydrapyridinyl, pyrimidinyl, pyridinonyl, piperdinyl, benzimidazole or piperazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen; - Y is:
a bond or a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O or N, and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; - Z is:
phenyl, heteroaryl selected from pyridinyl, imidazolyl, furanyl and thienyl, heterocycle selected from piperazinyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, morpholino, thiomorpholino and piperidinyl,
each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, morpholinocarbonyl, C1-3acyl, oxo, hydroxy, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, amino-S(O)m, C1-6 alkyl-S(O)m or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino;
or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6alkyl, C1-3alkyl, arylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)m— or arylC0-3alkyl-S(O)m— each of the aforementioned alkyl and aryl attached to the amino group are optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is hydroxy, hydroxyC1-3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by aroyl, C1-3acyl, C1-6alkyl, C1-5 alkoxyC1-3 alkyl, pyridinylC1-3alkyl, tetrahydrafuranylC1-3alkyl, nitrileC1-4alkyl or phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino,
or Z is C1-6alkyl branched or unbranched, C1-6alkoxy or nitrileC1-4alkyl; - R1 is:
C1-4 branched or unbranched alkyl optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an 30 analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S and NH;
C3-10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C1-5 branched or unbranched alkyl;
cyclopentenyl and cyclohexenyl optionally substituted with one to three C1-3 alkyl groups; - R2 is:
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile; - R3 is:
phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, heterocycle selected from the group hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally be partially or fully halogenated, C1-3 alkoxyC1-5alkyl, C1-3thioalkyl, C1-3thioalkylC1-5alkyl, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, amino-S(O)2, di-(C1-3)alkylamino-S(O)2, R4—C1-5 alkyl, R5—C1-5 alkoxy, R6—C(O)—C1-5 alkyl and R7—C1-5 alkyl(R8)N, carboxy-mono- or di-(C1-5)-alkyl-amino;
a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl; wherein the fused aryl is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1-4 alkyl-OC(O), C1-5 alkyl-C(O)—C1-4 branched or unbranched alkyl, an amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, R9—C1-5 alkyl, R10—C1-5 alkoxy, R11—C(O)—C1-5 alkyl and R12—C1-5alkyl(R13)N;
cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups; C1-6alkoxycarbonylC1-6alkyl;
or R1 and R2 taken together optionally form a fused phenyl or pyridinyl ring; - each R8 and R13 is independently selected from the group consisting of: hydrogen and C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and
- each R4, R5, R6, R7, R9, R10, R11 and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
wherein X is directly attached to one —Y-Z. - A yet more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia), as described in the immediate previous paragraph, wherein:
- Ar1 is pyrazole;
- X is:
cyclopentenyl, cyclohexenyl, cycloheptenyl, optionally substituted with an oxo group or one to three C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched;
phenyl, furanyl, thienyl, pyridinyl, pyrazinyl piperidinyl or pyrimidinyl each being optionally independently substituted with one to three C1-2 alkyl, C1-2alkoxy, hydroxy or halogen; - Z is:
phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino, thiomorpholino, thiomorpholino sulfoxide and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, morpholinocarbonyl, C1-3acyl, oxo, hydroxy, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, amino-S(O)m, C1-6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino;
or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6alkyl, C1-3alkyl, arylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)m—, pyridinylC0-3alkyl, tetrahydrafuranylC0-3alkyl, or arylC0-3alkyl-S(O)m— each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is hydroxy, hydroxyc1-3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-6alkyl, pyridinylC0-3alkyl, tetrahydrafuranylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-3acyl, nitrileC1-4alkyl or phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino,
or Z is C1-6alkyl branched or unbranched, C1-6alkoxy or nitrileC1-4alkyl; - R1 is:
C1-4 branched or unbranched alkyl optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S and NH;
C3-10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C1-3 branched or unbranched alkyl;
cyclopentenyl and cyclohexenyl optionally substituted with one to three C1-3 alkyl groups; - R2 is:
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile; - R3 is:
phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, heterocycle selected from the group hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, phenyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, C1-3thioalkyl, C1-3thioalkylC1-5alkyl, amino, mono- or di-(C1-3)alkylamino, NH2C(O) or a mono- or di-(C1-3)alkyl aminocarbonyl,
C1-6alkoxycarbonylC1-6alkyl;
or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups
or R1 and R2 taken together optionally form a fused phenyl or pyridinyl ring.
- A yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia), as described in the immediate previous paragraph, and wherein:
-
- Y is —CH2—, —O—(CH2)0-3—, —CH2CH2—, —CH2NH—, —CH2CH2—NH—, NH—CH2CH2—, —CH2—NH—CH2—, —NH—, —NH—C(O)—, —C(O)—, —CH(OH)—, —CH2(CH2CH3)— or a bond;
- X is:
cyclohexenyl optionally substituted with an oxo group or one to three C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched;
phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with one to three C1-2 alkyl, C1-2alkoxy, hydroxy or halogen; - Z is:
phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino, thiomorpholino, thiomorpholino sulfoxide and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, morpholinocarbonyl, C1-3acyl, oxo, hydroxy, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, amino-S(O)m, C1-6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino;
or Z is optionally substituted with one to three amino or aminocarbonyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6alkyl, C1-3alkyl, arylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)m— or arylC0-3alkyl-S(O)m— each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is hydroxy, hydroxyC1-3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-3alkyl, pyridinylC1-2alkyl, tetrahydrafuranylC1-2alkyl, C1-3 alkoxyC1-3 alkyl, C1-3acyl, nitrileC1-4alkyl, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino,
or Z is C1-6alkyl branched or unbranched, C1-6alkoxy or nitrileC1-4alkyl; - R1 is:
C1-4 branched or unbranched alkyl optionally partially or fully halogenated; - R2 is:
a C1-3 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile; - R3 is:
phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of C1-3 branched or unbranched alkyl which is optionally partially or fully halogenated, C1-3 alkoxy which optionally partially or fully halogenated, C1-3thioalkyl, C1-3thioalkylC1-5alkyl, amino or NH2C(O);
C1-3alkoxycarbonyl;
or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups.
- A further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia), as described in the immediate previous paragraph, and wherein:
-
- Ar1 is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring is substituted independently by one to two R2 or R3;
- X is:
cyclohexenyl;
phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with C1-2alkoxy or hydroxy; - Z is:
phenyl, heteroaryl selected from pyridinyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, tetrahydrofuranyl, piperazinyl, morpholino, thiomorpholino and piperidinyl, each of the aforementioned Z are optionally substituted with one to three C1-3 alkyl, C1-3 alkoxy, oxo, hydroxy or NH2C(O)—;
or Z is hydroxyc1-3alkyl, amino wherein the N atom is optionally independently mono- or di-substituted by pyridinylmethyl, tetrahydrafuranylmethyl, C1-3 alkoxyC1-3 alkyl, C1-3acyl or nitrileC1-4alkyl,
or Z is nitrileC1-4alkyl; - R3 is:
phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to two groups selected from the group consisting of C1-2 alkyl which is optionally partially or fully halogenated, C1-2 alkoxy which optionally partially or fully halogenated, C1-2thioalkyl, C1-2thioalkylC1-3alkyl, amino or NH2C(O);
C1-3alkoxycarbonyl;
or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups.
- A still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia), as described in the immediate previous paragraph, and wherein X is pyridinyl.
- A still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (Ia), as described in the immediate previous paragraph, and wherein:
- the pyridinyl is attached to Ar1 via the 3-pyridinyl position.
- The following compounds are representative of the compounds of formula (Ia) which are useful in the novel methods described herein:
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-methylphenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[3-(4-morpholin-4-yl-methylphenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-yl-methylfuran-2-yl)- naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)cyclohexenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-morpholin-4-yl)ethylphenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminomethylphenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyridin-2-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)- naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(morpholin-4-yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3,4-(morpholin-4-yl-methyl)phenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-methylpiperzin-1-yl-methyl)phenyl)- naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(piperdin-1-yl-methyl)phenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(pyridin-2-yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(pyridin-4-yl)ethylaminomethyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methylaminomethyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3,4-dimethoxyphenylmethyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)imidazol-1-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)imidazol-1-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hydroxybutylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(imidazol-2-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-hydroxymorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-2-methoxyethy-N-methylaminomethyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(4-hydroxymorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)cyclohexenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(tetrahydrofuran-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2-methoxyethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(3-cyanopropoxy)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-methyl-piperdinyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2-cyanoethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(1-morpholin-4-yl-indan-5-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(thiomorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-carboxamidomorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(2-methyl-3-oxo-piperzin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hydroxybutyloxy)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3-methoxyphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4carbonyl)pyrazin-2-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydrothiopyran-4-yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2,6-dimethylmorpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-aminoypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-oxo-1,6-dihydropyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4-carbonyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methyl)pyridin-3-yl)- naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(3-carbamylphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N-(pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N-(pyridin-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N-(tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)-4-methoxypyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-morpholin-4-yl-propyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3-methoxypropyl)amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3-methoxypropyl)-N-methylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′-methyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-benzyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-N-di-(2-cyanoethyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(4-carbamylphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiopyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′-(3-cyanopropyl)-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-methanesulfinylphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-methanesulfonylphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-sulfonamidophenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)carbonylphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(tetrahydrothiopyran-4yl-amino)pyrazin-2-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(methylcarbonylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4-carbonyl)phenyl) -naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′-(3-methylsulfanylpropyl)-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-carbonyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyrazin-2-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-aminopyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-methylpiperdin-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo-piperzin-1-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-carbonyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N,N-di-(2-methoxyethyl)aminomethyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyrazin-2-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo-piperzin-1-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-oxy)pyridin-3-yl)naphthalen-1-yl]-urea
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methoxypyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-carbamylpyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′-methyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-cyclopropylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(pyridin-3-yl-amino)pyrimidin-5-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiopyran-4-yl- amino)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyl)pyrimidin-5-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-amino-4-carbamylphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(hydroxy-pyridin-3-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5-yl)naphthalen-1-yl]-urea;
and the pharmaceutically acceptable derivatives thereof. - In another embodiment of the invention there are provided the following compounds of formula (Ia) which are useful in the novel methods described herein:
