JP5941513B2 - Bcr−ablの低分子のミリスチン酸エステル阻害剤及びその使用方法 - Google Patents
Bcr−ablの低分子のミリスチン酸エステル阻害剤及びその使用方法 Download PDFInfo
- Publication number
- JP5941513B2 JP5941513B2 JP2014204682A JP2014204682A JP5941513B2 JP 5941513 B2 JP5941513 B2 JP 5941513B2 JP 2014204682 A JP2014204682 A JP 2014204682A JP 2014204682 A JP2014204682 A JP 2014204682A JP 5941513 B2 JP5941513 B2 JP 5941513B2
- Authority
- JP
- Japan
- Prior art keywords
- trifluoromethoxy
- phenyl
- pyrimidin
- optionally substituted
- amine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 myristic acid ester Chemical class 0.000 title claims description 87
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 title claims description 57
- 239000003112 inhibitor Substances 0.000 title claims description 10
- 238000000034 method Methods 0.000 title description 44
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 title description 7
- 235000021360 Myristic acid Nutrition 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 183
- 125000003118 aryl group Chemical group 0.000 claims description 78
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 73
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 71
- 150000003839 salts Chemical class 0.000 claims description 54
- 201000010099 disease Diseases 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 45
- 206010028980 Neoplasm Diseases 0.000 claims description 35
- 239000012453 solvate Substances 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 230000000694 effects Effects 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 208000035475 disorder Diseases 0.000 claims description 25
- 108091000080 Phosphotransferase Proteins 0.000 claims description 24
- 102000020233 phosphotransferase Human genes 0.000 claims description 24
- 201000011510 cancer Diseases 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 21
- 239000002552 dosage form Substances 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 239000004480 active ingredient Substances 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 125000002619 bicyclic group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- QQDDFQKWZHOVDY-UHFFFAOYSA-N 2-[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-1-yl]ethanol Chemical compound N1=CN=C2N(CCO)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 QQDDFQKWZHOVDY-UHFFFAOYSA-N 0.000 claims description 11
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 11
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229940124597 therapeutic agent Drugs 0.000 claims description 10
- 125000002950 monocyclic group Chemical group 0.000 claims description 9
- 150000004677 hydrates Chemical class 0.000 claims description 8
- 208000032839 leukemia Diseases 0.000 claims description 8
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 7
- 208000015181 infectious disease Diseases 0.000 claims description 7
- CSXDRTVRHUMKKN-UHFFFAOYSA-N n-(2-morpholin-4-ylethyl)-3-[4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-7-yl]propanamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=CN2CCC(=O)NCCN1CCOCC1 CSXDRTVRHUMKKN-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 238000007911 parenteral administration Methods 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- VLRLEARKNHVWFN-UHFFFAOYSA-N CC(C1=CC=CC=C1)N1N=CC2=C(NC(C=C3)=CC=C3OC(F)(F)F)N=CN=C12 Chemical compound CC(C1=CC=CC=C1)N1N=CC2=C(NC(C=C3)=CC=C3OC(F)(F)F)N=CN=C12 VLRLEARKNHVWFN-UHFFFAOYSA-N 0.000 claims description 5
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- BORBQIBMVCBFML-UHFFFAOYSA-N n-[4-(trifluoromethoxy)phenyl]-1h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2 BORBQIBMVCBFML-UHFFFAOYSA-N 0.000 claims description 5
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 238000011200 topical administration Methods 0.000 claims description 5
- CVUFCAQRTGIGTF-UHFFFAOYSA-N 1-(oxolan-3-ylmethyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2CC1COCC1 CVUFCAQRTGIGTF-UHFFFAOYSA-N 0.000 claims description 4
- BPHIFPPYTIJFSP-UHFFFAOYSA-N 1-cyclohexyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2C1CCCCC1 BPHIFPPYTIJFSP-UHFFFAOYSA-N 0.000 claims description 4
- SAXPEWWZWJCVAP-UHFFFAOYSA-N 1-ethyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2N(CC)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 SAXPEWWZWJCVAP-UHFFFAOYSA-N 0.000 claims description 4
- MQXBCNJRTVABLK-UHFFFAOYSA-N 3-[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-1-yl]propanamide Chemical compound N1=CN=C2N(CCC(=O)N)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 MQXBCNJRTVABLK-UHFFFAOYSA-N 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 230000033115 angiogenesis Effects 0.000 claims description 4
- 229960002411 imatinib Drugs 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- DCUPINURJHRXSR-UHFFFAOYSA-N 1-(2,3-dimethylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound CC1=CC=CC(N2C3=NC=NC(NC=4C=CC(OC(F)(F)F)=CC=4)=C3C=N2)=C1C DCUPINURJHRXSR-UHFFFAOYSA-N 0.000 claims description 3
- YWFNMHPWCFIJPP-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2C1=CC=C(Cl)C=C1Cl YWFNMHPWCFIJPP-UHFFFAOYSA-N 0.000 claims description 3
- VSUBBLBCKOUWND-UHFFFAOYSA-N 1-(2-aminoethyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2N(CCN)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 VSUBBLBCKOUWND-UHFFFAOYSA-N 0.000 claims description 3
- WMFXDOZZAKBVKF-UHFFFAOYSA-N 1-(2-ethylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound CCC1=CC=CC=C1N1C2=NC=NC(NC=3C=CC(OC(F)(F)F)=CC=3)=C2C=N1 WMFXDOZZAKBVKF-UHFFFAOYSA-N 0.000 claims description 3
- LOMRIOIDRKGPDF-UHFFFAOYSA-N 1-(2-fluorophenyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound FC1=CC=CC=C1N1C2=NC=NC(NC=3C=CC(OC(F)(F)F)=CC=3)=C2C=N1 LOMRIOIDRKGPDF-UHFFFAOYSA-N 0.000 claims description 3
- LJCROKHKDOQWOA-UHFFFAOYSA-N 1-(pyridin-2-ylmethyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2CC1=CC=CC=N1 LJCROKHKDOQWOA-UHFFFAOYSA-N 0.000 claims description 3
- JOLSWPYDQLCFEP-UHFFFAOYSA-N 1-(pyridin-3-ylmethyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2CC1=CC=CN=C1 JOLSWPYDQLCFEP-UHFFFAOYSA-N 0.000 claims description 3
- MLAIONZVQZBMNT-UHFFFAOYSA-N 1-(pyridin-4-ylmethyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2CC1=CC=NC=C1 MLAIONZVQZBMNT-UHFFFAOYSA-N 0.000 claims description 3
- PHGJOWLVYAKQDN-UHFFFAOYSA-N 1-[[3-fluoro-4-(trifluoromethyl)phenyl]methyl]-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=C(C(F)(F)F)C(F)=CC(CN2C3=NC=NC(NC=4C=CC(OC(F)(F)F)=CC=4)=C3C=N2)=C1 PHGJOWLVYAKQDN-UHFFFAOYSA-N 0.000 claims description 3
- PJPQSVRZOPGBPP-UHFFFAOYSA-N 1-pyridin-2-yl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2C1=CC=CC=N1 PJPQSVRZOPGBPP-UHFFFAOYSA-N 0.000 claims description 3
- MZZOZIMQTLWYIP-UHFFFAOYSA-N 2-(hydroxymethyl)-5-[4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-7-yl]oxolane-3,4-diol Chemical compound OC1C(O)C(CO)OC1N1C2=NC=NC(NC=3C=CC(OC(F)(F)F)=CC=3)=C2C=C1 MZZOZIMQTLWYIP-UHFFFAOYSA-N 0.000 claims description 3
- DOSKDRMSPLEXAT-UHFFFAOYSA-N 2-(hydroxymethyl)-5-[6-[4-(trifluoromethoxy)anilino]purin-9-yl]oxolane-3,4-diol Chemical compound OC1C(O)C(CO)OC1N1C2=NC=NC(NC=3C=CC(OC(F)(F)F)=CC=3)=C2N=C1 DOSKDRMSPLEXAT-UHFFFAOYSA-N 0.000 claims description 3
- GVVYXIJQKZRKOZ-UHFFFAOYSA-N 2-[4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-7-yl]ethanol Chemical compound N1=CN=C2N(CCO)C=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 GVVYXIJQKZRKOZ-UHFFFAOYSA-N 0.000 claims description 3
- XLVMADINVYYTKE-UHFFFAOYSA-N 3-[4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-7-yl]propanamide Chemical compound N1=CN=C2N(CCC(=O)N)C=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 XLVMADINVYYTKE-UHFFFAOYSA-N 0.000 claims description 3
- HINMLOLPPYMZGW-UHFFFAOYSA-N 3-[[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-1-yl]methyl]phenol Chemical compound OC1=CC=CC(CN2C3=NC=NC(NC=4C=CC(OC(F)(F)F)=CC=4)=C3C=N2)=C1 HINMLOLPPYMZGW-UHFFFAOYSA-N 0.000 claims description 3
- QSOAMPBHXPSPJY-UHFFFAOYSA-N 7-[(4-methoxyphenyl)methyl]-n-[4-(trifluoromethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1CN1C2=NC=NC(NC=3C=CC(OC(F)(F)F)=CC=3)=C2C=C1 QSOAMPBHXPSPJY-UHFFFAOYSA-N 0.000 claims description 3
- PZVUYTSZTJYZKJ-UHFFFAOYSA-N 7-methyl-n-[4-(trifluoromethoxy)phenyl]purin-6-amine Chemical compound C=12N(C)C=NC2=NC=NC=1NC1=CC=C(OC(F)(F)F)C=C1 PZVUYTSZTJYZKJ-UHFFFAOYSA-N 0.000 claims description 3
- LVIKHBLLLLIECW-UHFFFAOYSA-N 7-methyl-n-[4-(trifluoromethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound N1=CN=C2N(C)C=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 LVIKHBLLLLIECW-UHFFFAOYSA-N 0.000 claims description 3
- SGAHPWXPVFRFHZ-UHFFFAOYSA-N 9-methyl-n-[4-(trifluoromethoxy)phenyl]purin-6-amine Chemical compound N1=CN=C2N(C)C=NC2=C1NC1=CC=C(OC(F)(F)F)C=C1 SGAHPWXPVFRFHZ-UHFFFAOYSA-N 0.000 claims description 3
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 claims description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 3
- 208000001344 Macular Edema Diseases 0.000 claims description 3
- 206010025415 Macular oedema Diseases 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 claims description 3
- 229960003736 bosutinib Drugs 0.000 claims description 3
- 208000035269 cancer or benign tumor Diseases 0.000 claims description 3
- 201000010230 macular retinal edema Diseases 0.000 claims description 3
- 230000009401 metastasis Effects 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- QZMKFYYJKDNZTG-UHFFFAOYSA-N n-(3-methoxypropyl)-3-[4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-7-yl]propanamide Chemical compound N1=CN=C2N(CCC(=O)NCCCOC)C=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 QZMKFYYJKDNZTG-UHFFFAOYSA-N 0.000 claims description 3
- JIHDZQXFAZNODD-UHFFFAOYSA-N n-[4-(trifluoromethoxy)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=CN2 JIHDZQXFAZNODD-UHFFFAOYSA-N 0.000 claims description 3
- BYIVBQFAXQMWDP-UHFFFAOYSA-N n-[4-(trifluoromethoxy)phenyl]thieno[2,3-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=CS2 BYIVBQFAXQMWDP-UHFFFAOYSA-N 0.000 claims description 3
- USEOGFKTXSMHKT-UHFFFAOYSA-N n-ethyl-3-[4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-7-yl]propanamide Chemical compound N1=CN=C2N(CCC(=O)NCC)C=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 USEOGFKTXSMHKT-UHFFFAOYSA-N 0.000 claims description 3
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 3
- 201000008968 osteosarcoma Diseases 0.000 claims description 3
- 230000002062 proliferating effect Effects 0.000 claims description 3
- OUKYUETWWIPKQR-UHFFFAOYSA-N saracatinib Chemical compound C1CN(C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CC=C3OCOC3=2)Cl)=NC=N2)C2=C1 OUKYUETWWIPKQR-UHFFFAOYSA-N 0.000 claims description 3
- 229950009919 saracatinib Drugs 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 241000288906 Primates Species 0.000 claims description 2
- 229940043355 kinase inhibitor Drugs 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 2
- 208000017520 skin disease Diseases 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 2
- JAVZBWSWWVGQLA-UHFFFAOYSA-N 1-[(3-bromophenyl)methyl]-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2CC1=CC=CC(Br)=C1 JAVZBWSWWVGQLA-UHFFFAOYSA-N 0.000 claims 1
- SQXVYSHQJVZCKW-UHFFFAOYSA-N 1-methyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2N(C)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 SQXVYSHQJVZCKW-UHFFFAOYSA-N 0.000 claims 1
- VVOYROSONSLQQK-UHFFFAOYSA-N 3-[2-[2-cyclopentyl-6-(4-dimethylphosphorylanilino)purin-9-yl]ethyl]phenol Chemical compound C1=CC(P(C)(=O)C)=CC=C1NC1=NC(C2CCCC2)=NC2=C1N=CN2CCC1=CC=CC(O)=C1 VVOYROSONSLQQK-UHFFFAOYSA-N 0.000 claims 1
- RCARNAASLAIBGF-UHFFFAOYSA-N 3-ethyl-n-[4-(trifluoromethoxy)phenyl]triazolo[4,5-d]pyrimidin-7-amine Chemical compound N1=CN=C2N(CC)N=NC2=C1NC1=CC=C(OC(F)(F)F)C=C1 RCARNAASLAIBGF-UHFFFAOYSA-N 0.000 claims 1
- MJXSYDOHSGWOQE-UHFFFAOYSA-N 3-methyl-n-[4-(trifluoromethoxy)phenyl]triazolo[4,5-d]pyrimidin-7-amine Chemical compound N1=CN=C2N(C)N=NC2=C1NC1=CC=C(OC(F)(F)F)C=C1 MJXSYDOHSGWOQE-UHFFFAOYSA-N 0.000 claims 1
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims 1
- LVEAXOBLYYBYKV-UHFFFAOYSA-N 7-(2-morpholin-4-ylethyl)-n-[4-(trifluoromethoxy)phenyl]pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=CN2CCN1CCOCC1 LVEAXOBLYYBYKV-UHFFFAOYSA-N 0.000 claims 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims 1
- NGZRAYBOWATPQF-UHFFFAOYSA-N CC(C)C(CCO)NC(=O)CCn1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc12 Chemical compound CC(C)C(CCO)NC(=O)CCn1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc12 NGZRAYBOWATPQF-UHFFFAOYSA-N 0.000 claims 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 claims 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims 1
- OUSQEHULWVRDCE-UHFFFAOYSA-N N-[2-(1-tert-butylpyrazolo[3,4-d]pyrimidin-4-yl)-4-(trifluoromethoxy)phenyl]-1-(2,2,2-trifluoroethyl)-N-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C(C)(C)(C)N1N=CC=2C1=NC=NC2C2=C(C=CC(=C2)OC(F)(F)F)N(C2=C1C(=NC=N2)N(N=C1)CC(F)(F)F)C1=CC=C(C=C1)OC(F)(F)F OUSQEHULWVRDCE-UHFFFAOYSA-N 0.000 claims 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 230000002917 arthritic effect Effects 0.000 claims 1
- 229960002448 dasatinib Drugs 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 claims 1
- 238000007918 intramuscular administration Methods 0.000 claims 1
- 238000001990 intravenous administration Methods 0.000 claims 1
- 229960001346 nilotinib Drugs 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims 1
- 125000006654 (C3-C12) heteroaryl group Chemical group 0.000 description 40
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 description 37
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 125000003710 aryl alkyl group Chemical group 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 125000004475 heteroaralkyl group Chemical group 0.000 description 19
- 238000011282 treatment Methods 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 125000005843 halogen group Chemical group 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 125000000753 cycloalkyl group Chemical group 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 208000024891 symptom Diseases 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 125000000304 alkynyl group Chemical group 0.000 description 9
- 125000004103 aminoalkyl group Chemical group 0.000 description 9
- 230000012010 growth Effects 0.000 description 9
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 239000000872 buffer Substances 0.000 description 8
- 230000001684 chronic effect Effects 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 210000003491 skin Anatomy 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- BCXYVVILJPQKQT-UHFFFAOYSA-N 2-[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-2-yl]ethanol Chemical compound N=1C=NC2=NN(CCO)C=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 BCXYVVILJPQKQT-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 206010029113 Neovascularisation Diseases 0.000 description 7
- 108091008606 PDGF receptors Proteins 0.000 description 7
- 102000001253 Protein Kinase Human genes 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 108060006633 protein kinase Proteins 0.000 description 7
- 210000000130 stem cell Anatomy 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- PUNXUDZKHWWTRE-UHFFFAOYSA-N 6-pyrrolo[2,3-b]pyridin-1-yl-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(N2C3=NC=CC=C3C=C2)=NC=N1 PUNXUDZKHWWTRE-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 6
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 208000025865 Ulcer Diseases 0.000 description 6
- 230000002159 abnormal effect Effects 0.000 description 6
- 125000002947 alkylene group Chemical group 0.000 description 6
- 125000001188 haloalkyl group Chemical group 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 206010023332 keratitis Diseases 0.000 description 6
- FJPXUTWUHOPZGD-UHFFFAOYSA-N n-(2-hydroxyethyl)-4-[4-(trifluoromethoxy)anilino]quinazoline-7-carboxamide Chemical compound N=1C=NC2=CC(C(=O)NCCO)=CC=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 FJPXUTWUHOPZGD-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000006168 tricyclic group Chemical group 0.000 description 6
- 231100000397 ulcer Toxicity 0.000 description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 5
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 5
- XUJFOSLZQITUOI-UHFFFAOYSA-N 4-(trifluoromethoxy)aniline Chemical compound NC1=CC=C(OC(F)(F)F)C=C1 XUJFOSLZQITUOI-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 150000001448 anilines Chemical group 0.000 description 5
- 206010003246 arthritis Diseases 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 230000010261 cell growth Effects 0.000 description 5
- 208000037976 chronic inflammation Diseases 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- QNCGDKWKXJVOLU-UHFFFAOYSA-N 1-ethylsulfonyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2N(S(=O)(=O)CC)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 QNCGDKWKXJVOLU-UHFFFAOYSA-N 0.000 description 4
- SFCLWZBOEVLSTH-UHFFFAOYSA-N 4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidine-6-carboxylic acid Chemical compound N1=CN=C2SC(C(=O)O)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 SFCLWZBOEVLSTH-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 208000009905 Neurofibromatoses Diseases 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 4
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 4
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 4
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 4
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 4
- 201000004681 Psoriasis Diseases 0.000 description 4
- 206010038934 Retinopathy proliferative Diseases 0.000 description 4
- 206010039710 Scleroderma Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000001668 ameliorated effect Effects 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000035578 autophosphorylation Effects 0.000 description 4
- MVXVYAKCVDQRLW-UHFFFAOYSA-N azain Natural products C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 210000001508 eye Anatomy 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- 125000005945 imidazopyridyl group Chemical group 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 210000003734 kidney Anatomy 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
- VLDDCJHAVARWGW-UHFFFAOYSA-N methyl 4-[4-(trifluoromethoxy)anilino]quinazoline-7-carboxylate Chemical compound N=1C=NC2=CC(C(=O)OC)=CC=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 VLDDCJHAVARWGW-UHFFFAOYSA-N 0.000 description 4
- 210000000214 mouth Anatomy 0.000 description 4
- 125000001419 myristoyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- PEZCUUGXYBPXDQ-UHFFFAOYSA-N n-(2-hydroxyethyl)-4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2SC(C(=O)NCCO)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 PEZCUUGXYBPXDQ-UHFFFAOYSA-N 0.000 description 4
- WWHOIOKPIKLNPC-UHFFFAOYSA-N n-(2-morpholin-4-ylethyl)-4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidine-6-carboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=C(C(=O)NCCN1CCOCC1)S2 WWHOIOKPIKLNPC-UHFFFAOYSA-N 0.000 description 4
- IMJXOERPCNYXHG-UHFFFAOYSA-N n-[4-(trifluoromethoxy)phenyl]-6-(1,3,5-trimethylpyrazol-4-yl)pyrimidin-4-amine Chemical compound CC1=NN(C)C(C)=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 IMJXOERPCNYXHG-UHFFFAOYSA-N 0.000 description 4
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 4
- 201000004931 neurofibromatosis Diseases 0.000 description 4
- 210000003800 pharynx Anatomy 0.000 description 4
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 230000000153 supplemental effect Effects 0.000 description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- 230000008733 trauma Effects 0.000 description 4
- 208000009999 tuberous sclerosis Diseases 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 3
- XRFMEYLNYKCTLG-UHFFFAOYSA-N 2-(3-nitrophenyl)-n-[4-(trifluoromethoxy)phenyl]imidazo[1,2-c]pyrimidin-7-amine Chemical compound [O-][N+](=O)C1=CC=CC(C=2N=C3C=C(NC=4C=CC(OC(F)(F)F)=CC=4)N=CN3C=2)=C1 XRFMEYLNYKCTLG-UHFFFAOYSA-N 0.000 description 3
- RHDUQQAIJZXKOT-UHFFFAOYSA-N 2-[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-1-yl]acetamide Chemical compound N1=CN=C2N(CC(=O)N)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 RHDUQQAIJZXKOT-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 3
- 101150049556 Bcr gene Proteins 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 208000007766 Kaposi sarcoma Diseases 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 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
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 210000003423 ankle Anatomy 0.000 description 3
- 125000001769 aryl amino group Chemical group 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 210000002808 connective tissue Anatomy 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 230000003176 fibrotic effect Effects 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 201000004614 iritis Diseases 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000008297 liquid dosage form Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 206010025135 lupus erythematosus Diseases 0.000 description 3
- 230000035168 lymphangiogenesis Effects 0.000 description 3
- 239000006166 lysate Substances 0.000 description 3
- 239000012139 lysis buffer Substances 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- MVVWNXKODNGJOT-UHFFFAOYSA-N methyl 4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=CN=C2SC(C(=O)OC)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 MVVWNXKODNGJOT-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 125000006574 non-aromatic ring group Chemical group 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000003373 pyrazinyl group Chemical group 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 210000000664 rectum Anatomy 0.000 description 3
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 3
- 201000000306 sarcoidosis Diseases 0.000 description 3
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- QEZRFGVBCBMPKX-UHFFFAOYSA-N (3,5-dimethylpiperazin-1-yl)-[4-[4-(trifluoromethoxy)anilino]quinazolin-7-yl]methanone Chemical compound C1C(C)NC(C)CN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 QEZRFGVBCBMPKX-UHFFFAOYSA-N 0.000 description 2
- CHBZTCMXSHRBNJ-UHFFFAOYSA-N (3-hydroxypyrrolidin-1-yl)-[4-[4-(trifluoromethoxy)anilino]quinazolin-7-yl]methanone Chemical compound C1C(O)CCN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 CHBZTCMXSHRBNJ-UHFFFAOYSA-N 0.000 description 2
- ZDDDFGLUOMGOJC-UHFFFAOYSA-N (4-bromopiperidin-1-yl)-[4-[4-(trifluoromethoxy)anilino]quinazolin-7-yl]methanone Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=CC(C(=O)N3CCC(Br)CC3)=CC=C12 ZDDDFGLUOMGOJC-UHFFFAOYSA-N 0.000 description 2
- GHVXKFSOQVBKAX-UHFFFAOYSA-N (4-hydroxypiperidin-1-yl)-[4-[4-(trifluoromethoxy)anilino]quinazolin-7-yl]methanone Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 GHVXKFSOQVBKAX-UHFFFAOYSA-N 0.000 description 2
- ZUOPGMKNZDWSIV-UHFFFAOYSA-N (4-hydroxypiperidin-1-yl)-[4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidin-6-yl]methanone Chemical compound C1CC(O)CCN1C(=O)C(SC1=NC=N2)=CC1=C2NC1=CC=C(OC(F)(F)F)C=C1 ZUOPGMKNZDWSIV-UHFFFAOYSA-N 0.000 description 2
- KPUWMDDBRXWOKP-UHFFFAOYSA-N (4-methoxypiperidin-1-yl)-[4-[4-(trifluoromethoxy)anilino]quinazolin-7-yl]methanone Chemical compound C1CC(OC)CCN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 KPUWMDDBRXWOKP-UHFFFAOYSA-N 0.000 description 2
- OIRHYGIYSGBDLP-UHFFFAOYSA-N (4-methoxypiperidin-1-yl)-[4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidin-6-yl]methanone Chemical compound C1CC(OC)CCN1C(=O)C(SC1=NC=N2)=CC1=C2NC1=CC=C(OC(F)(F)F)C=C1 OIRHYGIYSGBDLP-UHFFFAOYSA-N 0.000 description 2
- HUNRTJXKZPESRH-UHFFFAOYSA-N (4-methyl-1,4-diazepan-1-yl)-[4-[4-(trifluoromethoxy)anilino]quinazolin-7-yl]methanone Chemical compound C1CN(C)CCCN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 HUNRTJXKZPESRH-UHFFFAOYSA-N 0.000 description 2
- UKHOXYCPBAGGAN-UHFFFAOYSA-N (4-methylpiperazin-1-yl)-[4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidin-6-yl]methanone Chemical compound C1CN(C)CCN1C(=O)C(SC1=NC=N2)=CC1=C2NC1=CC=C(OC(F)(F)F)C=C1 UKHOXYCPBAGGAN-UHFFFAOYSA-N 0.000 description 2
- WQHXIMCGFHBRFN-UHFFFAOYSA-N (4-pyrrolidin-1-ylpiperazin-1-yl)-[4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidin-6-yl]methanone Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=C(C(=O)N1CCN(CC1)N1CCCC1)S2 WQHXIMCGFHBRFN-UHFFFAOYSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- TUCHOEWFDYRWEO-UHFFFAOYSA-N 1-(2,2,2-trifluoroethyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2N(CC(F)(F)F)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 TUCHOEWFDYRWEO-UHFFFAOYSA-N 0.000 description 2
- GEBRDOFFJUKKNL-UHFFFAOYSA-N 1-[4-[4-(trifluoromethoxy)anilino]quinazoline-7-carbonyl]piperidine-3-carboxamide Chemical compound C1C(C(=O)N)CCCN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 GEBRDOFFJUKKNL-UHFFFAOYSA-N 0.000 description 2
- XGPSFCRYCHAZTA-UHFFFAOYSA-N 1-[4-[4-(trifluoromethoxy)anilino]quinazoline-7-carbonyl]piperidine-4-carboxamide Chemical compound C1CC(C(=O)N)CCN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 XGPSFCRYCHAZTA-UHFFFAOYSA-N 0.000 description 2
- FKXDOEJLNIALCF-UHFFFAOYSA-N 1-[5-bromo-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]piperidine-3-carboxamide Chemical compound C1C(C(=O)N)CCCN1C1=NC=NC(NC=2C=CC(OC(F)(F)F)=CC=2)=C1Br FKXDOEJLNIALCF-UHFFFAOYSA-N 0.000 description 2
- ABLLDPDRPOYJDO-UHFFFAOYSA-N 1-[7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carbonyl]piperidine-3-carboxamide Chemical compound N1=CN=C2N(C)C(C(=O)N3CC(CCC3)C(N)=O)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 ABLLDPDRPOYJDO-UHFFFAOYSA-N 0.000 description 2
- FYSYHFPSHYVHFV-UHFFFAOYSA-N 1-[7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carbonyl]piperidine-4-carboxamide Chemical compound N1=CN=C2N(C)C(C(=O)N3CCC(CC3)C(N)=O)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 FYSYHFPSHYVHFV-UHFFFAOYSA-N 0.000 description 2
- HCPAYDMQUBMGRZ-UHFFFAOYSA-N 1-benzyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2CC1=CC=CC=C1 HCPAYDMQUBMGRZ-UHFFFAOYSA-N 0.000 description 2
- MXVNZGAOLLVTNU-UHFFFAOYSA-N 1-butyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2N(CCCC)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 MXVNZGAOLLVTNU-UHFFFAOYSA-N 0.000 description 2
- BSHFGHWGSPRPTL-UHFFFAOYSA-N 1-phenyl-8-[4-[4-(trifluoromethoxy)anilino]quinazoline-7-carbonyl]-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=CC(C(=O)N3CCC4(CC3)C(NCN4C=3C=CC=CC=3)=O)=CC=C12 BSHFGHWGSPRPTL-UHFFFAOYSA-N 0.000 description 2
- RWJIYVMIMXSSGS-UHFFFAOYSA-N 1-tert-butyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2N(C(C)(C)C)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 RWJIYVMIMXSSGS-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- NUWNGNJIGVPPBI-UHFFFAOYSA-N 2-(2,2,2-trifluoroethyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N=1C=NC2=NN(CC(F)(F)F)C=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 NUWNGNJIGVPPBI-UHFFFAOYSA-N 0.000 description 2
- KFGRLSWQPRCWRR-UHFFFAOYSA-N 2-(2,3-dimethylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound CC1=CC=CC(N2N=C3N=CN=C(NC=4C=CC(OC(F)(F)F)=CC=4)C3=C2)=C1C KFGRLSWQPRCWRR-UHFFFAOYSA-N 0.000 description 2
- JDFJPFGHLPDYRQ-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=NN(C=3C(=CC(Cl)=CC=3)Cl)C=C12 JDFJPFGHLPDYRQ-UHFFFAOYSA-N 0.000 description 2
- NVFVVIOTNMBPOE-UHFFFAOYSA-N 2-(2-ethylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound CCC1=CC=CC=C1N1N=C2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C2=C1 NVFVVIOTNMBPOE-UHFFFAOYSA-N 0.000 description 2
- RPBGBHSQTKSDJR-UHFFFAOYSA-N 2-(2-fluorophenyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound FC1=CC=CC=C1N1N=C2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C2=C1 RPBGBHSQTKSDJR-UHFFFAOYSA-N 0.000 description 2
- FVVSXHWEPRCNBT-UHFFFAOYSA-N 2-(2-phenylethyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(C1=C2)=NC=NC1=NN2CCC1=CC=CC=C1 FVVSXHWEPRCNBT-UHFFFAOYSA-N 0.000 description 2
- BLMKVAXYKFJWGE-UHFFFAOYSA-N 2-(oxolan-3-ylmethyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(C1=C2)=NC=NC1=NN2CC1COCC1 BLMKVAXYKFJWGE-UHFFFAOYSA-N 0.000 description 2
- CDYRTKATRGHFFA-UHFFFAOYSA-N 2-(pyridin-3-ylmethyl)-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(C1=C2)=NC=NC1=NN2CC1=CC=CN=C1 CDYRTKATRGHFFA-UHFFFAOYSA-N 0.000 description 2
- AFNFOVFLFOYQSF-UHFFFAOYSA-N 2-[(3-bromophenyl)methyl]-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(C1=C2)=NC=NC1=NN2CC1=CC=CC(Br)=C1 AFNFOVFLFOYQSF-UHFFFAOYSA-N 0.000 description 2
- LJLWZMUURKOAFD-UHFFFAOYSA-N 2-[2-[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]isoindole-1,3-dione Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2CCN1C(=O)C2=CC=CC=C2C1=O LJLWZMUURKOAFD-UHFFFAOYSA-N 0.000 description 2
- IMDGWPWAGISTBX-UHFFFAOYSA-N 2-[3-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenyl]acetonitrile Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C=2C=C(CC#N)C=CC=2)=NC=N1 IMDGWPWAGISTBX-UHFFFAOYSA-N 0.000 description 2
- VVJRFAWDTMHSLA-UHFFFAOYSA-N 2-[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-2-yl]acetamide Chemical compound N=1C=NC2=NN(CC(=O)N)C=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 VVJRFAWDTMHSLA-UHFFFAOYSA-N 0.000 description 2
- JZZQBCIIKUFMMM-UHFFFAOYSA-N 2-[[3-fluoro-4-(trifluoromethyl)phenyl]methyl]-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=C(C(F)(F)F)C(F)=CC(CN2N=C3N=CN=C(NC=4C=CC(OC(F)(F)F)=CC=4)C3=C2)=C1 JZZQBCIIKUFMMM-UHFFFAOYSA-N 0.000 description 2
- MCHVJFBHJMRGMC-UHFFFAOYSA-N 2-benzyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(C1=C2)=NC=NC1=NN2CC1=CC=CC=C1 MCHVJFBHJMRGMC-UHFFFAOYSA-N 0.000 description 2
- SBUPGNXPYZUHQG-UHFFFAOYSA-N 2-butyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N=1C=NC2=NN(CCCC)C=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 SBUPGNXPYZUHQG-UHFFFAOYSA-N 0.000 description 2
- DPLINHZLXGDQFX-UHFFFAOYSA-N 2-cyclohexyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=NN(C3CCCCC3)C=C12 DPLINHZLXGDQFX-UHFFFAOYSA-N 0.000 description 2
- LIDKCGAEWPHGIG-UHFFFAOYSA-N 2-ethyl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N=1C=NC2=NN(CC)C=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 LIDKCGAEWPHGIG-UHFFFAOYSA-N 0.000 description 2
- JIIHIIUBYIFMIV-UHFFFAOYSA-N 2-fluoro-5-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzaldehyde Chemical compound C1=C(C=O)C(F)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 JIIHIIUBYIFMIV-UHFFFAOYSA-N 0.000 description 2
- VQXDGLIYLQUWHX-UHFFFAOYSA-N 2-hydroxy-3-[7-[4-(trifluoromethoxy)anilino]imidazo[1,2-c]pyrimidin-2-yl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=C3C=C(NC=4C=CC(OC(F)(F)F)=CC=4)N=CN3C=2)=C1O VQXDGLIYLQUWHX-UHFFFAOYSA-N 0.000 description 2
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 2
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 2
- QHCBVLWYYBUGBB-UHFFFAOYSA-N 2-pyridin-2-yl-n-[4-(trifluoromethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=NN(C=3N=CC=CC=3)C=C12 QHCBVLWYYBUGBB-UHFFFAOYSA-N 0.000 description 2
- WNAQBIGREPRTDW-UHFFFAOYSA-N 3-(dimethylamino)-2-[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-1-yl]propanenitrile Chemical compound N1=CN=C2N(C(C#N)CN(C)C)N=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 WNAQBIGREPRTDW-UHFFFAOYSA-N 0.000 description 2
- RZRYDXYKZJHXBZ-UHFFFAOYSA-N 3-[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-1-yl]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(N2C3=NC=NC(NC=4C=CC(OC(F)(F)F)=CC=4)=C3C=N2)=C1 RZRYDXYKZJHXBZ-UHFFFAOYSA-N 0.000 description 2
- WCVPSQDWXSPPMV-UHFFFAOYSA-N 3-[5-methyl-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzamide Chemical compound N1=CN=C(C=2C=C(C=CC=2)C(N)=O)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 WCVPSQDWXSPPMV-UHFFFAOYSA-N 0.000 description 2
- RLGUETBWWFLPRX-UHFFFAOYSA-N 3-[5-methyl-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoic acid Chemical compound N1=CN=C(C=2C=C(C=CC=2)C(O)=O)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 RLGUETBWWFLPRX-UHFFFAOYSA-N 0.000 description 2
- ZUAOQFCLNQZGJC-UHFFFAOYSA-N 3-[[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-2-yl]methyl]phenol Chemical compound OC1=CC=CC(CN2N=C3N=CN=C(NC=4C=CC(OC(F)(F)F)=CC=4)C3=C2)=C1 ZUAOQFCLNQZGJC-UHFFFAOYSA-N 0.000 description 2
- INMZJAIOLSSGGZ-UHFFFAOYSA-N 4-[4-(trifluoromethoxy)anilino]-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1CC(=O)N2 INMZJAIOLSSGGZ-UHFFFAOYSA-N 0.000 description 2
- LTPKVOUUVMUSMW-UHFFFAOYSA-N 4-[4-(trifluoromethoxy)anilino]-n-[3-(trifluoromethyl)phenyl]quinazoline-7-carboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=CC(C(=O)NC=3C=C(C=CC=3)C(F)(F)F)=CC=C12 LTPKVOUUVMUSMW-UHFFFAOYSA-N 0.000 description 2
- ZTYKTASVHMUYBK-UHFFFAOYSA-N 4-[4-(trifluoromethoxy)anilino]quinazoline-7-carboxylic acid Chemical compound N=1C=NC2=CC(C(=O)O)=CC=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 ZTYKTASVHMUYBK-UHFFFAOYSA-N 0.000 description 2
- ZQZDOXHXBMDBRM-UHFFFAOYSA-N 4-[5-methyl-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzenesulfonamide Chemical compound N1=CN=C(C=2C=CC(=CC=2)S(N)(=O)=O)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 ZQZDOXHXBMDBRM-UHFFFAOYSA-N 0.000 description 2
- VBOGOLJBHVWYOV-UHFFFAOYSA-N 4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]-1h-pyridin-2-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C2=CC(=O)NC=C2)=NC=N1 VBOGOLJBHVWYOV-UHFFFAOYSA-N 0.000 description 2
- ZSQPHGUWLPMJKW-UHFFFAOYSA-N 4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 ZSQPHGUWLPMJKW-UHFFFAOYSA-N 0.000 description 2
- RJKBQZGBVXMAOR-UHFFFAOYSA-N 4-chloro-6-[4-(trifluoromethoxy)anilino]pyrimidine-5-carbaldehyde Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC(Cl)=C1C=O RJKBQZGBVXMAOR-UHFFFAOYSA-N 0.000 description 2
- SKCAZDLKOJAVET-UHFFFAOYSA-N 4-methoxy-n-[4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenyl]benzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)C=C1 SKCAZDLKOJAVET-UHFFFAOYSA-N 0.000 description 2
- UYSQCUMJJLORCR-UHFFFAOYSA-N 4-methyl-n-[4-[5-methyl-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenyl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=C(C=2C(=C(NC=3C=CC(OC(F)(F)F)=CC=3)N=CN=2)C)C=C1 UYSQCUMJJLORCR-UHFFFAOYSA-N 0.000 description 2
- RJQCFZGINNQJBM-UHFFFAOYSA-N 4-methyl-n-[4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenyl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=C(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)C=C1 RJQCFZGINNQJBM-UHFFFAOYSA-N 0.000 description 2
- POSSYNLLFHGQTJ-UHFFFAOYSA-N 4-n-(5-cyclopropyl-1h-pyrazol-3-yl)-6-n-[4-(trifluoromethoxy)phenyl]pyrimidine-4,6-diamine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(NC2=NNC(=C2)C2CC2)=NC=N1 POSSYNLLFHGQTJ-UHFFFAOYSA-N 0.000 description 2
- 125000005986 4-piperidonyl group Chemical group 0.000 description 2
- NGMGXEWKDVVKAN-UHFFFAOYSA-N 5-bromo-6-n-(2-morpholin-4-ylethyl)-4-n-[4-(trifluoromethoxy)phenyl]pyrimidine-4,6-diamine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC(NCCN2CCOCC2)=C1Br NGMGXEWKDVVKAN-UHFFFAOYSA-N 0.000 description 2
- SNTLJZCGWVXMHY-UHFFFAOYSA-N 5-methyl-6-(1-methylpyrazol-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound N1=CN=C(C2=CN(C)N=C2)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 SNTLJZCGWVXMHY-UHFFFAOYSA-N 0.000 description 2
- WOOUKFKCCPQPBI-UHFFFAOYSA-N 5-methyl-6-(4-methylsulfonylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound N1=CN=C(C=2C=CC(=CC=2)S(C)(=O)=O)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 WOOUKFKCCPQPBI-UHFFFAOYSA-N 0.000 description 2
- NEBPPJXHOHRQTE-UHFFFAOYSA-N 5-methyl-6-(4-phenylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound N1=CN=C(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 NEBPPJXHOHRQTE-UHFFFAOYSA-N 0.000 description 2
- XUWUMZJSLIUSPK-UHFFFAOYSA-N 5-methyl-6-(4-propan-2-ylsulfonylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(S(=O)(=O)C(C)C)=CC=C1C1=NC=NC(NC=2C=CC(OC(F)(F)F)=CC=2)=C1C XUWUMZJSLIUSPK-UHFFFAOYSA-N 0.000 description 2
- QUSNTJQPRNJGLT-UHFFFAOYSA-N 5-methyl-6-(5-methyl-1-phenylpyrazol-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound CC1=C(C=2C(=C(NC=3C=CC(OC(F)(F)F)=CC=3)N=CN=2)C)C=NN1C1=CC=CC=C1 QUSNTJQPRNJGLT-UHFFFAOYSA-N 0.000 description 2
- WYBQBMZXQPBDCA-UHFFFAOYSA-N 5-methyl-6-[1-(2-methylpropyl)pyrazol-4-yl]-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=NN(CC(C)C)C=C1C1=NC=NC(NC=2C=CC(OC(F)(F)F)=CC=2)=C1C WYBQBMZXQPBDCA-UHFFFAOYSA-N 0.000 description 2
- PEUYUQAGYHAXKT-UHFFFAOYSA-N 6-(1-benzothiophen-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C=2C=3C=CSC=3C=CC=2)=NC=N1 PEUYUQAGYHAXKT-UHFFFAOYSA-N 0.000 description 2
- VLOJTYVAZWJVKB-UHFFFAOYSA-N 6-(1-benzylpyrazol-4-yl)-5-methyl-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound N1=CN=C(C2=CN(CC=3C=CC=CC=3)N=C2)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 VLOJTYVAZWJVKB-UHFFFAOYSA-N 0.000 description 2
- RUDZVRRHBGESJG-UHFFFAOYSA-N 6-(1-benzylpyrazol-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C2=CN(CC=3C=CC=CC=3)N=C2)=NC=N1 RUDZVRRHBGESJG-UHFFFAOYSA-N 0.000 description 2
- FDVVAHFEGZKUBW-UHFFFAOYSA-N 6-(1-ethylsulfonylpyrazol-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=NN(S(=O)(=O)CC)C=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 FDVVAHFEGZKUBW-UHFFFAOYSA-N 0.000 description 2
- HWZFQQYDALNGQT-UHFFFAOYSA-N 6-(1-methylpyrazol-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=NN(C)C=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 HWZFQQYDALNGQT-UHFFFAOYSA-N 0.000 description 2
- MHLMKMHXIBHQDX-UHFFFAOYSA-N 6-(1h-indol-3-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C=2C3=CC=CC=C3NC=2)=NC=N1 MHLMKMHXIBHQDX-UHFFFAOYSA-N 0.000 description 2
- JOHGCEMGLYONCE-UHFFFAOYSA-N 6-(1h-indol-4-yl)-5-methyl-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound N1=CN=C(C=2C=3C=CNC=3C=CC=2)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 JOHGCEMGLYONCE-UHFFFAOYSA-N 0.000 description 2
- WHXMNERCRMKGIM-UHFFFAOYSA-N 6-(1h-indol-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C=2C=3C=CNC=3C=CC=2)=NC=N1 WHXMNERCRMKGIM-UHFFFAOYSA-N 0.000 description 2
- BHEMWXASQSITGI-UHFFFAOYSA-N 6-(1h-indol-5-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C=2C=C3C=CNC3=CC=2)=NC=N1 BHEMWXASQSITGI-UHFFFAOYSA-N 0.000 description 2
- YQXVNNKJNHKVLW-UHFFFAOYSA-N 6-(1h-pyrazol-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C2=CNN=C2)=NC=N1 YQXVNNKJNHKVLW-UHFFFAOYSA-N 0.000 description 2
- ROHKFCDNADXUJY-UHFFFAOYSA-N 6-(1h-pyrrolo[2,3-b]pyridin-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C=2C=3C=CNC=3N=CC=2)=NC=N1 ROHKFCDNADXUJY-UHFFFAOYSA-N 0.000 description 2
- HRCITRRSKGUPIX-UHFFFAOYSA-N 6-(2-methyl-1,3-thiazol-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound S1C(C)=NC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 HRCITRRSKGUPIX-UHFFFAOYSA-N 0.000 description 2
- VWFYIGKAWSIPJV-UHFFFAOYSA-N 6-(3-amino-5-cyclopropylpyrazol-1-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C=1C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=NC=1N1N=C(N)C=C1C1CC1 VWFYIGKAWSIPJV-UHFFFAOYSA-N 0.000 description 2
- QFGORASCKFJZPN-UHFFFAOYSA-N 6-(3-nitrophenyl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound [O-][N+](=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 QFGORASCKFJZPN-UHFFFAOYSA-N 0.000 description 2
- CZGACSOVIFVXIS-UHFFFAOYSA-N 6-(4-methylsulfonylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 CZGACSOVIFVXIS-UHFFFAOYSA-N 0.000 description 2
- OWYKLWUJPPDZMV-UHFFFAOYSA-N 6-(4-morpholin-4-ylsulfonylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C=2C=CC(=CC=2)S(=O)(=O)N2CCOCC2)=NC=N1 OWYKLWUJPPDZMV-UHFFFAOYSA-N 0.000 description 2
- HMDDBKGGGKCXFP-UHFFFAOYSA-N 6-(4-phenylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C=2C=CC(=CC=2)C=2C=CC=CC=2)=NC=N1 HMDDBKGGGKCXFP-UHFFFAOYSA-N 0.000 description 2
- MBJMKJJABLGJAJ-UHFFFAOYSA-N 6-(4-piperidin-1-ylsulfonylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C=2C=CC(=CC=2)S(=O)(=O)N2CCCCC2)=NC=N1 MBJMKJJABLGJAJ-UHFFFAOYSA-N 0.000 description 2
- IEERVTUDOXLMMK-UHFFFAOYSA-N 6-(4-propan-2-ylsulfonylphenyl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(S(=O)(=O)C(C)C)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 IEERVTUDOXLMMK-UHFFFAOYSA-N 0.000 description 2
- LFCCNGCPTCBROF-UHFFFAOYSA-N 6-(5-methoxynaphthalen-2-yl)-5-methyl-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C=1C=C2C(OC)=CC=CC2=CC=1C(C=1C)=NC=NC=1NC1=CC=C(OC(F)(F)F)C=C1 LFCCNGCPTCBROF-UHFFFAOYSA-N 0.000 description 2
- UHGLBINWPATDNU-UHFFFAOYSA-N 6-(5-methoxynaphthalen-2-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C=1C=C2C(OC)=CC=CC2=CC=1C(N=CN=1)=CC=1NC1=CC=C(OC(F)(F)F)C=C1 UHGLBINWPATDNU-UHFFFAOYSA-N 0.000 description 2
- LERATUINYXNVCF-UHFFFAOYSA-N 6-(5-methyl-1-phenylpyrazol-4-yl)-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound CC1=C(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)C=NN1C1=CC=CC=C1 LERATUINYXNVCF-UHFFFAOYSA-N 0.000 description 2
- VRLVMMQZIBLEME-UHFFFAOYSA-N 6-[1-(2-methylpropyl)pyrazol-4-yl]-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=NN(CC(C)C)C=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 VRLVMMQZIBLEME-UHFFFAOYSA-N 0.000 description 2
- NEVWISPIZUUKHD-UHFFFAOYSA-N 6-[1-(pyridin-3-ylmethyl)pyrazol-4-yl]-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C2=CN(CC=3C=NC=CC=3)N=C2)=NC=N1 NEVWISPIZUUKHD-UHFFFAOYSA-N 0.000 description 2
- MMFVBFLDLMKSHH-UHFFFAOYSA-N 6-[1-(pyridin-4-ylmethyl)pyrazol-4-yl]-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C2=CN(CC=3C=CN=CC=3)N=C2)=NC=N1 MMFVBFLDLMKSHH-UHFFFAOYSA-N 0.000 description 2
- KEYQMXZYZYAKKQ-UHFFFAOYSA-N 6-[2-(2-morpholin-4-ylethylamino)imidazol-1-yl]-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(N2C(=NC=C2)NCCN2CCOCC2)=NC=N1 KEYQMXZYZYAKKQ-UHFFFAOYSA-N 0.000 description 2
- HRCYKOFIVFDSTJ-UHFFFAOYSA-N 6-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1CN(C)CCN1C1=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=CC=N1 HRCYKOFIVFDSTJ-UHFFFAOYSA-N 0.000 description 2
- NROIBDPDLCVPGL-UHFFFAOYSA-N 6-[2-[4-(trifluoromethoxy)anilino]imidazol-1-yl]-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=CN1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 NROIBDPDLCVPGL-UHFFFAOYSA-N 0.000 description 2
- JTLORZMARQFUPI-UHFFFAOYSA-N 6-[4-(aminomethyl)phenyl]-5-methyl-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound N1=CN=C(C=2C=CC(CN)=CC=2)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 JTLORZMARQFUPI-UHFFFAOYSA-N 0.000 description 2
- RMQGDIDVDJNVDV-UHFFFAOYSA-N 6-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-n-[4-(trifluoromethoxy)phenyl]thieno[2,3-d]pyrimidin-4-amine Chemical compound C1C(N(C)C)CCN1CC(SC1=NC=N2)=CC1=C2NC1=CC=C(OC(F)(F)F)C=C1 RMQGDIDVDJNVDV-UHFFFAOYSA-N 0.000 description 2
- XQKICFGZSQFAOB-UHFFFAOYSA-N 6-chloro-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(Cl)=NC=N1 XQKICFGZSQFAOB-UHFFFAOYSA-N 0.000 description 2
- QRFXWSAVWRJPPT-UHFFFAOYSA-N 6-methyl-n-[4-(trifluoromethoxy)phenyl]thieno[2,3-d]pyrimidin-4-amine Chemical compound N1=CN=C2SC(C)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 QRFXWSAVWRJPPT-UHFFFAOYSA-N 0.000 description 2
- MIDKDZLJKGQWLJ-UHFFFAOYSA-N 6-n-[4-(trifluoromethoxy)phenyl]-4-n-[1-[3-(trifluoromethyl)phenyl]imidazol-2-yl]pyrimidine-4,6-diamine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(NC=2N(C=CN=2)C=2C=C(C=CC=2)C(F)(F)F)=NC=N1 MIDKDZLJKGQWLJ-UHFFFAOYSA-N 0.000 description 2
- SDZHSKORMUXEHO-UHFFFAOYSA-N 7-(diethylaminomethyl)-n-[4-(trifluoromethoxy)phenyl]quinazolin-4-amine Chemical compound N=1C=NC2=CC(CN(CC)CC)=CC=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 SDZHSKORMUXEHO-UHFFFAOYSA-N 0.000 description 2
- VVRBVDHDVLHQFS-UHFFFAOYSA-N 7-methyl-4-[4-(trifluoromethoxy)anilino]-5h-pyrrolo[2,3-d]pyrimidin-6-one Chemical compound CN1C(=O)CC2=C1N=CN=C2NC1=CC=C(OC(F)(F)F)C=C1 VVRBVDHDVLHQFS-UHFFFAOYSA-N 0.000 description 2
- ICPDGFRTTYYXFM-UHFFFAOYSA-N 7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2N(C)C(C(N)=O)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 ICPDGFRTTYYXFM-UHFFFAOYSA-N 0.000 description 2
- KFVDSQUAUCOVGS-UHFFFAOYSA-N 8-[7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carbonyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound N1=CN=C2N(C)C(C(=O)N3CCC4(CC3)C(NCN4C=3C=CC=CC=3)=O)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 KFVDSQUAUCOVGS-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 206010001257 Adenoviral conjunctivitis Diseases 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010061424 Anal cancer Diseases 0.000 description 2
- 201000003076 Angiosarcoma Diseases 0.000 description 2
- 208000007860 Anus Neoplasms Diseases 0.000 description 2
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 2
- 206010003645 Atopy Diseases 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 208000009137 Behcet syndrome Diseases 0.000 description 2
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010048964 Carotid artery occlusion Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 208000009043 Chemical Burns Diseases 0.000 description 2
- 208000018380 Chemical injury Diseases 0.000 description 2
- 208000006332 Choriocarcinoma Diseases 0.000 description 2
- 208000002691 Choroiditis Diseases 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 206010010996 Corneal degeneration Diseases 0.000 description 2
- 206010011017 Corneal graft rejection Diseases 0.000 description 2
- 206010055665 Corneal neovascularisation Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 208000006168 Ewing Sarcoma Diseases 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 2
- 208000002125 Hemangioendothelioma Diseases 0.000 description 2
- 208000001258 Hemangiosarcoma Diseases 0.000 description 2
- 208000009889 Herpes Simplex Diseases 0.000 description 2
- 208000007514 Herpes zoster Diseases 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010051151 Hyperviscosity syndrome Diseases 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- 102000000646 Interleukin-3 Human genes 0.000 description 2
- 208000016604 Lyme disease Diseases 0.000 description 2
- 206010025412 Macular dystrophy congenital Diseases 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 238000006751 Mitsunobu reaction Methods 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 208000003445 Mouth Neoplasms Diseases 0.000 description 2
- 206010062207 Mycobacterial infection Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 150000007945 N-acyl ureas Chemical class 0.000 description 2
- WGNUTNRGGMTNOF-UHFFFAOYSA-N N1(CCOCC1)CCN1C=CC2=C1N=CN=C2NNC2=CC=C(C=C2)OC(F)(F)F Chemical compound N1(CCOCC1)CCN1C=CC2=C1N=CN=C2NNC2=CC=C(C=C2)OC(F)(F)F WGNUTNRGGMTNOF-UHFFFAOYSA-N 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 208000010191 Osteitis Deformans Diseases 0.000 description 2
- 208000027868 Paget disease Diseases 0.000 description 2
- 206010034277 Pemphigoid Diseases 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 208000003971 Posterior uveitis Diseases 0.000 description 2
- 208000004210 Pressure Ulcer Diseases 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- 108700020978 Proto-Oncogene Proteins 0.000 description 2
- 102000052575 Proto-Oncogene Human genes 0.000 description 2
- 201000002154 Pterygium Diseases 0.000 description 2
- 206010038848 Retinal detachment Diseases 0.000 description 2
- 206010038910 Retinitis Diseases 0.000 description 2
- 241001303601 Rosacea Species 0.000 description 2
- 206010039705 Scleritis Diseases 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- 208000027073 Stargardt disease Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 2
- 201000005485 Toxoplasmosis Diseases 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 206010064996 Ulcerative keratitis Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 208000000558 Varicose Ulcer Diseases 0.000 description 2
- 206010058990 Venous occlusion Diseases 0.000 description 2
- 208000010011 Vitamin A Deficiency Diseases 0.000 description 2
- 208000013058 Weber syndrome Diseases 0.000 description 2
- 208000008383 Wilms tumor Diseases 0.000 description 2
- HNNWHEPJPXFXHU-UHFFFAOYSA-N [2-(hydroxymethyl)pyrrolidin-1-yl]-[4-[4-(trifluoromethoxy)anilino]quinazolin-7-yl]methanone Chemical compound OCC1CCCN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 HNNWHEPJPXFXHU-UHFFFAOYSA-N 0.000 description 2
- QIIUQUNYIINXKR-UHFFFAOYSA-N [2-(hydroxymethyl)pyrrolidin-1-yl]-[4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidin-6-yl]methanone Chemical compound OCC1CCCN1C(=O)C(SC1=NC=N2)=CC1=C2NC1=CC=C(OC(F)(F)F)C=C1 QIIUQUNYIINXKR-UHFFFAOYSA-N 0.000 description 2
- ZZMCAMAYHVUJGD-UHFFFAOYSA-N [3-(dimethylamino)pyrrolidin-1-yl]-[4-[4-(trifluoromethoxy)anilino]quinazolin-7-yl]methanone Chemical compound C1C(N(C)C)CCN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 ZZMCAMAYHVUJGD-UHFFFAOYSA-N 0.000 description 2
- FSPMZEQNZVUFNV-UHFFFAOYSA-N [3-(dimethylamino)pyrrolidin-1-yl]-[4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidin-6-yl]methanone Chemical compound C1C(N(C)C)CCN1C(=O)C(SC1=NC=N2)=CC1=C2NC1=CC=C(OC(F)(F)F)C=C1 FSPMZEQNZVUFNV-UHFFFAOYSA-N 0.000 description 2
- FTUBEYUUTIHWKL-UHFFFAOYSA-N [3-(hydroxymethyl)piperidin-1-yl]-[4-[4-(trifluoromethoxy)anilino]quinazolin-7-yl]methanone Chemical compound C1C(CO)CCCN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 FTUBEYUUTIHWKL-UHFFFAOYSA-N 0.000 description 2
- UYSOPHRRKFWYMB-UHFFFAOYSA-N [4-(furan-3-carbonyl)piperazin-1-yl]-[4-[4-(trifluoromethoxy)anilino]quinazolin-7-yl]methanone Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=CC(C(=O)N3CCN(CC3)C(=O)C3=COC=C3)=CC=C12 UYSOPHRRKFWYMB-UHFFFAOYSA-N 0.000 description 2
- WKSRTVKLHGBZCV-UHFFFAOYSA-N [4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidin-6-yl]-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]methanone Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=C(C(=O)N1CCN(CC1)C=1C=C(C=CC=1)C(F)(F)F)S2 WKSRTVKLHGBZCV-UHFFFAOYSA-N 0.000 description 2
- ROQCTOMAERRHLK-UHFFFAOYSA-N [4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidin-6-yl]methanol Chemical compound N1=CN=C2SC(CO)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 ROQCTOMAERRHLK-UHFFFAOYSA-N 0.000 description 2
- ZQVLHAWUDYDXFW-UHFFFAOYSA-N [7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-6-yl]methanol Chemical compound N1=CN=C2N(C)C(CO)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 ZQVLHAWUDYDXFW-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 201000011165 anus cancer Diseases 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 208000021328 arterial occlusion Diseases 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 125000003828 azulenyl group Chemical group 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 210000000133 brain stem Anatomy 0.000 description 2
- 201000007293 brain stem infarction Diseases 0.000 description 2
- 239000007894 caplet Substances 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000033077 cellular process Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 210000003679 cervix uteri Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 210000002987 choroid plexus Anatomy 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 201000000159 corneal neovascularization Diseases 0.000 description 2
- 201000007717 corneal ulcer Diseases 0.000 description 2
- 208000030381 cutaneous melanoma Diseases 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 201000011190 diabetic macular edema Diseases 0.000 description 2
- 125000004986 diarylamino group Chemical group 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 208000021373 epidemic keratoconjunctivitis Diseases 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- RBLUGQGHRAOFAU-UHFFFAOYSA-N ethyl 1-[4-[4-(trifluoromethoxy)anilino]quinazoline-7-carbonyl]piperidine-3-carboxylate Chemical compound C1C(C(=O)OCC)CCCN1C(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 RBLUGQGHRAOFAU-UHFFFAOYSA-N 0.000 description 2
- LRAKPOPLJXVGDT-UHFFFAOYSA-N ethyl 2-[2-[[4-[4-(trifluoromethoxy)anilino]quinazoline-7-carbonyl]amino]-1,3-thiazol-5-yl]acetate Chemical compound S1C(CC(=O)OCC)=CN=C1NC(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 LRAKPOPLJXVGDT-UHFFFAOYSA-N 0.000 description 2
- NAKVMKMIDXTMAD-UHFFFAOYSA-N ethyl 3-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)propanoate Chemical compound N1=CN=C2N(CCC(=O)OCC)C=CC2=C1Cl NAKVMKMIDXTMAD-UHFFFAOYSA-N 0.000 description 2
- BSVWQMDBSKVISJ-UHFFFAOYSA-N ethyl 7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carboxylate Chemical compound N1=CN=C2N(C)C(C(=O)OCC)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 BSVWQMDBSKVISJ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 201000005884 exanthem Diseases 0.000 description 2
- 208000024519 eye neoplasm Diseases 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 2
- DFNZYFAJQPLJFI-UHFFFAOYSA-N gentianine Chemical compound O=C1OCCC2=C1C=NC=C2C=C DFNZYFAJQPLJFI-UHFFFAOYSA-N 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 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 2
- 210000003128 head Anatomy 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 2
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 229940076264 interleukin-3 Drugs 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 201000010666 keratoconjunctivitis Diseases 0.000 description 2
- 238000000021 kinase assay Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000000867 larynx Anatomy 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 208000027202 mammary Paget disease Diseases 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000002297 mitogenic effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 208000027531 mycobacterial infectious disease Diseases 0.000 description 2
- 208000001491 myopia Diseases 0.000 description 2
- 230000004379 myopia Effects 0.000 description 2
- GCNKLLXZGOUIGM-UHFFFAOYSA-N n'-ethyl-4-[4-(trifluoromethoxy)anilino]quinazoline-7-carbohydrazide Chemical compound N=1C=NC2=CC(C(=O)NNCC)=CC=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 GCNKLLXZGOUIGM-UHFFFAOYSA-N 0.000 description 2
- GHZMWNPDDAWKSV-UHFFFAOYSA-N n,n-diethyl-4-[4-(trifluoromethoxy)anilino]quinazoline-7-carboxamide Chemical compound N=1C=NC2=CC(C(=O)N(CC)CC)=CC=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 GHZMWNPDDAWKSV-UHFFFAOYSA-N 0.000 description 2
- VJDPTCVVFNILQE-UHFFFAOYSA-N n,n-diethyl-4-[5-methyl-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N(CC)CC)=CC=C1C1=NC=NC(NC=2C=CC(OC(F)(F)F)=CC=2)=C1C VJDPTCVVFNILQE-UHFFFAOYSA-N 0.000 description 2
- LXWAWZXJJMIHBW-UHFFFAOYSA-N n,n-diethyl-4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N(CC)CC)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 LXWAWZXJJMIHBW-UHFFFAOYSA-N 0.000 description 2
- RWJNTUXSKJXRGO-UHFFFAOYSA-N n-(1-benzylpyrrolidin-3-yl)-4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidine-6-carboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=C(C(=O)NC1CN(CC=3C=CC=CC=3)CC1)S2 RWJNTUXSKJXRGO-UHFFFAOYSA-N 0.000 description 2
- GCLLDDZJALEGAY-UHFFFAOYSA-N n-(1-ethylpyrrolidin-2-yl)-7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound CCN1CCCC1NC(=O)C(N(C1=NC=N2)C)=CC1=C2NC1=CC=C(OC(F)(F)F)C=C1 GCLLDDZJALEGAY-UHFFFAOYSA-N 0.000 description 2
- PCNHERJBRQQDKF-UHFFFAOYSA-N n-(2-hydroxyethyl)-4-[5-methyl-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzamide Chemical compound N1=CN=C(C=2C=CC(=CC=2)C(=O)NCCO)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 PCNHERJBRQQDKF-UHFFFAOYSA-N 0.000 description 2
- LTJUZXVMFCCRAM-UHFFFAOYSA-N n-(2-hydroxyethyl)-4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NCCO)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 LTJUZXVMFCCRAM-UHFFFAOYSA-N 0.000 description 2
- UVTPMZBLAADVNQ-UHFFFAOYSA-N n-(2-hydroxyethyl)-n-methyl-4-[4-(trifluoromethoxy)anilino]quinazoline-7-carboxamide Chemical compound N=1C=NC2=CC(C(=O)N(CCO)C)=CC=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 UVTPMZBLAADVNQ-UHFFFAOYSA-N 0.000 description 2
- OKENXGKGAUIGLM-UHFFFAOYSA-N n-(3-methoxypropyl)-4-[4-(trifluoromethoxy)anilino]quinazoline-7-carboxamide Chemical compound N=1C=NC2=CC(C(=O)NCCCOC)=CC=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 OKENXGKGAUIGLM-UHFFFAOYSA-N 0.000 description 2
- JVBYUKONZCNFNZ-UHFFFAOYSA-N n-(3-methoxypropyl)-4-[5-methyl-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzamide Chemical compound C1=CC(C(=O)NCCCOC)=CC=C1C1=NC=NC(NC=2C=CC(OC(F)(F)F)=CC=2)=C1C JVBYUKONZCNFNZ-UHFFFAOYSA-N 0.000 description 2
- GAUZZOAAYMDPEF-UHFFFAOYSA-N n-(4-methylphenyl)sulfonyl-4-[4-(trifluoromethoxy)anilino]quinazoline-7-carboxamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)C1=CC=C(C(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N2)C2=C1 GAUZZOAAYMDPEF-UHFFFAOYSA-N 0.000 description 2
- IMDFGFSIBUNDBR-UHFFFAOYSA-N n-(diaminomethylidene)-7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2N(C)C(C(=O)NC(N)=N)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 IMDFGFSIBUNDBR-UHFFFAOYSA-N 0.000 description 2
- OGFBCFMPNKVYSM-UHFFFAOYSA-N n-[2-methyl-5-[[3-(trifluoromethyl)benzoyl]amino]phenyl]-4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidine-6-carboxamide Chemical compound C1=C(NC(=O)C=2SC3=NC=NC(NC=4C=CC(OC(F)(F)F)=CC=4)=C3C=2)C(C)=CC=C1NC(=O)C1=CC=CC(C(F)(F)F)=C1 OGFBCFMPNKVYSM-UHFFFAOYSA-N 0.000 description 2
- IFPZSCUAEBSQMU-UHFFFAOYSA-N n-[3-[5-methyl-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC(C=2C(=C(NC=3C=CC(OC(F)(F)F)=CC=3)N=CN=2)C)=C1 IFPZSCUAEBSQMU-UHFFFAOYSA-N 0.000 description 2
- BBZHARMXOWZXSV-UHFFFAOYSA-N n-[4-(trifluoromethoxy)phenyl]-1-[4-(trifluoromethyl)pyridin-2-yl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=NN2C1=CC(C(F)(F)F)=CC=N1 BBZHARMXOWZXSV-UHFFFAOYSA-N 0.000 description 2
- YVSZTUNIUQSAAH-UHFFFAOYSA-N n-[4-(trifluoromethoxy)phenyl]-2-[4-(trifluoromethyl)pyridin-2-yl]pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=NN(C=3N=CC=C(C=3)C(F)(F)F)C=C12 YVSZTUNIUQSAAH-UHFFFAOYSA-N 0.000 description 2
- HKDKVSRTUABPGU-UHFFFAOYSA-N n-[4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenyl]butane-1-sulfonamide Chemical compound C1=CC(NS(=O)(=O)CCCC)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 HKDKVSRTUABPGU-UHFFFAOYSA-N 0.000 description 2
- CVDGVVXFIYSUMS-UHFFFAOYSA-N n-[4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenyl]ethanesulfonamide Chemical compound C1=CC(NS(=O)(=O)CC)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 CVDGVVXFIYSUMS-UHFFFAOYSA-N 0.000 description 2
- IQTSERMRWSERDI-UHFFFAOYSA-N n-[4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenyl]methanesulfonamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 IQTSERMRWSERDI-UHFFFAOYSA-N 0.000 description 2
- WZGIJSGOZRKXTA-UHFFFAOYSA-N n-[4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenyl]pentane-2-sulfonamide Chemical compound C1=CC(NS(=O)(=O)C(C)CCC)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 WZGIJSGOZRKXTA-UHFFFAOYSA-N 0.000 description 2
- XGOQZEXVSYCWTN-UHFFFAOYSA-N n-[4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]phenyl]propane-2-sulfonamide Chemical compound C1=CC(NS(=O)(=O)C(C)C)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 XGOQZEXVSYCWTN-UHFFFAOYSA-N 0.000 description 2
- AXJOFXMJJVIVGB-UHFFFAOYSA-N n-[4-methyl-3-[[1-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]imidazol-2-yl]amino]phenyl]benzamide Chemical compound C1=C(NC=2N(C=CN=2)C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)C(C)=CC=C1NC(=O)C1=CC=CC=C1 AXJOFXMJJVIVGB-UHFFFAOYSA-N 0.000 description 2
- SFVCHDZUMIOMQJ-UHFFFAOYSA-N n-[5-(diethylamino)pentan-2-yl]-7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2N(C)C(C(=O)NC(C)CCCN(CC)CC)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 SFVCHDZUMIOMQJ-UHFFFAOYSA-N 0.000 description 2
- ZXJCTVGWBHRFOZ-UHFFFAOYSA-N n-ethyl-4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2SC(C(=O)NCC)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 ZXJCTVGWBHRFOZ-UHFFFAOYSA-N 0.000 description 2
- OSFUHYKVMTYNMJ-UHFFFAOYSA-N n-ethyl-4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NCC)=CC=C1C1=CC(NC=2C=CC(OC(F)(F)F)=CC=2)=NC=N1 OSFUHYKVMTYNMJ-UHFFFAOYSA-N 0.000 description 2
- MJSGVZNKKXZLGC-UHFFFAOYSA-N n-ethyl-7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2N(C)C(C(=O)NCC)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 MJSGVZNKKXZLGC-UHFFFAOYSA-N 0.000 description 2
- SYMAYMVIFXUUQE-UHFFFAOYSA-N n-methyl-4-[5-methyl-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NC)=CC=C1C1=NC=NC(NC=2C=CC(OC(F)(F)F)=CC=2)=C1C SYMAYMVIFXUUQE-UHFFFAOYSA-N 0.000 description 2
- KJIOPADPPQNDLS-UHFFFAOYSA-N n-methyl-n-(1-methylpiperidin-4-yl)-4-[4-(trifluoromethoxy)anilino]quinazoline-7-carboxamide Chemical compound C=1C=C2C(NC=3C=CC(OC(F)(F)F)=CC=3)=NC=NC2=CC=1C(=O)N(C)C1CCN(C)CC1 KJIOPADPPQNDLS-UHFFFAOYSA-N 0.000 description 2
- UGLJJGIXXVTVHQ-UHFFFAOYSA-N n-methyl-n-[2-(methylamino)ethyl]-4-[4-(trifluoromethoxy)anilino]quinazoline-7-carboxamide Chemical compound N=1C=NC2=CC(C(=O)N(C)CCNC)=CC=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 UGLJJGIXXVTVHQ-UHFFFAOYSA-N 0.000 description 2
- VUJNCOGZVMKZIG-UHFFFAOYSA-N n-tert-butylsulfonyl-4-[4-(trifluoromethoxy)anilino]quinazoline-7-carboxamide Chemical compound N=1C=NC2=CC(C(=O)NS(=O)(=O)C(C)(C)C)=CC=C2C=1NC1=CC=C(OC(F)(F)F)C=C1 VUJNCOGZVMKZIG-UHFFFAOYSA-N 0.000 description 2
- 210000003739 neck Anatomy 0.000 description 2
- 201000008026 nephroblastoma Diseases 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 201000008106 ocular cancer Diseases 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- JCSDWWOAIWNEQV-UHFFFAOYSA-N piperazin-1-yl-[4-[4-(trifluoromethoxy)anilino]thieno[2,3-d]pyrimidin-6-yl]methanone Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=NC=NC2=C1C=C(C(=O)N1CCNCC1)S2 JCSDWWOAIWNEQV-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 208000028172 protozoa infectious disease Diseases 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 206010037844 rash Diseases 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004264 retinal detachment Effects 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 201000004700 rosacea Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 201000006476 shipyard eye Diseases 0.000 description 2
- 208000007056 sickle cell anemia Diseases 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 206010040882 skin lesion Diseases 0.000 description 2
- 231100000444 skin lesion Toxicity 0.000 description 2
- 201000003708 skin melanoma Diseases 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 2
- 125000004963 sulfonylalkyl group Chemical group 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 208000006379 syphilis Diseases 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 2
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 2
- KFXDYZXVIHNBFD-UHFFFAOYSA-N tetrahydrothiopyranyl sulfone group Chemical group S1C(CCCC1)S(=O)(=O)C1SCCCC1 KFXDYZXVIHNBFD-UHFFFAOYSA-N 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- GKPIFULDHDHNBW-UHFFFAOYSA-N thieno[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=CN=C2SC(C(=O)N)=CC2=C1 GKPIFULDHDHNBW-UHFFFAOYSA-N 0.000 description 2
- 125000004306 triazinyl group Chemical group 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- 210000001364 upper extremity Anatomy 0.000 description 2
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 201000007790 vitelliform macular dystrophy Diseases 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- ZMKGDQSIRSGUDJ-VSROPUKISA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-30-propyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,1 Chemical compound CCC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-VSROPUKISA-N 0.000 description 1
- OINGEIAHAFUTAZ-UHFFFAOYSA-N (4-bromopiperidin-1-yl)-[7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-6-yl]methanone Chemical compound N1=CN=C2N(C)C(C(=O)N3CCC(Br)CC3)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 OINGEIAHAFUTAZ-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 description 1
- AKAIWNDBVZJOAJ-UHFFFAOYSA-N 1,4-dithiine Chemical compound S1C=CSC=C1 AKAIWNDBVZJOAJ-UHFFFAOYSA-N 0.000 description 1
- CPRVXMQHLPTWLY-UHFFFAOYSA-N 1,4-oxathiine Chemical compound O1C=CSC=C1 CPRVXMQHLPTWLY-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical group C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 description 1
- GZHPNIQBPGUSSX-UHFFFAOYSA-N 2-bromo-1-(3-nitrophenyl)ethanone Chemical compound [O-][N+](=O)C1=CC=CC(C(=O)CBr)=C1 GZHPNIQBPGUSSX-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- UEIZUEWXLJOVLD-UHFFFAOYSA-N 3-(1-methylpyrrolidin-3-yl)pyridine Chemical compound C1N(C)CCC1C1=CC=CN=C1 UEIZUEWXLJOVLD-UHFFFAOYSA-N 0.000 description 1
- RLXLGWHKWJMPEL-UHFFFAOYSA-N 3-[4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-7-yl]propanoic acid Chemical compound N1=CN=C2N(CCC(=O)O)C=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 RLXLGWHKWJMPEL-UHFFFAOYSA-N 0.000 description 1
- NUEYDUKUIXVKNB-UHFFFAOYSA-N 4,6-dichloro-5-methylpyrimidine Chemical compound CC1=C(Cl)N=CN=C1Cl NUEYDUKUIXVKNB-UHFFFAOYSA-N 0.000 description 1
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 1
- XQSJHQXYQAUDFC-UHFFFAOYSA-N 4,6-dichloropyrimidine-5-carbaldehyde Chemical compound ClC1=NC=NC(Cl)=C1C=O XQSJHQXYQAUDFC-UHFFFAOYSA-N 0.000 description 1
- ZAPMTSHEXFEPSD-UHFFFAOYSA-N 4-(2-chloroethyl)morpholine Chemical compound ClCCN1CCOCC1 ZAPMTSHEXFEPSD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- CMTKOAQLASVIQQ-UHFFFAOYSA-N 4-[5-methyl-6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]benzoic acid Chemical compound N1=CN=C(C=2C=CC(=CC=2)C(O)=O)C(C)=C1NC1=CC=C(OC(F)(F)F)C=C1 CMTKOAQLASVIQQ-UHFFFAOYSA-N 0.000 description 1
- WAMBTNMAAZOLRZ-UHFFFAOYSA-N 4-[6-[4-(trifluoromethoxy)anilino]pyrimidin-4-yl]furan-2-carbaldehyde Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C=2C=C(C=O)OC=2)=NC=N1 WAMBTNMAAZOLRZ-UHFFFAOYSA-N 0.000 description 1
- SIAVMDKGVRXFAX-UHFFFAOYSA-N 4-carboxyphenylboronic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C=C1 SIAVMDKGVRXFAX-UHFFFAOYSA-N 0.000 description 1
- VOWIADXMGURSLQ-UHFFFAOYSA-N 4-chloro-6-[4-(trifluoromethoxy)anilino]pyrimidine-5-carbaldehyde 2-[4-[4-(trifluoromethoxy)anilino]pyrazolo[3,4-d]pyrimidin-2-yl]ethanol Chemical compound ClC1=NC=NC(=C1C=O)NC1=CC=C(C=C1)OC(F)(F)F.FC(OC1=CC=C(C=C1)NC=1C=2C(N=CN1)=NN(C2)CCO)(F)F VOWIADXMGURSLQ-UHFFFAOYSA-N 0.000 description 1
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 1
- RLNWDXSAXWWYGC-UHFFFAOYSA-N 6-[1-[(4-methylsulfonylphenyl)methyl]pyrazol-4-yl]-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1CN1N=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 RLNWDXSAXWWYGC-UHFFFAOYSA-N 0.000 description 1
- PPRRNVMKPAMCSP-UHFFFAOYSA-N 6-chloro-5-methyl-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound CC1=C(Cl)N=CN=C1NC1=CC=C(OC(F)(F)F)C=C1 PPRRNVMKPAMCSP-UHFFFAOYSA-N 0.000 description 1
- JWPITWGCBBZALG-UHFFFAOYSA-N 7-chloro-2-(3-nitrophenyl)imidazo[1,2-c]pyrimidine 2-(3-nitrophenyl)-N-[4-(trifluoromethoxy)phenyl]imidazo[1,2-c]pyrimidin-7-amine Chemical compound ClC1=CC=2N(C=N1)C=C(N2)C2=CC(=CC=C2)[N+](=O)[O-].[N+](=O)([O-])C=2C=C(C=CC2)C=2N=C1N(C=NC(=C1)NC1=CC=C(C=C1)OC(F)(F)F)C2 JWPITWGCBBZALG-UHFFFAOYSA-N 0.000 description 1
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical group N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 1
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 229920001817 Agar Polymers 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
- 239000004475 Arginine Substances 0.000 description 1
- 206010051113 Arterial restenosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000032800 BCR-ABL1 positive blast phase chronic myelogenous leukemia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000004860 Blast Crisis Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 208000008720 Bone Marrow Neoplasms Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010006448 Bronchiolitis Diseases 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 238000011537 Coomassie blue staining Methods 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 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 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000019878 Eales disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- XOXYHGOIRWABTC-UHFFFAOYSA-N Gentisin Natural products C1=C(O)C=C2C(=O)C3=C(O)C=C(OC)C=C3OC2=C1 XOXYHGOIRWABTC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 206010061188 Haematotoxicity Diseases 0.000 description 1
- 208000031953 Hereditary hemorrhagic telangiectasia Diseases 0.000 description 1
- 241000228402 Histoplasma Species 0.000 description 1
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- OWYWGLHRNBIFJP-UHFFFAOYSA-N Ipazine Chemical compound CCN(CC)C1=NC(Cl)=NC(NC(C)C)=N1 OWYWGLHRNBIFJP-UHFFFAOYSA-N 0.000 description 1
- 206010065630 Iris neovascularisation Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-M L-tartrate(1-) Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010057180 Liver and spleen enlargement Diseases 0.000 description 1
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 1
- 101710087603 Mast/stem cell growth factor receptor Kit Proteins 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 1
- HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101001033276 Mus musculus Interleukin-3 Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- ZMKGDQSIRSGUDJ-UHFFFAOYSA-N NVa2 cyclosporine Natural products CCCC1NC(=O)C(C(O)C(C)CC=CC)N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-UHFFFAOYSA-N 0.000 description 1
- 229910020700 Na3VO4 Inorganic materials 0.000 description 1
- 201000004404 Neurofibroma Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920001774 Perfluoroether Polymers 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000007135 Retinal Neovascularization Diseases 0.000 description 1
- 201000007737 Retinal degeneration Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 102000000395 SH3 domains Human genes 0.000 description 1
- 108050008861 SH3 domains Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 206010041101 Small intestinal obstruction Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 108010076818 TEV protease Proteins 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- 206010047663 Vitritis Diseases 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- HZYIMVPGYXVFEO-UHFFFAOYSA-N [2-(methoxymethyl)pyrrolidin-1-yl]-[7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-6-yl]methanone Chemical compound COCC1CCCN1C(=O)C(N(C1=NC=N2)C)=CC1=C2NC1=CC=C(OC(F)(F)F)C=C1 HZYIMVPGYXVFEO-UHFFFAOYSA-N 0.000 description 1
- NAFMMAKRPXRYSH-UHFFFAOYSA-N [3-(hydroxymethyl)piperidin-1-yl]-[7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-6-yl]methanone Chemical compound N1=CN=C2N(C)C(C(=O)N3CC(CO)CCC3)=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 NAFMMAKRPXRYSH-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KNYAHOBESA-N [[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] dihydroxyphosphoryl hydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)O[32P](O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KNYAHOBESA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000036676 acute undifferentiated leukemia Diseases 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000005819 alkenylalkoxy group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 1
- 125000004947 alkyl aryl amino group Chemical group 0.000 description 1
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 238000011316 allogeneic transplantation Methods 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000009925 apoptotic mechanism Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000005141 aryl amino sulfonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- ZDQSOHOQTUFQEM-PKUCKEGBSA-N ascomycin Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C\C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-PKUCKEGBSA-N 0.000 description 1
- ZDQSOHOQTUFQEM-XCXYXIJFSA-N ascomycin Natural products CC[C@H]1C=C(C)C[C@@H](C)C[C@@H](OC)[C@H]2O[C@@](O)([C@@H](C)C[C@H]2OC)C(=O)C(=O)N3CCCC[C@@H]3C(=O)O[C@H]([C@H](C)[C@@H](O)CC1=O)C(=C[C@@H]4CC[C@@H](O)[C@H](C4)OC)C ZDQSOHOQTUFQEM-XCXYXIJFSA-N 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 208000003373 basosquamous carcinoma Diseases 0.000 description 1
- 108010056708 bcr-abl Fusion Proteins Proteins 0.000 description 1
- 102000004441 bcr-abl Fusion Proteins Human genes 0.000 description 1
- 206010004398 benign neoplasm of skin Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 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
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 201000006491 bone marrow cancer Diseases 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004090 cyclononenyl group Chemical group C1(=CCCCCCCC1)* 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001945 cyclooctatrienyl group Chemical group C1(=CC=CC=CCC1)* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 108010019249 cyclosporin G Proteins 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical group C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- UKWLRLAKGMZXJC-QIECWBMSSA-L disodium;[4-chloro-3-[(3r,5s)-1-chloro-3'-methoxyspiro[adamantane-4,4'-dioxetane]-3'-yl]phenyl] phosphate Chemical compound [Na+].[Na+].O1OC2([C@@H]3CC4C[C@H]2CC(Cl)(C4)C3)C1(OC)C1=CC(OP([O-])([O-])=O)=CC=C1Cl UKWLRLAKGMZXJC-QIECWBMSSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000007904 elastic gelatin capsule Substances 0.000 description 1
- 210000004177 elastic tissue Anatomy 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- VIUDRTOSNGCXHI-UHFFFAOYSA-N ethyl 1-[7-methyl-4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidine-6-carbonyl]piperidine-3-carboxylate Chemical compound C1C(C(=O)OCC)CCCN1C(=O)C(N(C1=NC=N2)C)=CC1=C2NC1=CC=C(OC(F)(F)F)C=C1 VIUDRTOSNGCXHI-UHFFFAOYSA-N 0.000 description 1
- JHKRJQIIWASWKP-UHFFFAOYSA-N ethyl 3-[4-[4-(trifluoromethoxy)anilino]pyrrolo[2,3-d]pyrimidin-7-yl]propanoate Chemical compound N1=CN=C2N(CCC(=O)OCC)C=CC2=C1NC1=CC=C(OC(F)(F)F)C=C1 JHKRJQIIWASWKP-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 208000037824 growth disorder Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 231100000226 haematotoxicity Toxicity 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- DEBVVCQFYJWTDA-UHFFFAOYSA-N hexadecylalumanylformic acid Chemical compound C([AlH]CCCCCCCCCCCCCCCC)(=O)O DEBVVCQFYJWTDA-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000013653 hyalitis Diseases 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 201000001371 inclusion conjunctivitis Diseases 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 150000002475 indoles Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 210000003593 megakaryocyte Anatomy 0.000 description 1
- 125000005358 mercaptoalkyl group Chemical group 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 description 1
- BYHDRGRVVXBJIP-UHFFFAOYSA-N methyl 4-chloroquinazoline-7-carboxylate Chemical compound ClC1=NC=NC2=CC(C(=O)OC)=CC=C21 BYHDRGRVVXBJIP-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
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 229950000844 mizoribine Drugs 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 229940105132 myristate Drugs 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 201000003142 neovascular glaucoma Diseases 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000015927 pasta Nutrition 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- DCWXELXMIBXGTH-QMMMGPOBSA-N phosphonotyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-QMMMGPOBSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 108091005981 phosphorylated proteins Proteins 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000004258 retinal degeneration Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 231100000046 skin rash Toxicity 0.000 description 1
- 230000015590 smooth muscle cell migration Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 239000003860 topical agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Physical Education & Sports Medicine (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本出願は、2007年11月28日に出願された米国仮出願第61/004,462号の優先権を主張する。前記の米国仮出願に開示されたすべての事項は、引用により本願に援用されている。
プロテインキナーゼは、広範囲にわたる細胞のプロセスの調節及び細胞の機能に関する調節の維持に主要な役割を果たす、大きなタンパク質のファミリーに相当する。これらのキナーゼとしては、血小板由来成長因子受容体キナーゼ(PDGF-R)のような受容体型チロシンキナーゼ、幹細胞ファクターのための受容体キナーゼ、c-Kit、及び融合型チロシンキナーゼBcr-ablのような非受容体チロシンキナーゼが挙げられる。
一つの態様において、本発明は、式I:
[式中、X1、X2又はX3の各々が独立して、NR1、CR1、C(O)、O又はSであり;
各R1が独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、任意に置換されたC1-6アラルキル、任意に置換されたC1-6ヘテロアラルキル、任意に置換されたC1-6ハロアルキル、任意に置換された(CH2)nC3-12ヘテロシクロアルキル、任意に置換された(CH2)nC3-12アリール、任意に置換された(CH2)nC3-12ヘテロアリール、任意に置換された(CH2)nC3-12シクロアルキル、C1-6ハロアルキル、C1-6アミノアルキル、ハロ、 (CH2)nC(O)Rx、(CH2)nC(O)ORx、(CH2)nC(O)NRxRx、(CH2)nC(O)NRxRxS(O)2Rx、-C(O)Rx、-C(S)Rx、-C(NR)Rx、-SRx、-S(O)Rx、-S(O)2Rx、-ORx、-NRxRx、ニトロ、シアノ又は存在しない、から選ばれ;
各Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、C1-6ハロアルキル、NHNHR2又はC(NH)NH2であり;
R2がH又はC1-6アルキルであり;
YがH、OH、NH2又はCH3であり;
mが1又は2であり;及び
各nが独立して、0、1又は2である。]で表される化合物又はその薬学的に受容される塩、その溶媒和物又はその水和物を提供する。
[式中、R1がH、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、任意に置換されたC1-6アラルキル、任意に置換されたC1-6ヘテロアラルキル、任意に置換されたC1-6ハロアルキル、任意に置換された(CH2)nC3-12ヘテロシクロアルキル、任意に置換された(CH2)nC3-12アリール、任意に置換された(CH2)nC3-12ヘテロアリール、任意に置換された(CH2)nC3-12シクロアルキル、(CH2)nC(O)Rx、(CH2)nC(O)ORx、(CH2)nC(O)NRxRx、-C(O)Rx、-C(S)Rx、-C(NR)Rx、ハロ、C1-6ハロアルキル、-S(O)Rx又は-S(O)2Rxから選ばれ;
各Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール又はC1-6ハロアルキルであり;及び
各nが独立して、0、1又は2である。]で表される化合物又はその薬学的に受容される塩、その溶媒和物又はその水和物を提供する。
[式中、R1がH、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、任意に置換されたC1-6アラルキル、任意に置換されたC1-6ヘテロアラルキル、任意に置換されたC1-6ハロアルキル、任意に置換された(CH2)nC3-12ヘテロシクロアルキル、任意に置換された(CH2)nC3-12アリール、任意に置換された(CH2)nC3-12ヘテロアリール、任意に置換された(CH2)nC3-12シクロアルキル、(CH2)nC(O)Rx、(CH2)nC(O)ORx、(CH2)nC(O)NRxRx、-C(O)Rx、-C(S)Rx、-C(NR)Rx、ハロ、C1-6ハロアルキル、-S(O)Rx又は-S(O)2Rxから選ばれ;
各Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール又はC1-6ハロアルキルであり;及び
各nが独立して、0、1又は2である。]で表される化合物又はその薬学的に受容される塩、その溶媒和物又はその水和物を提供する。
各Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール又はC1-6ハロアルキルであり;及び
各nが独立して、0、1又は2である。]で表される化合物又はその薬学的に受容される塩、その溶媒和物又はその水和物を提供する。
各Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、NHNHR2又はC(NH)NH2であり;
R1’が、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、任意に置換されたC1-6アラルキル、任意に置換されたC1-6ヘテロアラルキル、任意に置換されたC1-6ハロアルキル、任意に置換された(CH2)nC3-12ヘテロシクロアルキル、任意に置換された(CH2)nC3-12アリール、任意に置換された(CH2)nC3-12ヘテロアリール、任意に置換された(CH2)nC3-12シクロアルキル、(CH2)nC(O)Ry、(CH2)nC(O)ORy、(CH2)nC(O)NRyRy、-C(O)Ry、-C(S)Ry、-C(NR)Ry、ハロ、C1-6ハロアルキル、-S(O)Ry又は-S(O)2Ryから選ばれ、
各Ryが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール又はC1-6ハロアルキルであり、
各nが独立して、0、1又は2であり;及び
R2がH又はC1-4アルキルである。]で表される化合物又はその薬学的に受容される塩、その溶媒和物又はその水和物を提供する。
各Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、NHNHR2又は C(NH)NH2であり;及び
R2がH又はC1-4アルキルである。
各Ryが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、又はC1-6ハロアルキルである。
各Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、NHNHR2又はC(NH)NH2から選ばれ;
R2がH又はC1-4アルキルであり;及び
各nが独立して、0、1又は2である。]で表される化合物又はその薬学的に受容される塩、その溶媒和物又はその水和物を提供する。
各Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、NHNHR2又はC(NH)NH2であり;
R2がH又はC1-4アルキルであり;
mが1又は2であり;及び
各nが独立して、0、1又は2である。]で表される化合物又はその薬学的に受容される塩、その溶媒和物又はその水和物を提供する。
R1が、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、任意に置換されたC1-6アラルキル、任意に置換されたC1-6ヘテロアラルキル、任意に置換されたC1-6ハロアルキル、任意に置換された(CH2)nC3-12ヘテロシクロアルキル、任意に置換された(CH2)nC3-12アリール、任意に置換された(CH2)nC3-12ヘテロアリール、任意に置換された(CH2)nC3-12シクロアルキル、(CH2)nC(O)Rx、(CH2)nC(O)ORx、(CH2)nC(O)NRxRx、-C(O)Rx、-C(S)Rx、-C(NR)Rx、ハロ、C1-6ハロアルキル、-S(O)Rx又は-S(O)2Rxから選ばれ、
各Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール又はC1-6ハロアルキルであり;及び
各nが独立して、0、1又は2である。]で表される化合物又はその薬学的に受容される塩、その溶媒和物又はその水和物を提供する。
LがNR3、O、S、 S(O)、S(O)2、C(O)、C(S)、C(NR)、C(NRx)NRx、C(O)NRx、C(O)NRxNRx、C(O)ONRx、C(O)NRxO、C(O)O、OC(O)、OC(O)O又は結合であり;
各Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、C1-6ハロアルキル、NHNHR2又はC(NH)NH2であり;
Aが任意に置換されたC1-6アルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、任意に置換されたC3-12シクロアルキル又は任意に置換されたC3-12ヘテロシクロアルキルである。]で表される化合物、その薬学的に受容される塩、その溶媒和物又はその水和物を提供する。
各R15が独立して、水素、C3-14アラルキル、C1-6アルキル、C3-12シクロアルキル、C3-12アリール、C3-12ヘテロシクロアルキル又はC3-12ヘテロアリールであり、
各R16が独立して、水素、C3-14アラルキル又はC1-6アルキルであり、
各R17が独立して、H、C1-6アルキル、C1-6ヒドロキシアルキル、C1-6アルコキシ、C3-12シクロアルキル、C3-12アリール、C3-12ヘテロアリール、C3-12ヘテロシクロアルキル、ヒドロキシルであるか、又はもう一つのR17とともにヘテロシクロアルキル環を形成してもよく、
ここにおいて、A、R15、R16及びR17のそれぞれが、C1-6アルキル、C1-6アルコキシ、C1-6ハロアルコキシ、C3-12ヘテロシクロアルキル、アミノ、ハロゲン、C1-6ハロアルキル、SO2アルキル又はNHC(O)アリールにより任意にさらに置換されていてもよく;及び
各pが独立して0-6である。
各R1が独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、任意に置換されたC2-6アラルキル、任意に置換されたC2-12ヘテロアラルキル、任意に置換されたC1-6ハロアルキル、任意に置換された(CH2)nC3-12アリール、任意に置換された(CH2)nC3-12ヘテロアリール、任意に置換された(CH2)nC3-12シクロアルキル、任意に置換された(CH2)nC3-12ヘテロシクロアルキル、C1-6ハロアルキル、C1-6アミノアルキル、ハロ、(CH2)nC(O)Rx、(CH2)nC(O)ORx、(CH2)nC(O)NRxRx、-(CH2)nC(O)NRxRxS(O)2Rx、-C(O)Rx、-C(S)Rx、-C(NR)Rx、-SRx、-S(O)Rx、-S(O)2Rx、-ORx、-NRxRx、ニトロ又は存在しない、から選ばれ;
Rxが存在する場合に独立して、H、任意に置換されたC1-6アルキル、任意に置換されたC3-12シクロアルキル、任意に置換されたC3-12ヘテロシクロアルキル、任意に置換されたC3-12アリール、任意に置換されたC3-12ヘテロアリール、C1-6ハロアルキル、C1-6ハロアルキル、NHNHR2又はC(NH)NH2であり;
R2がH又はC1-6アルキルであり;及び
各nが独立して、0、1又は2である。]で表される化合物、その薬学的に受容される塩、その溶媒和物又はその水和物を提供する。
a)Bcr-ablと、前記Bcr-ablのキナーゼ活性の調節に適切な条件下で化合物と接触させるステップ、及び
b)前記化合物による前記Bcr-ablのキナーゼ活性の調節を検出するステップであって、前記化合物がBcr-ablのミリスチン酸結合サイトと相互作用することができる、ステップを含む。
本発明の化合物
本発明の化合物の例としては、その化学構造が表1−9に示された以下の化合物が挙げられる。
2−(4−(4−(トリフルオロメトキシ)フェニルアミノ)−lH−ピラゾロ[3,4−d]ピリミジン−l−イル)エタノール(1);
(1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(2);
(1−エチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(3);
(1−エタンスルホニル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(4);
(1−シクロヘキシル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(5);
2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−l−イル]−エタノール(6);
2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−l−イル]−アセトアミド(7);
3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−l−イル]−プロピオンアミド(8);
[1−(テトラヒドロ−フラン−3−イルメチル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(9);
3−ジメチルアミノ−2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−l−イル]−プロピオニトリル(10);
(1−ブチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(11);
(1−tert−ブチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(12);
[1−(2,2,2−トリフルオロ−エチル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(13);
(1−ベンジル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(14);
(1−フェネチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(15);
[1−(3−フルオロ−4−トリフルオロメチル−ベンジル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(16);
[1−(3−ブロモ−ベンジル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(17);
3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−1−イルメチル]−フェノール(18);
(1−ピリジン−3−イルメチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(19);
(1−ピリジン−2−イルメチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(20);
(1−ピリジン−4−イルメチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(21);
2−{2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−1−イル]−エチル}−イソインドール−1,3−ジオン(22);
[1−(2−アミノ−エチル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(23);
(4−トリフルオロメトキシ−フェニル)−[1−(4−トリフルオロメチル−ピリジン−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−アミン(24);
[1−(2,3−ジメチル−フェニル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(25);
[1−(2−フルオロ−フェニル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(26);
[1−(2,4−ジクロロ−フェニル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(27);
[1−(2−エチル−フェニル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(28);
(1−ピリジン−2−イル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(29);
3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−1−イル]−ベンゼンスルホンアミド(30);
(2−エチル−2H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(32);
(2−シクロヘキシル−2H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(33);
2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−2−イル]−エタノール(34);
2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−2−イル]−アセトアミド(35);
[2−(テトラヒドロ−フラン−3−イルメチル)−2H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(36);
(2−ブチル−2H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(37);
[2−(2,2,2−トリフルオロ−エチル)−2H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(38);
(2−ベンジル−2H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(39);
(2−フェネチル−2H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(40);
[2−(3−フルオロ−4−トリフルオロメチル−ベンジル)−2H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(41);
[2−(3−ブロモ−ベンジル)−2H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(42);
3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−2−イルメチル]−フェノール(43);
(2−ピリジン−3−イルメチル−2H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(44);
(4−トリフルオロメトキシ−フェニル)−[2−(4−トリフルオロメチル−ピリジン−2−イル)−2H−ピラゾロ[3,4−d]ピリミジン−4−イル]−アミン(45);
[2−(2,3−ジメチル−フェニル)−2H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(46);
[2−(2−フルオロ−フェニル)−2H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(47);
[2−(2,4−ジクロロ−フェニル)−2H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(48);
[2−(2−エチル−フェニル)−2H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(49);
(2−ピリジン−2−イル−2H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(50);
(7−メチル−7H−プリン−6−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(52);
2−ヒドロキシメチル−5−[6−(4−トリフルオロメトキシ−フェニルアミノ)−プリン−9−イル]−テトラヒドロ−フラン−3,4−ジオール(53);
[9−(2−モルホリン−4−イル−エチル)−9H−プリン−6−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(54);
2−ヒドロキシメチル−5−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−テトラヒドロ−フラン−3,4−ジオール(56);
(7H−ピロロ[2,3−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(57);
(7−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(58);
2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−エタノール(59);
[7−(2−モルホリン−4−イル−エチル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニルアミノ)−アミン(60);
[7−(4−メトキシ−ベンジル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(61);
3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド(62);
N−エチル−3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド(63);
N−(3−メトキシ−プロピル)−3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド(64);
N−(2−モルホリン−4−イル−エチル)−3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド(65);
7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−カルボン酸エチルエステル(66);
(4−ブロモ−ピペリジン−1−イル)−[7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−イル]−メタノン(67);
1−[7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−カルボニル]−ピペリジン−4−カルボン酸アミド(68);
1−[7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−カルボニル]−ピペリジン−3−カルボン酸アミド(69);
1−[7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−カルボニル]−ピペリジン−3−カルボン酸エチルエステル;
(3−ヒドロキシメチル−ピペリジン−1−イル)−[7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−イル]−メタノン(71);
8−[7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−カルボニル]−1−フェニル−1,3,8−トリアザ−スピロ[4,5]デカン−4−オン(72);
[7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−イル]−メタノール(73);
(2−メトキシメチル−ピロリジン−1−イル)−[7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−イル]−メタノン(74);
7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−カルボン酸アミド(75);
7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−カルボン酸エチルアミド(76);
7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−カルボン酸(1−エチル−ピロリジン−2−イル)−アミド(77);
N−[7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−カルボニル]グアニジン(78);
7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−7H−ピロロ[2,3−d]ピリミジン−6−カルボン酸(4−ジエチルアミノ−1−メチル−ブチル)−アミド(79);
4−(2−ブロモ−4−トリフルオロメトキシ−フェニルアミノ)−1−(2−モルホリン−4−イル−エチル)−1H−ピロロ[2,3−d]ピリジン−5−カルバルデヒド(80);
チエノ[2,3−d]ピリミジン−4−イル−(4−トリフルオロメトキシ−フェニル)−アミン(82);
(6−メチル−チエノ[2,3−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(83);
4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−カルボン酸メチルエステル(84);
4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−カルボン酸(85);
4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−カルボン酸(2−モルホリン−4−イル−エチル)−アミド(86);
[4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−イル]−メタノール(87);
4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−カルボン酸エチルアミド(88);
4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−カルボン酸(2−ヒドロキシ−エチル)−アミド(89);
[6−(3−ジメチルアミノ−ピロリジン−1−イルメチル)−チエノ[2,3−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(90);
(3−ジメチルアミノ−ピロリジン−1−イル)−[4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−イル]−メタノン(91);
4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−カルボン酸(1−ベンジル−ピロリジン−3−イル)−アミド(92);
(2−ヒドロキシメチル−ピロリジン−1−イル)−[4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−イル]−メタノン(93);
ピペラジン−1−イル−[4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−イル]−メタノン(94);
(4−ピロリジン−1−イル−ピペラジン−1−イル)−[4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−イル]−メタノン(95);
[4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−イル]−[4−(3−トリフルオロメチル−フェニル)−ピペラジン−1−イル]−メタノン(96);
4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−カルボン酸(2−モルホリン−4−イル−エチル)−アミド(97);
(4−メチル−ピペラジン−1−イル)−[4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−イル]−メタノン(98);
(4−ヒドロキシ−ピペリジン−1−イル)−[4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−イル]−メタノン(99);
(4−メトキシ−ピペリジン−1−イル)−[4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−イル]−メタノン(100);
4−(4−トリフルオロメトキシ−フェニルアミノ)−チエノ[2,3−d]ピリミジン−6−カルボン酸[2−メチル−5−(3−トリフルオロメチル−ベンゾイルアミノ)
−フェニル]−アミド(101);
4−(4−(トリフルオロメトキシ)フェニルアミノ)−キナゾリン−7−カルボン酸メチルエステル(103);
[4−(4−(トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノール(104);
(7−ジエチルアミノメチル−キナゾリン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(105);
4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボン酸ジエチルアミド(106);
[4−(フラン−3−イル−カルボニル)―ピペラジン−1−イル]―[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノン(107);
4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボン酸(3−トリフルオロメチル−フェニル)−アミド(108);
4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボン酸(3−メトキシ−プロピル)−アミド(109);
4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボン酸N’−エチル−ヒドラジド(110);
(2−{[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボニル]−アミノ}−チアゾール−5−イル)−酢酸エチルエステル(111);
(4−メトキシ−ピペリジン−1−イル)−[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノン(112);
(3−ヒドロキシ−ピロリジン−1−イル)−[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノン(113);
(2−ヒドロキシメチル−ピロリジン−1−イル)−[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノン(114);
(3−ジメチルアミノ−ピロリジン−1−イル)−[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノン(115);
4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボン酸(2−ヒドロキシ−エチル)−メチル−アミド(116);
4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボン酸メチル−(1−メチル−ピペリジン−4−イル)−アミド(117);
4−メチル−N−[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボニル]−ベンゼンスルホンアミド(118);
2−メチル−プロパン−2−スルホン酸[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボニル]−アミド(119);
(4−メチル−[1,4]ジアゼパン−1−イル)―[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノン(120);
(3,5−ジメチル−ピペラジン−1−イル)―[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノン(121);
(4−ヒドロキシ−ピペリジン−1−イル)―[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノン(122);
4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボン酸メチル−(2−メチルアミノ−エチル)−アミド(123);
4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボン酸(2−ヒドロキシ−エチル)−アミド(124);
1−フェニル−8−[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボニル]−1,3,8−トリアザ−スピロ[4.5]デカン−4−オン(125);
(4−ブロモ−ピペリジン−1−イル)―[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノン(126);
1−[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボニル]−ピペリジン−4−カルボン酸アミド(127);
1−[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボニル]−ピペリジン−3−カルボン酸アミド(128);
1−[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−カルボニル]−ピペリジン−3−カルボン酸エチルエステル(129);
(3−ヒドロキシメチル−ピペリジン−1−イル)―[4−(4−トリフルオロメトキシ−フェニルアミノ)−キナゾリン−7−イル]−メタノン(130);
7−メチル−4−(4−トリフルオロメトキシ−フェニルアミノ)−5,7−ジヒドロ−ピロロ[2,3−d]ピリミジン−6−オン(132);
6−(1H−ピロロ[2,3−b]ピリジン−1−イル)−N−(4−(トリフルオロメトキシ)フェニル)ピリミジン−4−アミン(134);
N−(4−(トリフルオロメトキシ)フェニル)−6−(1,3,5−トリメチル−1H−ピラゾール−4−イル)ピリミジン−4−アミン(135);
4−[6−(4−(トリフルオロメトキシ)フェニルアミノ)−ピリミジン−4−イル]−ベンゼンスルホンアミド(136);
4−[5−メチル−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ベンゼンスルホンアミド(137);
N−メチル−4−[5−メチル−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ベンゼンスルホンアミド(138);
N−エチル−4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ベンゼンスルホンアミド(139);
N−(2−ヒドロキシ−エチル)−4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ベンゼンスルホンアミド(140);
[6−(4−メタンスルホニル−フェニル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(141);
[6−(4−メタンスルホニル−フェニル)−5−メチル−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(142);
{6−[4−(プロパン−2−スルホニル)−フェニル]−ピリミジン−4−イル}−(4−トリフルオロメトキシ−フェニル)−アミン(143);
{5−メチル−6−[4−(プロパン−2−スルホニル)−フェニル]−ピリミジン−4−イル}−(4−トリフルオロメトキシ−フェニル)−アミン(144);
N,N−ジエチル−4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ベンゼンスルホンアミド(145);
N,N−ジエチル−4−[5−メチル−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ベンゼンスルホンアミド(146);
{6−[4−(ピペリジン−1−スルホニル)−フェニル]−ピリミジン−4−イル}−(4−トリフルオロメトキシ−フェニル)−アミン(147);
4−メチル−N−{4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フェニル}−ベンゼンスルホンアミド(148);
4−メチル−N−{4−[5−メチル−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フェニル}−ベンゼンスルホンアミド(149);
{6−[4−(モルホリン−4−スルホニル)−フェニル]−ピリミジン−4−イル}−(4−トリフルオロメトキシ−フェニル)−アミン(150);
N−{4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フェニル}−メタンスルホンアミド(151);
エタンスルホン酸{4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フェニル}−アミド(152);
ブタン−1−スルホン酸{4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フェニル}−アミド(153);
プロパン−2−スルホン酸{4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フェニル}−アミド(154);
ペンタン−2−スルホン酸{4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フェニル}−アミド(155);
N−(2−ヒドロキシ−エチル)−4−[5−メチル−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ベンズアミド(156);
4−[5−メチル−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−N−(2−モルホリン−4−イル−エチル)ベンズアミド(157);
N−(3−メトキシ−プロピル)−4−[5−メチル−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ベンズアミド(158);
N−{3−[5−メチル−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フェニル}−アセトアミド(159);
3−[5−メチル−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ベンズアミド(160);
3−[5−メチル−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−安息香酸(161);
(6−ビフェニル−4−イル−ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(162);
(6−ビフェニル−4−イル−5−メチル−ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(163);
[6−(5−メトキシ−ナフタレン−2−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(164);
[6−(5−メトキシ−ナフタレン−2−イル)−5−メチル−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(165);
{3−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フェニル}−アセトニトリル(166);
[6−(3−ニトロ−フェニル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(167);
4−メトキシ−N−{4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フェニル}−ベンズアミド(168);
[6−(4−アミノメチル−フェニル)−5−メチル−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(169);
5−ブロモ−N−(2−モルホリン−4−イル−エチル)−N’−(4−トリフルオロメトキシ−フェニル)−ピリミジン−4,6−ジアミン(170);
1−[5−ブロモ−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ピペリジン−3−カルボン酸アミド(171);
{6−[2−(2−モルホリン−4−イル−エチルアミノ)−イミダゾール−1−イル]−ピリミジン−4−イル}−(4−トリフルオロメトキシ−フェニル)−アミン(172);
(4−トリフルオロメトキシ−フェニル)−{6−[2−(4−トリフルオロメトキシ−フェニルアミノ)−イミダゾール−1−イル]−ピリミジン−4−イル}−アミン(173);
N−(5−シクロプロピル−1H−ピラゾール−3−イル)−N’−(4−トリフルオロメトキシ−フェニル)−ピリミジン−4,6−ジアミン(174);
[6−(3−アミノ−5−シクロプロピル−ピラゾール−1−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(175);
N−(4−トリフルオロメトキシ−フェニル)−N’−[1−(3−トリフルオロメチル−フェニル)−1H−イミダゾール−2−イル]−ピリミジン−4,6−ジアミン(176);
(6−ピロロ[2,3−b]ピリジン−1−イル−ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(177);
[6−(1H−ピラゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(178);
[6−(1−メチル−1H−ピラゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(179);
[6−(1−イソブチル−1H−ピラゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(180);
[6−(1−イソブチル−1H−ピラゾール−4−イル)−5−メチル−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(181);
(4−トリフルオロメトキシ−フェニル)−[6−(1,3,5−トリメチル−1H−ピラゾール−4−イル)−ピリミジン−4−イル]−アミン(182);
{6−[1−(4−メタンスルホニル−ベンジル)−1H−ピラゾール−4−イル]−ピリミジン−4−イル}−(4−トリフルオロメトキシ−フェニル)−アミン;(183)
[6−(1−エタンスルホニル−1H−ピラゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(184);
[6−(1−ピリジン−4−イルメチル−1H−ピラゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(185);
N6−(2−モリホリン−4−イル−エチル)−N6’−(4−トリフルオロメトキシ−フェニル)−[4,4’]ビピリミジニル−6,6’−ジアミン(186);
[5−メチル−6−(1−メチル−1H−ピラゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(187);
[6−(5−メチル−1−フェニル−1H−ピラゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(188);
[5−メチル−6−(5−メチル−1−フェニル−1H−ピラゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(189);
[6−(1H−インドール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(190);
[6−(1H−インドール−3−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(191);
[6−(1H−インドール−5−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(192);
4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−フラン−2−カルバルデヒド;(193)
(6−ベンゾ[b]チオフェン−4−イル−ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン(194);
[6−(1H−インドール−4−イル)−5−メチル−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(195);
(6−ジベンゾフラン−4−イル−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(196);
[6−(1−ベンジル−1H−ピラゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(197);
[6−(1−ベンジル−1H−ピラゾール−4−イル)−5−メチル−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(198);
N6,N6’−ビス−(4−トリフルオロメトキシ−フェニル)−[4,4’]ビピリミジニル−6,6’−ジアミン(199);
N6−(2−モルホリン−4−イル−エチル)−N6’−(4−トリフルオロメトキシ−フェニル)−[4,4’]ビピリミジニル−6,6’−ジアミン(200);
N−(4−メチル−3−{1−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−1H−イミダゾール−2−イルアミノ}−フェニル)−ベンズアミド(201);
N−(4−メチル−3−{1−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−1H−イミダゾール−2−イルアミノ}−フェニル)−4−モルホリン−4−イルメチル−3−トリフルオロメチル−ベンズアミド(202);
[6−(1−ピリジン−3−イルメチル−1H−ピラゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(203);
[6−(1H−ピロロ[2,3−b]ピリジン−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(204);
4−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−1H−ピリジン−2−オン(205);
[6−(2−メチル−チアゾール−4−イル)−ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン(206);
2−フルオロ−5−[6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−4−イル]−ベンズアルデヒド(207);
{6−[2−(4−メチル−ピペラジン−1−イル)−ピリジン−4−イル]−ピリミジン−4−イル}−(4−トリフルオロメトキシ−フェニル)−アミン(208);
2−ヒドロキシ−3−[7−(4−トリフルオロメトキシ−フェニルアミノ)−イミダゾ[1,2−c]ピリミジン−2−イル]−ベンズアミド(210);
式II及び式IIIの化合物は、二段階の反応に亘り形成された。最初に、塩素化されたヘテロアリール化合物を塩基性条件下でハロアルコキシ基が置換したアニリン誘導体に結合させた。ついで、得られた化合物をヒドラジン誘導体で処理すると、式II及び式IIIの化合物の混合物が得られ、ついでクロマトグラフィーにより分離した(スキームI)。
スキーム1
スキーム2
スキーム3
スキーム4
スキーム5
スキーム6
スキーム7
遊離形態又は薬学的に受容される塩の形態の本発明の化合物は、例えば、以下に示す「アッセイ」に開示されているin vitro試験法により示されるように、価値ある薬理作用を示すことから、本発明の化合物は、Bcr-abl活性に関連する疾患及び障害の治療への使用を示唆する。Bcr-ablに関して、好ましくは、本発明の化合物は、1×10-10から1×10-5Mの範囲、好ましくは1μM未満のIC50を、野生型Bcr-abl及び少なくとも二つのBcr-ablの突然変異株(突然変異株はG250E、E255V、T315I、F317L及びM351Tから選ばれる。)に関して示す。
「腫瘍」という用語は、細胞の増殖が正常な組織よりも速く、かつ新たな成長の終止を開始する刺激の後も成長を続ける場合に起こる、組織における異常な成長を意味する。一般に、腫瘍は、構造的な組織及び正常な組織との協同の一部又はすべての欠落を呈し、そして良性(良性腫瘍)又は悪性(カルシノーマ)であるかもしれない組織の識別できる塊を通常形成する。腫瘍は高度に血管新生化される傾向がある。
注目すべき態様では、Bcr-ablのキナーゼ活性の阻害は、本発明の重要な態様である。より詳細には、本発明は、慢性骨髄性白血病を含む癌を治療する方法に関するものであって、本明細書に開示された化合物の少なくとも一つの阻害又は治療上有効な量又は濃度で前記の癌に接触させるステップを含む、方法である。前記の方法は、本発明の化合物の一つ以上に対する患者の癌の感受性を決定するためのみならず、関連するアナログの活性を決定するためのアッセイのような比較試験において治療学的に使用されてもよい。
本発明の化合物の薬学的組成物及び剤形は、本明細書に開示された一つ以上の活性成分を含む。本発明の化合物の薬学的組成物及び剤形は、また、典型的には一つ以上の薬学的に受容される賦形剤又は希釈剤を含む。
同様に、非経腸投与用の剤形は、前記と同一の疾患又は障害に使用される経口の剤形よりも少量の、それが含む前記の活性成分の一つ以上を含んでいてもよい。本発明により包含される具体的な剤形がお互いに異なるであろう、これらの点及び他の点は当業者にとって容易に明らかであろう。例えば、Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990)を参照されたい。
本明細書で使用されているように、「アルキル」という用語は、1乃至12個の炭素原子含む、直鎖又は分岐した鎖状の炭化水素基を意味する。「低級アルキル」という用語は、C1-C6アルキル鎖を意味する。アルキル基の例としては、メチル、エチル、n-プロピル、イソプロピル、tert-ブチル及びn-ペンチルが挙げられる。アルキル基は、任意に一つ以上の置換基で置換されてもよい。
(i)アルキル、ハロアルキル、アリール、ハロゲン、ヒドロキシ、アルコキシ、ヒドロキシアルキル、アミノ、モノ−アルキルアミン、ジ−アルキルアミン、シアノ、CONH2、CO2アルキル、SO2NH2、又は
(ii)モルホリン、
実施例1
2−(4−(4−(トリフルオロメトキシ)フェニルアミノ)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)エタノール及び
2−(4−(4−(トリフルオロメトキシ)フェニルアミノ)−2H−ピラゾロ[3,4−d]ピリミジン−2−イル)エタノールの調製
4−クロロ−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−5−カルバルデヒド
4,6−ジクロロ−ピリミジン−5−カルバルデヒド(3.06g,17.5mmol)のTHF(15mL)溶液に、4−トリフルオロメトキシアニリン(3.09g,17.45mmol)を0℃で添加した。得られた混合物を2時間攪拌後、酢酸エチル(100mL)を添加した。得られた有機層をブラインから分離し、Na2SO4で乾燥し、ついで濃縮すると表題の化合物が黄色の固体として得られた。ついで得られた化合物をシリカゲルカラムクロマトグラフィーで精製すると、表題に化合物((2.9g,収率:55%);MSm/z318.2(M+1))が黄色の結晶として得られた。
ステップ2:
2−(4−(4−(トリフルオロメトキシ)フェニルアミノ)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)エタノール及び
2−(4−(4−(トリフルオロメトキシ)フェニルアミノ)−2H−ピラゾロ[3,4−d]ピリミジン−2−イル)エタノール
4−クロロ−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−5−カルバルデヒド(50g,0.15mmol)を含むsec−BuOH溶液にNa2CO3(30mg,0.26mmol)及びヒドラジン(20mg,0.18mmol)を添加した。得られた反応液を60℃で8時間攪拌した。得られた反応液を水100mL及び酢酸エチル100mLに分配し、酢酸エチルで3回抽出した。得られた有機層を合わせ、ついでブラインで洗浄し、Na2SO4で乾燥した。得られた粗生成物を、展開剤としてヘキサン−酢酸エチルを使用するシリカゲルフラッシュクロマトグラフィーで精製すると、2−(4−(4−(トリフルオロメトキシ)フェニルアミノ)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)エタノール及び2−(4−(4−(トリフルオロメトキシ)フェニルアミノ)−2H−ピラゾロ[3,4−d]ピリミジン−2−イル)エタノールを、4:1の割合で含む黄色固体が得られた。
2−(4−(4−(トリフルオロメトキシ)フェニルアミノ)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)エタノール(20mg):
1H NMR 400 MHz (DMSO-d6) δ 10.30 (s, 1H), 8.45 {s, 1H (6-Ar-H)}, 8.32 {s, 1H (3-Ar-H), 7.98 (d, 2H, J = 9.6 Hz), 7.41 (d, 2H, J = 9.6 Hz), 4.40 (t, 2H, J = 3.0 Hz), 3.83 (t, 2H, J = 3.0 Hz); MS m/z 340.2 (M + 1)
2−(4−(4−(トリフルオロメトキシ)フェニルアミノ)−2H−ピラゾロ[3,4−d]ピリミジン−2−イル)エタノール(5mg):
1H NMR 400 MHz (DMSO-d6) δ 10.75 (s, 1H), 8.68 {s, 1H (3-Ar-H)}, 8.57 {s, 1H (6-Ar-H), 7.97 (d, 2H, J = 9.6 Hz), 7.45 (d, 2H, J = 9.6 Hz), 4.41 (t, 2H, J = 3.0 Hz), 3.85 (t, 2H, J = 3.0 Hz); MS m/z 340.2 (M + 1)
N−(2−モルホリン−4−イル−エチル)−3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド
3−(4−クロロ−ピロロ[2,3−d]ピリミジン−7−イル)−プロピオン酸エチルエステル
1H NMR 600 MHz (DMSO-d6) δ 9.01 (s, 1H), 6.26 (d, 1H, J = 3.0 Hz), 5.91 (d, 1H, J = 3.0 Hz), 4.24 (t, 2H, J = 5.4 Hz), 4.12 (t, 2H, J = 5.0 Hz), 2.73 (d, 2H, J = 5 Hz), 1.21 (d, 3H, J = 4 Hz); MS m/z 254.2 (M + 1).
ステップ2
3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオン酸エチルエステル
ステップ3:
3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオン酸
ステップ4:
N−(2−モルホリン−4−イル−エチル)−3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド
3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオン酸(25mg,0.068mmol)を、DIEA(0.030ml,0.172mmol)及びHATU(28.5mg,0.071mmol)のDMF(2ml)溶液に室温で混合した。0.5時間後に得られた反応混合物に2−モルホリン−4−イル−エチルアミン(9.7μL,0.074mmol)を、添加した。室温で2時間攪拌後、得られた反応混合物を濃縮し、ついで分取HPLC(Prep−HPLC)で精製すると表題の化合物がTFA塩(MS m/z 479.2 (M + 1))として得られた。
N−(2−ヒドロキシエチル)−4−(4−(トリフルオロメトキシ)フェニルアミノ)チエノ[2,3−d]ピリミジン−6−カルボキサミドの調製
ステップ1:
メチル 4−(4−(トリフルオロメトキシ)フェニルアミノ)チエノ[2,3−d]ピリミジン−6−カルボシラート
4−クロロ−6−(4−トリフルオロメトキシ−フェニルアミノ)−ピリミジン−5−カルバルデヒド(500g,1.5mmol)のDMF(2mL)溶液を、K2CO3(620mg,4.5mmol)のDMF(1mL)懸濁液に室温で添加した。30分間攪拌後、チオグリコール酸メチル(210mg,1.9mmol)を徐々に、得られた反応混合物に添加した。ついで、得られた反応混合物を90℃で1時間加熱した。ついで、得られた反応混合物を室温にまで冷却し、そして氷冷した水中に注入した。生じた残渣を濾取し、洗浄及び乾燥すると、表題の化合物(400g,収率:72%;MS m/z 370.2 (M + 1))が白色固体として得られた。
ステップ2:
4−(4−(トリフルオロメトキシ)フェニルアミノ)チエノ[2,3−d]ピリミジン−6−カルボン酸
ステップ3:
N−(2−ヒドロキシエチル)−4−(4−(トリフルオロメトキシ)フェニルアミノ)チエノ[2,3−d]ピリミジン−6−カルボキサミド:
4−(4−(トリフルオロメトキシ)フェニルアミノ)チエノ[2,3−d]ピリミジン−6−カルボン酸(30mg,0.08mmol)を、室温でDIEA(30μL,0.172mmol)及びHATU(39mg,0.1mmol)を含むDMF(2mL)溶液と混合した。0.5時間後、得られた反応混合物に2−アミノエタノール(6.1mg,0.1mmol)を加えた。室温で2時間攪拌後、得られた反応混合物を濃縮し、ついで分取HPLCで精製すると、表題の化合物がTFA塩(25mg,収率:61%)として得られた。
1H NMR 400 MHz (DMSO-d6) δ 10.10 (s, 1H), 9.26 (s, 1H), 8.82 (s, 1H), 8.21 (d, 2H, J = 8.8 Hz), 7.85 (d, 2H, J = 8.8 Hz), 7.34 (s, 1H), 3.02 (t, 2H, J = 6.4 Hz), 2.65 (t, 2H, J = 6.4 Hz). MS m/z 399.12 (M + 1).
4−(4−(トリフロオロメトキシ)フェニルアミノ)−N−(2−ヒドロキシエチル)キナゾリン−7−カルボキサミド:
メチル 4−(4−(トリフルオロメトキシ)フェニルアミノ)キナゾリン−7−カルボキシラート:
ついで、溶媒を溜去し、得られた化合物をCHCl3−Et2O(3:1)混合溶媒中で結晶化させた。析出した白色結晶を濾取し、ついでEt2Oで洗浄した(890mg、収率:91%;MS m/z 364.10 (M + 1)。
ステップ2:
4−(4−(トリフルオロメトキシ)フェニルアミノ)キナゾリン−7−カルボン酸:
1H NMR 400 MHz (DMSO-d6) δ 12.25 (s, 1H), 10.12 (s, 1H), 8.68 (s, 1H), 8.65 (d, 1H, J = 1.6 Hz), 8.20-8.11 (m, 2H), 8.02 (d, 2 H, J = 8.8 Hz), 7.42 (d, 2H, J = 8.8 Hz. MS m/z 350.1 (M + 1).
ステップ3:
4−(4−(トリフロオロメトキシ)フェニルアミノ)−N−(2−ヒドロキシエチル)キナゾリン−7−カルボキサミド:
4−(4−(トリフルオロメトキシ)フェニルアミノ)キナゾリン−7−カルボン酸(30mg,0.09mmol)を、DIEA(30μL,0.172mmol)及びHATU(39mg,0.1mmol)のDMF(2mL)溶液と室温で混合した。0.5時間後に得られた反応混合物に、2−アミノエタノール(6.1mg,0.1mmol)を添加した。室温で2時間攪拌後、得られた反応混合物を濃縮し、ついで分取HPLCで精製すると、表題の化合物がTFA塩(29mg,収率:82%;MS m/z 393.04 (M + 1) )として得られた。
4−(6−(4−(トリフルオロメトキシ)フェニルアミノ)−5−メチルピリミジン−4−イル)−N−(2−モルホリノエチル)ベンズアミドの調製
ステップ1:
6−クロロ−5−メチル−N−(4−(トリフルオロメトキシ)フェニル)ピリミジン−4−アミン:
ステップ2:
4−(6−(4−(トリフルオロメトキシ)フェニルアミノ)−5−メチルピリミジン−4−イル)安息香酸:
ステップ3:
4−(6−(4−(トリフルオロメトキシ)フェニルアミノ)−5−メチルピリミジン−4−イル)−N−(2−モルホリノエチル)ベンズアミド:
2(21mg,0.55mmol)、2−アミノエタノール(4.3mg,0.066mmol)及びDIEA(37μL,0.21mmol)を、DMF(1.5ml)に溶解し、5分間攪拌した。26.5mg(0.07mmol)を添加し、得られた反応混合物をさらに室温で6時間攪拌した。質量分析(mass triggered)HPLCで精製すると目的の生成物がTFA塩(22mg、収率:75%;MS m/z 502.23 (M + 1))として得られた。
6−(1H−ピロロ[2,3−b]ピリジン−1−イル)−N−(4−(トリフルオロメトキシ)フェニル)ピリミジン−4−アミンの調製
ステップ1:
6−クロロ−N−(4−(トリフルオロメトキシ)フェニル)ピリミジン−4−アミン:
ステップ2:
6−(1H−ピロロ[2,3−b]ピリジン−1−イル)−N−(4−(トリフルオロメトキシ)フェニル)ピリミジン−4−アミン:
7−アザインドール(18mg,0.15mmol)のsec−BuOH(5mL)溶液に、DIEA(0.20mL)を添加し、そして得られた反応混合物を室温で15分間攪拌した。ついで、6−クロロ−N−(4−(トリフルオロメトキシ)フェニル)ピリミジン−4−アミン(29mg,0.1mmol)を添加し、90℃に加熱し、さらに16時間攪拌を継続した。得られた反応液を濃縮し、ついで分取HPLCで精製すると表題の化合物(15mg,収率:40%;MS m/z 372.10 (M + 1))が得られた。
N−(4−(トリフルオロメトキシ)フェニル)−6−(1,3,5−トリメチル−1H−ピラゾール−4−イル)ピリミジン−4−アミンの調製
6−クロロ−N−(4−(トリフルオロメトキシ)フェニル)ピリミジン−4−アミン中間体(5.2mg,0.17mmol)、1,3,5−トリメチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1H−ピラゾール(40mg,0.17mmol)、Pd(PPh3)4(10mg, 0.085mmol)及び炭酸ナトリウム(73mg,0.69mmol)を、アセトニトリル:水(v/v 1:1;,10ml)に溶解した。得られた混合物を95℃で5時間攪拌した。得られた反応液を濃縮し、ついで直接分取HPLCで精製すると、表題の化合物がTFA塩(65mg、収率:80%)として得られた。
1H NMR 400 MHz (DMSO-d6) δ 10.32 (s, 1H), 8.75 (s, 1H), 8.39 (s, 2H), 7.84 (d, 2H, J = 9.2 Hz), 7.45 (d, 2H, J = 9.2 Hz), 3.84 (s, 3H), 2.89 (s, 3H), 2.24 (s, 3H). MS m/z 364.11 (M + 1)
2−(3−ニトロフェニル)−N−(4−(トリフルオロメトキシ)フェニル)イミダゾ[1,2−c]ピリミジン−7−アミンの調製
ステップ1:
7−クロロ−2−(3−ニトロフェニル)イミダゾ[1,2−c]ピリミジン
ステップ2:
2−(3−ニトロフェニル)−N−(4−(トリフルオロメトキシ)フェニル)イミダゾ[1,2−c]ピリミジン−7−アミン
7−クロロ−2−(3−ニトロフェニル)イミダゾ[1,2−c]ピリミジン(30mg,0.11mmol)及び(58mg,0.32mmol)を120℃で1時間加熱した。
得られた残渣をDMSOに溶解し、ついで直接分取HPLCで精製すると、表題の化合物がTFA塩(8mg、収率:13%)として得られた。
1H NMR 400 MHz (DMSO-d6) δ 10.42 (s, 1H), 8.88 (s, 1H), 8.67 (s, 1H), 8.01-7.99 (m, 3H), 7.92 (d, 2H, J = 9.2 Hz), 7.53 (d, 2H, J = 9.2 Hz), 7.45 (s, 1H), 7.22 (s, 1H). MS m/z 416.12 (M + 1)
細胞培養
インターロイキン−3(IL−3)依存性マウスプロB細胞株であるBa/F3及びマウス骨髄前駆細胞株である32DをL−グルタミン、10%FBS及び10U/ml組換えマウスIL−3(Roche)を補充したRPMI−1640培地で維持した。Mo7eヒト巨核球系細胞株を、L−グルタミン、20%FBS及び5ng/ml組換えヒト顆粒球マクロファージコロニー刺激因子(GM−CSF)(R&D Systems)又は200ng/ml幹細胞因子(SCF)を補充したRPMI−1640培地で発育させた。Flt−3−ITDキナーゼにより変異されたBa/F3細胞のみならず、野生型Bcr−abl発現32D(32D.p210)及びBa/F3(Ba/F3.p210)細胞及びBcr−abl発現突然変異細胞株Ba/F3.p210G250E、Ba/F3.p210E255V、Ba/F3.p210T315I、Ba/F3.p210F317L及びBa/F3.p210M351T更なるアッセイには、融合タンパク質キナーゼを発現するBa/F3細胞TEL−PDGFRβ TEL−JAK1、NPM−ALK、TEL−cKit、Tel−Bmx、Tel−FGR3、Tel−Lck及びBa/F3.TPR−met cellsを使用した。全ての前記の細胞株は、L−グルタミン、10%FBS及び1mg/ml ジェネテシン(Gibco)を含むRPMI−1640倍地で維持した。ヒト白血病性細胞株K562(p210 Bcr−abl発現慢性骨髄性白血病)、HL−60(急性前骨髄球性白血病)、SUP/B15(p190Bcr−abl発現急性リンパ芽球性白血病)及びJurkat(急性T細胞白血病)は、アメリカ合衆国培養細胞系統保存機関(ATCC)から購入し、ATCCの推奨に従い培養した。
薬物濃度(0.005−10μM)を増加させた96−ウエルプレートに、二重又は三重に細胞(0.3−0.6×106/ml)を播種した。5%CO2雰囲気下37℃で48時間インキュベート後、前記の化合物の前記の細胞の成育への効果をMTT(Promega)比色染料脱色法により測定した。細胞の増殖の阻害は、DMSOで処理された細胞の成育のパーセントとして算定し、そしてIC50値をMicrosoft Excel XLfit3により算定した。
異なる濃度の化合物を含む培地で24時間か又は48時間生育させた細胞を遠心分離(10分間,4°C)で集め、PBSで2回洗浄し、そして−20℃で70%エタノールにより固定した。固定化後、遠心分離(10分間,4°C)でエタノールを除き、得られた細胞を1mM EDTA及び100μg/ml RNAse A(Sigma)を含むPBSに懸濁し、ついで37°Cで30分間インキュベートした。細胞をヨウ化プロピジウム(10μg/ml)により染色し、ついでフローサイトメトリー(FACScan, Becton Dickinson)によりDNA含量を決定した。
Bcr−ablの全の細胞チロシンのリン酸化レベルを、最初にcapture ELISAを使用して決定した。異なる濃度の試験化合物により90分間処理されたBcr−abl発現細胞を、溶解バッファー(50 mM Tris.HCl pH7.4、150 mM NaCl、5 mM EDTA、1 mM EGTA、1% NP−40, 2 mM Na3VO4及びprotease inhibitor cocktail(Roche))中でホモゲナイズし、ついで得られた溶解産物を、吸着された抗Abl SH3ドメインポリクローナル抗体(Upstate Biotechnology)を含む96ウェルプレートに播種した。そのプレートを4℃で4時間インキュベートし、ついでPBS/0.05% Tween 20バッファーで洗浄した。ホスホチロシン残基を検出するために、アルカリホスファターゼを結合したモノクローナル抗ホスホチロシン抗体を各ウェルに添加し、そのプレートを4℃で一夜インキュベートした。ついでそのウェルをPBS/0.05% Tween 20バッファーで洗浄し、Emerald−II(登録商標) enhancer substrate (Applied Biosystems)を有するCDP−Star(登録商標) Substrateの100μl/ウェルを添加した。45分間後、GeminiXS microplate reader (Molecular Devices)により発光量を定量した。Bcr−ablホスホチロシン含量を、非処理の細胞のホスホチロシンのパーセントとして算定し、そしてIC50値はMicrosoft Excel XLfit3により決定した。薬剤による処理後における細胞のBcr−ablのチロシンのリン酸化及びその基質であるStat5の状態は、リンに特異的な抗体を使用するウエスタンブロッティング法により決定された。Ba/F3.p210及びBa/F3.p210E255V細胞を様々な濃度のGNF−2の存在下で1.5時間インキュベート後、溶解バッファー(20mM Tris−HCl (pH7.5)、150 mM NaCl、1 mM Na2EDTA、1 mM EGTA、1% Triton、2.5 mMニリン酸ナトリウム、1 mMベータ−グリセロリン酸、1 mM Na3VO4、1 μg/mlロイペプチンl、1 mM PMSF)中で溶解させた。等量の溶解産物(50μg)をSDS−PAGEにかけ、ついでBcr−ablのリン酸化サイトを認知できるリンに特異的な抗体、すなわち、anti−phospho−c−Abl (Tyr 245)及びanti−phospho−Stat5 (Tyr 694) (Cell signaling) 抗体又はBcr−ablに対する抗体 (Ab−3, Oncogene Science)及びStat5 (C−17, Santa Cruz Biotechnology)による免疫ブロッテイング法を行なった。タンパク質を、改良された化学発光分析法(ECL−plus, Amersham)により製造者の使用手順書に従い、検出した。
前記のようにBac−to−Bac baculovirus expression system (Invitrogen)を使用して、Sf9昆虫細胞においてHis6 tag融合タンパク質として組換えc−abl(残基46−531)を発現させた。簡潔に言えば、感染させた細胞を48時間発育させ、遠心分離により採取し、溶解バッファー(50mM Tris pH 8.0、300mM NaCl、5%グリセロール、10mM 2−メルカプトエタノール及びprotease inhibitor cocktail (Roche))に懸濁させ、ついで超音波処理により溶解させた。遠心分離後、得られた細胞抽出物をNi−NTA affinity columnにかけ、ついでAblを250mMイミダゾールにより溶出させた。Ablを含むフラクションを集め、ついで透析によりイミダゾールの濃度を20 mMまで低下させた。得られたタンパク質をCiPアルカリホスファターゼ(Invitrogen)により処理し、ついでsecond Ni affinity chromatographyにより精製した。前記のHis6 tagをTEV protease (Invitrogen)による処理により除き、ついでSDS−PAGE及びcoomassie blue stainingによりNi−NTA columnから回収された前記のタンパク質は〜90%の純度であった。
In vitroにおけるキナーゼアッセイを、SH3、SH2及びキナーゼドメイン(残基46−531)及び全長免疫沈降Bcr−ablを含む組換えネズミc−ablを使用して実施した。組換えablをSf9昆虫細胞に発現させ、前記の方法で精製した。前記のBa/F3.p210溶解産物からBcr−abl免疫複合体を、Ab−3抗−abl モノクローナル抗体(Oncogene Science)により得た。1μgの組換えabl又は免疫沈降されたBcr−abl(3×106細胞を使用)を、様々な濃度の試験化合物(0.1、1及び10μM)と共にキナーゼバッファー(50mM Tris−HCl pH7.5、10mM MgCl2、100mM EDTA、1mM DTT、0.015% Brij 35)、100μM ATP及び1μCi [γ−32P]−ATP中30℃で30分間インキュベートした(Calbiochem buffer and protocol)。
前記の反応をLaemmli bufferを加えて止め、ついで前記のタンパク質を、4−20%ゲルのSDS−PAGEにより分析した。
前記のリン酸化されたタンパク質を放射能写真撮影法により可視化し、ついでphosphoimager (STORM, Molecular Devices)により前記の自己リン酸化を定量した。その結果は、以下の表に示した。
本明細書において引用されたすべての参照文献は、印刷体、電子フォーム、コンピュータ可読媒体又はその他の形態であろうとそれらのすべての内容が引用により明確に援用されている。前記の参照文献としては、要約、記事、ジャーナル、出版物、教科書、専門書、技術データシート、インターネットウエブサイト、データベース、特許、特許出願及び特許出版物が挙げられるが、これらに限定されるものではない。
当業者ならば、確立された実験程度で本明細書に開示された本発明の具体的な態様を認知するであろうし、又は確認できるであろう。前記の均等物は、以下のクレームに包含されていることを意図されている。
Claims (34)
- 式(I):
(式中、
X1がNR1又はSであり;
X2がN又はCHであり;
X3がN又はCHであり;そして
各R1が
H;
OH、NR15R16、ハロゲン、又はCNから選択される一つ以上の置換基で任意に置換されたC1−6アルキル;
3乃至8員環の単環式シクロアルキル;
(CH2)nヘテロシクロアルキル(式中、前記ヘテロシクロアルキルはO又はNから選択される1乃至2個のヘテロ原子を含有すると共に、OH又はR17から独立に選択される1個以上の置換基で任意に置換される3乃至8員環の単環式環である);
SO 2 NR 15 R 16 で置換されたフェニル;
2,3−ジメチル−フェニル;
2−フルオロ−フェニル;
2,4−ジクロロ−フェニル;
2−エチル−フェニル;
(CH2)アリール(式中、前記アリールは、ハロゲン、OR15、又はC1−C2ペルフルオロアルキルから独立に選択される一個以上の置換基で任意に置換されたフェニルである);
(CH 2 ) 2 フェニル;
(CH2)nヘテロアリール(式中、前記ヘテロアリールは、一個のC 1 −C 2 ペルフルオロアルキルで任意に置換されたピリジニル、あるいはNである一個のヘテロ原子を含有すると共に、一個以上の=Oで任意に置換された、8乃至12員環の二環式環である);
(CH2)nC(O)NRxRx;又は
S(O)2Rx;
から独立に選択され;あるいは
X1がNであり;
X2がCHであり;
X3がNR1であり;そして
R1がC1−6アルキルであり;
但し式中、Rxが存在する場合に独立して
H;又は
モルホリニル又はOR15で任意に置換されたC1−6アルキルであり、
R15がH又はC1−6アルキルであり;
R16がH又はC1−4アルキルであり;
R17がOH又はC1−4アルコキシで任意に置換されたC1−4アルキルであり;
YがHであり;
mが1であり;そして
各nは独立に0、1又は2であり、
但し、式(I)の化合物は、
3−メチル−N−[4−(トリフルオロメトキシ)フェニル]−3H−1,2,3−トリアゾロ[4,5−d]ピリミジン−7−アミン、
3−エチル−N−[4−(トリフルオロメトキシ)フェニル]−3H−1,2,3−トリアゾロ[4,5−d]ピリミジン−7−アミン、
1−メチル−N−[4−(トリフルオロメトキシ)フェニル]−1H−ピラゾロ[3,4−d]ピリミジン−4−アミン、及び
N−[4−(トリフルオロメトキシ)フェニル]−9H−プリン−6−アミンではない)で表される化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物。 - 式(II):
(但し式中、R1はH;OH、NR15R16、ハロゲン、又はCNから選択される1個以上の置換基で任意に置換されたC1−6アルキル;3乃至8員環の単環式シクロアルキル;
式:(CH2)ヘテロシクロアルキルで表される基(式中、ヘテロシクロアルキルが一個のO原子を含有する3乃至8員環の単環式環である);
SO 2 NR 15 R 16 で置換されたフェニル;
2,3−ジメチル−フェニル;
2−フルオロ−フェニル;
2,4−ジクロロ−フェニル;
2−エチル−フェニル;
式:(CH2)nアリールで表される基(式中、アリールが、ハロゲン、OR15、又はC1−C2ペルフルオロアルキルから独立して選択される一個以上の置換基で任意に置換されたフェニルである);
(CH 2 ) 2 フェニル;
式:(CH2)nヘテロアリールで表される基(式中、ヘテロアリールが、一個のC 1 −C 2 ペルフルオロアルキルで任意に置換されたピリジル、あるいは、Nである一個のヘテロ原子を含有すると共に、一個以上の=Oで任意に置換された8乃至12員環の二環式環である);
式:(CH2)nC(O)NRxRxで表される基;
式:S(O)2Rxで表される基;であり;そして
Rxが存在する場合に独立して、H又はC1−6アルキルである)で表される請求項1に記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物。 - 2−(4−(4−(トリフルオロメトキシ)フェニルアミノ)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)エタノール;(1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;(1−エチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;(1−エタンスルホニル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;(1−シクロヘキシル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−1−イル]−アセトアミド;3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−1−イル]−プロピオンアミド;[1−(テトラヒドロ−フラン−3−イルメチル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシフェニル)−アミン;3−ジメチルアミノ−2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−1−イル]プロピオンニトリル;(1−ブチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;(1−tert−ブチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;[1−(2,2,2−トリフルオロ−エチル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン;(1−ベンジル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;(1−フェネチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;[1−(3−フルオロ−4−トリフルオロメチル−ベンジル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン;[1−(3−ブロモ−ベンジル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン;3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−1−イルメチル]−フェノール;(1−ピリジン−3−イルメチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;(1−ピリジン−2−イルメチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;(1−ピリジン−4−イルメチル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;2−{2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−l−イル]−エチル}−イソインドール−1,3−ジオン;[1−(2−アミノ−エチル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン;(4−トリフルオロメトキシ−フェニル)−[1−(4−トリフルオロメチル−ピリジン−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−アミン;[1−(2,3−ジメチル−フェニル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン;[1−(2−フルオロ−フェニル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン;
[1−(2,4−ジクロロ−フェニル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン;[1−(2−エチル−フェニル)−1H−ピラゾロ[3,4−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン;
(1−ピリジン−2−イル−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピラゾロ[3,4−d]ピリミジン−1−イル]ベンゼンスルホンアミド;から選択される、請求項2に記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物。 - X1がNR1であり;X2がCHであり;X3がNであり;そしてR1が独立してC1−6アルキル;又は式:(CH2)nヘテロシクロアルキルで表される基(式中、ヘテロシクロアルキルが、O又はNから選択される1乃至2個のヘテロ原子を含有すると共に、OH又はR17から独立に選択される一個以上の置換基で任意に置換される3乃至8員環の単環式環である);から選択され、あるいはX1がNであり;X2がCHであり;X3がNR1であり;そしてR1がC1−6アルキルである;
請求項1に記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物。 - (9−メチル−9H−プリン−6−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;
(7−メチル−7H−プリン−6−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;
2−ヒドロキシメチル−5−[6−(4−トリフルオロメトキシ−フェニルアミノ)−プリン−9−イル]−テトラヒドロ−フラン−3,4−ジオール;及び
[9−(2−モルホリン−4−イル−エチル)−9H−プリン−6−イル]−(4−トリフルオロメトキシ−フェニル)−アミン、
から選択される、請求項4に記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物。 - 式(V):
(但し式中、R1がHであり;
R1’が
H;
一個のOHで任意に置換されたC1−6アルキル;
式:(CH2)nヘテロシクロアルキルで表される基(式中、ヘテロシクロアルキルが、O又はNから選択される1乃至2個のヘテロ原子を含有すると共に、OH又はR17から独立に選択される1個以上の置換基で任意に置換された3乃至8員環の単環式環である);
式:(CH2)nアリールで表される基(式中、アリールがOR15で任意に置換されたフェニルである);又は
式:(CH2)nC(O)NRyRyで表される基から選択され;及び
Ryが存在する場合に独立して、
H;又は
OR15又はモルホリニルで任意に置換されたC1−6アルキルであり;
R 15 がH又はC 1−6 アルキルであり;
R 17 がOH又はC 1−4 アルコキシで任意に置換されたC 1−4 アルキルであり;そして
各nは独立に0、1又は2である)
で表される、請求項1に記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物。 - N−(2−モルホリン−4−イル−エチル)−3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド;
2−ヒドロキシメチル−5−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−テトラヒドロ−フラン−3,4−ジオール;
(7H−ピロロ[2,3−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;
(7−メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−(4−トリフルオロメトキシ−フェニル)−アミン;
2−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−エタノール;
[7−(2−モルホリン−4−イル−エチル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン;
[7−(4−メトキシ−ベンジル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]−(4−トリフルオロメトキシ−フェニル)−アミン;
3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド;
N−エチル−3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド;
N−(3−メトキシ−プロピル)−3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド;
N−(1−ヒドロキシ−4−メチル−ペント−3−イル)−3−[4−(4−トリフルオロメトキシ−フェニルアミノ)−ピロロ[2,3−d]ピリミジン−7−イル]−プロピオンアミド、
から選択される請求項6に記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物。 - 式(VI):
(但し式中、R1がHである)
で表される、請求項1に記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物。 - チエノ[2,3−d]ピリミジン−4−イル−(4−トリフルオロメトキシ−フェニル)−アミンである請求項8に記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物。
- 対象のキナーゼ活性障害を処置するための医薬の製造における、請求項1乃至9のいずれかに記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物の使用。
- 前記医薬がキナーゼ阻害剤である、請求項10に記載の使用。
- 前記医薬がBcr−ablと相互作用する、請求項11に記載の使用。
- 前記医薬がBcr−ablの結合部位を標的とする、請求項12に記載の使用。
- 前記対象が、キナーゼを阻害する必要があると特定された対象である、請求項11に記載の使用。
- 前記対象が、キナーゼ活性関連障害であると特定された対象である、請求項10に記載の使用。
- 前記医薬が、細胞増殖性障害又は疾患を処置するための医薬である、請求項10に記載の使用。
- 前記障害又は疾患が、癌、腫瘍、新生物、血管新生、血管化、心臓血管疾患、転移、感染、血餅、アテローム性硬化症、黒色腫、皮膚障害、リウマチ様関節炎、糖尿病性網膜症、黄斑性浮腫及び黄斑性変性、炎症性及び関節炎性疾患、又は骨肉腫である、請求項16に記載の使用。
- 前記障害が、固形癌又は播種性癌である、請求項17に記載の使用。
- 前記癌が、白血病、多発性骨髄腫又はリンパ腫である、請求項18に記載の使用。
- 前記白血病が、慢性骨髄性白血病である、請求項19に記載の使用。
- 対象の癌を処置するための医薬の製造における、請求項1乃至9のいずれかに記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物の使用。
- 前記医薬が付加的な治療薬を更に含む、請求項10又は請求項21に記載の使用。
- 前記付加的な治療薬がATP部位阻害剤である、請求項22に記載の使用。
- 前記ATP部位阻害剤がイマチニブ、ニロチニブ、ダサチニブ、AP23464、AZD0530、及びSKI−606から選択される、請求項23に記載の使用。
- 前記対象が哺乳動物である、請求項10又は請求項21に記載の使用。
- 前記対象が霊長類又はヒトである、請求項25に記載の使用。
- 前記医薬が経口、局所、非経口、静脈内又は筋肉内投与用である、請求項10又は請求項21に記載の使用。
- 前記医薬が薬学的に適した医薬品添加物を含む、請求項27に記載の使用。
- 前記医薬が、0.01μg/kg/日乃至100mg/kg/日の投薬量の前記化合物を含む医薬である、請求項10又は請求項21に記載の使用。
- 請求項1乃至9のいずれかに記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物を有効成分とする対象のキナーゼ活性阻害剤。
- 請求項1乃至9のいずれかに記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物を含む医薬組成物。
- 付加的な治療薬を更に含む、請求項31に記載の組成物。
- 前記付加的な治療薬がATP部位阻害剤である、請求項32に記載の組成物。
- 細胞増殖性障害に罹患した又は易罹患性の対象に前記化合物を投与するための指示書と一緒に、単位剤形の請求項1乃至9のいずれかに記載の化合物、若しくはその薬学的に許容可能な塩、それらの溶媒和物、又はそれらの水和物を有効量含む医薬を含むキット。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US446207P | 2007-11-28 | 2007-11-28 | |
US61/004,462 | 2007-11-28 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010536015A Division JP5779778B2 (ja) | 2007-11-28 | 2008-11-28 | Bcr−ablの低分子のミリスチン酸エステル阻害剤及びその使用方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2015051977A JP2015051977A (ja) | 2015-03-19 |
JP5941513B2 true JP5941513B2 (ja) | 2016-06-29 |
Family
ID=40718412
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010536015A Active JP5779778B2 (ja) | 2007-11-28 | 2008-11-28 | Bcr−ablの低分子のミリスチン酸エステル阻害剤及びその使用方法 |
JP2014204682A Active JP5941513B2 (ja) | 2007-11-28 | 2014-10-03 | Bcr−ablの低分子のミリスチン酸エステル阻害剤及びその使用方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010536015A Active JP5779778B2 (ja) | 2007-11-28 | 2008-11-28 | Bcr−ablの低分子のミリスチン酸エステル阻害剤及びその使用方法 |
Country Status (12)
Country | Link |
---|---|
US (7) | US8921336B2 (ja) |
EP (4) | EP3150593B8 (ja) |
JP (2) | JP5779778B2 (ja) |
KR (1) | KR20100130583A (ja) |
CN (3) | CN101917849B (ja) |
AU (1) | AU2008331867B2 (ja) |
BR (1) | BRPI0819453A2 (ja) |
CA (1) | CA2707046A1 (ja) |
EA (1) | EA019869B1 (ja) |
ES (3) | ES2893580T3 (ja) |
MX (3) | MX2010005671A (ja) |
WO (1) | WO2009073153A2 (ja) |
Families Citing this family (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA019869B1 (ru) * | 2007-11-28 | 2014-06-30 | Дана Фарбер Кансер Инститьют, Инк. | Низкомолекулярные миристатные ингибиторы тирозинкиназы bcr-abl и способы их применения |
LT2300013T (lt) | 2008-05-21 | 2017-12-27 | Ariad Pharmaceuticals, Inc. | Fosforo dariniai kaip kinazių inhibitoriai |
US9273077B2 (en) | 2008-05-21 | 2016-03-01 | Ariad Pharmaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
BRPI0914404A2 (pt) | 2008-10-31 | 2019-03-06 | Genentech Inc | "compostos, composição farmacêutica e método para tratar ou atenuar a gravidade de uma doença ou condição responsiva à inibição da atividade jak quinase em um paciente" |
UA110324C2 (en) | 2009-07-02 | 2015-12-25 | Genentech Inc | Jak inhibitory compounds based on pyrazolo pyrimidine |
TW201111385A (en) * | 2009-08-27 | 2011-04-01 | Biocryst Pharm Inc | Heterocyclic compounds as janus kinase inhibitors |
MX2012009735A (es) * | 2010-02-26 | 2012-09-12 | Boehringer Ingelheim Int | 4-[cicloalquiloxi (hetero) arilamino] tieno [2,3-d] pirimidinas que tienen actividad inhibitoria de mnk1/mnk2 para composiciones farmaceuticas. |
AR080328A1 (es) * | 2010-02-26 | 2012-03-28 | Boehringer Ingelheim Int | Tienopirimidinas que contienen un grupo alquilo sustituido inhibidoras de quinasas mnk1 y/o mnk2, composiciones farmaceuticas que las contienen y uso de las mismas para el tratamiento de trastornos metabolicos tales como diabetes y obesidad, y trastornos hiperproliferativos, entre otros |
UY33241A (es) * | 2010-02-26 | 2011-09-30 | Boehringer Ingelheim Int | ?Tienopirimidinas que contienen heterocicloalquilo para composiciones farmacéuticas?. |
JP5607241B2 (ja) | 2010-05-21 | 2014-10-15 | ケミリア・エービー | 新規ピリミジン誘導体 |
WO2012035039A1 (en) | 2010-09-15 | 2012-03-22 | F. Hoffmann-La Roche Ag | Azabenzothiazole compounds, compositions and methods of use |
CN103313987A (zh) * | 2010-11-19 | 2013-09-18 | 弗·哈夫曼-拉罗切有限公司 | 吡唑并吡啶化合物、吡唑并吡啶化合物以及它们作为tyk2抑制剂的用途 |
WO2012088266A2 (en) | 2010-12-22 | 2012-06-28 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3 |
AU2012230229A1 (en) | 2011-03-24 | 2013-10-10 | Noviga Research Ab | Novel pyrimidine derivatives |
CN103501612B (zh) | 2011-05-04 | 2017-03-29 | 阿里亚德医药股份有限公司 | 抑制表皮生长因子受体导致的癌症中细胞增殖的化合物 |
EP2548878A1 (en) * | 2011-07-21 | 2013-01-23 | Laboratorios Del. Dr. Esteve, S.A. | Pyrazolo[3,4-d]pyrimidine compounds, their preparation and use as sigma ligands |
ES2567552T3 (es) * | 2012-01-30 | 2016-04-25 | Cephalon, Inc. | Imidazo [4,5-b] derivados de piridina como los moduladores ALK y JAK para el tratamiento de trastornos proliferativos |
WO2013169401A1 (en) | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
PT3495367T (pt) | 2012-06-13 | 2020-11-12 | Incyte Holdings Corp | Compostos tricíclicos substituídos como inibidores de fgfr |
CN102746308B (zh) * | 2012-07-09 | 2014-12-31 | 四川大学 | 别嘌醇衍生物及其制备方法和用途 |
CN102746306B (zh) * | 2012-07-09 | 2014-11-19 | 四川国康药业有限公司 | 别嘌醇类衍生物及其制备方法和用途 |
WO2014026125A1 (en) | 2012-08-10 | 2014-02-13 | Incyte Corporation | Pyrazine derivatives as fgfr inhibitors |
US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
US10150742B2 (en) * | 2013-03-15 | 2018-12-11 | President And Fellows Of Harvard College | Substituted heterocyclic compounds for treating or preventing viral infections |
US9611283B1 (en) | 2013-04-10 | 2017-04-04 | Ariad Pharmaceuticals, Inc. | Methods for inhibiting cell proliferation in ALK-driven cancers |
TWI715901B (zh) | 2013-04-19 | 2021-01-11 | 美商英塞特控股公司 | 作為fgfr抑制劑之雙環雜環 |
MX2016015062A (es) | 2014-05-23 | 2017-02-27 | Hoffmann La Roche | Compuestos de 5-cloro-2-difluorometoxifenil pirazolopirimidina los cuales son inhibidores de janus cinasas (jak). |
EP3171874B1 (en) * | 2014-07-21 | 2020-11-18 | Dana-Farber Cancer Institute, Inc. | Imidazolyl kinase inhibitors and uses thereof |
DK3172213T3 (da) | 2014-07-21 | 2021-12-13 | Dana Farber Cancer Inst Inc | Makrocykliske kinasehæmmere og anvendelser deraf |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
WO2016134294A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr4 inhibitors |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
CN113004278B (zh) | 2015-02-20 | 2023-07-21 | 因赛特控股公司 | 作为fgfr抑制剂的双环杂环 |
WO2016173557A1 (zh) * | 2015-04-30 | 2016-11-03 | 中国科学院上海药物研究所 | 一类具有激酶抑制活性的化合物、制备方法和用途 |
CN105561040A (zh) * | 2016-02-24 | 2016-05-11 | 梁功 | 一种治疗偏瘫的中药组合物 |
CN105777657A (zh) * | 2016-03-01 | 2016-07-20 | 张宏业 | 一种治疗偏瘫的药物组合物 |
US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
CN110225914A (zh) | 2016-07-05 | 2019-09-10 | 布罗德研究所股份有限公司 | 双环脲激酶抑制剂及其用途 |
WO2018053373A1 (en) | 2016-09-16 | 2018-03-22 | The General Hospital Corporation | Uses of satl-inducible kinase (sik) inhibitors for treating osteoporosis |
AU2017363257B2 (en) * | 2016-11-22 | 2021-08-19 | Dana-Farber Cancer Institute, Inc. | Degradation of protein kinases by conjugation of protein kinase inhibitors with E3 ligase ligand and methods of use |
JP7296318B2 (ja) | 2017-02-28 | 2023-06-22 | ザ ジェネラル ホスピタル コーポレイション | Sikインヒビターとしてのピリミドピリミジノンの使用 |
CR20190520A (es) | 2017-05-22 | 2020-01-21 | Hoffmann La Roche | Composiciones y compuestos terapéuticos y métodos para utilizarlos |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
WO2019213544A2 (en) | 2018-05-04 | 2019-11-07 | Incyte Corporation | Solid forms of an fgfr inhibitor and processes for preparing the same |
CR20200591A (es) | 2018-05-04 | 2021-03-31 | Incyte Corp | Sales de un inhibidor de fgfr |
AU2019291099A1 (en) * | 2018-06-21 | 2021-01-07 | Janssen Pharmaceutica Nv | Oga inhibitor compounds |
CN113302175A (zh) | 2018-11-09 | 2021-08-24 | 维瓦斯治疗公司 | 双环化合物 |
WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
WO2020214734A1 (en) | 2019-04-16 | 2020-10-22 | Vivace Therapeutics, Inc. | Bicyclic compounds |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
TW202128685A (zh) | 2019-10-14 | 2021-08-01 | 美商英塞特公司 | 作為fgfr抑制劑之雙環雜環 |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
EP4069696A1 (en) | 2019-12-04 | 2022-10-12 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
CA3162010A1 (en) | 2019-12-04 | 2021-06-10 | Incyte Corporation | Derivatives of an fgfr inhibitor |
US12012409B2 (en) | 2020-01-15 | 2024-06-18 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US20240025913A1 (en) * | 2020-10-21 | 2024-01-25 | Vivace Therapeutics, Inc. | Tertiary carboxamide compounds |
EP4351574A1 (en) * | 2021-06-07 | 2024-04-17 | The General Hospital Corporation | Inhibitors of ttbk1 |
CA3220274A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL112249A (en) * | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
WO1998012184A1 (fr) * | 1996-09-19 | 1998-03-26 | Nippon Soda Co., Ltd. | Composes de pyrimidine, procede de preparation correspondant et agents de lutte antiparasitaire |
KR20000057228A (ko) * | 1996-11-27 | 2000-09-15 | 디. 제이. 우드, 스피겔 알렌 제이 | 축합된 비사이클릭 피리미딘 유도체 |
HUP0100287A3 (en) * | 1997-11-11 | 2003-04-28 | Pfizer Prod Inc | Thienopyrimidine and thienopyridine derivatives useful as anticancer agents |
EA005852B1 (ru) * | 1998-06-19 | 2005-06-30 | Пфайзер Продактс Инк. | ПИРРОЛО[2,3-d]ПИРИМИДИНЫ |
US6258820B1 (en) * | 1999-03-19 | 2001-07-10 | Parker Hughes Institute | Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines |
ES2225577T3 (es) | 2000-07-06 | 2005-03-16 | Alcan International Limited | Metodo para fabricar una hoja de aluminio para aletas. |
AU2002228922A1 (en) * | 2000-12-12 | 2002-06-24 | Cytovia, Inc. | Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators of caspases and inducers of apoptosis and the use thereof |
CZ294535B6 (cs) * | 2001-08-02 | 2005-01-12 | Ústav Experimentální Botaniky Avčr | Heterocyklické sloučeniny na bázi N6-substituovaného adeninu, způsoby jejich přípravy, jejich použití pro přípravu léčiv, kosmetických přípravků a růstových regulátorů, farmaceutické přípravky, kosmetické přípravky a růstové regulátory tyto sloučeniny obsahující |
CA2463563A1 (en) * | 2001-10-12 | 2003-04-17 | Irm Llc | Kinase inhibitor scaffolds and methods for their preparation |
MXPA04006882A (es) | 2002-01-17 | 2004-12-06 | Neurogen Corp | Analogos substituidos de quinazolin-4-ilamina como moduladores de receptores de capsaicina. |
TW200400034A (en) * | 2002-05-20 | 2004-01-01 | Bristol Myers Squibb Co | Pyrazolo-pyrimidine aniline compounds useful as kinase inhibitors |
AU2003299750A1 (en) * | 2002-12-20 | 2004-07-22 | Irm Llc | Differential tumor cytotoxocity compounds and compositions |
CN1798734A (zh) * | 2003-04-04 | 2006-07-05 | Irm责任有限公司 | 作为蛋白激酶抑制剂的新化合物和组合物 |
US20050014753A1 (en) * | 2003-04-04 | 2005-01-20 | Irm Llc | Novel compounds and compositions as protein kinase inhibitors |
EP1651648A4 (en) * | 2003-07-29 | 2009-09-02 | Irm Llc | COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS |
US7338957B2 (en) * | 2003-08-28 | 2008-03-04 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
GB0326168D0 (en) * | 2003-11-10 | 2003-12-17 | Arrow Therapeutics Ltd | Chemical compounds |
CA2581454A1 (en) * | 2004-09-23 | 2006-03-30 | Reddy Us Therapeutics, Inc. | Novel pyrimidine compounds, process for their preparation and compositions containing them |
US20070009977A1 (en) | 2005-01-12 | 2007-01-11 | Boyce James P | Kinase-directed, activity-based probes |
WO2006124874A2 (en) * | 2005-05-12 | 2006-11-23 | Kalypsys, Inc. | Inhibitors of b-raf kinase |
CA2655799A1 (en) * | 2005-06-22 | 2006-12-28 | Develogen Aktiengesellschaft | Thienopyrimidines for pharmaceutical compositions |
US20080004253A1 (en) * | 2006-06-30 | 2008-01-03 | Bryan James Branstetter | Thiazolopyrimidine modulators of TRPV1 |
EA019869B1 (ru) * | 2007-11-28 | 2014-06-30 | Дана Фарбер Кансер Инститьют, Инк. | Низкомолекулярные миристатные ингибиторы тирозинкиназы bcr-abl и способы их применения |
-
2008
- 2008-11-28 EA EA201070595A patent/EA019869B1/ru not_active IP Right Cessation
- 2008-11-28 US US12/745,496 patent/US8921336B2/en active Active
- 2008-11-28 JP JP2010536015A patent/JP5779778B2/ja active Active
- 2008-11-28 ES ES19170210T patent/ES2893580T3/es active Active
- 2008-11-28 AU AU2008331867A patent/AU2008331867B2/en not_active Ceased
- 2008-11-28 CN CN200880123462.5A patent/CN101917849B/zh active Active
- 2008-11-28 CA CA2707046A patent/CA2707046A1/en not_active Abandoned
- 2008-11-28 EP EP16197611.3A patent/EP3150593B8/en active Active
- 2008-11-28 EP EP08857261.5A patent/EP2222162B1/en active Active
- 2008-11-28 WO PCT/US2008/013219 patent/WO2009073153A2/en active Application Filing
- 2008-11-28 BR BRPI0819453-0A2A patent/BRPI0819453A2/pt not_active IP Right Cessation
- 2008-11-28 EP EP19170210.9A patent/EP3536687B8/en active Active
- 2008-11-28 KR KR1020107013953A patent/KR20100130583A/ko not_active Application Discontinuation
- 2008-11-28 EP EP21184206.7A patent/EP3912973A3/en active Pending
- 2008-11-28 MX MX2010005671A patent/MX2010005671A/es active IP Right Grant
- 2008-11-28 ES ES16197611T patent/ES2734288T3/es active Active
- 2008-11-28 ES ES08857261.5T patent/ES2610190T3/es active Active
- 2008-11-28 CN CN201410497500.0A patent/CN104311563B/zh active Active
- 2008-11-28 CN CN201410497692.5A patent/CN104327084B/zh active Active
-
2012
- 2012-03-16 MX MX2012003309A patent/MX2012003309A/es not_active Application Discontinuation
- 2012-03-16 MX MX2012003311A patent/MX2012003311A/es not_active Application Discontinuation
-
2014
- 2014-10-03 JP JP2014204682A patent/JP5941513B2/ja active Active
- 2014-11-13 US US14/540,919 patent/US9670214B2/en active Active
-
2017
- 2017-04-28 US US15/582,004 patent/US20170349595A1/en not_active Abandoned
-
2018
- 2018-10-25 US US16/170,921 patent/US10787455B2/en active Active
-
2020
- 2020-07-20 US US16/933,095 patent/US11254682B2/en active Active
-
2022
- 2022-01-12 US US17/574,132 patent/US11932646B2/en active Active
-
2024
- 2024-01-24 US US18/421,738 patent/US20240158403A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5941513B2 (ja) | Bcr−ablの低分子のミリスチン酸エステル阻害剤及びその使用方法 | |
CA2740792C (en) | Pyrazolopyrimidine jak inhibitor compounds and methods | |
US7390805B2 (en) | 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives | |
CN103781780B (zh) | 作为jak抑制剂的杂环基嘧啶类似物 | |
TW201632530A (zh) | Erk抑制劑 | |
JP2012504157A (ja) | 複素環式jakキナーゼ阻害剤 | |
CN111153891B (zh) | 一种取代苯并咪唑类PI3Kα/mTOR双靶点抑制剂及其药物组合物和应用 | |
US7323469B2 (en) | 7H-pyrrolo[2,3-d]pyrimidine derivatives | |
AU2014215991A1 (en) | Small molecule myristate inhibitors of bcr-abl and methods of use | |
KR20220090443A (ko) | 헤테로아릴 유도체 화합물 및 이의 용도 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150811 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20151105 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20151111 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20151105 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20160510 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20160520 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5941513 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |