AU2009326149B2 - P38 MAP kinase inhibitors - Google Patents

Info

Publication number

AU2009326149B2

AU2009326149B2 AU2009326149A AU2009326149A AU2009326149B2 AU 2009326149 B2 AU2009326149 B2 AU 2009326149B2 AU 2009326149 A AU2009326149 A AU 2009326149A AU 2009326149 A AU2009326149 A AU 2009326149A AU 2009326149 B2 AU2009326149 B2 AU 2009326149B2

Authority

AU

Australia

Prior art keywords

tert

pyrazol

butyl

tolyl

ureido

Prior art date

2008-12-11

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.)

Ceased

Links

• Espacenet
• Global Dossier
• Discuss

• 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 title abstract description 41
• 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 title abstract description 41
• 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 title abstract description 11
• 150000001875 compounds Chemical class 0.000 claims abstract description 364
• 238000011282 treatment Methods 0.000 claims abstract description 33
• 150000003839 salts Chemical class 0.000 claims abstract description 16
• 230000000155 isotopic effect Effects 0.000 claims abstract description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims description 234
• 125000000217 alkyl group Chemical group 0.000 claims description 149
• 229910052757 nitrogen Inorganic materials 0.000 claims description 115
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 101
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 97
• 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 91
• 125000000623 heterocyclic group Chemical group 0.000 claims description 82
• 125000005842 heteroatom Chemical group 0.000 claims description 76
• 125000001424 substituent group Chemical group 0.000 claims description 69
• 229920006395 saturated elastomer Polymers 0.000 claims description 60
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 58
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 55
• 239000004202 carbamide Substances 0.000 claims description 53
• 229910052736 halogen Inorganic materials 0.000 claims description 48
• 150000002367 halogens Chemical class 0.000 claims description 48
• 229910052799 carbon Inorganic materials 0.000 claims description 46
• -1 methylphenoxy Chemical group 0.000 claims description 46
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 41
• 125000003545 alkoxy group Chemical group 0.000 claims description 39
• 125000003118 aryl group Chemical group 0.000 claims description 38
• 125000001072 heteroaryl group Chemical group 0.000 claims description 37
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 37
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
• 125000001188 haloalkyl group Chemical group 0.000 claims description 27
• 229910052717 sulfur Inorganic materials 0.000 claims description 24
• 239000001257 hydrogen Substances 0.000 claims description 22
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 21
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 21
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
• 238000000034 method Methods 0.000 claims description 17
• 208000006673 asthma Diseases 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
• 239000003814 drug Substances 0.000 claims description 13
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
• 230000005764 inhibitory process Effects 0.000 claims description 12
• 125000001624 naphthyl group Chemical group 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 125000002947 alkylene group Chemical group 0.000 claims description 9
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 9
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
• 125000004429 atom Chemical group 0.000 claims description 8
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
• 239000001301 oxygen Substances 0.000 claims description 8
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
• IXWAAWQRRFJLQU-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-methylsulfanylacetamide Chemical compound C1=NC(NC(=O)CSC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 IXWAAWQRRFJLQU-UHFFFAOYSA-N 0.000 claims description 7
• MQDVUDAZJMZQMF-UHFFFAOYSA-N pyridin-2-ylurea Chemical compound NC(=O)NC1=CC=CC=N1 MQDVUDAZJMZQMF-UHFFFAOYSA-N 0.000 claims description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• YPSPPJRTCRMQGD-UHFFFAOYSA-N morpholine-3-carboxamide Chemical compound NC(=O)C1COCCN1 YPSPPJRTCRMQGD-UHFFFAOYSA-N 0.000 claims description 6
• ZKWFSTHEYLJLEL-UHFFFAOYSA-N morpholine-4-carboxamide Chemical compound NC(=O)N1CCOCC1 ZKWFSTHEYLJLEL-UHFFFAOYSA-N 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
• 101100289867 Mus musculus Lyl1 gene Proteins 0.000 claims description 5
• 201000004681 Psoriasis Diseases 0.000 claims description 5
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 5
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
• 201000010105 allergic rhinitis Diseases 0.000 claims description 5
• 201000008937 atopic dermatitis Diseases 0.000 claims description 5
• 206010006451 bronchitis Diseases 0.000 claims description 5
• 239000000969 carrier Substances 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 5
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
• 125000004434 sulfur atom Chemical group 0.000 claims description 5
• FBPBSLVHEURFAU-UHFFFAOYSA-N 1-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-1-methylurea Chemical compound C1=NC(N(C(N)=O)C)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 FBPBSLVHEURFAU-UHFFFAOYSA-N 0.000 claims description 4
• 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 4
• 206010006187 Breast cancer Diseases 0.000 claims description 4
• 208000026310 Breast neoplasm Diseases 0.000 claims description 4
• 206010006458 Bronchitis chronic Diseases 0.000 claims description 4
• 206010006895 Cachexia Diseases 0.000 claims description 4
• 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
• 206010010741 Conjunctivitis Diseases 0.000 claims description 4
• 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 4
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 4
• 206010012434 Dermatitis allergic Diseases 0.000 claims description 4
• 206010012442 Dermatitis contact Diseases 0.000 claims description 4
• 206010014561 Emphysema Diseases 0.000 claims description 4
• 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 4
• 206010027476 Metastases Diseases 0.000 claims description 4
• 206010028980 Neoplasm Diseases 0.000 claims description 4
• 206010033645 Pancreatitis Diseases 0.000 claims description 4
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
• 208000002205 allergic conjunctivitis Diseases 0.000 claims description 4
• 208000024998 atopic conjunctivitis Diseases 0.000 claims description 4
• 208000010668 atopic eczema Diseases 0.000 claims description 4
• 201000008275 breast carcinoma Diseases 0.000 claims description 4
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 208000007451 chronic bronchitis Diseases 0.000 claims description 4
• 208000010247 contact dermatitis Diseases 0.000 claims description 4
• 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 4
• 206010017758 gastric cancer Diseases 0.000 claims description 4
• 208000010749 gastric carcinoma Diseases 0.000 claims description 4
• 125000005843 halogen group Chemical group 0.000 claims description 4
• 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 201000001441 melanoma Diseases 0.000 claims description 4
• 230000009401 metastasis Effects 0.000 claims description 4
• 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 4
• 201000008482 osteoarthritis Diseases 0.000 claims description 4
• 206010039083 rhinitis Diseases 0.000 claims description 4
• 201000000306 sarcoidosis Diseases 0.000 claims description 4
• 201000009890 sinusitis Diseases 0.000 claims description 4
• 201000000498 stomach carcinoma Diseases 0.000 claims description 4
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 3
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
• HZMXEQDABFTNOS-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-hydroxyacetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)CO)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 HZMXEQDABFTNOS-UHFFFAOYSA-N 0.000 claims description 3
• UTKDGEYLIRNNON-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]oxane-4-carboxamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)C4CCOCC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 UTKDGEYLIRNNON-UHFFFAOYSA-N 0.000 claims description 3
• PVBNMOSWYWSNHS-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-3-yl]-2-(2-methoxyethoxy)acetamide Chemical compound COCCOCC(=O)NC1=CN=CC=C1COC(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)C=C1 PVBNMOSWYWSNHS-UHFFFAOYSA-N 0.000 claims description 3
• DQTZMOTXLGCWQY-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-3-yl]-2-methoxyacetamide Chemical compound COCC(=O)NC1=CN=CC=C1COC(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)C=C1 DQTZMOTXLGCWQY-UHFFFAOYSA-N 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 3
• ISDHACALPXDRBK-QHCPKHFHSA-N (2s)-n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-(methylamino)propanamide Chemical compound C1=NC(NC(=O)[C@H](C)NC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 ISDHACALPXDRBK-QHCPKHFHSA-N 0.000 claims description 2
• DXLIDCWBUAERSC-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[2-(cyclopropylcarbamoylamino)pyrimidin-4-yl]oxynaphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3N=C(NC(=O)NC4CC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 DXLIDCWBUAERSC-UHFFFAOYSA-N 0.000 claims description 2
• UOFXPWJDDNZHGC-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[2-[2-(carbamoylamino)pyridin-4-yl]ethoxy]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCCC=3C=C(NC(N)=O)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 UOFXPWJDDNZHGC-UHFFFAOYSA-N 0.000 claims description 2
• GRXPDPAENZUFKQ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[[2-(methylcarbamoylamino)pyridin-4-yl]methoxy]naphthalen-1-yl]urea Chemical compound C1=NC(NC(=O)NC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 GRXPDPAENZUFKQ-UHFFFAOYSA-N 0.000 claims description 2
• KYWXRBNOYGGPIZ-UHFFFAOYSA-N 1-morpholin-4-ylethanone Chemical compound CC(=O)N1CCOCC1 KYWXRBNOYGGPIZ-UHFFFAOYSA-N 0.000 claims description 2
• MJBQULVSEVUDGR-UHFFFAOYSA-N 2-[[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]carbamoylamino]acetic acid Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(=O)NCC(O)=O)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 MJBQULVSEVUDGR-UHFFFAOYSA-N 0.000 claims description 2
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
• 125000003047 N-acetyl group Chemical group 0.000 claims description 2
• UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 2
• 230000001684 chronic effect Effects 0.000 claims description 2
• IZVDYFCDVQANSW-UHFFFAOYSA-N n-[4-[1-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxyethyl]pyridin-2-yl]-2-methoxyacetamide Chemical compound C1=NC(NC(=O)COC)=CC(C(C)OC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 IZVDYFCDVQANSW-UHFFFAOYSA-N 0.000 claims description 2
• OSYGDWRURYLVIZ-UHFFFAOYSA-N n-[4-[2-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxyethyl]pyridin-3-yl]-2-methoxyacetamide Chemical compound COCC(=O)NC1=CN=CC=C1CCOC(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)C=C1 OSYGDWRURYLVIZ-UHFFFAOYSA-N 0.000 claims description 2
• OBALKFHHXFROHH-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-(dimethylamino)acetamide Chemical compound C1=NC(NC(=O)CN(C)C)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 OBALKFHHXFROHH-UHFFFAOYSA-N 0.000 claims description 2
• LSPOFOIAYVFYPY-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-(methylamino)acetamide Chemical compound C1=NC(NC(=O)CNC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 LSPOFOIAYVFYPY-UHFFFAOYSA-N 0.000 claims description 2
• HNSNMKWKSZCKCZ-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-[(4-methoxyphenyl)methyl-methylamino]acetamide Chemical compound C1=CC(OC)=CC=C1CN(C)CC(=O)NC1=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=CC=N1 HNSNMKWKSZCKCZ-UHFFFAOYSA-N 0.000 claims description 2
• ITENSOATZCMKDD-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-methylsulfonylacetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)CS(C)(=O)=O)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 ITENSOATZCMKDD-UHFFFAOYSA-N 0.000 claims description 2
• UBWALTPIDHCQBF-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-morpholin-4-ylacetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)CN4CCOCC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 UBWALTPIDHCQBF-UHFFFAOYSA-N 0.000 claims description 2
• WFJLURLWTCHRMQ-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-pyrrolidin-1-ylacetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)CN4CCCC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 WFJLURLWTCHRMQ-UHFFFAOYSA-N 0.000 claims description 2
• LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 claims description 2
• KXRKCQMMJPNVJH-UHFFFAOYSA-N 2-[[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]carbamoylamino]-n-(3-imidazol-1-ylpropyl)acetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(=O)NCC(=O)NCCCN4C=NC=C4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 KXRKCQMMJPNVJH-UHFFFAOYSA-N 0.000 claims 2
• CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims 2
• 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims 1
• JDSCOPALPVVAMI-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[2-(carbamoylamino)pyridin-4-yl]oxynaphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(N)=O)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 JDSCOPALPVVAMI-UHFFFAOYSA-N 0.000 claims 1
• YTTNMTQRALUGRX-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[2-(carbamoylamino)pyrimidin-4-yl]oxynaphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3N=C(NC(N)=O)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 YTTNMTQRALUGRX-UHFFFAOYSA-N 0.000 claims 1
• HOWYJHYHNQTBNF-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[2-(methylcarbamoylamino)pyrimidin-4-yl]oxynaphthalen-1-yl]urea Chemical compound CNC(=O)NC1=NC=CC(OC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=N1 HOWYJHYHNQTBNF-UHFFFAOYSA-N 0.000 claims 1
• JCKFIXSIXRNIDE-UHFFFAOYSA-N 2-[[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]carbamoylamino]-n-(2-morpholin-4-ylethyl)acetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(=O)NCC(=O)NCCN4CCOCC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 JCKFIXSIXRNIDE-UHFFFAOYSA-N 0.000 claims 1
• KCTUDTQELNAVHE-UHFFFAOYSA-N 2-[[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]carbamoylamino]-n-(2-pyridin-4-ylethyl)acetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(=O)NCC(=O)NCCC=4C=CN=CC=4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 KCTUDTQELNAVHE-UHFFFAOYSA-N 0.000 claims 1
• SGHDEYQIMDEDSS-UHFFFAOYSA-N 2-[[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]carbamoylamino]-n-methylacetamide Chemical compound C1=NC(NC(=O)NCC(=O)NC)=CC(OC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 SGHDEYQIMDEDSS-UHFFFAOYSA-N 0.000 claims 1
• SZVBINLROMAAJO-UHFFFAOYSA-N 3-[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyrimidin-2-yl]-1,1-dimethylurea Chemical compound CN(C)C(=O)NC1=NC=CC(OC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=N1 SZVBINLROMAAJO-UHFFFAOYSA-N 0.000 claims 1
• JJUNTENKMQXWST-UHFFFAOYSA-N 3-[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyrimidin-2-yl]morpholine-4-carboxamide Chemical compound C(C)(C)(C)C1=NN(C(=C1)NC(NC1=CC=C(C2=CC=CC=C12)OC1=NC(=NC=C1)C1N(CCOC1)C(=O)N)=O)C1=CC=C(C=C1)C JJUNTENKMQXWST-UHFFFAOYSA-N 0.000 claims 1
• DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims 1
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
• JAZBEDYFRCSDJC-UHFFFAOYSA-N n-[2-[[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]amino]-2-oxoethyl]-2,6-difluoro-3-[2-(2-methoxyethoxy)ethoxy]benzamide Chemical compound COCCOCCOC1=CC=C(F)C(C(=O)NCC(=O)NC=2N=CC=C(OC=3C4=CC=CC=C4C(NC(=O)NC=4N(N=C(C=4)C(C)(C)C)C=4C=CC(C)=CC=4)=CC=3)C=2)=C1F JAZBEDYFRCSDJC-UHFFFAOYSA-N 0.000 claims 1
• DMUQGBCYZATOMY-UHFFFAOYSA-N n-[2-[[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]amino]-2-oxoethyl]-3-morpholin-4-ylpropanamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(=O)CNC(=O)CCN4CCOCC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 DMUQGBCYZATOMY-UHFFFAOYSA-N 0.000 claims 1
• CRTSPNMFWCENOV-UHFFFAOYSA-N n-[2-[[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]amino]-2-oxoethyl]morpholine-4-carboxamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(=O)CNC(=O)N4CCOCC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 CRTSPNMFWCENOV-UHFFFAOYSA-N 0.000 claims 1
• UPBBOCRQZZBDGZ-UHFFFAOYSA-N n-[2-[[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]amino]-2-oxoethyl]oxane-4-carboxamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(=O)CNC(=O)C4CCOCC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 UPBBOCRQZZBDGZ-UHFFFAOYSA-N 0.000 claims 1
• QBTIJQJNAFHVLA-UHFFFAOYSA-N n-[2-[[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]amino]-2-oxoethyl]pyridine-4-carboxamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(=O)CNC(=O)C=4C=CN=CC=4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 QBTIJQJNAFHVLA-UHFFFAOYSA-N 0.000 claims 1
• JXPFBRYPSJLQII-UHFFFAOYSA-N n-[4-[2-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxyethyl]pyridin-2-yl]-2-methoxyacetamide Chemical compound C1=NC(NC(=O)COC)=CC(CCOC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 JXPFBRYPSJLQII-UHFFFAOYSA-N 0.000 claims 1
• SNEANVKQJYWEHG-UHFFFAOYSA-N n-[4-[2-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxyethyl]pyridin-3-yl]-2-(2-methoxyethoxy)acetamide Chemical compound COCCOCC(=O)NC1=CN=CC=C1CCOC(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)C=C1 SNEANVKQJYWEHG-UHFFFAOYSA-N 0.000 claims 1
• PPPQWFKCBMWVSQ-UHFFFAOYSA-N n-[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]-2-(carbamoylamino)acetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(=O)CNC(N)=O)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 PPPQWFKCBMWVSQ-UHFFFAOYSA-N 0.000 claims 1
• RFPCDTMBOWMHOI-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-(2-methoxyethylsulfanyl)acetamide Chemical compound C1=NC(NC(=O)CSCCOC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 RFPCDTMBOWMHOI-UHFFFAOYSA-N 0.000 claims 1
• IKKNUEWYLJUICE-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-[2-(2-methoxyethoxy)ethylsulfanyl]acetamide Chemical compound C1=NC(NC(=O)CSCCOCCOC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 IKKNUEWYLJUICE-UHFFFAOYSA-N 0.000 claims 1
• HDCPXJGHIXMQRE-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-3-methoxypropanamide Chemical compound C1=NC(NC(=O)CCOC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 HDCPXJGHIXMQRE-UHFFFAOYSA-N 0.000 claims 1
• RVRBIRJDPKWHFW-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-3-methylsulfonyl-2-oxoimidazolidine-1-carboxamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)N4C(N(CC4)S(C)(=O)=O)=O)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 RVRBIRJDPKWHFW-UHFFFAOYSA-N 0.000 claims 1
• PLYNOQRDVZFNRR-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-4-methylpiperazine-1-carboxamide Chemical compound C1CN(C)CCN1C(=O)NC1=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=CC=N1 PLYNOQRDVZFNRR-UHFFFAOYSA-N 0.000 claims 1
• UFSCPCUZCQBBOT-UHFFFAOYSA-N n-[6-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]phenoxy]pyrimidin-4-yl]-2-methoxyacetamide Chemical compound C1=NC(NC(=O)COC)=CC(OC=2C=CC(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=N1 UFSCPCUZCQBBOT-UHFFFAOYSA-N 0.000 claims 1
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims 1
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims 1
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 1
• 210000004072 lung Anatomy 0.000 abstract description 14
• 239000003112 inhibitor Substances 0.000 abstract description 9
• 238000002560 therapeutic procedure Methods 0.000 abstract description 6
• 208000027866 inflammatory disease Diseases 0.000 abstract description 4
• 108091000080 Phosphotransferase Proteins 0.000 abstract description 2
• 102000020233 phosphotransferase Human genes 0.000 abstract description 2
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 370
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 363
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 224
• 239000000243 solution Substances 0.000 description 215
• 239000000543 intermediate Substances 0.000 description 203
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 193
• 239000000203 mixture Substances 0.000 description 161
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 134
• 239000011541 reaction mixture Substances 0.000 description 132
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 115
• 235000019439 ethyl acetate Nutrition 0.000 description 107
• 239000007787 solid Substances 0.000 description 103
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 102
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 79
• 238000010828 elution Methods 0.000 description 78
• 229910004298 SiO 2 Inorganic materials 0.000 description 65
• 238000005481 NMR spectroscopy Methods 0.000 description 57
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
• 235000013877 carbamide Nutrition 0.000 description 50
• 238000003818 flash chromatography Methods 0.000 description 50
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 48
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 44
• 239000012267 brine Substances 0.000 description 43
• 239000000725 suspension Substances 0.000 description 41
• 239000002904 solvent Substances 0.000 description 38
• 238000003756 stirring Methods 0.000 description 35
• 238000004440 column chromatography Methods 0.000 description 34
• 238000006243 chemical reaction Methods 0.000 description 33
• WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
• 239000000047 product Substances 0.000 description 31
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 28
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 26
• HQSBZAVHGCZGPX-UHFFFAOYSA-N 4-[(4-nitronaphthalen-1-yl)oxymethyl]pyridin-2-amine Chemical compound C1=NC(N)=CC(COC=2C3=CC=CC=C3C([N+]([O-])=O)=CC=2)=C1 HQSBZAVHGCZGPX-UHFFFAOYSA-N 0.000 description 25
• 210000004027 cell Anatomy 0.000 description 25
• 239000010410 layer Substances 0.000 description 25
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
• 239000000284 extract Substances 0.000 description 21
• 239000012044 organic layer Substances 0.000 description 21
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
• AUIRNGLMBHIITH-UHFFFAOYSA-N 4-nitronaphthalen-1-ol Chemical compound C1=CC=C2C(O)=CC=C([N+]([O-])=O)C2=C1 AUIRNGLMBHIITH-UHFFFAOYSA-N 0.000 description 20
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 19
• 239000003921 oil Substances 0.000 description 19
• 235000019198 oils Nutrition 0.000 description 19
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 19
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
• 229910000104 sodium hydride Inorganic materials 0.000 description 18
• XVDSBUCGMJBTNO-UHFFFAOYSA-N 1-fluoro-4-nitronaphthalene Chemical compound C1=CC=C2C([N+](=O)[O-])=CC=C(F)C2=C1 XVDSBUCGMJBTNO-UHFFFAOYSA-N 0.000 description 17
• 239000012634 fragment Substances 0.000 description 17
• 239000003039 volatile agent Substances 0.000 description 17
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical compound COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 15
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
• ZRJJXXDQIQFZBW-UHFFFAOYSA-N (2-aminopyridin-4-yl)methanol Chemical compound NC1=CC(CO)=CC=N1 ZRJJXXDQIQFZBW-UHFFFAOYSA-N 0.000 description 14
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 13
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 13
• 238000009472 formulation Methods 0.000 description 13
• ITHNHEWXIBNEDG-UHFFFAOYSA-N 5-tert-butyl-2-(4-methylphenyl)pyrazol-3-amine Chemical compound C1=CC(C)=CC=C1N1C(N)=CC(C(C)(C)C)=N1 ITHNHEWXIBNEDG-UHFFFAOYSA-N 0.000 description 12
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• TXDOPQKWPQENRR-UHFFFAOYSA-N ethyl 2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]pyridin-4-yl]acetate Chemical compound CCOC(=O)CC1=CC=NC(NC(=O)OC(C)(C)C)=C1 TXDOPQKWPQENRR-UHFFFAOYSA-N 0.000 description 12
• 238000001914 filtration Methods 0.000 description 12
• 210000000440 neutrophil Anatomy 0.000 description 12
• 125000001309 chloro group Chemical group Cl* 0.000 description 11
• 125000004193 piperazinyl group Chemical group 0.000 description 11
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
• 102000001708 Protein Isoforms Human genes 0.000 description 10
• 108010029485 Protein Isoforms Proteins 0.000 description 10
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 10
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
• MFDZGDBPQSJAIC-UHFFFAOYSA-N ethyl 2-(2-chloropyridin-4-yl)acetate Chemical compound CCOC(=O)CC1=CC=NC(Cl)=C1 MFDZGDBPQSJAIC-UHFFFAOYSA-N 0.000 description 10
• 239000012312 sodium hydride Substances 0.000 description 10
• 238000012360 testing method Methods 0.000 description 10
• 108700012920 TNF Proteins 0.000 description 9
• SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 9
• 229940079593 drug Drugs 0.000 description 9
• 230000000694 effects Effects 0.000 description 9
• 239000012442 inert solvent Substances 0.000 description 9
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
• XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 9
• 239000000843 powder Substances 0.000 description 9
• 125000006239 protecting group Chemical group 0.000 description 9
• 230000009467 reduction Effects 0.000 description 9
• 239000003981 vehicle Substances 0.000 description 9
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 8
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
• RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 8
• QKDDXHMEOPACQB-UHFFFAOYSA-N 4-[(4-aminonaphthalen-1-yl)oxymethyl]pyridin-2-amine Chemical compound C1=NC(N)=CC(COC=2C3=CC=CC=C3C(N)=CC=2)=C1 QKDDXHMEOPACQB-UHFFFAOYSA-N 0.000 description 8
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 8
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
• 125000004432 carbon atom Chemical group C* 0.000 description 8
• 239000006196 drop Substances 0.000 description 8
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
• VRJHZDGTSGUGDE-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-(2-morpholin-4-ylethylsulfanyl)acetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)CSCCN4CCOCC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 VRJHZDGTSGUGDE-UHFFFAOYSA-N 0.000 description 8
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
• 230000026731 phosphorylation Effects 0.000 description 8
• 238000006366 phosphorylation reaction Methods 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
• 239000000377 silicon dioxide Substances 0.000 description 8
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
• XVRFLQKMSAFVJU-UHFFFAOYSA-N tert-butyl n-[4-[2-(4-aminonaphthalen-1-yl)oxypropyl]pyridin-2-yl]carbamate Chemical compound C=1C=C(N)C2=CC=CC=C2C=1OC(C)CC1=CC=NC(NC(=O)OC(C)(C)C)=C1 XVRFLQKMSAFVJU-UHFFFAOYSA-N 0.000 description 8
• CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 8
• ADYRHCYVKFIEKB-UHFFFAOYSA-N 4-[(4-nitronaphthalen-1-yl)oxymethyl]pyridin-3-amine Chemical compound NC1=CN=CC=C1COC1=CC=C([N+]([O-])=O)C2=CC=CC=C12 ADYRHCYVKFIEKB-UHFFFAOYSA-N 0.000 description 7
• FVSPAROJEPVUCJ-UHFFFAOYSA-N 4-[1-(4-aminonaphthalen-1-yl)oxyethyl]pyridin-2-amine Chemical compound C=1C=C(N)C2=CC=CC=C2C=1OC(C)C1=CC=NC(N)=C1 FVSPAROJEPVUCJ-UHFFFAOYSA-N 0.000 description 7
• QVMOINRTPRSSMV-UHFFFAOYSA-N 4-[2-(4-aminonaphthalen-1-yl)ethoxy]pyridin-2-amine Chemical compound C1=NC(N)=CC(OCCC=2C3=CC=CC=C3C(N)=CC=2)=C1 QVMOINRTPRSSMV-UHFFFAOYSA-N 0.000 description 7
• CVZVPTNIHZXWLF-UHFFFAOYSA-N 4-[2-(4-nitronaphthalen-1-yl)oxyethyl]pyridin-3-amine Chemical compound NC1=CN=CC=C1CCOC1=CC=C([N+]([O-])=O)C2=CC=CC=C12 CVZVPTNIHZXWLF-UHFFFAOYSA-N 0.000 description 7
• 102000004190 Enzymes Human genes 0.000 description 7
• 108090000790 Enzymes Proteins 0.000 description 7
• 150000001412 amines Chemical class 0.000 description 7
• 235000019504 cigarettes Nutrition 0.000 description 7
• 239000013058 crude material Substances 0.000 description 7
• 239000012043 crude product Substances 0.000 description 7
• ZUCIZCBNFDGLAA-UHFFFAOYSA-N ethyl 2-(2-chloropyridin-4-yl)propanoate Chemical compound CCOC(=O)C(C)C1=CC=NC(Cl)=C1 ZUCIZCBNFDGLAA-UHFFFAOYSA-N 0.000 description 7
• 125000001153 fluoro group Chemical group F* 0.000 description 7
• CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 7
• 125000005647 linker group Chemical group 0.000 description 7
• 125000002757 morpholinyl group Chemical group 0.000 description 7
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
• 239000012074 organic phase Substances 0.000 description 7
• 239000002244 precipitate Substances 0.000 description 7
• 230000008569 process Effects 0.000 description 7
• VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 7
• 150000003254 radicals Chemical class 0.000 description 7
• 239000000779 smoke Substances 0.000 description 7
• MDQILLZPWLSAQM-UHFFFAOYSA-N tert-butyl n-(4-formylnaphthalen-1-yl)carbamate Chemical compound C1=CC=C2C(NC(=O)OC(C)(C)C)=CC=C(C=O)C2=C1 MDQILLZPWLSAQM-UHFFFAOYSA-N 0.000 description 7
• YPFOHUUHTBXUJU-UHFFFAOYSA-N tert-butyl n-[4-(2-hydroxyethyl)naphthalen-1-yl]carbamate Chemical compound C1=CC=C2C(NC(=O)OC(C)(C)C)=CC=C(CCO)C2=C1 YPFOHUUHTBXUJU-UHFFFAOYSA-N 0.000 description 7
• ZFLRUCZDQWFGIB-UHFFFAOYSA-N tert-butyl n-[4-(2-hydroxypropyl)pyridin-2-yl]carbamate Chemical compound CC(O)CC1=CC=NC(NC(=O)OC(C)(C)C)=C1 ZFLRUCZDQWFGIB-UHFFFAOYSA-N 0.000 description 7
• RGSVPIAPCRDAGR-UHFFFAOYSA-N tert-butyl n-[4-(2-oxopropyl)pyridin-2-yl]carbamate Chemical compound CC(=O)CC1=CC=NC(NC(=O)OC(C)(C)C)=C1 RGSVPIAPCRDAGR-UHFFFAOYSA-N 0.000 description 7
• OLHQEMFDOBCTGB-UHFFFAOYSA-N tert-butyl n-[4-[2-(2-chloropyridin-4-yl)oxyethyl]naphthalen-1-yl]carbamate Chemical compound C12=CC=CC=C2C(NC(=O)OC(C)(C)C)=CC=C1CCOC1=CC=NC(Cl)=C1 OLHQEMFDOBCTGB-UHFFFAOYSA-N 0.000 description 7
• 230000000699 topical effect Effects 0.000 description 7
• GCMMYIYEKSCNRT-UHFFFAOYSA-N 1-(2-aminopyridin-4-yl)ethanol Chemical compound CC(O)C1=CC=NC(N)=C1 GCMMYIYEKSCNRT-UHFFFAOYSA-N 0.000 description 6
• JPYJLMQRRCKDNJ-UHFFFAOYSA-N 2-(3-aminopyridin-4-yl)ethanol Chemical compound NC1=CN=CC=C1CCO JPYJLMQRRCKDNJ-UHFFFAOYSA-N 0.000 description 6
• HEHDMLJGMNLCAM-UHFFFAOYSA-N 4-[1-(4-nitronaphthalen-1-yl)oxyethyl]pyridin-2-amine Chemical compound C=1C=C([N+]([O-])=O)C2=CC=CC=C2C=1OC(C)C1=CC=NC(N)=C1 HEHDMLJGMNLCAM-UHFFFAOYSA-N 0.000 description 6
• KNESKGAEOSZHEL-UHFFFAOYSA-N 4-[2-(4-aminonaphthalen-1-yl)oxyethyl]pyridin-3-amine Chemical compound NC1=CN=CC=C1CCOC1=CC=C(N)C2=CC=CC=C12 KNESKGAEOSZHEL-UHFFFAOYSA-N 0.000 description 6
• HGTPZEQQRDZTEO-UHFFFAOYSA-N 4-[2-(4-aminonaphthalen-1-yl)oxypropan-2-yl]pyridin-2-amine Chemical compound C=1C=C(N)C2=CC=CC=C2C=1OC(C)(C)C1=CC=NC(N)=C1 HGTPZEQQRDZTEO-UHFFFAOYSA-N 0.000 description 6
• RFCCXEQQAUMUBD-UHFFFAOYSA-N 4-[2-(4-nitronaphthalen-1-yl)oxypropan-2-yl]pyridin-2-amine Chemical compound C=1C=C([N+]([O-])=O)C2=CC=CC=C2C=1OC(C)(C)C1=CC=NC(N)=C1 RFCCXEQQAUMUBD-UHFFFAOYSA-N 0.000 description 6
• FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 6
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
• 241001465754 Metazoa Species 0.000 description 6
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• 239000002253 acid Substances 0.000 description 6
• 125000003282 alkyl amino group Chemical group 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
• 239000003246 corticosteroid Substances 0.000 description 6
• 230000008878 coupling Effects 0.000 description 6
• 238000010168 coupling process Methods 0.000 description 6
• 238000005859 coupling reaction Methods 0.000 description 6
• HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 6
• MVCOAUNKQVWQHZ-UHFFFAOYSA-N doramapimod Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCCN3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 MVCOAUNKQVWQHZ-UHFFFAOYSA-N 0.000 description 6
• 230000002401 inhibitory effect Effects 0.000 description 6
• IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 6
• 239000000463 material Substances 0.000 description 6
• HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 6
• 238000002360 preparation method Methods 0.000 description 6
• 125000004076 pyridyl group Chemical group 0.000 description 6
• 238000004007 reversed phase HPLC Methods 0.000 description 6
• 239000007858 starting material Substances 0.000 description 6
• ZFPZSDRSZRSVMV-UHFFFAOYSA-N tert-butyl n-[4-(2-hydroxyethyl)pyridin-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(CCO)=CC=N1 ZFPZSDRSZRSVMV-UHFFFAOYSA-N 0.000 description 6
• FDKRPBYBTTVWGM-UHFFFAOYSA-N tert-butyl n-[4-[2-(4-nitronaphthalen-1-yl)oxyethyl]pyridin-2-yl]carbamate Chemical compound C1=NC(NC(=O)OC(C)(C)C)=CC(CCOC=2C3=CC=CC=C3C([N+]([O-])=O)=CC=2)=C1 FDKRPBYBTTVWGM-UHFFFAOYSA-N 0.000 description 6
• GUQZSQVOEUPDGP-UHFFFAOYSA-N tert-butyl n-[4-[2-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypropyl]pyridin-2-yl]carbamate Chemical compound C=1C=C(NC(=O)NC=2N(N=C(C=2)C(C)(C)C)C=2C=CC(C)=CC=2)C2=CC=CC=C2C=1OC(C)CC1=CC=NC(NC(=O)OC(C)(C)C)=C1 GUQZSQVOEUPDGP-UHFFFAOYSA-N 0.000 description 6
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
• OZNURVDNAKVKGM-UHFFFAOYSA-N 1-(2-aminopyridin-4-yl)ethanone Chemical compound CC(=O)C1=CC=NC(N)=C1 OZNURVDNAKVKGM-UHFFFAOYSA-N 0.000 description 5
• MSUDKROAZXOJRR-UHFFFAOYSA-N 2-(2-aminopyridin-4-yl)propan-2-ol Chemical compound CC(C)(O)C1=CC=NC(N)=C1 MSUDKROAZXOJRR-UHFFFAOYSA-N 0.000 description 5
• SJKIFYCVPXGDBO-UHFFFAOYSA-N 3-tert-butyl-5-isocyanato-1-(4-methylphenyl)pyrazole Chemical compound C1=CC(C)=CC=C1N1C(N=C=O)=CC(C(C)(C)C)=N1 SJKIFYCVPXGDBO-UHFFFAOYSA-N 0.000 description 5
• SJXJRXPHWXLESY-UHFFFAOYSA-N 4-(2-chloropyridin-4-yl)oxynaphthalen-1-amine Chemical compound C12=CC=CC=C2C(N)=CC=C1OC1=CC=NC(Cl)=C1 SJXJRXPHWXLESY-UHFFFAOYSA-N 0.000 description 5
• XQBCDDPLGWDVMD-UHFFFAOYSA-N 4-(4-aminonaphthalen-1-yl)oxypyridin-2-amine Chemical compound C1=NC(N)=CC(OC=2C3=CC=CC=C3C(N)=CC=2)=C1 XQBCDDPLGWDVMD-UHFFFAOYSA-N 0.000 description 5
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
• ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 5
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
• 108010010803 Gelatin Proteins 0.000 description 5
• 238000009825 accumulation Methods 0.000 description 5
• 230000009471 action Effects 0.000 description 5
• 229910021529 ammonia Inorganic materials 0.000 description 5
• 239000007864 aqueous solution Substances 0.000 description 5
• 238000003556 assay Methods 0.000 description 5
• UMSLODGSROAKDB-UHFFFAOYSA-N ethyl 2-[[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]carbamoylamino]acetate Chemical compound C1=NC(NC(=O)NCC(=O)OCC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 UMSLODGSROAKDB-UHFFFAOYSA-N 0.000 description 5
• 238000001704 evaporation Methods 0.000 description 5
• 230000008020 evaporation Effects 0.000 description 5
• 239000000706 filtrate Substances 0.000 description 5
• 238000002866 fluorescence resonance energy transfer Methods 0.000 description 5
• 239000008273 gelatin Substances 0.000 description 5
• 229920000159 gelatin Polymers 0.000 description 5
• 235000019322 gelatine Nutrition 0.000 description 5
• 235000011852 gelatine desserts Nutrition 0.000 description 5
• XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
• 239000007788 liquid Substances 0.000 description 5
• 210000002540 macrophage Anatomy 0.000 description 5
• SVWWNEYBEFASMP-UHFFFAOYSA-N methyl 2-aminopyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(N)=C1 SVWWNEYBEFASMP-UHFFFAOYSA-N 0.000 description 5
• KFFSNKRGAQPGOJ-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-3-methylsulfanylpropanamide Chemical compound C1=NC(NC(=O)CCSC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 KFFSNKRGAQPGOJ-UHFFFAOYSA-N 0.000 description 5
• 239000000546 pharmaceutical excipient Substances 0.000 description 5
• 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
• XLLXGCSEUXKUAG-YTTGMZPUSA-N tert-butyl (3s)-3-[[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]carbamoyl]morpholine-4-carboxylate Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)[C@H]4N(CCOC4)C(=O)OC(C)(C)C)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 XLLXGCSEUXKUAG-YTTGMZPUSA-N 0.000 description 5
• PNOASSMOENAHGT-SANMLTNESA-N tert-butyl n-[(2s)-1-[[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]amino]-1-oxopropan-2-yl]-n-methylcarbamate Chemical compound C1=NC(NC(=O)[C@@H](N(C)C(=O)OC(C)(C)C)C)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 PNOASSMOENAHGT-SANMLTNESA-N 0.000 description 5
• IQXSYDNVLIBFFQ-UHFFFAOYSA-N tert-butyl n-[1-[[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]amino]-2-methyl-1-oxopropan-2-yl]-n-methylcarbamate Chemical compound C1=NC(NC(=O)C(C)(C)N(C(=O)OC(C)(C)C)C)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 IQXSYDNVLIBFFQ-UHFFFAOYSA-N 0.000 description 5
• SVLYUKBOQGXBJB-UHFFFAOYSA-N tert-butyl n-[4-[2-(4-aminonaphthalen-1-yl)oxyethyl]pyridin-2-yl]carbamate Chemical compound C1=NC(NC(=O)OC(C)(C)C)=CC(CCOC=2C3=CC=CC=C3C(N)=CC=2)=C1 SVLYUKBOQGXBJB-UHFFFAOYSA-N 0.000 description 5
• VDGFJIVJSSOLCA-UHFFFAOYSA-N tert-butyl n-[4-[2-(4-nitronaphthalen-1-yl)oxypropyl]pyridin-2-yl]carbamate Chemical compound C=1C=C([N+]([O-])=O)C2=CC=CC=C2C=1OC(C)CC1=CC=NC(NC(=O)OC(C)(C)C)=C1 VDGFJIVJSSOLCA-UHFFFAOYSA-N 0.000 description 5
• QHCWJQBKHWGFFZ-UHFFFAOYSA-N tert-butyl n-[4-[2-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxyethyl]pyridin-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCCC=3C=C(NC(=O)OC(C)(C)C)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 QHCWJQBKHWGFFZ-UHFFFAOYSA-N 0.000 description 5
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
• 210000001519 tissue Anatomy 0.000 description 5
• 150000003672 ureas Chemical class 0.000 description 5
• TWYCDZQLLFNFGK-UHFFFAOYSA-N (2-aminopyrimidin-4-yl)methanol Chemical compound NC1=NC=CC(CO)=N1 TWYCDZQLLFNFGK-UHFFFAOYSA-N 0.000 description 4
• VXHFPFMVXWCZLH-UHFFFAOYSA-N (3-aminopyridin-4-yl)methanol Chemical compound NC1=CN=CC=C1CO VXHFPFMVXWCZLH-UHFFFAOYSA-N 0.000 description 4
• SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 4
• IGMNPRJAMCOILX-UHFFFAOYSA-N 2-(2-methoxyethoxy)acetamide Chemical compound COCCOCC(N)=O IGMNPRJAMCOILX-UHFFFAOYSA-N 0.000 description 4
• GDAQJZHHPBHSQP-UHFFFAOYSA-N 2-(3-nitropyridin-4-yl)ethanol Chemical compound OCCC1=CC=NC=C1[N+]([O-])=O GDAQJZHHPBHSQP-UHFFFAOYSA-N 0.000 description 4
• UWONNLWKQIUWRA-UHFFFAOYSA-N 2-chloro-2-methyl-1h-pyridine Chemical compound CC1(Cl)NC=CC=C1 UWONNLWKQIUWRA-UHFFFAOYSA-N 0.000 description 4
• MTEZLAATISORQK-UHFFFAOYSA-N 2-methoxyacetamide Chemical compound COCC(N)=O MTEZLAATISORQK-UHFFFAOYSA-N 0.000 description 4
• GLEMAVSLXIVMDG-UHFFFAOYSA-N 4-[(4-aminonaphthalen-1-yl)oxymethyl]pyrimidin-2-amine Chemical compound NC1=NC=CC(COC=2C3=CC=CC=C3C(N)=CC=2)=N1 GLEMAVSLXIVMDG-UHFFFAOYSA-N 0.000 description 4
• NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 4
• ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 4
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
• 241000699670 Mus sp. Species 0.000 description 4
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
• 108010058846 Ovalbumin Proteins 0.000 description 4
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 4
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 4
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
• 229960000583 acetic acid Drugs 0.000 description 4
• 239000000443 aerosol Substances 0.000 description 4
• 150000001408 amides Chemical class 0.000 description 4
• 230000003110 anti-inflammatory effect Effects 0.000 description 4
• 238000013459 approach Methods 0.000 description 4
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
• UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
• 229910000024 caesium carbonate Inorganic materials 0.000 description 4
• SWJVPBNDGTWRCT-UHFFFAOYSA-N ethyl 2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]pyridin-4-yl]propanoate Chemical compound CCOC(=O)C(C)C1=CC=NC(NC(=O)OC(C)(C)C)=C1 SWJVPBNDGTWRCT-UHFFFAOYSA-N 0.000 description 4
• 229960000289 fluticasone propionate Drugs 0.000 description 4
• WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 4
• 239000006260 foam Substances 0.000 description 4
• 125000002883 imidazolyl group Chemical group 0.000 description 4
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
• 238000010829 isocratic elution Methods 0.000 description 4
• 239000012948 isocyanate Substances 0.000 description 4
• 150000002513 isocyanates Chemical class 0.000 description 4
• 229960004592 isopropanol Drugs 0.000 description 4
• ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 4
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
• VEYNQUNIKFVDOM-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-methoxyacetamide Chemical compound C1=NC(NC(=O)COC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(CO[Si](C)(C)C(C)(C)C)=CC=3)=CC=2)=C1 VEYNQUNIKFVDOM-UHFFFAOYSA-N 0.000 description 4
• 239000010502 orange oil Substances 0.000 description 4
• 229940092253 ovalbumin Drugs 0.000 description 4
• 239000002953 phosphate buffered saline Substances 0.000 description 4
• 125000003386 piperidinyl group Chemical group 0.000 description 4
• IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
• 108090000765 processed proteins & peptides Proteins 0.000 description 4
• 239000003380 propellant Substances 0.000 description 4
• PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 4
• 239000000600 sorbitol Substances 0.000 description 4
• 235000010356 sorbitol Nutrition 0.000 description 4
• 239000012258 stirred mixture Substances 0.000 description 4
• 239000006228 supernatant Substances 0.000 description 4
• XLLXGCSEUXKUAG-JGCGQSQUSA-N tert-butyl (3r)-3-[[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]carbamoyl]morpholine-4-carboxylate Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)[C@@H]4N(CCOC4)C(=O)OC(C)(C)C)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 XLLXGCSEUXKUAG-JGCGQSQUSA-N 0.000 description 4
• QEBCZVLJBKCUDW-UHFFFAOYSA-N tert-butyl n-[4-[1-(4-aminonaphthalen-1-yl)oxypropan-2-yl]pyridin-2-yl]carbamate Chemical compound C=1C=C(N)C2=CC=CC=C2C=1OCC(C)C1=CC=NC(NC(=O)OC(C)(C)C)=C1 QEBCZVLJBKCUDW-UHFFFAOYSA-N 0.000 description 4
• ZTVGHEPGUUEHFR-UHFFFAOYSA-N tert-butyl n-[4-[1-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxy-2-methylpropan-2-yl]pyridin-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC(C)(C)C=3C=C(NC(=O)OC(C)(C)C)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 ZTVGHEPGUUEHFR-UHFFFAOYSA-N 0.000 description 4
• NYYRJJILUNKMQA-UHFFFAOYSA-N tert-butyl n-[4-[1-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypropan-2-yl]pyridin-2-yl]carbamate Chemical compound C=1C=NC(NC(=O)OC(C)(C)C)=CC=1C(C)COC(C1=CC=CC=C11)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NN1C1=CC=C(C)C=C1 NYYRJJILUNKMQA-UHFFFAOYSA-N 0.000 description 4
• UFINYZLNKXBNTB-UHFFFAOYSA-N tert-butyl n-[4-[4-(ditert-butylcarbamoyl)naphthalen-1-yl]oxypyridin-2-yl]carbamate Chemical compound C1=NC(NC(=O)OC(C)(C)C)=CC(OC=2C3=CC=CC=C3C(C(=O)N(C(C)(C)C)C(C)(C)C)=CC=2)=C1 UFINYZLNKXBNTB-UHFFFAOYSA-N 0.000 description 4
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 4
• 238000011200 topical administration Methods 0.000 description 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
• OZJZCCMIOZPPIT-UHFFFAOYSA-N 2-(2-methoxyethoxy)acetyl chloride Chemical compound COCCOCC(Cl)=O OZJZCCMIOZPPIT-UHFFFAOYSA-N 0.000 description 3
• FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 3
• PLDCTVWSNGRFRX-UHFFFAOYSA-N 2-methoxy-n-[4-[(4-nitronaphthalen-1-yl)oxymethyl]pyridin-2-yl]acetamide Chemical compound C1=NC(NC(=O)COC)=CC(COC=2C3=CC=CC=C3C([N+]([O-])=O)=CC=2)=C1 PLDCTVWSNGRFRX-UHFFFAOYSA-N 0.000 description 3
• HPBNFHMSOYVHAU-UHFFFAOYSA-N 4-(5-amino-3-tert-butylpyrazol-1-yl)benzoic acid Chemical compound N1=C(C(C)(C)C)C=C(N)N1C1=CC=C(C(O)=O)C=C1 HPBNFHMSOYVHAU-UHFFFAOYSA-N 0.000 description 3
• PCALIFZBKDADEY-UHFFFAOYSA-N 4-[(4-nitronaphthalen-1-yl)oxymethyl]pyrimidin-2-amine Chemical compound NC1=NC=CC(COC=2C3=CC=CC=C3C([N+]([O-])=O)=CC=2)=N1 PCALIFZBKDADEY-UHFFFAOYSA-N 0.000 description 3
• AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 3
• 241000349731 Afzelia bipindensis Species 0.000 description 3
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
• 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 description 3
• FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
• FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
• 206010061218 Inflammation Diseases 0.000 description 3
• 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 3
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
• 102100034069 MAP kinase-activated protein kinase 2 Human genes 0.000 description 3
• 101710141394 MAP kinase-activated protein kinase 2 Proteins 0.000 description 3
• 238000000134 MTT assay Methods 0.000 description 3
• 231100000002 MTT assay Toxicity 0.000 description 3
• 235000019502 Orange oil Nutrition 0.000 description 3
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 3
• 208000002606 Paramyxoviridae Infections Diseases 0.000 description 3
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
• DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
• 102100040247 Tumor necrosis factor Human genes 0.000 description 3
• XGDUKVNXAPLGSA-UHFFFAOYSA-N [4-(5-amino-3-tert-butylpyrazol-1-yl)phenyl]methanol Chemical compound N1=C(C(C)(C)C)C=C(N)N1C1=CC=C(CO)C=C1 XGDUKVNXAPLGSA-UHFFFAOYSA-N 0.000 description 3
• 239000004480 active ingredient Substances 0.000 description 3
• 238000004458 analytical method Methods 0.000 description 3
• 125000001246 bromo group Chemical group Br* 0.000 description 3
• 239000002775 capsule Substances 0.000 description 3
• 239000000460 chlorine Substances 0.000 description 3
• 238000011161 development Methods 0.000 description 3
• 231100000673 dose–response relationship Toxicity 0.000 description 3
• 150000002148 esters Chemical class 0.000 description 3
• MYPFGXSYMUFVTJ-UHFFFAOYSA-N ethyl 2-(2-chloropyridin-4-yl)-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)C1=CC=NC(Cl)=C1 MYPFGXSYMUFVTJ-UHFFFAOYSA-N 0.000 description 3
• 239000002024 ethyl acetate extract Substances 0.000 description 3
• 150000002431 hydrogen Chemical group 0.000 description 3
• 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
• 238000001727 in vivo Methods 0.000 description 3
• 208000015181 infectious disease Diseases 0.000 description 3
• 230000004054 inflammatory process Effects 0.000 description 3
• 239000008101 lactose Substances 0.000 description 3
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
• 235000019341 magnesium sulphate Nutrition 0.000 description 3
• 239000002480 mineral oil Substances 0.000 description 3
• 235000010446 mineral oil Nutrition 0.000 description 3
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 3
• 239000012071 phase Substances 0.000 description 3
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
• 238000010992 reflux Methods 0.000 description 3
• 150000003384 small molecules Chemical class 0.000 description 3
• 239000011734 sodium Substances 0.000 description 3
• 239000012279 sodium borohydride Substances 0.000 description 3
• 229910000033 sodium borohydride Inorganic materials 0.000 description 3
• 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
• 239000000126 substance Substances 0.000 description 3
• 239000004094 surface-active agent Substances 0.000 description 3
• XISJUPHSHNWMPW-UHFFFAOYSA-N tert-butyl n-[4-(1-hydroxy-2-methylpropan-2-yl)pyridin-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(C(C)(C)CO)=CC=N1 XISJUPHSHNWMPW-UHFFFAOYSA-N 0.000 description 3
• BUELCVMCCYCVQZ-UHFFFAOYSA-N tert-butyl n-[4-(1-hydroxypropan-2-yl)pyridin-2-yl]carbamate Chemical compound OCC(C)C1=CC=NC(NC(=O)OC(C)(C)C)=C1 BUELCVMCCYCVQZ-UHFFFAOYSA-N 0.000 description 3
• QBDASQQYCWUMDA-UHFFFAOYSA-N tert-butyl n-[4-[1-(4-nitronaphthalen-1-yl)oxypropan-2-yl]pyridin-2-yl]carbamate Chemical compound C=1C=C([N+]([O-])=O)C2=CC=CC=C2C=1OCC(C)C1=CC=NC(NC(=O)OC(C)(C)C)=C1 QBDASQQYCWUMDA-UHFFFAOYSA-N 0.000 description 3
• JEKALVKIPVVPDA-UHFFFAOYSA-N tert-butyl n-[4-[2-methyl-1-(4-nitronaphthalen-1-yl)oxypropan-2-yl]pyridin-2-yl]carbamate Chemical compound C1=NC(NC(=O)OC(C)(C)C)=CC(C(C)(C)COC=2C3=CC=CC=C3C([N+]([O-])=O)=CC=2)=C1 JEKALVKIPVVPDA-UHFFFAOYSA-N 0.000 description 3
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
• RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 3
• 230000001225 therapeutic effect Effects 0.000 description 3
• 238000001665 trituration Methods 0.000 description 3
• 238000005406 washing Methods 0.000 description 3
• QGSYUMLGCMFTKN-QHCPKHFHSA-N (2s)-n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-methoxypropanamide Chemical compound C1=NC(NC(=O)[C@H](C)OC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 QGSYUMLGCMFTKN-QHCPKHFHSA-N 0.000 description 2
• FDBQTRARWCKEJY-UHFFFAOYSA-N (4-hydroxynaphthalen-1-yl)azanium;chloride Chemical compound [Cl-].C1=CC=C2C([NH3+])=CC=C(O)C2=C1 FDBQTRARWCKEJY-UHFFFAOYSA-N 0.000 description 2
• LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 2
• BMEMBBFDTYHTLH-UHFFFAOYSA-N 1-(2-methoxyethyl)piperazine Chemical compound COCCN1CCNCC1 BMEMBBFDTYHTLH-UHFFFAOYSA-N 0.000 description 2
• PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
• FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
• BRLVAADCUUVYBX-UHFFFAOYSA-N 1-chloro-n,n-dimethylethenamine Chemical compound CN(C)C(Cl)=C BRLVAADCUUVYBX-UHFFFAOYSA-N 0.000 description 2
• 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 2
• CDBORKXXLPAUKJ-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanethiol Chemical compound COCCOCCS CDBORKXXLPAUKJ-UHFFFAOYSA-N 0.000 description 2
• WKJOQYHMXRVQDK-UHFFFAOYSA-N 2-(dimethylamino)acetamide Chemical compound CN(C)CC(N)=O WKJOQYHMXRVQDK-UHFFFAOYSA-N 0.000 description 2
• MDUTYEVSZVGAMU-UHFFFAOYSA-N 2-[bis(2-methoxyethyl)amino]-n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]acetamide Chemical compound C1=NC(NC(=O)CN(CCOC)CCOC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 MDUTYEVSZVGAMU-UHFFFAOYSA-N 0.000 description 2
• FGSAQRJRWCZLOB-UHFFFAOYSA-N 2-chloro-4-fluoropyridine Chemical compound FC1=CC=NC(Cl)=C1 FGSAQRJRWCZLOB-UHFFFAOYSA-N 0.000 description 2
• IBZKBSXREAQDTO-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)ethanamine Chemical compound COCCNCCOC IBZKBSXREAQDTO-UHFFFAOYSA-N 0.000 description 2
• ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 2
• VHXDADVHQVXSKC-UHFFFAOYSA-N 2-methoxyethanethiol Chemical compound COCCS VHXDADVHQVXSKC-UHFFFAOYSA-N 0.000 description 2
• TTXPTDCYRCXFHQ-UHFFFAOYSA-N 2-methylsulfinylacetamide Chemical compound CS(=O)CC(N)=O TTXPTDCYRCXFHQ-UHFFFAOYSA-N 0.000 description 2
• NYEHUAQIJXERLP-UHFFFAOYSA-N 2-methylsulfonylacetic acid Chemical compound CS(=O)(=O)CC(O)=O NYEHUAQIJXERLP-UHFFFAOYSA-N 0.000 description 2
• YZVWMFBVTTUSAW-UHFFFAOYSA-N 2-morpholin-4-ylethanethiol Chemical compound SCCN1CCOCC1 YZVWMFBVTTUSAW-UHFFFAOYSA-N 0.000 description 2
• BPXCLLWXDHBFRH-UHFFFAOYSA-N 3-methoxypropanamide Chemical compound COCCC(N)=O BPXCLLWXDHBFRH-UHFFFAOYSA-N 0.000 description 2
• BKNIWNVWNVXGDI-UHFFFAOYSA-N 3-methylsulfonylpropanamide Chemical compound CS(=O)(=O)CCC(N)=O BKNIWNVWNVXGDI-UHFFFAOYSA-N 0.000 description 2
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
• OQINWXZQCAIVNK-UHFFFAOYSA-N 4-(dimethoxymethyl)pyrimidin-2-amine Chemical compound COC(OC)C1=CC=NC(N)=N1 OQINWXZQCAIVNK-UHFFFAOYSA-N 0.000 description 2
• YGTHBVOCTPFJHQ-UHFFFAOYSA-N 4-(dimethylamino)butanamide Chemical compound CN(C)CCCC(N)=O YGTHBVOCTPFJHQ-UHFFFAOYSA-N 0.000 description 2
• FYJORSKXVAOJFZ-UHFFFAOYSA-N 4-methylpiperazine-1-carboxamide Chemical compound CN1CCN(C(N)=O)CC1 FYJORSKXVAOJFZ-UHFFFAOYSA-N 0.000 description 2
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
• WKYYYFIJGMOIOL-UHFFFAOYSA-N 5-tert-butyl-2-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]pyrazol-3-amine Chemical compound N1=C(C(C)(C)C)C=C(N)N1C1=CC=C(CO[Si](C)(C)C(C)(C)C)C=C1 WKYYYFIJGMOIOL-UHFFFAOYSA-N 0.000 description 2
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
• 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
• NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
• VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
• 102000004127 Cytokines Human genes 0.000 description 2
• 108090000695 Cytokines Proteins 0.000 description 2
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
• 241000588724 Escherichia coli Species 0.000 description 2
• 102000003676 Glucocorticoid Receptors Human genes 0.000 description 2
• 108090000079 Glucocorticoid Receptors Proteins 0.000 description 2
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
• 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
• 240000007472 Leucaena leucocephala Species 0.000 description 2
• 102000043136 MAP kinase family Human genes 0.000 description 2
• 108091054455 MAP kinase family Proteins 0.000 description 2
• 229940122696 MAP kinase inhibitor Drugs 0.000 description 2
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
• 241000699666 Mus <mouse, genus> Species 0.000 description 2
• 206010029379 Neutrophilia Diseases 0.000 description 2
• 102000007399 Nuclear hormone receptor Human genes 0.000 description 2
• 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
• 108091005804 Peptidases Proteins 0.000 description 2
• YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
• 239000002202 Polyethylene glycol Substances 0.000 description 2
• 239000004365 Protease Substances 0.000 description 2
• 102000001253 Protein Kinase Human genes 0.000 description 2
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
• 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
• 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
• 241000700605 Viruses Species 0.000 description 2
• 230000004913 activation Effects 0.000 description 2
• 125000005213 alkyl heteroaryl group Chemical group 0.000 description 2
• 210000001132 alveolar macrophage Anatomy 0.000 description 2
• 238000010171 animal model Methods 0.000 description 2
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
• 239000000010 aprotic solvent Substances 0.000 description 2
• 230000009286 beneficial effect Effects 0.000 description 2
• 230000008901 benefit Effects 0.000 description 2
• 239000012455 biphasic mixture Substances 0.000 description 2
• 229910000085 borane Inorganic materials 0.000 description 2
• 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
• 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
• 125000004452 carbocyclyl group Chemical group 0.000 description 2
• 150000001721 carbon Chemical group 0.000 description 2
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
• 239000003054 catalyst Substances 0.000 description 2
• 230000003833 cell viability Effects 0.000 description 2
• 230000008859 change Effects 0.000 description 2
• 208000037976 chronic inflammation Diseases 0.000 description 2
• 208000037893 chronic inflammatory disorder Diseases 0.000 description 2
• ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
• 238000010511 deprotection reaction Methods 0.000 description 2
• 238000001514 detection method Methods 0.000 description 2
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 2
• 235000019404 dichlorodifluoromethane Nutrition 0.000 description 2
• 201000010099 disease Diseases 0.000 description 2
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
• KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
• 239000006185 dispersion Substances 0.000 description 2
• 239000002552 dosage form Substances 0.000 description 2
• 239000012065 filter cake Substances 0.000 description 2
• 239000012530 fluid Substances 0.000 description 2
• 235000019253 formic acid Nutrition 0.000 description 2
• 239000012362 glacial acetic acid Substances 0.000 description 2
• 125000004992 haloalkylamino group Chemical group 0.000 description 2
• 238000005984 hydrogenation reaction Methods 0.000 description 2
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
• 238000000338 in vitro Methods 0.000 description 2
• 238000011065 in-situ storage Methods 0.000 description 2
• 238000011534 incubation Methods 0.000 description 2
• 229940125369 inhaled corticosteroids Drugs 0.000 description 2
• 229910052500 inorganic mineral Inorganic materials 0.000 description 2
• 239000000787 lecithin Substances 0.000 description 2
• 235000010445 lecithin Nutrition 0.000 description 2
• 229940067606 lecithin Drugs 0.000 description 2
• DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
• 230000004199 lung function Effects 0.000 description 2
• 235000019359 magnesium stearate Nutrition 0.000 description 2
• 238000005259 measurement Methods 0.000 description 2
• LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 2
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
• 235000010755 mineral Nutrition 0.000 description 2
• 239000011707 mineral Substances 0.000 description 2
• 239000003226 mitogen Substances 0.000 description 2
• 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 2
• XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 2
• RKEMWDQHGMKDCM-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-(2-methoxyethylamino)acetamide Chemical compound C1=NC(NC(=O)CNCCOC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 RKEMWDQHGMKDCM-UHFFFAOYSA-N 0.000 description 2
• APQQQTYZTVYEGV-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-[4-(2-methoxyethyl)piperazin-1-yl]acetamide Chemical compound C1CN(CCOC)CCN1CC(=O)NC1=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=CC=N1 APQQQTYZTVYEGV-UHFFFAOYSA-N 0.000 description 2
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
• 239000007923 nasal drop Substances 0.000 description 2
• 229940100662 nasal drops Drugs 0.000 description 2
• 125000006574 non-aromatic ring group Chemical group 0.000 description 2
• 210000000056 organ Anatomy 0.000 description 2
• DGOYLVBDCVINQZ-UHFFFAOYSA-N oxane-4-carboxamide Chemical compound NC(=O)C1CCOCC1 DGOYLVBDCVINQZ-UHFFFAOYSA-N 0.000 description 2
• PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 2
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
• 239000003880 polar aprotic solvent Substances 0.000 description 2
• 229920001223 polyethylene glycol Polymers 0.000 description 2
• 239000003755 preservative agent Substances 0.000 description 2
• 230000000770 proinflammatory effect Effects 0.000 description 2
• 108060006633 protein kinase Proteins 0.000 description 2
• 102000004169 proteins and genes Human genes 0.000 description 2
• 108090000623 proteins and genes Proteins 0.000 description 2
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 2
• 238000010791 quenching Methods 0.000 description 2
• 238000011084 recovery Methods 0.000 description 2
• 208000023504 respiratory system disease Diseases 0.000 description 2
• 238000003118 sandwich ELISA Methods 0.000 description 2
• 230000035945 sensitivity Effects 0.000 description 2
• 239000000741 silica gel Substances 0.000 description 2
• 229910002027 silica gel Inorganic materials 0.000 description 2
• 229910000029 sodium carbonate Inorganic materials 0.000 description 2
• 239000011780 sodium chloride Substances 0.000 description 2
• 239000012453 solvate Substances 0.000 description 2
• 239000000375 suspending agent Substances 0.000 description 2
• 230000002459 sustained effect Effects 0.000 description 2
• QIAWPPSMGRAAAS-UHFFFAOYSA-N tert-butyl n-(4-ethenylnaphthalen-1-yl)carbamate Chemical compound C1=CC=C2C(NC(=O)OC(C)(C)C)=CC=C(C=C)C2=C1 QIAWPPSMGRAAAS-UHFFFAOYSA-N 0.000 description 2
• ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
• 231100000331 toxic Toxicity 0.000 description 2
• 230000002588 toxic effect Effects 0.000 description 2
• 210000003437 trachea Anatomy 0.000 description 2
• 230000009466 transformation Effects 0.000 description 2
• 230000001052 transient effect Effects 0.000 description 2
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 2
• 238000000825 ultraviolet detection Methods 0.000 description 2
• 238000011144 upstream manufacturing Methods 0.000 description 2
• 235000015112 vegetable and seed oil Nutrition 0.000 description 2
• 239000008158 vegetable oil Substances 0.000 description 2
• XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
• UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 description 1
• HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 1
• JNUZADQZHYFJGW-JOCHJYFZSA-N (2R)-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide Chemical compound FC=1C(=NC(=NC=1)NC1=C(C(=CC=C1)S(=O)(=O)C)F)C1=CNC2=C(C=CC=C12)NC([C@@H](COC)N1CCN(CC1)C)=O JNUZADQZHYFJGW-JOCHJYFZSA-N 0.000 description 1
• KEEKMOIRJUWKNK-CABZTGNLSA-N (2S)-2-[[2-[(4R)-4-(difluoromethyl)-2-oxo-1,3-thiazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide Chemical compound FC([C@H]1N(C(SC1)=O)C=1N=C2N(CCOC3=C2C=CC(=C3)N[C@H](C(=O)N)C)C=1)F KEEKMOIRJUWKNK-CABZTGNLSA-N 0.000 description 1
• ICPWFHKNYYRBSZ-GSVOUGTGSA-N (2r)-2-methoxypropanoic acid Chemical compound CO[C@H](C)C(O)=O ICPWFHKNYYRBSZ-GSVOUGTGSA-N 0.000 description 1
• ICPWFHKNYYRBSZ-VKHMYHEASA-N (2s)-2-methoxypropanoic acid Chemical compound CO[C@@H](C)C(O)=O ICPWFHKNYYRBSZ-VKHMYHEASA-N 0.000 description 1
• KVXXEKIGMOEPSA-SSDOTTSWSA-N (3r)-4-[(2-methylpropan-2-yl)oxycarbonyl]morpholine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCOC[C@@H]1C(O)=O KVXXEKIGMOEPSA-SSDOTTSWSA-N 0.000 description 1
• LJMGRXNLZNVURM-GDLZYMKVSA-N (3r)-n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]morpholine-3-carboxamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)[C@@H]4NCCOC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 LJMGRXNLZNVURM-GDLZYMKVSA-N 0.000 description 1
• KVXXEKIGMOEPSA-ZETCQYMHSA-N (3s)-4-[(2-methylpropan-2-yl)oxycarbonyl]morpholine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCOC[C@H]1C(O)=O KVXXEKIGMOEPSA-ZETCQYMHSA-N 0.000 description 1
• LJMGRXNLZNVURM-LJAQVGFWSA-N (3s)-n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]morpholine-3-carboxamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)[C@H]4NCCOC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 LJMGRXNLZNVURM-LJAQVGFWSA-N 0.000 description 1
• KZEDPVFJLQLDIZ-UHFFFAOYSA-N (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1.C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZEDPVFJLQLDIZ-UHFFFAOYSA-N 0.000 description 1
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 1
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 1
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
• 125000006545 (C1-C9) alkyl group Chemical group 0.000 description 1
• LCFFREMLXLZNHE-GBOLQPHISA-N (e)-2-[(3r)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile Chemical compound C12=C(N)N=CN=C2N([C@@H]2CCCN(C2)C(=O)C(/C#N)=C/C(C)(C)N2CCN(CC2)C2COC2)N=C1C(C(=C1)F)=CC=C1OC1=CC=CC=C1 LCFFREMLXLZNHE-GBOLQPHISA-N 0.000 description 1
• YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
• DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
• CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
• WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
• OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
• AIJFPNKGGAPZFJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)-n-methylmethanamine Chemical compound CNCC1=CC=C(OC)C=C1 AIJFPNKGGAPZFJ-UHFFFAOYSA-N 0.000 description 1
• WVQUVKNUYLOGPM-UHFFFAOYSA-N 1-[4-[(2-aminopyridin-4-yl)methoxy]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(OCC=3C=C(N)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 WVQUVKNUYLOGPM-UHFFFAOYSA-N 0.000 description 1
• CTLVZTMBHKZFIR-UHFFFAOYSA-N 1-[4-[2-(3-aminopyridin-4-yl)ethoxy]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(OCCC=3C(=CN=CC=3)N)=CC=2)=CC(C(C)(C)C)=N1 CTLVZTMBHKZFIR-UHFFFAOYSA-N 0.000 description 1
• XQQKILZJJJNJBN-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[6-(carbamoylamino)pyrimidin-4-yl]oxynaphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3N=CN=C(NC(N)=O)C=3)=CC=2)=CC(C(C)(C)C)=N1 XQQKILZJJJNJBN-UHFFFAOYSA-N 0.000 description 1
• DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 1
• 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 description 1
• 238000005160 1H NMR spectroscopy Methods 0.000 description 1
• GRNOZCCBOFGDCL-UHFFFAOYSA-N 2,2,2-trichloroacetyl isocyanate Chemical compound ClC(Cl)(Cl)C(=O)N=C=O GRNOZCCBOFGDCL-UHFFFAOYSA-N 0.000 description 1
• KJUCPVIVNLPLEE-UHFFFAOYSA-N 2,6-difluoro-n-[2-fluoro-5-[5-[2-[(6-morpholin-4-ylpyridin-3-yl)amino]pyrimidin-4-yl]-2-propan-2-yl-1,3-thiazol-4-yl]phenyl]benzenesulfonamide Chemical compound S1C(C(C)C)=NC(C=2C=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C(F)=CC=2)=C1C(N=1)=CC=NC=1NC(C=N1)=CC=C1N1CCOCC1 KJUCPVIVNLPLEE-UHFFFAOYSA-N 0.000 description 1
• SWPRQXGWCYGNIN-UHFFFAOYSA-N 2-(2-methoxyethylamino)acetamide Chemical compound COCCNCC(N)=O SWPRQXGWCYGNIN-UHFFFAOYSA-N 0.000 description 1
• PUGFPMCUYACZBX-UHFFFAOYSA-N 2-(2-methoxyethylsulfanyl)acetamide Chemical compound COCCSCC(N)=O PUGFPMCUYACZBX-UHFFFAOYSA-N 0.000 description 1
• XWHOVWLGNDBPGO-UHFFFAOYSA-N 2-(2-morpholin-4-ylethylsulfonyl)acetamide Chemical compound NC(=O)CS(=O)(=O)CCN1CCOCC1 XWHOVWLGNDBPGO-UHFFFAOYSA-N 0.000 description 1
• NFODSNOCEFVBRY-UHFFFAOYSA-N 2-(carbamoylamino)acetamide Chemical compound NC(=O)CNC(N)=O NFODSNOCEFVBRY-UHFFFAOYSA-N 0.000 description 1
• CBBFWSMELCDMPZ-UHFFFAOYSA-N 2-(methylamino)acetamide Chemical compound CNCC(N)=O CBBFWSMELCDMPZ-UHFFFAOYSA-N 0.000 description 1
• ZHRVPXZAPOUWHB-UHFFFAOYSA-N 2-[(4-methoxyphenyl)methyl-methylamino]acetamide Chemical compound COC1=CC=C(CN(C)CC(N)=O)C=C1 ZHRVPXZAPOUWHB-UHFFFAOYSA-N 0.000 description 1
• KDDPNNXAZURUGP-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)-3-[2-(piperidin-3-ylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound ClC=1C=C(C=CC=1Cl)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NC1CNCCC1 KDDPNNXAZURUGP-UHFFFAOYSA-N 0.000 description 1
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
• FQHWQFIPEVBFKT-UHFFFAOYSA-N 2-[5-[cyclopropylmethyl(1,2-dihydroacenaphthylen-5-yl)amino]-3-methoxypyridine-2-carbonyl]cyclopropane-1-carboxylic acid Chemical compound C1(CC1)CN(C=1C=C(C(=NC=1)C(=O)C1C(C1)C(=O)O)OC)C1=CC=C2CCC=3C=CC=C1C=32 FQHWQFIPEVBFKT-UHFFFAOYSA-N 0.000 description 1
• RQVKVJIRFKVPBF-VWLOTQADSA-N 2-[[(2s)-2-amino-3-phenylpropyl]amino]-3-methyl-5-naphthalen-2-yl-6-pyridin-4-ylpyrimidin-4-one Chemical compound C([C@H](N)CNC=1N(C(C(C=2C=C3C=CC=CC3=CC=2)=C(C=2C=CN=CC=2)N=1)=O)C)C1=CC=CC=C1 RQVKVJIRFKVPBF-VWLOTQADSA-N 0.000 description 1
• JVAZHQLRQSWMBO-UHFFFAOYSA-N 2-[[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]carbamoylamino]-n-(2-methoxyethyl)acetamide Chemical compound C1=NC(NC(=O)NCC(=O)NCCOC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 JVAZHQLRQSWMBO-UHFFFAOYSA-N 0.000 description 1
• LHASZEBEQGPCFM-CJFMBICVSA-N 2-amino-4-[(1r)-1-[[(6r)-6-[(5-chloro-2-methoxyphenyl)methyl]-7-oxo-3-(phenoxyamino)-5,6-dihydro-2h-1,4-diazepine-1-carbonyl]amino]propyl]benzoic acid Chemical compound C([C@@H]1CNC(CN(C1=O)C(=O)N[C@H](CC)C=1C=C(N)C(C(O)=O)=CC=1)=NOC=1C=CC=CC=1)C1=CC(Cl)=CC=C1OC LHASZEBEQGPCFM-CJFMBICVSA-N 0.000 description 1
• ZPMWWAIBJJFPPQ-UHFFFAOYSA-N 2-ethoxyacetyl chloride Chemical compound CCOCC(Cl)=O ZPMWWAIBJJFPPQ-UHFFFAOYSA-N 0.000 description 1
• TZGPACAKMCUCKX-UHFFFAOYSA-N 2-hydroxyacetamide Chemical compound NC(=O)CO TZGPACAKMCUCKX-UHFFFAOYSA-N 0.000 description 1
• KPDLITGXUYMJEC-UHFFFAOYSA-N 2-methyl-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid Chemical compound OC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C KPDLITGXUYMJEC-UHFFFAOYSA-N 0.000 description 1
• ZBLUAVADFAWYLL-UHFFFAOYSA-N 2-methylsulfonylacetamide Chemical compound CS(=O)(=O)CC(N)=O ZBLUAVADFAWYLL-UHFFFAOYSA-N 0.000 description 1
• BWRNWWSQZROEOA-UHFFFAOYSA-N 2-morpholin-4-ylacetamide Chemical compound NC(=O)CN1CCOCC1 BWRNWWSQZROEOA-UHFFFAOYSA-N 0.000 description 1
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
• RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
• MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
• UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
• AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
• BVGDAZBTIVRTGO-UONOGXRCSA-N 3-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[4-methoxy-6-[(2s)-2-methylpiperazin-1-yl]pyridin-3-yl]pyridin-2-amine Chemical compound C1([C@@H](C)OC=2C(N)=NC=C(C=2)C2=CN=C(C=C2OC)N2[C@H](CNCC2)C)=C(Cl)C=CC(F)=C1Cl BVGDAZBTIVRTGO-UONOGXRCSA-N 0.000 description 1
• HTNUUDFQRYBJPH-UHFFFAOYSA-N 3-methoxypropanehydrazide Chemical compound COCCC(=O)NN HTNUUDFQRYBJPH-UHFFFAOYSA-N 0.000 description 1
• ZWTPALHHEULAPI-UHFFFAOYSA-N 3-methylsulfonyl-2-oxoimidazolidine-1-carbonyl chloride Chemical compound CS(=O)(=O)N1CCN(C(Cl)=O)C1=O ZWTPALHHEULAPI-UHFFFAOYSA-N 0.000 description 1
• MXZMACXOMZKYHJ-UHFFFAOYSA-N 4,4-dimethyl-3-oxopentanenitrile Chemical compound CC(C)(C)C(=O)CC#N MXZMACXOMZKYHJ-UHFFFAOYSA-N 0.000 description 1
• OXOWTLDONRGYOT-UHFFFAOYSA-N 4-(dimethylamino)butanoic acid Chemical compound CN(C)CCCC(O)=O OXOWTLDONRGYOT-UHFFFAOYSA-N 0.000 description 1
• 150000005007 4-aminopyrimidines Chemical class 0.000 description 1
• PCNFLKVWBDNNOW-UHFFFAOYSA-N 4-hydrazinylbenzoic acid Chemical compound NNC1=CC=C(C(O)=O)C=C1 PCNFLKVWBDNNOW-UHFFFAOYSA-N 0.000 description 1
• FYSRKRZDBHOFAY-UHFFFAOYSA-N 6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)-3-pyridinecarboxamide Chemical compound FC=1C=CC=C(F)C=1N(C(=O)N)C(N=1)=CC=C(C(N)=O)C=1C1=CC=C(F)C=C1F FYSRKRZDBHOFAY-UHFFFAOYSA-N 0.000 description 1
• SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-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
• LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
• 238000013296 A/J mouse Methods 0.000 description 1
• 235000019489 Almond oil Nutrition 0.000 description 1
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
• 241000416162 Astragalus gummifer Species 0.000 description 1
• KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 1
• 239000005711 Benzoic acid Substances 0.000 description 1
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
• 238000006418 Brown reaction Methods 0.000 description 1
• VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
• 101150041968 CDC13 gene Proteins 0.000 description 1
• 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
• 241000700198 Cavia Species 0.000 description 1
• 229920002261 Corn starch Polymers 0.000 description 1
• 101100457345 Danio rerio mapk14a gene Proteins 0.000 description 1
• 101100457347 Danio rerio mapk14b gene Proteins 0.000 description 1
• 206010012438 Dermatitis atopic Diseases 0.000 description 1
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
• 229920002307 Dextran Polymers 0.000 description 1
• 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
• OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
• BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
• 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 1
• 102100023401 Dual specificity mitogen-activated protein kinase kinase 6 Human genes 0.000 description 1
• 102100035650 Extracellular calcium-sensing receptor Human genes 0.000 description 1
• GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
• 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
• 208000018522 Gastrointestinal disease Diseases 0.000 description 1
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
• 239000007995 HEPES buffer Substances 0.000 description 1
• 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 1
• 101000624426 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 6 Proteins 0.000 description 1
• 101000947102 Homo sapiens Extracellular calcium-sensing receptor Proteins 0.000 description 1
• 101000628954 Homo sapiens Mitogen-activated protein kinase 12 Proteins 0.000 description 1
• 101001074035 Homo sapiens Zinc finger protein GLI2 Proteins 0.000 description 1
• 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
• 206010020751 Hypersensitivity Diseases 0.000 description 1
• WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
• 108090001007 Interleukin-8 Proteins 0.000 description 1
• 241000824268 Kuma Species 0.000 description 1
• 208000019693 Lung disease Diseases 0.000 description 1
• 108700012928 MAPK14 Proteins 0.000 description 1
• 101150003941 Mapk14 gene Proteins 0.000 description 1
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
• 102100026932 Mitogen-activated protein kinase 12 Human genes 0.000 description 1
• 102000054819 Mitogen-activated protein kinase 14 Human genes 0.000 description 1
• MGJKQDOBUOMPEZ-UHFFFAOYSA-N N,N'-dimethylurea Chemical compound CNC(=O)NC MGJKQDOBUOMPEZ-UHFFFAOYSA-N 0.000 description 1
• 244000061176 Nicotiana tabacum Species 0.000 description 1
• 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
• 208000030880 Nose disease Diseases 0.000 description 1
• ZBEPMOZEXLGCTF-UHFFFAOYSA-N O=C(C1CC1)N1CCCC(C1)NC1=NC(=CC=N1)N1C(CC#N)=CN=C1C1=CC2=C(OC=C2)C=C1 Chemical compound O=C(C1CC1)N1CCCC(C1)NC1=NC(=CC=N1)N1C(CC#N)=CN=C1C1=CC2=C(OC=C2)C=C1 ZBEPMOZEXLGCTF-UHFFFAOYSA-N 0.000 description 1
• UQONAEXHTGDOIH-AWEZNQCLSA-N O=C(N1CC[C@@H](C1)N1CCCC1=O)C1=CC2=C(NC3(CC3)CCO2)N=C1 Chemical compound O=C(N1CC[C@@H](C1)N1CCCC1=O)C1=CC2=C(NC3(CC3)CCO2)N=C1 UQONAEXHTGDOIH-AWEZNQCLSA-N 0.000 description 1
• 235000019483 Peanut oil Nutrition 0.000 description 1
• 208000021063 Respiratory fume inhalation disease Diseases 0.000 description 1
• GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 1
• 239000004147 Sorbitan trioleate Substances 0.000 description 1
• PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
• 229920002472 Starch Polymers 0.000 description 1
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
• 229930006000 Sucrose Natural products 0.000 description 1
• UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
• 210000001744 T-lymphocyte Anatomy 0.000 description 1
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
• DQHNAVOVODVIMG-UHFFFAOYSA-M Tiotropium bromide Chemical compound [Br-].C1C(C2C3O2)[N+](C)(C)C3CC1OC(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 DQHNAVOVODVIMG-UHFFFAOYSA-M 0.000 description 1
• 229920001615 Tragacanth Polymers 0.000 description 1
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
• 208000036142 Viral infection Diseases 0.000 description 1
• 102100035558 Zinc finger protein GLI2 Human genes 0.000 description 1
• FYJKEHKQUPSJDH-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;potassium Chemical compound [K].C[Si](C)(C)N[Si](C)(C)C FYJKEHKQUPSJDH-UHFFFAOYSA-N 0.000 description 1
• 238000002835 absorbance Methods 0.000 description 1
• 230000002378 acidificating effect Effects 0.000 description 1
• 150000007513 acids Chemical class 0.000 description 1
• 239000012190 activator Substances 0.000 description 1
• 239000000654 additive Substances 0.000 description 1
• 229960001456 adenosine triphosphate Drugs 0.000 description 1
• 230000002411 adverse Effects 0.000 description 1
• NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
• 125000005037 alkyl phenyl group Chemical group 0.000 description 1
• 208000026935 allergic disease Diseases 0.000 description 1
• 230000007815 allergy Effects 0.000 description 1
• 239000008168 almond oil Substances 0.000 description 1
• 230000009435 amidation Effects 0.000 description 1
• 238000007112 amidation reaction Methods 0.000 description 1
• 125000003277 amino group Chemical group 0.000 description 1
• 235000019270 ammonium chloride Nutrition 0.000 description 1
• 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
• 239000003443 antiviral agent Substances 0.000 description 1
• 208000002399 aphthous stomatitis Diseases 0.000 description 1
• 239000007900 aqueous suspension Substances 0.000 description 1
• 239000012298 atmosphere Substances 0.000 description 1
• 229950000210 beclometasone dipropionate Drugs 0.000 description 1
• 235000013871 bee wax Nutrition 0.000 description 1
• 239000012166 beeswax Substances 0.000 description 1
• RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
• 235000010233 benzoic acid Nutrition 0.000 description 1
• 235000019445 benzyl alcohol Nutrition 0.000 description 1
• 229960004217 benzyl alcohol Drugs 0.000 description 1
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
• 229940125388 beta agonist Drugs 0.000 description 1
• 239000011230 binding agent Substances 0.000 description 1
• AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
• 229940098773 bovine serum albumin Drugs 0.000 description 1
• 210000004556 brain Anatomy 0.000 description 1
• 229960004436 budesonide Drugs 0.000 description 1
• 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
• 239000001506 calcium phosphate Substances 0.000 description 1
• 229910000389 calcium phosphate Inorganic materials 0.000 description 1
• 235000011010 calcium phosphates Nutrition 0.000 description 1
• CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
• 239000008116 calcium stearate Substances 0.000 description 1
• 235000013539 calcium stearate Nutrition 0.000 description 1
• 244000309466 calf Species 0.000 description 1
• 150000001723 carbon free-radicals Chemical class 0.000 description 1
• 239000001768 carboxy methyl cellulose Substances 0.000 description 1
• 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
• 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
• 229940105329 carboxymethylcellulose Drugs 0.000 description 1
• 239000004359 castor oil Substances 0.000 description 1
• 235000019438 castor oil Nutrition 0.000 description 1
• 230000003197 catalytic effect Effects 0.000 description 1
• 238000005341 cation exchange Methods 0.000 description 1
• 230000007541 cellular toxicity Effects 0.000 description 1
• 238000005119 centrifugation Methods 0.000 description 1
• KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
• 239000000812 cholinergic antagonist Substances 0.000 description 1
• 238000004587 chromatography analysis Methods 0.000 description 1
• 238000003776 cleavage reaction Methods 0.000 description 1
• 238000010549 co-Evaporation Methods 0.000 description 1
• 239000003240 coconut oil Substances 0.000 description 1
• 235000019864 coconut oil Nutrition 0.000 description 1
• 239000003026 cod liver oil Substances 0.000 description 1
• 235000012716 cod liver oil Nutrition 0.000 description 1
• 238000007796 conventional method Methods 0.000 description 1
• 239000008120 corn starch Substances 0.000 description 1
• 229960001334 corticosteroids Drugs 0.000 description 1
• 235000001671 coumarin Nutrition 0.000 description 1
• 229960000956 coumarin Drugs 0.000 description 1
• 125000004122 cyclic group Chemical group 0.000 description 1
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
• DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
• 238000013461 design Methods 0.000 description 1
• 229910052805 deuterium Inorganic materials 0.000 description 1
• UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
• 230000009266 disease activity Effects 0.000 description 1
• 238000006073 displacement reaction Methods 0.000 description 1
• CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
• 239000000975 dye Substances 0.000 description 1
• XUZICJHIIJCKQQ-ZDUSSCGKSA-N eclitasertib Chemical compound C(C1=CC=CC=C1)C=1NC(=NN=1)C(=O)N[C@@H]1C(N(C2=C(OC1)C=CC=N2)C)=O XUZICJHIIJCKQQ-ZDUSSCGKSA-N 0.000 description 1
• 238000000132 electrospray ionisation Methods 0.000 description 1
• 239000003995 emulsifying agent Substances 0.000 description 1
• 210000002889 endothelial cell Anatomy 0.000 description 1
• 238000005516 engineering process Methods 0.000 description 1
• 239000012259 ether extract Substances 0.000 description 1
• DUVOZUPPHBRJJO-UHFFFAOYSA-N ethyl 2-isocyanatoacetate Chemical compound CCOC(=O)CN=C=O DUVOZUPPHBRJJO-UHFFFAOYSA-N 0.000 description 1
• 125000004494 ethyl ester group Chemical group 0.000 description 1
• 230000007717 exclusion Effects 0.000 description 1
• 238000002474 experimental method Methods 0.000 description 1
• 201000001264 familial hypocalciuric hypercalcemia 1 Diseases 0.000 description 1
• 239000003925 fat Substances 0.000 description 1
• 235000019197 fats Nutrition 0.000 description 1
• 239000000945 filler Substances 0.000 description 1
• 239000000796 flavoring agent Substances 0.000 description 1
• 235000019634 flavors Nutrition 0.000 description 1
• GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
• 229960001469 fluticasone furoate Drugs 0.000 description 1
• XTULMSXFIHGYFS-VLSRWLAYSA-N fluticasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 description 1
• 229960002848 formoterol Drugs 0.000 description 1
• BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
• 210000001035 gastrointestinal tract Anatomy 0.000 description 1
• 230000030279 gene silencing Effects 0.000 description 1
• 235000011187 glycerol Nutrition 0.000 description 1
• ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
• BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical group NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 1
• 150000002334 glycols Chemical class 0.000 description 1
• 229940093915 gynecological organic acid Drugs 0.000 description 1
• 239000007887 hard shell capsule Substances 0.000 description 1
• 238000011597 hartley guinea pig Methods 0.000 description 1
• 210000002216 heart Anatomy 0.000 description 1
• UKACHOXRXFQJFN-UHFFFAOYSA-N heptafluoropropane Chemical compound FC(F)C(F)(F)C(F)(F)F UKACHOXRXFQJFN-UHFFFAOYSA-N 0.000 description 1
• 150000004677 hydrates Chemical class 0.000 description 1
• OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
• 238000006197 hydroboration reaction Methods 0.000 description 1
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
• 230000007062 hydrolysis Effects 0.000 description 1
• 238000006460 hydrolysis reaction Methods 0.000 description 1
• WICNYNXYKZNNSN-UHFFFAOYSA-N hydron;4-methylpiperazine-1-carbonyl chloride;chloride Chemical compound Cl.CN1CCN(C(Cl)=O)CC1 WICNYNXYKZNNSN-UHFFFAOYSA-N 0.000 description 1
• MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
• 238000007654 immersion Methods 0.000 description 1
• 230000001771 impaired effect Effects 0.000 description 1
• 239000012535 impurity Substances 0.000 description 1
• 238000000099 in vitro assay Methods 0.000 description 1
• 238000010874 in vitro model Methods 0.000 description 1
• 238000005462 in vivo assay Methods 0.000 description 1
• 230000002458 infectious effect Effects 0.000 description 1
• 206010022000 influenza Diseases 0.000 description 1
• 230000000977 initiatory effect Effects 0.000 description 1
• 210000000936 intestine Anatomy 0.000 description 1
• 238000007918 intramuscular administration Methods 0.000 description 1
• 238000001990 intravenous administration Methods 0.000 description 1
• 125000002346 iodo group Chemical group I* 0.000 description 1
• 229910052742 iron Inorganic materials 0.000 description 1
• 238000002955 isolation Methods 0.000 description 1
• VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 1
• 210000003734 kidney Anatomy 0.000 description 1
• 231100001231 less toxic Toxicity 0.000 description 1
• 239000006193 liquid solution Substances 0.000 description 1
• 239000006194 liquid suspension Substances 0.000 description 1
• 210000004185 liver Anatomy 0.000 description 1
• 239000000314 lubricant Substances 0.000 description 1
• 210000004698 lymphocyte Anatomy 0.000 description 1
• 230000001404 mediated effect Effects 0.000 description 1
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
• RGLRLSBCOMWGKL-UHFFFAOYSA-N methoxymethylbenzene Chemical compound CO[CH]C1=CC=CC=C1 RGLRLSBCOMWGKL-UHFFFAOYSA-N 0.000 description 1
• 229920000609 methyl cellulose Polymers 0.000 description 1
• 239000001923 methylcellulose Substances 0.000 description 1
• 235000010981 methylcellulose Nutrition 0.000 description 1
• 238000000386 microscopy Methods 0.000 description 1
• 238000003032 molecular docking Methods 0.000 description 1
• 229960002744 mometasone furoate Drugs 0.000 description 1
• WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 1
• 125000002950 monocyclic group Chemical group 0.000 description 1
• 210000004877 mucosa Anatomy 0.000 description 1
• GUOONOJYWQOJJP-DCMFLLSESA-N n-[(2s,3r)-3-hydroxy-1-phenyl-4-[[3-(trifluoromethoxy)phenyl]methylamino]butan-2-yl]-3-[methyl(methylsulfonyl)amino]-5-[(2r)-2-(4-methyl-1,3-thiazol-2-yl)pyrrolidine-1-carbonyl]benzamide Chemical compound C1([C@H]2CCCN2C(=O)C=2C=C(C=C(C=2)N(C)S(C)(=O)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)[C@H](O)CNCC=2C=C(OC(F)(F)F)C=CC=2)=NC(C)=CS1 GUOONOJYWQOJJP-DCMFLLSESA-N 0.000 description 1
• HIVWBOCXSUYQQN-UHFFFAOYSA-N n-[4-[1-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypropan-2-yl]pyridin-2-yl]-2-methoxyacetamide Chemical compound C1=NC(NC(=O)COC)=CC(C(C)COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 HIVWBOCXSUYQQN-UHFFFAOYSA-N 0.000 description 1
• DMPPZLQPLPCJQQ-UHFFFAOYSA-N n-[4-[2-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]ethoxy]pyridin-2-yl]-2-methoxyacetamide Chemical compound C1=NC(NC(=O)COC)=CC(OCCC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 DMPPZLQPLPCJQQ-UHFFFAOYSA-N 0.000 description 1
• KXYSWSCUTMYNEX-UHFFFAOYSA-N n-[4-[2-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxy-2-methylpropyl]pyridin-2-yl]-2-methoxyacetamide Chemical compound C1=NC(NC(=O)COC)=CC(CC(C)(C)OC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 KXYSWSCUTMYNEX-UHFFFAOYSA-N 0.000 description 1
• OZBAYKRJSOIGFG-UHFFFAOYSA-N n-[4-[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxypyridin-2-yl]-2-methylsulfonylacetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OC=3C=C(NC(=O)CS(C)(=O)=O)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 OZBAYKRJSOIGFG-UHFFFAOYSA-N 0.000 description 1
• MEHHBMIDOADJTJ-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-(2-morpholin-4-ylethylsulfonyl)acetamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)CS(=O)(=O)CCN4CCOCC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 MEHHBMIDOADJTJ-UHFFFAOYSA-N 0.000 description 1
• HSAUVTQDPJVUSH-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-(4-methylpiperazin-1-yl)acetamide Chemical compound C1CN(C)CCN1CC(=O)NC1=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=CC=N1 HSAUVTQDPJVUSH-UHFFFAOYSA-N 0.000 description 1
• RTDCVLCTBQDLBW-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-methoxyacetamide Chemical compound C1=NC(NC(=O)COC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 RTDCVLCTBQDLBW-UHFFFAOYSA-N 0.000 description 1
• XMBOYOLYVHKXOL-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-methyl-2-(methylamino)propanamide Chemical compound C1=NC(NC(=O)C(C)(C)NC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=C1 XMBOYOLYVHKXOL-UHFFFAOYSA-N 0.000 description 1
• WQJBZQGFGJVAEK-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]morpholine-4-carboxamide Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCC=3C=C(NC(=O)N4CCOCC4)N=CC=3)=CC=2)=CC(C(C)(C)C)=N1 WQJBZQGFGJVAEK-UHFFFAOYSA-N 0.000 description 1
• ALDIAZDWIIEJIN-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyrimidin-2-yl]-2-methoxyacetamide Chemical compound COCC(=O)NC1=NC=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(C)=CC=3)=CC=2)=N1 ALDIAZDWIIEJIN-UHFFFAOYSA-N 0.000 description 1
• FFALYOYCQQXGJJ-UHFFFAOYSA-N n-[4-[[4-[[5-tert-butyl-2-[4-(hydroxymethyl)phenyl]pyrazol-3-yl]carbamoylamino]naphthalen-1-yl]oxymethyl]pyridin-2-yl]-2-methoxyacetamide Chemical compound C1=NC(NC(=O)COC)=CC(COC=2C3=CC=CC=C3C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=CC(CO)=CC=3)=CC=2)=C1 FFALYOYCQQXGJJ-UHFFFAOYSA-N 0.000 description 1
• WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
• 150000002790 naphthalenes Chemical class 0.000 description 1
• 239000012299 nitrogen atmosphere Substances 0.000 description 1
• VWBWQOUWDOULQN-UHFFFAOYSA-N nmp n-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
• 230000000269 nucleophilic effect Effects 0.000 description 1
• XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
• 238000006772 olefination reaction Methods 0.000 description 1
• 239000003605 opacifier Substances 0.000 description 1
• 239000006186 oral dosage form Substances 0.000 description 1
• 150000007524 organic acids Chemical class 0.000 description 1
• 235000005985 organic acids Nutrition 0.000 description 1
• IVMHDOBGNQOUHO-UHFFFAOYSA-N oxathiane Chemical compound C1CCSOC1 IVMHDOBGNQOUHO-UHFFFAOYSA-N 0.000 description 1
• 230000003647 oxidation Effects 0.000 description 1
• 238000007254 oxidation reaction Methods 0.000 description 1
• 125000004430 oxygen atom Chemical group O* 0.000 description 1
• 229910052763 palladium Inorganic materials 0.000 description 1
• 210000000496 pancreas Anatomy 0.000 description 1
• 238000007911 parenteral administration Methods 0.000 description 1
• 230000036961 partial effect Effects 0.000 description 1
• 239000002245 particle Substances 0.000 description 1
• 230000037361 pathway Effects 0.000 description 1
• 239000000312 peanut oil Substances 0.000 description 1
• 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
• 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
• 230000002085 persistent effect Effects 0.000 description 1
• 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
• JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical compound NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 description 1
• 239000004014 plasticizer Substances 0.000 description 1
• 229910052697 platinum Inorganic materials 0.000 description 1
• 229920001515 polyalkylene glycol Polymers 0.000 description 1
• 125000003367 polycyclic group Chemical group 0.000 description 1
• 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
• 229920005862 polyol Polymers 0.000 description 1
• 150000003077 polyols Chemical class 0.000 description 1
• BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
• 230000003389 potentiating effect Effects 0.000 description 1
• 102000004196 processed proteins & peptides Human genes 0.000 description 1
• AMMGCGVWJMRTQI-UHFFFAOYSA-N prop-1-en-2-yl carbonochloridate Chemical compound CC(=C)OC(Cl)=O AMMGCGVWJMRTQI-UHFFFAOYSA-N 0.000 description 1
• VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
• NMHFEBGIAJWIPC-UHFFFAOYSA-N propanamide Chemical compound C[CH]C(N)=O NMHFEBGIAJWIPC-UHFFFAOYSA-N 0.000 description 1
• 238000011321 prophylaxis Methods 0.000 description 1
• 235000013772 propylene glycol Nutrition 0.000 description 1
• 239000003586 protic polar solvent Substances 0.000 description 1
• 230000002685 pulmonary effect Effects 0.000 description 1
• 238000000746 purification Methods 0.000 description 1
• USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
• DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
• CYVBUBORVHPEGF-UHFFFAOYSA-N pyridin-2-yl carbamate Chemical compound NC(=O)OC1=CC=CC=N1 CYVBUBORVHPEGF-UHFFFAOYSA-N 0.000 description 1
• ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
• 239000012048 reactive intermediate Substances 0.000 description 1
• 102000005962 receptors Human genes 0.000 description 1
• 108020003175 receptors Proteins 0.000 description 1
• 230000007115 recruitment Effects 0.000 description 1
• BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
• 239000011347 resin Substances 0.000 description 1
• 229920005989 resin Polymers 0.000 description 1
• 230000000717 retained effect Effects 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 229960002052 salbutamol Drugs 0.000 description 1
• 229960004017 salmeterol Drugs 0.000 description 1
• 230000007017 scission Effects 0.000 description 1
• 230000001235 sensitizing effect Effects 0.000 description 1
• 210000002966 serum Anatomy 0.000 description 1
• 230000011664 signaling Effects 0.000 description 1
• 235000020374 simple syrup Nutrition 0.000 description 1
• 210000002027 skeletal muscle Anatomy 0.000 description 1
• 208000017520 skin disease Diseases 0.000 description 1
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
• RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
• 239000011877 solvent mixture Substances 0.000 description 1
• 235000019337 sorbitan trioleate Nutrition 0.000 description 1
• 229960000391 sorbitan trioleate Drugs 0.000 description 1
• 241000894007 species Species 0.000 description 1
• 238000004611 spectroscopical analysis Methods 0.000 description 1
• 229940046810 spiriva Drugs 0.000 description 1
• 239000007921 spray Substances 0.000 description 1
• 239000008107 starch Substances 0.000 description 1
• 235000019698 starch Nutrition 0.000 description 1
• 239000008223 sterile water Substances 0.000 description 1
• 150000003431 steroids Chemical class 0.000 description 1
• 239000011550 stock solution Substances 0.000 description 1
• 238000007920 subcutaneous administration Methods 0.000 description 1
• 239000005720 sucrose Substances 0.000 description 1
• 235000000346 sugar Nutrition 0.000 description 1
• 150000008163 sugars Chemical class 0.000 description 1
• 239000000829 suppository Substances 0.000 description 1
• 208000024891 symptom Diseases 0.000 description 1
• 238000003786 synthesis reaction Methods 0.000 description 1
• 235000020357 syrup Nutrition 0.000 description 1
• 239000006188 syrup Substances 0.000 description 1
• 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
• 231100000057 systemic toxicity Toxicity 0.000 description 1
• 239000000454 talc Substances 0.000 description 1
• 229910052623 talc Inorganic materials 0.000 description 1
• 229960000195 terbutaline Drugs 0.000 description 1
• HAJAGHHFQDXDEY-UHFFFAOYSA-N tert-butyl n-(4-bromonaphthalen-1-yl)carbamate Chemical compound C1=CC=C2C(NC(=O)OC(C)(C)C)=CC=C(Br)C2=C1 HAJAGHHFQDXDEY-UHFFFAOYSA-N 0.000 description 1
• BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
• 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 210000001550 testis Anatomy 0.000 description 1
• WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
• 125000006173 tetrahydropyranylmethyl group Chemical group 0.000 description 1
• WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
• 229960000278 theophylline Drugs 0.000 description 1
• 238000011287 therapeutic dose Methods 0.000 description 1
• BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
• 229930192474 thiophene Natural products 0.000 description 1
• 210000000115 thoracic cavity Anatomy 0.000 description 1
• LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
• 229940110309 tiotropium Drugs 0.000 description 1
• 125000003944 tolyl group Chemical group 0.000 description 1
• 231100000419 toxicity Toxicity 0.000 description 1
• 230000001988 toxicity Effects 0.000 description 1
• 239000000196 tragacanth Substances 0.000 description 1
• 235000010487 tragacanth Nutrition 0.000 description 1
• 229940116362 tragacanth Drugs 0.000 description 1
• 238000000844 transformation Methods 0.000 description 1
• 150000003626 triacylglycerols Chemical class 0.000 description 1
• QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
• 229940029284 trichlorofluoromethane Drugs 0.000 description 1
• 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
• MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 description 1
• UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
• 235000013311 vegetables Nutrition 0.000 description 1
• 230000009385 viral infection Effects 0.000 description 1
• 230000003612 virological effect Effects 0.000 description 1
• KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
• 239000003643 water by type Substances 0.000 description 1
• 125000005023 xylyl group Chemical group 0.000 description 1