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyridin-2-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(pyridin-2-yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methylaminomethyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hydroxybutylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-hydroxypiperidin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(4-hydroxymorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)cyclohexenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(tetrahydrofuran-3-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2-methoxyethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(3-cyanopropoxy)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-methyl-piperdinyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2-45 cyanoethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(thiomorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-carboxamidopiperidin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(2-methyl-3-oxo-piperzin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hydroxybutyloxy)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydrothiopyran-4-yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2,6-dimethylmorpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-aminoypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4-carbonyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl) -N-(pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N-(tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)-4-methoxypyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-morpholin-4-yl-propyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′-methyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiopyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(tetrahydrothiopyran-4yl-amino)pyrazin-2-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(methylcarbonylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′-(3-methylsulfanylpropyl)-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[3-tert-butyl-1′-methyl-1′H-[1,4′]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiopyran-4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyl)pyrimidin-5-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
- 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5-yl)naphthalen-1-yl]-urea and
the pharmaceutically acceptable derivatives thereof. - In a third broad generic aspect, there is provided a method of treating a cytokine mediated disease or condition chosen from: acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula (II) disclosed in WO 00/55139 which is the PCT case of U.S. application Ser. No. 09/505,582:
-
- wherein:
- G is:
an aromatic C6-10 carbocycle or a nonaromatic C3-10 carbocycle saturated or unsaturated;
a 6-10 membered heteroaryl containing 1 or more heteroatoms chosen from O, N and S;
a 5-8 membered monocyclic heterocycle containing one or more heteroatoms chosen from O, N and S;
or
an 8-11 membered bicyclic heterocycle, containing one or more heteroatoms chosen from O, N and S;
wherein G is substituted by one or more R1, R2 or R3; - Ar is:
phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R4 or R5; - X is:
a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains;
phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; - Y is:
a bond or a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; - Z is:
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl each being optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, amino, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, CN, CONH2, COOH or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy;
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylene sulfonyl each being optionally substituted with one to three nitrile, C1-6 alkyl, C1-6 alkoxy, hydroxy, amino, mono- or di-(C1-3 alkyl)amino-C1-3 alkyl, CONH2, phenylamino-C1-3 alkyl or C1-3 alkoxy-C1-3 alkyl;
halogen, C1-4 alkyl, nitrile, amino, hydroxy, C1-6 alkoxy, NH2C(O), mono- or di(C1-3alkyl) aminocarbonyl, mono- or di(C1-6 alkyl)amino, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1-3 alkyl or C1-5 alkoxyalkyl, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, carboxamide-C1-3 alkyl, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino;
C1-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino; - each R1 is independently:
C1-10 alkyl optionally be partially or fully halogenated, and optionally substituted with one to three C3-10 cycloalkanyl, hydroxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C1-6 alkyl which is optionally partially or fully halogenated, C3-8 cycloalkanyl, C5-8 cycloalkenyl, hydroxy, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated or NH2C(O), mono- or di(C1-3alkyl)amino, and mono- or di(C1-3alkyl)aminocarbonyl;
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC1-3alkyl or aryl;
or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C═O, >C═S or NH;
phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC1-3alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by N;
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC1-3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C═O, >C═S or NH;
C3-10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally be substituted with one to three C1-5 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with zero to five halogen, C1-6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or di(C1-3alkyl)aminocarbonyl; the C3-10 branched or unbranced alkenyl being optionally interrupted by one or more heteroatoms chosen from O, N and S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups;
nitrile, halogen;
methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;
silyl containing three C1-4 alkyl groups optionally partially or fully halogenated;
C3-6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrrolidinyl, pyrrolyl, one or more C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-3 alkyl)amino optionally substituted by one or more halogen atoms;
each R2, R4, and R5 is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, nitrile, methoxycarbonyl, C1-3 alkyl-S(O)m optionally partially or fully halogenated, or phenylsulfonyl;
C1-6 alkoxy, hydroxy, amino, or mono- or di-(C1-4 alkyl)amino, nitrile, halogen;
OR6;
nitro; or
mono- or di-(C1-4 alkyl)amino-S(O)2 optionally partially or fully halogenated, or H2NSO2; - each R3 is independently:
phenyl, naphthyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3alkyl)amino-C1-5 alkyl, amino-S(O)2, di-(C1-3alkyl)amino-S(O)2, R7—C1-5 alkyl, R8—C1-5 alkoxy, R9—C(O)—C1-5 alkyl, R10—C1-5 alkyl(R11)N, carboxy-mono- or di-(C1-5alkyl)-amino;
a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C1-6 alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), mono- or di-(C1-3alkyl)aminocarbonyl, C1-4 alkyl-OC(O), C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, R12—C1-5 alkyl, R13—C1-5 alkoxy, R14—C(O)—C1-5 alkyl or R15—C1-5 alkyl(R16)N;
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C═O, >C═S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-4 alkyl-phenyl-C(O)—C1-4 alkyl-, C1-4 alkyl-C(O)—C1-4 alkyl- or C1-4 alkyl-phenyl-S(O)m—C1-4 alkyl-;
C1-6 alkyl or C1-6 branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C1-6 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-5alkyl)amino optionally substituted with R19;
R20C(O)N(R21)—, R22O— or R23R24NC(O)—; R26(CH2)mC(O)N(R21)— or R26C(O)(CH2)mN(R21)—; —C2-6alkenyl substituted by R23R24NC(O)—;
C2-6 alkynyl branched or unbranched carbon chain, optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-4 alkyl)amino optionally substituted by one or more halogen atoms; or
aroyl; - R6 is a:
C1-4 alkyl optionally partially or fully halogenated and optionally substituted with R26; - each R7, R8, R9, R10, R12, R13, R14, R15, R17, R19, R25 and R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C1-4alkyl)amino optionally partially or fully halogenated;
- each R11 and R16 is independently:
hydrogen or C1-4 alkyl optionally partially or fully halogenated; - R18 is independently:
hydrogen or a C1-4 alkyl optionally independently substituted with oxo or R25; - R20 is independently:
C1-10 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl; - R21 is independently:
hydrogen or C1-3 alkyl optionally partially or fully halogenated; - each R22, R23 and R24 is independently:
hydrogen, C1-6 alkyl optionally partially or fully halogenated, said C1-6 alkyl is optionally interrupted by one or more O, N or S, said C1-6 alkyl also being independently optionally substituted by mono- or di-(C1-3alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- or di-(C1-4alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(C1-3alkyl)amino;
or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
- m=0, 1 or 2;
- W is O or S and
the pharmaceutically acceptable derivatives thereof. - A preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II) as provided above and wherein:
- G is:
- phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
- pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl;
- oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl;
- wherein G is substituted by one or more R1, R2 or R3;
- A more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II) as provided above and wherein:
- G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indenyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more R1, R2 or R3;
-
- Ar is:
naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R4 or R5 groups; - X is:
phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl - Y is:
a bond or
a C1-4 saturated or unsaturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; - Z is:
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted with one to three nitrile, C1-3 alkyl, C1-3 alkoxy, amino, mono- or di-(C1-3 alkyl)amino, CONH2 or OH;
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl which are optionally substituted with one to three nitrile, C1-3 alkyl, C1-3 alkoxy, amino, mono- or di-(C1-3 alkyl)amino, CONH2, or OH; nitrile, C1-6 alkyl-S(O)m, halogen, hydroxy, C1-4 alkoxy, amino, mono- or di-(C1-6 alkyl)amino, mono- or di-(C1-3 alkyl)aminocarbonyl or NH2C(O); - each R1 is independently:
C3-6 alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3-6cycloalkyl, phenyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to three groups selected from halogen, C1-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or C1-3alkoxy which is optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC1-3alkyl or phenyl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C═O, >C═S or NH; or
silyl containing three C1-4 alkyl groups optionally partially or fully halogenated; - R2 is independently:
halogen, C1-3 alkoxy, C1-3 alkyl-S(O)m optionally partially or fully halogenated, phenylsulfonyl or nitrile; - R3 is independently:
phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolylidinyl, imidazolyl, pyrazolyl, each being optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, oxo, hydroxy, nitrile, C1-3 alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl)aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, mono- or di-(C1-3alkyl)amino, mono- or di-(C1-3)alkylamino-C1-5 alkyl, mono- or di-(C1-3alkyl)amino-S(O)2, R7—C1-5 alkyl, R8—C1-5 alkoxy, R9—C(O)—C1-5 alkyl, R10—C1-5 alkyl(R11)N, carboxy-mono- or di-(C1-5)-alkyl-amino;
C1-3 alkyl or C1-4 alkoxy each being optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C1-6 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-5 alkyl)amino optionally substituted with R19;
R20C(O)N(R21)—, R22O—; R23R24NC(O)—; R26CH2C(O)N(R21)— or R26C(O)CH2N(R21)—; C2-4alkenyl substituted by R23R24NC(O)—; or
C2-4 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated and optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; and
R23 and R24 taken together optionally form imidazolyl, piperidinyl, morpholinyl, piperazinyl or a pyridinyl ring.
- Ar is:
- A yet more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II), as described in the immediate previous paragraph, wherein:
- G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more R1, R2 or R3;
-
- Ar is naphthyl;
- X is
phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen; - Y is:
a bond or
a C1-4 saturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with an oxo group; - Z is:
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl or pyrrolidinyl which are optionally substituted with one to two C1-2 alkyl or C1-2 alkoxy;
tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl which are optionally substituted with one to two C1-2 alkyl or C1-2 alkoxy; or
C1-3 alkoxy; - each R1 is independently:
C3-5 alkyl optionally partially or fully halogenated, and optionally substituted with phenyl substituted with zero to three halogen, C1-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or C1-3alkoxy which is optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC1-3alkyl or phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring methylene group is replaced by O; and
silyl containing three C1-2 independently alkyl groups optionally partially or fully halogenated; - each R2 is independently:
bromo, chloro, fluoro, methoxy, methylsulfonyl or nitrile; - each R3 is independently:
phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, pyrazolyl, each of the aforementioned is optionally substituted with one to three C1-3 alkyl which is optionally partially or fully halogenated, halogen, oxo, hydroxy, nitrile and C1-3 alkyloxy optionally partially or fully halogenated;
C1-3 alkyl or C1-3 alkoxy each being optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C1-3 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-3 alkyl)amino optionally substituted with R19;
R20C(O)N(R21)—, R22O—; R23R24NC(O)—; R26CH2C(O)N(R21)— or R26C(O)CH2N(R21)—;
C2-4 alkenyl substituted by R23R24NC(O)—; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl; and
R23 and R24 taken together optionally form morpholino.
- A yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II), as described in the immediate previous paragraph, and wherein:
- G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, indolinyl, indolonyl, or indolinonyl, wherein G is substituted by one or more R1, R2 or R3;
-
-
- Ar is 1-naphthyl;
- X is:
phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl; - Y is:
a bond or —CH2—, —CH2CH2—, —C(O)—, —O—, —S—, —NH—CH2CH2CH2—, —N(CH3)—, or —NH—; - each R1 is independently:
C3-5 alkyl optionally partially or fully halogenated, and optionally substituted with phenyl;
cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or fully halogenated, CN, hydroxymethyl or phenyl; or 2-tetrahydrofuranyl substituted by methyl; or
trimethyl silyl; - each R3 is independently:
phenyl, morpholinyl, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl, imidazolyl or pyrazolyl, wherein any of the aforementioned is optionally substituted with C1-2 alkyl which is optionally partially or fully halogenated;
C1-3 alkyl or C1-3 alkoxy each being optionally partially or fully halogenated or optionally substituted with diethylamino;
OR18 or C1-3 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-3 alkyl)amino optionally substituted with R19;
CH3C(O)NH—, R22O—; R23R24NC(O)—; R26CH2C(O)N(R21)— or R26C(O)CH2N(R21)—;
C2-4alkenyl substituted by R23R24NC(O)—; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;
R23 and R24 are H or R23 and R24 taken together optionally form morpholino; and
R26 is morpholino.
- A further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II), as described in the immediate previous paragraph, and wherein:
-
- G is
phenyl, pyridinyl or naphthyl wherein G is substituted by one or more R1, R2 or R3; - X is:
imidazolyl or pyridinyl; - Y is:
—CH2-, —NH—CH2CH2CH2— or —NH—; - Z is morpholino;
- each R1 is independently:
tert-butyl, sec-butyl, tert-amyl or phenyl; - R2 is chloro;
- R3 is independently:
methyl, methoxy, methoxymethyl, hydroxypropyl, acetamide, morpholino or morpholinocarbonyl.
- G is
- A still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II), as described in the immediate previous paragraph, and wherein X is pyridinyl.
- A still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (II), as described immediately above, and wherein the pyridinyl is attached to Ar via the 3-pyridinyl position.
- The following compounds are representative of the compounds of formula (II) which are useful in the novel methods described herein:
- 1-(3-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Fluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Chloro-2-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Iodo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-m-tolyl-urea;
- 1-(4-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Chloro-4-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Chloro-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,5-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen-2-yl-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-phenyl-urea;
- 1-(3-Chloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,6-trichloro-phenyl)-urea;
- 1-(2-Methyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Methyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,3-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methoxy-5-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Chloro-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,4-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Methyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,3-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3,4,5-trimethoxy-phenyl)-urea;
- 1-Biphenyl-4-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,5-Difluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Benzyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Fluoro-6-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,5-trimethyl-phenyl)-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethyl-phenyl)-urea;
- 1-(3-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Fluoro-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4,5-Dimethyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-Chloro-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Isopropyl-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Ethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Butoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 4-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoic acid ethyl ester;
- 1-(4-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,6-Dibromo-4-isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethylsulfanyl-phenyl)-urea;
- 5-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-isophthalic acid dimethyl ester;
- 1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 3-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoic acid ethyl ester;
- 1-(5-tert-Butyl-2-hydroxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Hydroxymethyl-4-phenyl-cyclohexyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methylsulfanyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-pentyloxy-biphenyl-3-yl)-urea;
- 4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoic acid methyl ester;
- 1-(2,5-Diethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-Benzothiazol-6-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(2,5-Diethoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-benzamide;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-phenoxy-phenyl)-urea;
- 1-(5-Ethanesulfonyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-N-phenyl-benzamide;
- 1-(2-Methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-Butyl-4-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzenesulfonamide;
- 1-[3-(2-Methyl-[1,3]dioxolan-2-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,4-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methyl-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methoxy-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Chloro-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethylsulfanyl-phenyl)-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-phenoxy-phenyl)-urea;
- 1-(2-Methoxy-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-imidazol-1-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-morpholin-4-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethyl-phenyl)-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea;
- 1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
- 2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-acetamide;
- 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide
and the pharmaceutically acceptable derivatives thereof. - In addtion to the abovementioned representative compounds the following prophetic compounds of the formula (II) may be useful in the novel methods described herein:
- 1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(2-methyl-3-oxo-piperazin-1-ylmethyl)-phenyl]-naphthalen-1-yl}-urea
- 1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(1-oxo-11-thiomorpholin-4-ylmethyl)-phenyl]-naphthalen-1-yl}-urea;
- 1-[4-(4-{[Bis-(2-cyano-ethyl)-amino]-methyl}-phenyl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
- 1-(2-Methoxy-5-pentafluoroethyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methoxy-5-trifluoromethyl-pyridin-3-yl)-3-{4-[2-(4-oxo-piperidin-1-ylmethyl)-pyrimidin-5-yl]-naphthalen-1-yl}-urea;
- 1-(2-Methoxy-5-trimethylsilanyl-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-phenyl]-naphthalen-1-yl}-urea;
- 1-(3-Methoxy-naphthalen-2-yl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;
- 1-(3-Methyl-naphthalen-2-yl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-(3-tert-Butyl-5-methanesulfinyl-phenyl)-3-{4-[6-(1-methyl-piperidin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(3-tert-Butyl-phenyl)-3-[4-(3-pyridin-3-yl-propoxy)-naphthalen-1-yl]-urea;
- 1-(3-tert-Butyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-(4-Methoxy-biphenyl-3-yl)-3-{4-[4-(tetrahydro-pyran-4-ylmethyl)-imidazol-1-yl]-naphthalen-1-yl}-urea;
- 1-(4-Methyl-biphenyl-3-yl)-3-{4-[4-(2-pyridin-4-yl-ethyl)-piperazin-1-yl]-naphthalen-1-yl}-urea;
- 1-(4-tert-Butyl-biphenyl-2-yl)-3-[4- pyridin-4-ylmethoxy)-naphthalen-1-yl]-urea;
- 1-(4-tert-Butyl-biphenyl-2-yl)-3-{4-[2-(1-oxo-114-thiomorpholin-4-ylmethyl)-3H-imidazol-4-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-hydroxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-{4-[4-(pyrrolidine-1-carbonyl)-phenyl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-phenyl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-{4-[6-(4-oxo-piperidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-pyridin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-phenoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(4-methoxy-6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-{4-[2-(2,6-dimethyl-morpholin-4-ylmethyl)-pyrimidin-5-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-4′-dimethylamino-biphenyl-3-yl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
- 1-(6-Methoxy-3,3-dimethyl-indan-5-yl)-3-{4-[4-(morpholine-4-carbonyl)-phenyl]-naphthalen-1-yl}-urea;
- 1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(6-tert-Butyl-benzo[1,3]dioxol-4-yl)-3-{4-[6-(morpholin-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(7-Methoxy-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-6-yl)-3-{4-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(7-tert-Butyl-2,4-dimethyl-benzooxazol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[2-Methoxy-5-(1-methyl-1-phenyl-ethyl)-phenyl]-3-{4-[6-(2-pyridin-4-yl-ethyl)-pyridazin-3-yl]-naphthalen-1-yl}-urea;
- 1-[2-Methoxy-5-(1-methyl-cyclohexyl)-phenyl]-3-{4-[4-(1-methyl-piperidin-4-ylsulfanyl)-phenyl]-naphthalen-1-yl}-urea;
- 1-[2-Methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
- 1-[2-Methoxy-5-(2-methyl-tetrahydro-furan-2-yl)-phenyl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-urea;
- 1-[2-Methoxy-5-(3-trifluoromethyl-bicyclo[1.1.1]pent-1-yl)-phenyl]-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-[3-tert-Butyl-5-(1-methyl-1H-imidazol-4-yl)-phenyl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-urea;
- 1-[3-tert-Butyl-5-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3-{4-[6-(1-methyl-piperidin-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-[3-tert-Butyl-5-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Imidazol-1-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-[2-methoxy-5-(1-phenyl-cyclopropyl)-phenyl]-urea;
- 1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
- 1-[5-(1-Hydroxymethyl-cyclopropyl)-2-methoxy-phenyl]-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-1-(2-diethylamino-ethyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-3-{4-[6-(1-methyl-piperidin-4-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-{4-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-naphthalen-1-yl}-urea;
- 1-[5-tert-Butyl-2-(2,5-dioxo-pyrrolidin-1-yl)-phenyl]-3-{4-[6-(1H-imidazol-2-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(5-pyridin-4-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(2-morpholin-4-yl-2-oxo-ethoxy)-phenyl]-3-{4-[6-(2-pyridin-4-yl-ethyl)-pyridazin-3-yl]-naphthalen-1-yl}-urea;
- 1-[5-tert-Butyl-2-(2-morpholin-4-yl-2-oxo-ethylamino)-phenyl]-3-{4-[4-(1-methyl- piperidin-4-ylamino)-piperidin-1-yl]-naphthalen-1-yl}-urea;
- 1-[5-tert-Butyl-2-(6-methyl-pyridin-3-yl)-phenyl]-3-{4-[5-(2-pyrrolidin-1-yl-ethyl)-pyridin-2-yl]-naphthalen-1-yl}-urea;
- 1-[5-tert-Butyl-2-methoxy-3-(3-morpholin-4-yl-3-oxo-propenyl)-phenyl]-3-[4-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(2-diethylamino-ethoxy)-2-methoxy-phenyl]-3-{4-[4-(tetrahydro-pyran-4-yloxy)-phenyl]-naphthalen-1-yl}-urea;
- 1-[5-tert-Butyl-3-(2-pyrrolidin-1-yl-ethyl)-benzofuran-7-yl]-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-[6-tert-Butyl-4-(2-dimethylamino-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-3-{4-[6-(thiomorpholin-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-{5-tert-Butyl-2-methoxy-3-[2-(1-methyl-piperidin-4-yloxy)-ethyl]-phenyl}-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 2-(4-tert-Butyl-2-{3-[4-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-ureido}-phenoxy)-N-methyl-acetamide;
- 2-[4-tert-Butyl-2-(3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-ureido)-phenoxy]-acetamide;
- 3-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acrylamide;
- 3-{3-tert-Butyl-5-[3-(4-{4-[2-(1-oxo-114-thiazolidin-3-yl)-ethyl]-phenyl}- naphthalen-1-yl)-ureido]-phenyl}-N,N-dimethyl-propionamide;
- 3-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-benzamide;
- 4-tert-Butyl-2-{3-[4-(2-chloro-4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-ureido}-benzamide;
- N-(4-tert-Butyl-2-{3-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-2-morpholin-4-yl-acetamide;
- N-[3-tert-Butyl-5-(3-{4-[5-(tetrahydro-pyran-4-ylamino)-pyridin-2-yl]-naphthalen-1-yl}-ureido)-phenyl]-2-morpholin-4-yl-acetamide;
- N-[4-tert-Butyl-2-(3-{4-[4-(1-methyl-piperidin-4-yloxy)-phenyl]-naphthalen-1-yl}-ureido)-phenyl]-acetamide
and the pharmaceutically acceptable derivatives thereof. - In another embodiment of the invention there are provided the following compounds of formula (II) which are useful in the novel methods described herein:
- 1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-tert-Butyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-phenyl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-imidazol-1-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-morpholin-4-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[2-Methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethyl-phenyl)-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea;
- 1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
- 1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(5-pyridin-4-ylmethyl-pyridin-2-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 2-[4-tert-Butyl-2-(3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-ureido)-phenoxy]-acetamide;
- 3-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-benzamide;
- 4-tert-Butyl-2-{3-[4-(2-chloro-4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-ureido}-benzamide;
and the pharmaceutically acceptable derivatives thereof. - In another embodiment of the invention there are provided the following compounds of formula (II) which are useful in the novel methods described herein:
- 1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide
and the pharmaceutically acceptable derivatives thereof. - In a fourth broad generic aspect, there is provided a method of treating a cytokine mediated disease or condition chosen from: acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula (III) disclosed in WO 00/55139 which is the PCT case of U.S. application Ser. No. 09/505,582:
-
- wherein:
- E is carbon or a heteroatom group chosen from —O—, —NH— and —S—;
- G is:
an aromatic C6-10 carbocycle or a nonaromatic C3-10carbocycle saturated or unsaturated;
a 6-14 membered monocyclic, bicyclic or tricyclic heteroaryl containing 1 or more heteroatoms chosen from O, N and S;
a 6-8 membered monocyclic heterocycle containing one or more heteroatoms chosen from O, N and S; or
an 8-11 membered bicyclic heterocycle, containing one or more heteroatoms chosen from O, N and S;
wherein G is optionally substituted by one or more R1, R2 or R3; - Ar is:
phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R4 or R5; - X is:
a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched;
aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen; - Y is:
a bond or a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; - Z is:
aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, C1-3acyl, oxo, hydroxy, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino;
or Z is optionally substituted with one to three amino or amino-C1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6alkyl, C1-3alkyl, arylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)m— or arylC0-3alkyl-S(O)m— each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is hydroxy, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-3acyl, C1-6alkyl or C1-3alkoxyC1-3alkyl, C1-6alkyl branched or unbranched, C1-6alkoxy, C1-3acylamino, nitrileC1-4alkyl, C 16 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino; - each R1 is independently:
C1-10 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O)m, and wherein said C1-10 alkyl is optionally substituted with one to three C3-10 cycloalkyl, hydroxy, oxo, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C1-6 alkyl which is optionally partially or fully halogenated, C3-8 cycloalkanyl, C5-8 cycloalkenyl, hydroxy, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated or NH2C(O), mono- or di(C1-3 alkyl)amino, and mono- or di(C1-3alkyl)aminocarbonyl;
or R1 is
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C═O, >C═S or NH;
phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by N;
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C═O, >C═S or NH;
C3-10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally substituted with one to three C1-5 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with one to five halogen, C1-6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or di(C1-3alkyl)aminocarbonyl; the C3-10 branched or unbranced alkenyl being optionally interrupted by one or more heteroatoms chosen from O, N and S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups;
oxo, nitrile, halogen;
silyl containing three C1-4 alkyl groups optionally partially or fully halogenated; or
C3-6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or more C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-3 alkyl)amino optionally substituted by one or more halogen atoms; - each R2, R4, and R5 is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-6acyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C1-3 alkyl-S(O)m optionally partially or fully halogenated, or phenyl-S(O)m;
OR6, C1-6 alkoxy, hydroxy, nitrile, nitro, halogen;
or amino-S(O)m— wherein the N atom is optionally independently mono- or di-substituted by C1-6alkyl or arylC0-3alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C1-3alkyl, arylC0-3alkyl, C1-6acyl, C1-6alkyl-S(O)m— or arylC0-3alkyl-S(O)m—, each of the aforementioned alkyl and aryl in this subparagraph are optionally partially or fully halogenated and optionally substituted with one to two C1-6 alkyl or C1-6 alkoxy; - each R3 is independently:
phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-5alkyl)amino, mono- or di-(C1-3alkyl)amino-C1-5 alkyl, amino-S(O)2, di-(C1-3alkyl)amino-S(O)2, R7—C1-5 alkyl, R8—C1-5 alkoxy, R9—C(O)—C1-5 alkyl, R10—C1-5 alkyl(R11)N, carboxy-mono- or di-(C1-5alkyl)-amino;
a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C1-6 alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), mono- or di-(C1-3alkyl)aminocarbonyl, C1-4 alkyl-OC(O), C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, R12—C1-5 alkyl, R13—C1-5 alkoxy, R14—C(O)—C1-5 alkyl or R15—C1-5 alkyl(R16)N;
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C═O, >C═S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-4 alkyl-phenyl-C(O)—C1-4 alkyl-, C1-4 alkyl-C(O)—C1-4 alkyl- or C1-4 alkyl-phenyl-S(O)m—C1-4 alkyl-;
C1-6 alkyl or C1-6 branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C1-6 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-5alkyl)amino optionally substituted with R19;
R20C(O)N(R21)—, R22O— or R23R24NC(O)—; R26(CH2)mC(O)N(R21)—, R23R24NC(O)—C1-3alkoxy or R26C(O)(CH2)mN(R21)—;
C2-6alkenyl substituted by R23R24NC(O)—;
C2-6 alkynyl branched or unbranched carbon chain, optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-4 alkyl)amino optionally substituted by one or more halogen atoms;
C1-6acyl or aroyl; - R6 is a:
C1-4 alkyl optionally partially or fully halogenated and optionally substituted with R26; - each R7, R8, R9, R10, R12, R13, R14, R15, R17, R19, R25 and R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C1-4alkyl)amino optionally partially or fully halogenated;
- each R11 and R16 is independently:
hydrogen or C1-4 alkyl optionally partially or fully halogenated; - R18 is independently:
hydrogen or a C1-4 alkyl optionally independently substituted with oxo or R25; - R20 is independently:
C1-10 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl; - R21 is independently:
hydrogen or C1-3 alkyl optionally partially or fully halogenated; - each R22, R23 and R24 is independently:
hydrogen, C1-6 alkyl optionally partially or fully halogenated, said C1-6 alkyl is optionally interrupted by one or more O, N or S, said C1-6 alkyl also being independently optionally substituted by mono- or di-(C1-3alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- or di-(C1-4alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(C1-3alkyl)amino;
or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
- m=0, 1 or 2;
- W is 0 or S and
the pharmaceutically acceptable derivatives thereof. - A preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III) as provided above and wherein:
- E is —CH2—, —NH— or —O—;
- W is O;
and - G is:
phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzooxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dibenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, 2,3-dihydro-1H-indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, chromoyl;
oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholino, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is optionally substituted by one or more R1, R2 or R3. - A more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III) as provided above and wherein:
-
- E is —NH—;
- G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzooxazolyl, benzooxazolonyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, indanyl, indenyl, indolyl, indolinyl, indolonyl, 2,3-dihydro-1H-indolyl or indolinonyl, wherein G is optionally substituted by one or more R1, R2 or R3;
- Ar is:
naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R4 or R5 groups; - X is:
phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen; - Y is:
a bond or
a C1-4 saturated or unsaturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; - Z is:
phenyl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl and pyranyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyrrolidinyl and dioxolanyl which are optionally substituted with one to three nitrile, C1-3 alkyl, C1-3 alkoxy, amino, mono- or di-(C1-3 alkyl)amino, CONH2 or OH;
or Z is optionally substituted by phenyl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-3 alkyl or C1-3 alkoxy;
or Z is nitrile, nitrileC1-3 alkyl, C1-6 alkyl-S(O)m, halogen, hydroxy, C1-3 alkyl, C1-3 acylamino, C1-4 alkoxy, amino, mono- or di-(C1-3 alkyl)aminocarbonyl, or amino mono or di-substituted by aminoC1-6 alkyl or C1-3alkoxyC1-3alkyl; - each R1 is independently:
C1-6 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O)m, and wherein said C1-6 alkyl is optionally substituted with one to three C3-6cycloalkyl, oxo, phenyl, dioxolanyl, pyrrolidinyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to three groups selected from halogen, C1-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile and C1-3alkoxy which is optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or phenyl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C═O, >C═S or NH;
oxo;
C3-6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-3alkyl)amino optionally substituted by one or more halogen atoms; or
silyl containing three C1-4 alkyl groups optionally partially or fully halogenated; - R2 is independently:
a C1-5 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C1-2 alkyl-S(O)m optionally partially or fully halogenated, or phenyl-S(O)m;
C1-3 alkoxy, hydroxy, nitrile, nitro, halogen;
or amino-S(O)m— wherein the N atom is optionally independently mono- or di-substituted by C1-3alkyl or arylC0-3alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C1-3alkyl, arylC0-3alkyl, C1-3acyl, C1-4alkyl-S(O)m— or arylC0-3alkyl-S(O)m—, each of the aforementioned alkyl and aryl in this subparagraph are optionally partially or fully halogenated and optionally substituted with one to two C1-3 alkyl or C1-3 alkoxy; - R3 is independently:
phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, [1,3,4]oxadiazol, pyrazolyl, each is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, oxo, hydroxy, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl)aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, mono- or di-(C1-3alkyl)amino, mono- or di-(C1-3)alkylamino-C1-5 alkyl, mono- or di-(C1-3alkyl)amino-S(O)2, R7—C1-5 alkyl, R8—C1-5 alkoxy, R9—C(O)—C1-5 alkyl, R10—C1-5 alkyl(R11)N, carboxy-mono- or di-(C1-5)-alkyl-amino;
C1-3 alkyl or C1-4 alkoxy each being optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C1-6 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-5 alkyl)amino optionally substituted with R19;
R20C(O)N(R21)—, R22O—; R23R24NC(O)—; R26CH2C(O)N(R21)—, R23R24NC(O)—C1-2alkoxy or R26C(O)CH2N(R21)—;
C2-4alkenyl substituted by R23R24NC(O)—; or
C2-4 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated wherein one of the methylene groups is optionally replaced by O, and optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
C1-3acyl; and
R23 and R24 taken together optionally form imidazolyl, piperidinyl, morpholino, piperazinyl or a pyridinyl ring.
- A yet more preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III), as described in the immediate previous paragraph, wherein:
- G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is optionally substituted by one or more R1, R2 or R3;
-
- Ar is naphthyl;
- X is
phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen; - Y is:
a bond or
a C1-4 saturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with nitrile or oxo; - Z is:
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl, pyrrolidinyl, phenylpiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, dioxolanyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl each of which are optionally substituted with one to two C1-2 alkyl or C1-2 alkoxy; or
Z is hydroxy, C1-3 alkyl, C1-3 alkoxy, C1-3 acylamino, C1-3 alkylsulfonyl, nitrile C1-3 alkyl or amino mono or di-substituted by C1-3 alkoxyC1-3 alkyl; - each R1 is independently:
C1-5 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O)m, and wherein said C1-5 alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl each optionally substituted with one to three halogen, C1-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile and C1-3alkoxy which is optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring methylene group is replaced by O;
oxo;
C2-4 alkynyl optionally partially or fully halogenated wherein one or more methylene groups are optionally replaced by O, and optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-3alkyl)amino optionally substituted by one or more halogen atoms; or
silyl containing three C1-2 alkyl groups optionally partially or fully halogenated; - each R2 is independently:
a C1-4 alkyl optionally partially or fully halogenated, C1-4 alkoxy optionally partially or fully halogenated, bromo, chloro, fluoro, methoxycarbonyl, methyl-S(O)m, ethyl-S(O)m each optionally partially or fully halogenated or phenyl-S(O)m;
or R2 is mono- or di-C1-3acylamino, amino-S(O)m or S(O)mamino wherein the N atom is mono- or di-substituted by C1-3alkyl or phenyl, nitrile, nitro or amino; - each R3 is independently:
phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol, pyrazolyl, each of the aforementioned is optionally substituted with one to three C1-3 alkyl which is optionally partially or fully halogenated, halogen, oxo, hydroxy, nitrile and C1-3 alkoxy optionally partially or fully halogenated;
C1-3 alkyl or C1-3 alkoxy optionally partially or fully halogenated or optionally substituted with R1 7;
OR18 or C1-3 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-3 alkyl)amino optionally substituted with R19;
R20C(O)N(R21)—, R22O—; R23R24NC(O)—; R26CH2C(O)N(R21)—, NH2C(O)methoxy or R26C(O)CH2N(R21)—;
C2-4 alkenyl substituted by R23R24NC(O)—; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;
C1-3acyl and
R23 and R24 taken together optionally form morpholino.
- A yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III), as described in the immediate previous paragraph, and wherein:
- G is phenyl, pyridinyl, pyridonyl, 2-naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl, indolinyl, indolonyl, or indolinonyl, wherein G is optionally substituted by one or more R1, R2 or R3;
-
- Ar is 1-naphthyl;
- X is:
phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl; - Y is:
a bond or
—CH2—, —CH2CH2—, —C(O)—, —O—, —S—, —NH—CH2CH2CH2—, —N(CH3)—, CH2(CN)CH2—NH—CH2 or —NH—; - Z is
morpholino, dioxolanyl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, C1-3alkoxyphenylpiperazinyl, hydroxy, C1-3alkyl, N,N-diC1-3alkoxyC1-3alkylamino, C1-3acylamino, C1-3alkylsulfonyl or nitrileC1-3alkyl;
each R1 is independently:
C1-5 alkyl optionally partially or fully halogenated wherein one or more C atoms are optionally independently replaced by O or N, and wherein said C1-5 alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl optionally substituted by C1-3alkoxy;
cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or fully halogenated, nitrile, hydroxymethyl or phenyl; or 2-tetrahydrofuranyl substituted by methyl; or trimethyl silyl;
propynyl substituted hydroxy or tetrahydropyran-2-yloxy; - R2 is
is mono- or di-C1-3acylamino, amino-S(O)m or S(O)m amino wherein the N atom is mono- or di-substituted by C1-3alkyl or phenyl, bromo, chloro, fluoro, nitrile, nitro, amino, methylsulfonyl optionally partially or fully halogenated or phenylsulfonyl; - each R3 is independently:
phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol or pyrazolyl, each is optionally substituted with C1-2 alkyl which is optionally partially or fully halogenated;
C1-3 alkyl or C1-3 alkoxy each being optionally partially or fully halogenated or optionally substituted with diethylamino;
OR18 or C1-3 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-3 alkyl)amino optionally substituted with R19;
CH3C(O)NH—, R22O—; R23R24NC(O)—; R26CH2C(O)N(R21)—, NH2C(O)methoxy or R26C(O)CH2N(R21)—;
C2-4alkenyl substituted by R23R24NC(O)—; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;
C1-2acyl; and
R23 and R24 are H or R23 and R24 taken together optionally form morpholino; and
R26 is morpholino.
- A further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III), as described in the immediate previous paragraph, and wherein:
-
- G is
phenyl, pyridinyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl or 2-naphthyl wherein G is optionally substituted by one or more R1, R2 or R3; - X is:
imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl; - Y is:
a bond, CH2(CN)CH2—NH—CH2, —CH2—, —NH—CH2CH2CH2— or —NH—; - Z is morpholin-4yl, dioxolan-2yl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5yl, methoxyphenylpiperazinyl, hydroxy, methyl, N,N-dimethoxyethylamino, acetylamino, methylsulfonyl or cyanoethyl;
- each R1 is independently:
tert-butyl, sec-butyl, tert-amyl, phenyl, tetrahydropyran-2-yloxypropynyl, hydroxypropynyl, trihalomethyl, 2,2-diethylpropionyl or cyclohexanyl; - R2 is chloro, nitro, amino, nitrile, methylsulfonylamino, diacetylamino, phenylsulfonylamino, N,N-di(methylsulfonyl)amino, methylsulfonyl or trihalomethylsulfonyl;
- R3 is independently:
methyl, C1-3 alkoxy, methoxymethyl, hydroxypropyl, dimethylamino, C1-4alkylamino, NH2C(O)methoxy, acetyl, pyrrolidinyl, imidazolyl, pyrazolyl, morpholino or morpholinocarbonyl.
- G is
- A still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III), as described in the immediate previous paragraph, and wherein:
-
- X is pyridinyl.
- A still yet further preferred subgeneric aspect of the invention comprises a method of using the compounds of the formula (III), as described immediately above, and wherein
-
- the pyridinyl is attached to Ar via the 3-pyridinyl position.
- The following compounds are representative of the compounds of formula (II) which are useful in the novel methods described herein:
- 1-(4-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;
- 1-(6-Chloro-4-trifluoromethyl-pyridin-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(4-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[2-Methoxy-5-(1-methyl-1-phenyl-ethyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- (5-tert-Butyl-2-methyl-phenyl)-carbamic acid 3-(5-{4-[3-(5-tert-butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylamino)-propyl ester;
- 1-(6-tert-Butyl-benzo[1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
- 1,3-Bis-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-p-tolyloxy-5-trifluoromethyl-phenyl)-urea;
- 1-[2-(2-Methoxy-phenoxy)-5-trifluoromethyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen-1-yl-urea;
- 1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-{5-tert-Butyl-2-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-Hydroxymethyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methoxy-dibenzofuran-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,5-Di-tert-butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[3-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-oxazol-5-yl-phenyl)-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-[1,3,4]oxadiazol-2-yl-phenyl)-urea;
- 1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- Furan-2-carboxylic acid (4-tert-butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
- 1-(2-Methoxy-4-phenylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Hydroxy-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N,N-Diethyl-4-methoxy-3-{3-[4-(6- morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzenesulfonamide;
- 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-(1,1-Dimethyl-propyl)-2-phenoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 2-Chloro-5-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoic acid isopropyl ester;
- 1-(4-Amino-3,5-dibromo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-acetamide;
- 1-(2-Methoxy-5-phenoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-cyclopentyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-pyridin-3-yl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
- 1-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[6-tert-Butyl-4-(2-morpholin-4-yl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide;
- 1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-bis(methanesulfon)amide;
- 1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Ethanesulfonyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-dimethylamino-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-pyrrolidin-3-yl]-acetamide;
- 1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-propionamide;
- 1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethanesulfonyl-phenyl)-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-isobutyramide;
- 2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenoxy)-acetamide;
- 1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(6-tert-Butyl-3-cyano-2-methoxymethoxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(6-tert-Butyl-3-cyano-2-hydroxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl)-urea;
- 1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-benzenesulfonamide;
- Ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
- N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazin-2-yl)-methanesulfonamide;
- 1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-morpholin-4-yl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperidine-3-carboxylic acid amide;
- 1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperidine-4-carboxylic acid amide;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridin-pg,120 3-yl]-naphthalen-1-yl}-urea;
- 1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-{4-[6-(4-Acetyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
- 4-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperazine-1-carboxylic acid ethyl ester;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-pyridin-3-yl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-methylsulfanyl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-piperazin-1-yl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyridin-2-yl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1-ylmethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-thia-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-naphthalen-1-yl]-urea;
- 1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl)-acetamide;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-N-methyl-acetamide;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- [4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid 3-tert-butyl-phenyl ester;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide and
the pharmaceutically acceptable derivatives thereof. - In another embodiment of the invention there are provided the following compounds of formula (III) which are useful in the novel methods described herein:
- 1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
- 1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
- 1-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-bis(methanesulfon)amide;
- 1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
- N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-pyrrolidin-3-yl]-acetamide;
- 1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-propionamide;
- 1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethanesulfonyl-phenyl)-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-isobutyramide;
- 2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenoxy)-acetamide;
- 1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-benzenesulfonamide;
- Ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
- N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazin-2-yl)-methanesulfonamide;
- 1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperidine-3-carboxylic acid amide;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1-ylmethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-naphthalen-1-yl]-urea;
- 1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl)-acetamide;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-N-methyl-acetamide;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide;
- 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
- [4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid 3-tert-butyl-phenyl ester;
- N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide and
the pharmaceutically acceptable derivatives thereof. - In addtion to the abovementioned compounds the following prophetic compounds of the formula (III) may be useful in the novel methods described herein:
- 1-(5-tert-Butyl-2-methylsulfanyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-chloro-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- 1-(5-tert-Butyl-2-methylamino-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
- N-(5-tert-Butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-2-oxo-2H-pyridin-1-yl)-methanesulfonamide;
- 5-tert-Butyl-7-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzooxazole-2-carboxylic acid amide;
- 2-(5-tert-Butyl-7-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzooxazol-2-yl)-acetamide;
- 5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzamide and
the pharmaceutically acceptable derivatives thereof. - The invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
- Some of the compounds of formulas (I), (Ia), (II) and (III) can exist in more than one tautomeric form. The invention includes methods using all such tautomers.
- All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, “C1-4alkoxy” is a C1-4alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
- The term “aroyl” as used in the present specification shall be understood to mean “benzoyl” or “naphthoyl”.
- The term “carbocycle” shall be understood to mean an aliphatic hydrocarbon radical containing from three to twelve carbon atoms. Carbocycles include hydrocarbon rings containing from three to ten carbon atoms. These carbocycles may be either aromatic and non-aromatic ring systems. The non-aromatic ring systems may be mono- or polyunsaturated. Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be used inerchangeably.
- The term “heterocycle” refers to a stable nonaromatic 4-8 membered (but preferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated. Each heterocycle consists of carbon atoms and one or more, preferably from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure. Unless otherwise stated, heterocycles include but are not limited to, for example oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl, dithianyl or 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl.
- The term “heteroaryl” shall be understood to mean an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring containing 1-4 heteroatoms such as N,O and S. Unless otherwise stated, such heteroaryls include: pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl.
- The invention includes methods of using pharmaceutically acceptable derivatives of compounds of formula (I), (Ia), (II) and (III). A “pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt or ester, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a pharmacologically active metabolite or pharmacologically active residue thereof. A pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the formulas (I), (Ia), (II) or (III).
- Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N—(C1-C4 alkyl)4 + salts.
- In addition, within the scope of the invention is use of prodrugs of compounds of the formula (I), (Ia), (II) and (III). Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.
- In accordance with the invention, there are provided novel methods of using the compounds of the formulas (I), (Ia), (II) and (III). as described in WO 00/55139 and U.S. application Ser. No. 09/505,582. The compounds disclosed therein effectively block inflammatory cytokine production from cells. The inhibition of cytokine production is an attractive means for preventing and treating a variety of cytokine mediated diseases or conditions associated with excess cytokine production, e.g., diseases and pathological conditions involving inflammation. Thus, the compounds are described in WO 00/55139 as being useful for the treatment of the following conditions and diseases: osteoarthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus and insulin-dependent diabetes mellitus, rheumatoid arthritis, Alzheimer's disease, toxic shock syndrome, diabetes, inflammatory bowel diseases, acute and chronic pain as well as symptoms of inflammation and cardiovascular disease, stroke, myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing entrerocolitis.
- Suprisingly, it has been discovered for the first time that the compounds disclosed in WO 00/55139 are useful in methods for treating: acute and chronic inflammation in the lung caused by inhalation of smoke, endometriosis, Behcet's disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer's disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease and congestive heart failure.
- For therapeutic use, the compounds may be administered in any conventional dosage form in any conventional manner. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, topically or by inhalation. The preferred modes of administration are oral and intravenous.
- The compounds may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutic compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. The above described compounds may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Reference is this regard may be made to Cappola et al.: U.S. patent application Ser. No. 09/902,822 and PCT/US 01/21860 each incorporated by reference herein in their entirety. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formulas (I), (Ia), (II) and (III) (w/w) or a combination thereof. The optimum percentage (w/w) of a compound of the invention may vary and is within the purview of those skilled in the art. Alternatively, the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
- As mentioned above, dosage forms of the compounds described herein include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition thereto, and the judgment of the treating physician.
- The compounds described hereinabove may be prepared by Method A, B, or C as illustrated in Scheme I, preferably method C, in WO 00/55139. Starting materials used are either commercially available or easily prepared from commercially available materials known by those skilled in the art. Further reference in this regard may be made to U.S. application Ser. Nos. 09/505,582, 09/484,638, 09/714,539, 09/611,109, 09/698,442 and U.S. provisional application No. 60/216,283. Each of the aforementioned incorporated herein by reference in their entirety.
- Inhibition of TNF Production in THP Cells
- The inhibition of cytokine production can be observed by measuring inhibition of TNFα in lipopolysaccharide stimulated THP cells (for example, see W. Prichett et al., 1995, J Inflammation, 45, 97). All cells and reagents were diluted in RPMI 1640 with phenol red and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and streptomycin (50 units/ml each) and fetal bovine serum (FBS, 3%) (GIBCO, all conc. final). Assay was performed under sterile conditions; only test compound preparation was nonsterile. Initial stock solutions were made in DMSO followed by dilution into RPMI 1640 2-fold higher than the desired final assay concentration. Confluent THP.1 cells (2×106 cells/ml, final conc.; American Type Culture Company, Rockville, Md.) were added to 96 well polypropylene round bottomed culture plates (Costar 3790; sterile) containing 125 μl test compound (2 fold concentrated) or DMSO vehicle (controls, blanks). DMSO concentration did not exceed 0.2% final. Cell mixture was allowed to preincubate for 30 min, 37° C., 5% CO2 prior to stimulation with lipopolysaccharide (LPS; 1 μg/ml final; Siga L-2630, from E.coli serotype 0111. B4; stored as 1 mg/ml stock in endotoxin screened distilled H2O at −80° C.). Blanks (unstimulated) received H2O vehicle; final incubation volume was 250 μl. Overnight incubation (18-24 hr) proceeded as described above. Assay was terminated by centrifuging plates 5 min, room temperature, 1600 rpm (400×g); supernatants were transferred to clean 96 well plates and stored −80° C. until analyzed for human TNFα by a commercially available ELISA kit (Biosource #KHC3015, Camarillo, Calif.). Data was analyzed by non-linear regression (Hill equation) to generate a dose response curve using SAS Software System (SAS institute, Inc., Cary, NC). The calculated IC50 value is the concentration of the test compound that caused a 50% decrease in the maximal TNFα production.
- Preferred compounds including those from the synthetic examples above were evaluated and had IC50<10 uM in this assay.
- Inhibition of Other Cytokines
- By similar methods using peripheral blood monocytic cells, appropriate stimuli, and commercially available ELISA kits (or other method of detection such as radioimmunoassay), for a particular cytokine, inhibition of IL-1beta, GM-CSF, IL-6 and IL-8 can be demonstrated for preferred compounds (for example, see J. C. Lee et al., 1988, Int. J. Immunopharmacol., 10,835).
Claims (16)
1. A method of treating cancer, said method comprising administering to a patient a therapeutically effective amount of a compound of the formula (III):
wherein:
E is carbon or a heteroatom group chosen from —O—, —NH— and —S—;
G is:
an aromatic C6-10 carbocycle or a nonaromatic C3-10carbocycle saturated or unsaturated;
a 6-14 membered monocyclic, bicyclic or tricyclic heteroaryl containing 1 or more heteroatoms chosen from O, N and S;
a 6-8 membered monocyclic heterocycle containing one or more heteroatoms chosen from O, N and S; or
an 8-11 membered bicyclic heterocycle, containing one or more heteroatoms chosen from O, N and S;
wherein G is optionally substituted by one or more R1, R2 or R3;
Ar is:
phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R4 or R5;
X is:
a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched;
aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
Y is:
a bond or a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
Z is:
aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, C1-3acyl, oxo, hydroxy, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino;
or Z is optionally substituted with one to three amino or amino-C1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6alkyl, C1-3alkyl, arylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)m— or arylC0-3alkyl-S(O)m— each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-6 alkyl or C1-6 alkoxy;
or Z is hydroxy, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-3acyl, C1-6alkyl or C1-3alkoxyC1-3alkyl, C1-6alkyl branched or unbranched, C1-6alkoxy, C1-3acylamino, nitrileC1-4 alkyl, C1-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
each R1 is independently:
C1-10 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O)m, and wherein said C1-10 alkyl is optionally substituted with one to three C3-10 cycloalkyl, hydroxy, oxo, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C1-6 alkyl which is optionally partially or fully halogenated, C3-8 cycloalkanyl, C5-8 cycloalkenyl, hydroxy, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated or NH2C(O), mono- or di(C1-3 alkyl)amino, and mono- or di(C1-3alkyl)aminocarbonyl;
or R1 is
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C═O, >C═S or NH;
phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by N;
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C═O, >C═S or NH;
C3-10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally substituted with one to three C1-5 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with one to five halogen, C1-6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or diC1-3alkyl)aminocarbonyl; the C3-10 branched or unbranced alkenyl being optionally interrupted by one or more heteroatoms chosen from O, N and S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups;
oxo, nitrile, halogen;
silyl containing three C1-4 alkyl groups optionally partially or fully halogenated; or
C3-6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or more C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-3alkyl)amino optionally substituted by one or more halogen atoms;
each R2, R4, and R5 is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-6acyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C1-3 alkyl-S(O)m optionally partially or fully halogenated, or phenyl-S(O)m;
OR6, C1-6 alkoxy, hydroxy, nitrile, nitro, halogen;
or amino-S(O)m— wherein the N atom is optionally independently mono- or di-substituted by C1-6alkyl or arylC0-3alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C1-3alkyl, arylC0-3alkyl, C1-6acyl, C1-6alkyl-S(O)m— or arylC0-3alkyl-S(O)m—, each of the aforementioned alkyl and aryl in this subparagraph are optionally partially or fully halogenated and optionally substituted with one to two C1-6 alkyl or C1-6 alkoxy;
each R3 is independently:
phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl)aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-5alkyl)amino, mono- or di-(C1-3alkyl)amino-C1-5 alkyl, amino-S(O)2, di-(C1-3alkyl)amino-S(O)2, R7—C1-5 alkyl, R8—C1-5 alkoxy, R9—C(O)—C1-5 alkyl, R10—C1-5 alkyl(R11)N, carboxy-mono- or di-(C1-5alkyl)-amino;
a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C1-6 alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), mono- or di-(C1-3alkyl)aminocarbonyl, C1-4 alkyl-OC(O), C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, R12—C1-5 alkyl, R13—C1-5 alkoxy, R14—C(O)—C1-5 alkyl or R15—C1-5 alkyl(R16)N;
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C═O, >C═S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-4 alkyl-phenyl-C(O)—C1-4 alkyl-, C1-4 alkyl-C(O)—C1-4 alkyl- or C1-4 alkyl-phenyl-S(O)m—C1-4 alkyl-;
C1-6 alkyl or C1-6 branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C1-6 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-5alkyl)amino optionally substituted with R19;
R20C(O)N(R21)—, R22O— or R23R24NC(O)—; R26(CH2)mC(O)N(R21)—, R23R24NC(O)—C1-3alkoxy or R26C(O)(CH2)mN(R21)—;
C2-6alkenyl substituted by R23R24NC(O)—;
C2-6 alkynyl branched or unbranched carbon chain, optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-4 alkyl)amino optionally substituted by one or more halogen atoms;
C1-6acyl or aroyl;
R6 is a:
C1-4 alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R7, R8, R9, R10, R12, R13, R14, R15, R17, R19, R25 and R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C1-4alkyl)amino optionally partially or fully halogenated;
each R11 and R16 is independently:
hydrogen or C1-4 alkyl optionally partially or fully halogenated;
R18 is independently:
hydrogen or a C1-4 alkyl optionally independently substituted with oxo or R25;
R20 is independently:
C1-10 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
R21 is independently:
hydrogen or C1-3 alkyl optionally partially or fully halogenated;
each R22, R23 and R24 is independently:
hydrogen, C1-6 alkyl optionally partially or fully halogenated, said C1-6 alkyl is optionally interrupted by one or more O, N or S, said C1-6 alkyl also being independently optionally substituted by mono- or di-(C1-3alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- or di-(C1-4alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(C1-3alkyl)amino;
or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
m=0, 1 or 2;
W is O or S and
the pharmaceutically acceptable salts thereof.
2. The method according to claim 1 wherein
E is —CH2—, —NH— or —O—;
W is O; and
G is:
phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzooxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dibenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, 2,3-dihydro-1H-indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, chromoyl;
oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholino, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is optionally substituted by one or more R1, R2 or R3.
3. The method according to claim 2 wherein
E is —NH—;
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzooxazolyl, benzooxazolonyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, indanyl, indenyl, indolyl, indolinyl, indolonyl, 2,3-dihydro-1H-indolyl or indolinonyl, wherein G is optionally substituted by one or more R1, R2 or R3;
Ar is:
naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R4 or R5 groups;
X is:
phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
Y is:
a bond or
a C1-4 saturated or unsaturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
Z is:
phenyl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl and pyranyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyrrolidinyl and dioxolanyl which are optionally substituted with one to three nitrile, C1-3 alkyl, C1-3 alkoxy, amino, mono- or di-(C1-3 alkyl)amino, CONH2 or OH;
or Z is optionally substituted by phenyl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-3 alkyl or C1-3 alkoxy;
or Z is nitrile, nitrileC1-3 alkyl, C1-6 alkyl-S(O)m, halogen, hydroxy, C1-3 alkyl, C1-3 acylamino, C1-4 alkoxy, amino, mono- or di-(C1-3 alkyl)aminocarbonyl, or amino mono or di-substituted by aminoC1-6 alkyl or C1-3alkoxyC1-3alkyl;
each R1 is independently:
C1-6 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O)m, and wherein said C1-6 alkyl is optionally substituted with one to three C3-6cycloalkyl, oxo, phenyl, dioxolanyl, pyrrolidinyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to three groups selected from halogen, C1-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile and C1-3alkoxy which is optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or phenyl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C═O, >C═S or NH;
oxo;
C3-6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-3alkyl)amino optionally substituted by one or more halogen atoms; or
silyl containing three C1-4 alkyl groups optionally partially or fully halogenated;
R2 is independently:
a C1-5 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C1-2 alkyl-S(O)m optionally partially or fully halogenated, or phenyl-S(O)m;
C1-3 alkoxy, hydroxy, nitrile, nitro, halogen;
or amino-S(O)m— wherein the N atom is optionally independently mono- or di-substituted by C1-3alkyl or arylC0-3alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C1-3alkyl, arylC0-3alkyl, C1-3acyl, C1-4alkyl-S(O)m— or arylC0-3alkyl-S(O)m—, each of the aforementioned alkyl and aryl in this subparagraph are optionally partially or fully halogenated and optionally substituted with one to two C1-3 alkyl or C1-3 alkoxy;
R3 is independently:
phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, [1,3,4]oxadiazol, pyrazolyl, each is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, oxo, hydroxy, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl)aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, mono- or di-(C1-3alkyl)amino, mono- or di-(C1-3)alkylamino-C1-5 alkyl, mono- or di-(C1-3alkyl)amino-S(O)2, R7—C1-5 alkyl, R8—C1-5 alkoxy, R9—C(O)—C1-5 alkyl, R10—C1-5 alkyl(R11)N, carboxy-mono- or di-(C1-5)-alkyl-amino;
C1-3 alkyl or C1-4 alkoxy each being optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C1-6 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-5 alkyl)amino optionally substituted with R19;
R20C(O)N(R21)—, R22O—; R23R24NC(O)—; R26CH2C(O)N(R21)—, R23R24NC(O)—C1-2alkoxy or R26C(O)CH2N(R21)—;
C2-4alkenyl substituted by R23R24NC(O)—; or
C2-4 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated wherein one of the methylene groups is optionally replaced by O, and optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
C1-3acyl; and
R23 and R24 taken together optionally form imidazolyl, piperidinyl, morpholino, piperazinyl or a pyridinyl ring.
4. The method according to claim 3 wherein:
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is optionally substituted by one or more R1, R2 or R3;
Ar is naphthyl;
X is
phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
Y is:
a bond or
a C1-4 saturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with nitrile or oxo;
Z is:
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl, pyrrolidinyl, phenylpiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, dioxolanyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl each of which are optionally substituted with one to two C1-2 alkyl or C1-2 alkoxy; or
Z is hydroxy, C1-3 alkyl, C1-3 alkoxy, C1-3 acylamino, C1-3 alkylsulfonyl, nitrile C1-3 alkyl or amino mono or di-substituted by C1-3 alkoxyC1-3 alkyl;
each R1 is independently:
C1-5 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O)m, and wherein said C1-5 alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl each optionally substituted with one to three halogen, C1-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile and C1-3alkoxy which is optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyc1-3alkyl or phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring methylene group is replaced by O;
oxo;
C2-4 alkynyl optionally partially or fully halogenated wherein one or more methylene groups are optionally replaced by O, and optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-3 alkyl)amino optionally substituted by one or more halogen atoms; or
silyl containing three C1-2 alkyl groups optionally partially or fully halogenated;
each R2 is independently:
a C1-4 alkyl optionally partially or fully halogenated, C1-4 alkoxy optionally partially or fully halogenated, bromo, chloro, fluoro, methoxycarbonyl, methyl-S(O)m, ethyl-S(O)m each optionally partially or fully halogenated or phenyl-S(O)m;
or R2 is mono- or di-C1-3 acylamino, amino-S(O)m or S(O)mamino wherein the N atom is mono- or di-substituted by C1-3alkyl or phenyl, nitrile, nitro or amino;
each R3 is independently:
phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol, pyrazolyl, each of the aforementioned is optionally substituted with one to three C1-3 alkyl which is optionally partially or fully halogenated, halogen, oxo, hydroxy, nitrile and C1-3 alkoxy optionally partially or fully halogenated;
C1-3 alkyl or C1-3 alkoxy optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C1-3 alkyl optionally substituted with OR18; amino or mono- or di-(C1-3 alkyl)amino optionally substituted with R19;
R20C(O)N(R21)—, R22O—; R23R24NC(O)—; R26CH2C(O)N(R21)—, NH2C(O)methoxy or R26C(O)CH2N(R21)—;
C2-4 alkenyl substituted by R23R24NC(O)—; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;
C1-3acyl and
R23 and R24 taken together optionally form morpholino.
5. The method according to claim 4 wherein
G is phenyl, pyridinyl, pyridonyl, 2-naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl, indolinyl, indolonyl, or indolinonyl, wherein G is optionally substituted by one or more R1, R2 or R3;
Ar is 1-naphthyl;
X is:
phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl;
Y is:
a bond or
—CH2—, —CH2CH2—, —C(O)—, —O—, —S—, —NH—CH2CH2CH2—, —N(CH3)—, CH2(CN)CH2—NH—CH2 or —NH—;
Z is
morpholino, dioxolanyl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, C1-3alkoxyphenylpiperazinyl, hydroxy, C1-3alkyl, N,N-diC1-3alkoxyC1-3alkylamino, C1-3acylamino, C1-3alkylsulfonyl or nitrileC1-3alkyl;
each R1 is independently:
C1-5 alkyl optionally partially or fully halogenated wherein one or more C atoms are optionally independently replaced by 0 or N, and wherein said C1-5 alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl optionally substituted by C1-3alkoxy;
cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or fully halogenated, nitrile, hydroxymethyl or phenyl; or 2-tetrahydrofuranyl substituted by methyl; or trimethyl silyl;
propynyl substituted hydroxy or tetrahydropyran-2-yloxy;
R2 is
is mono- or di-C1-3acylamino, amino-S(O)m or S(O)m amino wherein the N atom is mono- or di-substituted by C1-3alkyl or phenyl, bromo, chloro, fluoro, nitrile, nitro, amino, methylsulfonyl optionally partially or fully halogenated or phenylsulfonyl;
each R3 is independently:
phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, [1,3,4]oxadiazol or pyrazolyl, each is optionally substituted with C1-2 alkyl which is optionally partially or fully halogenated;
C1-3 alkyl or C1-3 alkoxy each being optionally partially or fully halogenated or optionally substituted with diethylamino;
OR18 or C1-3 alkyl optionally substituted with OR18;
amino or mono- or di-(C1-3 alkyl)amino optionally substituted with R19;
CH3C(O)NH—, R22O—; R23R24NC(O)—; R26CH2C(O)N(R21)—, NH2C(O)methoxy or R26C(O)CH2N(R21)—;
C2-4alkenyl substituted by R23R24NC(O)—; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;
C1-2acyl; and
R23 and R24 are H or R23 and R24 taken together optionally form morpholino; and
R26 is morpholino.
6. The method according to claim 5 wherein
G is
phenyl, pyridinyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl or 2-naphthyl wherein G is optionally substituted by one or more R1, R2 or R3;
X is:
imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl;
Y is:
a bond, CH2(CN)CH2—NH—CH2, —CH2—, —NH—CH2CH2CH2— or —NH—;
Z is morpholin-4yl, dioxolan-2yl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5yl, methoxyphenylpiperazinyl, hydroxy, methyl, N,N-dimethoxyethylamino, acetylamino, methylsulfonyl or cyanoethyl;
each R1 is independently:
tert-butyl, sec-butyl, tert-amyl, phenyl, tetrahydropyran-2-yloxypropynyl, hydroxypropynyl, trihalomethyl, 2,2-diethylpropionyl or cyclohexanyl;
R2 is chloro, nitro, amino, nitrile, methylsulfonylamino, diacetylamino, phenylsulfonylamino, N,N-di(methylsulfonyl)amino, methylsulfonyl or trihalomethylsulfonyl;
R3 is independently:
methyl, C1-3 alkoxy, methoxymethyl, hydroxypropyl, dimethylamino, C1-4alkylamino, NH2C(O)methoxy, acetyl, pyrrolidinyl, imidazolyl, pyrazolyl, morpholino or morpholinocarbonyl.
7. The method according to claim 6 wherein
X is pyridinyl.
8. The method according to claim 7 wherein
the pyridinyl is attached to Ar via the 3-pyridinyl position.
9. A method of treating cancer, said method comprising administering to a patient a therapeutically effective amount of a compound chosen from:
1-(4-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;
1-(6-Chloro-4-trifluoromethyl-pyridin-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(4-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[2-Methoxy-5-(1-methyl-1-phenyl-ethyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
(5-tert-Butyl-2-methyl-phenyl)-carbamic acid 3-(5-{4-[3-(5-tert-butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylamino)-propyl ester;
1-(6-tert-Butyl-benzo[1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
1,3-Bis-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-p-tolyloxy-5-trifluoromethyl-phenyl)-urea;
1-[2-(2-Methoxy-phenoxy)-5-trifluoromethyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen-1-yl-urea;
1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-{5-tert-Butyl-2-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-Hydroxymethyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2-Methoxy-dibenzofuran-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2,5-Di-tert-butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[3-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-oxazol-5-yl-phenyl)-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-[1,3,4]oxadiazol-2-yl-phenyl)-urea;
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
Furan-2-carboxylic acid (4-tert-butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
1-(2-Methoxy-4-phenylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Hydroxy-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N,N-Diethyl-4-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzenesulfonamide;
1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-(1,1-Dimethyl-propyl)-2-phenoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
2-Chloro-5-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoic acid isopropyl ester;
1-(4-Amino-3,5-dibromo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-acetamide;
1-(2-Methoxy-5-phenoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-cyclopentyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-pyridin-3-yl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
1-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[6-tert-Butyl-4-(2-morpholin-4-yl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide;
1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-bis(methanesulfon)amide;
1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2-Ethanesulfonyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-dimethylamino-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-pyrrolidin-3-yl]-acetamide;
1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-propionamide;
1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethanesulfonyl-phenyl)-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-isobutyramide;
2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenoxy)-acetamide;
1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-3-cyano-2-methoxymethoxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-3-cyano-2-hydroxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl)-urea;
1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-benzenesulfonamide;
Ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazin-2-yl)-methanesulfonamide;
1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-morpholin-4-yl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperidine-3-carboxylic acid amide;
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperidine-4-carboxylic acid amide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-{4-[6-(4-Acetyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
4-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperazine-1-carboxylic acid ethyl ester;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-pyridin-3-yl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-methylsulfanyl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-piperazin-1-yl-ethylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyridin-2-yl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1-ylmethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-thia-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl)-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-N-methyl-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid 3-tert-butyl-phenyl ester and
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide or
the pharmaceutically acceptable salts thereof.
10. A method of treating cancer, said method comprising administering to a patient a therapeutically effective amount of a compound chosen from:
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-acetamide;
1-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-bis(methanesulfon)amide;
1-[5-tert-Butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-pyrrolidin-3-yl]-acetamide;
1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-propionamide;
1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethanesulfonyl-phenyl)-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-isobutyramide;
2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenoxy)-acetamide;
1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-benzenesulfonamide;
Ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazin-2-yl)-methanesulfonamide;
1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-ylmethyl)-piperidine-3-carboxylic acid amide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1-ylmethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl)-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-N-methyl-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalen-1-yl}-urea;
[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid 3-tert-butyl-phenyl ester and
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide and
or the pharmaceutically salts thereof.
11. A method of treating cancer, said method comprising administering to a patient a therapeutically effective amount of a compound chosen from:
1-(5-tert-Butyl-2-methylsulfanyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-chloro-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methylamino-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-2-oxo-2H-pyridin-1-yl)-methanesulfonamide;
5-tert-Butyl-7-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzooxazole-2-carboxylic acid amide;
2-(5-tert-Butyl-7-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzooxazol-2-yl)-acetamide;
5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-methanesulfonamide;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea and
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea or
the pharmaceutically acceptable salts thereof.
12. The method according to claims 1, 9, 10 or 11 wherein the cancer is chosen from cancer cachexia, multiple myeloma, acute myelogenous leukemia and Castleman's disease.
13. The method according to claims 1, 9, 10 or 11 wherein the method involves inhibiting proliferation of acute myelogenous leukemia blasts.
14. The method according to claims 1, 9, 10 or 11 wherein the cancer is a plasma cell dyscrasias.
15. The method according to claim 1 , 9 , 10 or 11 wherein treament is done in conjunction with genotoxic therapy.
16. The method according to claim 1 , 9 , 10 or 11 wherein the method involves treating tumor cells.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/684,173 US20070155724A1 (en) | 2001-09-13 | 2007-03-09 | Methods of Treating Cytokine Mediated Diseases |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US31895801P | 2001-09-13 | 2001-09-13 | |
US10/237,306 US7211575B2 (en) | 2001-09-13 | 2002-09-09 | Methods of treating cytokine mediated diseases |
US11/684,173 US20070155724A1 (en) | 2001-09-13 | 2007-03-09 | Methods of Treating Cytokine Mediated Diseases |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/237,306 Division US7211575B2 (en) | 2001-09-13 | 2002-09-09 | Methods of treating cytokine mediated diseases |
Publications (1)
Publication Number | Publication Date |
---|---|
US20070155724A1 true US20070155724A1 (en) | 2007-07-05 |
Family
ID=23240282
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/237,306 Active 2025-05-28 US7211575B2 (en) | 2001-09-13 | 2002-09-09 | Methods of treating cytokine mediated diseases |
US11/684,173 Abandoned US20070155724A1 (en) | 2001-09-13 | 2007-03-09 | Methods of Treating Cytokine Mediated Diseases |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/237,306 Active 2025-05-28 US7211575B2 (en) | 2001-09-13 | 2002-09-09 | Methods of treating cytokine mediated diseases |
Country Status (5)
Country | Link |
---|---|
US (2) | US7211575B2 (en) |
EP (1) | EP1427412A1 (en) |
JP (1) | JP2005503400A (en) |
CA (1) | CA2458029A1 (en) |
WO (1) | WO2003022273A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8809372B2 (en) | 2011-09-30 | 2014-08-19 | Asana Biosciences, Llc | Pyridine derivatives |
US9199975B2 (en) | 2011-09-30 | 2015-12-01 | Asana Biosciences, Llc | Biaryl imidazole derivatives for regulating CYP17 |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030220336A1 (en) * | 2002-04-05 | 2003-11-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Method of treating mucus hypersecretion |
ES2327834T3 (en) | 2002-11-21 | 2009-11-04 | Neurosearch A/S | DERIVATIVES OF DIARILUREIDO AND ITS MEDICAL USE. |
US7144911B2 (en) | 2002-12-31 | 2006-12-05 | Deciphera Pharmaceuticals Llc | Anti-inflammatory medicaments |
US7202257B2 (en) * | 2003-12-24 | 2007-04-10 | Deciphera Pharmaceuticals, Llc | Anti-inflammatory medicaments |
US8338120B2 (en) | 2003-05-05 | 2012-12-25 | Probiodrug Ag | Method of treating inflammation with glutaminyl cyclase inhibitors |
AU2004266719A1 (en) * | 2003-08-22 | 2005-03-03 | Boehringer Ingelheim France S.A.S. | Methods of treating COPD and pulmonary hypertension |
JP4895811B2 (en) * | 2003-09-11 | 2012-03-14 | ケミア,インコーポレイテッド | Cytokine inhibitor |
KR20070028591A (en) * | 2004-06-25 | 2007-03-12 | 이코스 코포레이션 | Bisarylurea derivatives useful for inhibiting chk1 |
CA2592118C (en) | 2004-12-23 | 2015-11-17 | Deciphera Pharmaceuticals, Llc | Urea derivatives as enzyme modulators |
TWI370130B (en) | 2005-11-24 | 2012-08-11 | Eisai R&D Man Co Ltd | Two cyclic cinnamide compound |
TWI378091B (en) | 2006-03-09 | 2012-12-01 | Eisai R&D Man Co Ltd | Multi-cyclic cinnamide derivatives |
US20080064717A1 (en) * | 2006-05-19 | 2008-03-13 | Rajesh Iyengar | Inhibitors of diacylglycerol O-acyltransferase type 1 enzyme |
US20080015227A1 (en) * | 2006-05-19 | 2008-01-17 | Kym Philip R | Inhibitors of diacylglycerol O-acyltransferase type 1 enzyme |
JPWO2007135969A1 (en) * | 2006-05-19 | 2009-10-01 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Urea-cinnamide derivatives |
US8188113B2 (en) | 2006-09-14 | 2012-05-29 | Deciphera Pharmaceuticals, Inc. | Dihydropyridopyrimidinyl, dihydronaphthyidinyl and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
WO2008039794A1 (en) * | 2006-09-25 | 2008-04-03 | Arete Therapeutics, Inc. | Soluble epoxide hydrolase inhibitors |
US7790756B2 (en) | 2006-10-11 | 2010-09-07 | Deciphera Pharmaceuticals, Llc | Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases |
PE20081791A1 (en) | 2007-02-28 | 2009-02-07 | Eisai Randd Man Co Ltd | TWO CYCLIC DERIVATIVES OF OXOMORPHOLIN |
EP2117540A1 (en) * | 2007-03-01 | 2009-11-18 | Probiodrug AG | New use of glutaminyl cyclase inhibitors |
JP2010524970A (en) * | 2007-04-20 | 2010-07-22 | デシフェラ ファーマシューティカルズ,エルエルシー | Kinase inhibitors useful for the treatment of myeloproliferative disorders and other proliferative disorders |
US20110189167A1 (en) * | 2007-04-20 | 2011-08-04 | Flynn Daniel L | Methods and Compositions for the Treatment of Myeloproliferative Diseases and other Proliferative Diseases |
EP2559693B1 (en) | 2007-08-31 | 2014-11-26 | Eisai R&D Management Co., Ltd. | Polycyclic compound |
US7935815B2 (en) | 2007-08-31 | 2011-05-03 | Eisai R&D Management Co., Ltd. | Imidazoyl pyridine compounds and salts thereof |
EP2365752B1 (en) * | 2008-10-29 | 2014-09-24 | Deciphera Pharmaceuticals, Llc | Cyclopropane amides and analogs exhibiting anti-cancer and anti-proliferative activities |
US20130035326A1 (en) * | 2009-08-19 | 2013-02-07 | Ambit Biosciences Corporation | Biaryl compounds and methods of use thereof |
US8461179B1 (en) | 2012-06-07 | 2013-06-11 | Deciphera Pharmaceuticals, Llc | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
CN112020500A (en) | 2017-12-22 | 2020-12-01 | 拉文纳制药公司 | Aminopyridine derivatives as inhibitors of phosphatidylinositol phosphokinase |
JP2022544234A (en) | 2019-08-12 | 2022-10-17 | デシフェラ・ファーマシューティカルズ,エルエルシー | Ripretinib for treating gastrointestinal stromal tumors |
TW202122082A (en) | 2019-08-12 | 2021-06-16 | 美商迪賽孚爾製藥有限公司 | Methods of treating gastrointestinal stromal tumors |
MX2022008097A (en) | 2019-12-30 | 2022-09-19 | Deciphera Pharmaceuticals Llc | Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-d ihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea. |
EP4084778B1 (en) | 2019-12-30 | 2023-11-01 | Deciphera Pharmaceuticals, LLC | Amorphous kinase inhibitor formulations and methods of use thereof |
US11779572B1 (en) | 2022-09-02 | 2023-10-10 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6319921B1 (en) * | 1999-01-19 | 2001-11-20 | Boerhinger Ingelheim Pharmaceuticals, Inc. | Aromatic heterocyclic compound as antiinflammatory agents |
US6358945B1 (en) * | 1999-03-12 | 2002-03-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
US6608052B2 (en) * | 2000-02-16 | 2003-08-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
US6720321B2 (en) * | 2001-06-05 | 2004-04-13 | Boehringer Ingelheim Pharmaceuticals, Inc. | 1,4-disubstituted benzo-fused cycloalkyl urea compounds |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU1367599A (en) | 1997-11-03 | 1999-05-24 | Boehringer Ingelheim Pharmaceuticals, Inc. | Aromatic heterocyclic compounds as anti-inflammatory agents |
ATE556713T1 (en) | 1999-01-13 | 2012-05-15 | Bayer Healthcare Llc | OMEGA-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS P38 KINASE INHIBITORS |
-
2002
- 2002-09-09 CA CA002458029A patent/CA2458029A1/en not_active Abandoned
- 2002-09-09 US US10/237,306 patent/US7211575B2/en active Active
- 2002-09-09 JP JP2003526402A patent/JP2005503400A/en active Pending
- 2002-09-09 EP EP02797884A patent/EP1427412A1/en not_active Withdrawn
- 2002-09-09 WO PCT/US2002/028615 patent/WO2003022273A1/en active Application Filing
-
2007
- 2007-03-09 US US11/684,173 patent/US20070155724A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6319921B1 (en) * | 1999-01-19 | 2001-11-20 | Boerhinger Ingelheim Pharmaceuticals, Inc. | Aromatic heterocyclic compound as antiinflammatory agents |
US6358945B1 (en) * | 1999-03-12 | 2002-03-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
US6608052B2 (en) * | 2000-02-16 | 2003-08-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
US6720321B2 (en) * | 2001-06-05 | 2004-04-13 | Boehringer Ingelheim Pharmaceuticals, Inc. | 1,4-disubstituted benzo-fused cycloalkyl urea compounds |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8809372B2 (en) | 2011-09-30 | 2014-08-19 | Asana Biosciences, Llc | Pyridine derivatives |
US9199975B2 (en) | 2011-09-30 | 2015-12-01 | Asana Biosciences, Llc | Biaryl imidazole derivatives for regulating CYP17 |
US9266873B2 (en) | 2011-09-30 | 2016-02-23 | Asana Biosciences, Llc | Pyridine derivatives |
US9371316B2 (en) | 2011-09-30 | 2016-06-21 | Asana Biosciences, Llc | Pyridine derivatives |
US9533981B2 (en) | 2011-09-30 | 2017-01-03 | Asana Biosciences, Llc | Pyridine derivatives |
Also Published As
Publication number | Publication date |
---|---|
US7211575B2 (en) | 2007-05-01 |
JP2005503400A (en) | 2005-02-03 |
EP1427412A1 (en) | 2004-06-16 |
WO2003022273A1 (en) | 2003-03-20 |
US20030060455A1 (en) | 2003-03-27 |
CA2458029A1 (en) | 2003-03-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7211575B2 (en) | Methods of treating cytokine mediated diseases | |
US7019006B2 (en) | Compounds useful as anti-inflammatory agents | |
US20070099832A1 (en) | Combination Therapy with p38 MAP Kinase Inhibitors and their Pharmaceutical Compositions | |
US7041669B2 (en) | 1,4-benzofused urea compounds useful in treating cytokine mediated diseases | |
CA2490819A1 (en) | Compounds useful as anti-inflammatory agents | |
EP1466906A1 (en) | Heterocyclic urea and related compounds useful as anti-inflammatory agents | |
ZA200107446B (en) | Compounds useful as anti-inflammatory agents. | |
RU2298008C2 (en) | Compounds, pharmaceutical compositions containing thereof and method for treatment of cytokine-mediated disease | |
EP1690854A1 (en) | Heterocyclic urea and related compounds useful as anti-inflammatory agents | |
AU2004200240B2 (en) | Compounds useful as anti-inflammatory agents | |
MXPA01009163A (en) | Compounds useful as anti-inflammatory agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |