EP1351691A1 - 2-aryl-4-arylaminopyrimidines substituees et analogues en tant qu'activateurs de caspases et qu'inducteurs d'apoptose, et utilisation associee - Google Patents
2-aryl-4-arylaminopyrimidines substituees et analogues en tant qu'activateurs de caspases et qu'inducteurs d'apoptose, et utilisation associeeInfo
- Publication number
- EP1351691A1 EP1351691A1 EP01990048A EP01990048A EP1351691A1 EP 1351691 A1 EP1351691 A1 EP 1351691A1 EP 01990048 A EP01990048 A EP 01990048A EP 01990048 A EP01990048 A EP 01990048A EP 1351691 A1 EP1351691 A1 EP 1351691A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pyrimidine
- pyridinyl
- trifluoromethyl
- methyl
- chloro
- 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.)
- Withdrawn
Links
- 230000006907 apoptotic process Effects 0.000 title claims abstract description 58
- 108010076667 Caspases Proteins 0.000 title claims abstract description 41
- 102000011727 Caspases Human genes 0.000 title claims abstract description 41
- 239000000411 inducer Substances 0.000 title claims abstract description 27
- 239000012190 activator Substances 0.000 title claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 348
- 230000030833 cell death Effects 0.000 claims abstract description 11
- 230000002159 abnormal effect Effects 0.000 claims abstract description 7
- 230000004222 uncontrolled growth Effects 0.000 claims abstract description 3
- -1 carbocycloalkyl Chemical group 0.000 claims description 109
- 238000000034 method Methods 0.000 claims description 57
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 206010028980 Neoplasm Diseases 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 238000011282 treatment Methods 0.000 claims description 25
- 239000002246 antineoplastic agent Substances 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 229940002612 prodrug Drugs 0.000 claims description 21
- 239000000651 prodrug Substances 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 241001465754 Metazoa Species 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 208000035475 disorder Diseases 0.000 claims description 17
- BQDJLAWUTBCDHK-UHFFFAOYSA-N 2-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=NC=CC=N1 BQDJLAWUTBCDHK-UHFFFAOYSA-N 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 16
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000004423 acyloxy group Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- IZWJTHWVHVLINE-UHFFFAOYSA-N 4-methyl-3-n-[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]benzene-1,3-diamine Chemical compound CC1=CC=C(N)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=CN=CC=2)=N1 IZWJTHWVHVLINE-UHFFFAOYSA-N 0.000 claims description 12
- 208000026310 Breast neoplasm Diseases 0.000 claims description 12
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 12
- JVPNEEDSHIJUSR-UHFFFAOYSA-N n-(3-methoxyphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 JVPNEEDSHIJUSR-UHFFFAOYSA-N 0.000 claims description 12
- 206010006187 Breast cancer Diseases 0.000 claims description 11
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 11
- 125000002837 carbocyclic group Chemical group 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
- 150000003573 thiols Chemical class 0.000 claims description 11
- 150000001356 alkyl thiols Chemical class 0.000 claims description 10
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 10
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 10
- 125000005015 aryl alkynyl group Chemical group 0.000 claims description 10
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 10
- 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 10
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 10
- 125000005312 heteroarylalkynyl group Chemical group 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 208000023275 Autoimmune disease Diseases 0.000 claims description 9
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 9
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 9
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims description 8
- FIDRAVVQGKNYQK-UHFFFAOYSA-N 1,2,3,4-tetrahydrotriazine Chemical compound C1NNNC=C1 FIDRAVVQGKNYQK-UHFFFAOYSA-N 0.000 claims description 8
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 8
- 201000009030 Carcinoma Diseases 0.000 claims description 8
- 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 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 8
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 8
- 125000001041 indolyl group Chemical group 0.000 claims description 8
- 229960000485 methotrexate Drugs 0.000 claims description 8
- HCOLXSUORGDFEV-UHFFFAOYSA-N 2,5-dimethyl-4-[[2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol hydrochloride Chemical compound Cl.C1=C(O)C(C)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1C HCOLXSUORGDFEV-UHFFFAOYSA-N 0.000 claims description 7
- 201000004681 Psoriasis Diseases 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000001475 halogen functional group Chemical group 0.000 claims description 7
- XOFRTQBPJBUNBO-UHFFFAOYSA-N n-(2,5-dimethoxyphenyl)-2,6-dipyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=C(OC)C(NC=2N=C(N=C(C=2)C=2N=CC=CC=2)C=2N=CC=CC=2)=C1 XOFRTQBPJBUNBO-UHFFFAOYSA-N 0.000 claims description 7
- LQWCPHXCMCQJNS-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-2-pyrimidin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.COC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CN=2)=C1 LQWCPHXCMCQJNS-UHFFFAOYSA-N 0.000 claims description 7
- FRVWGWADDLRSNU-UHFFFAOYSA-N n-(3,4-dimethoxyphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=C(OC)C(OC)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=CC=2)=N1 FRVWGWADDLRSNU-UHFFFAOYSA-N 0.000 claims description 7
- YLLRMECPBMTDIC-UHFFFAOYSA-N n-(3-fluorophenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C)=CC=1NC1=CC=CC(F)=C1 YLLRMECPBMTDIC-UHFFFAOYSA-N 0.000 claims description 7
- CEDVMKWHSKOBMU-UHFFFAOYSA-N n-(3-methoxyphenyl)-2-phenyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CC=CC=2)=C1 CEDVMKWHSKOBMU-UHFFFAOYSA-N 0.000 claims description 7
- VZWANBRUDXSYIR-UHFFFAOYSA-N n-(4,5-dimethoxy-2-methylphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC(C)=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=NC=2)=N1 VZWANBRUDXSYIR-UHFFFAOYSA-N 0.000 claims description 7
- ZMNMUZVFHGTDDE-UHFFFAOYSA-N n-(5-methoxy-2-nitrophenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C([N+]([O-])=O)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1 ZMNMUZVFHGTDDE-UHFFFAOYSA-N 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 125000003107 substituted aryl group Chemical group 0.000 claims description 7
- CMPNFGCTNYCXOS-UHFFFAOYSA-N 1-[4,5-dimethoxy-2-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]ethanone Chemical compound C1=C(OC)C(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1C(C)=O CMPNFGCTNYCXOS-UHFFFAOYSA-N 0.000 claims description 6
- PYNAEOLNVSMVRT-UHFFFAOYSA-N 2,5-dimethyl-4-[[2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol hydrochloride Chemical compound Cl.C1=C(O)C(C)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1C PYNAEOLNVSMVRT-UHFFFAOYSA-N 0.000 claims description 6
- XNPJJKQFDALEPK-UHFFFAOYSA-N 2,5-dimethyl-4-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound C1=C(O)C(C)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1C XNPJJKQFDALEPK-UHFFFAOYSA-N 0.000 claims description 6
- IPCVUSUZMSPKSW-UHFFFAOYSA-N 2,5-dimethyl-4-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound C1=C(O)C(C)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1C IPCVUSUZMSPKSW-UHFFFAOYSA-N 0.000 claims description 6
- GTLDJFMQUCVNBR-UHFFFAOYSA-N 2-methyl-n-[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]-1h-indol-5-amine Chemical compound C=1C=C2NC(C)=CC2=CC=1NC(N=1)=CC(C(F)(F)F)=NC=1C1=CC=CN=C1 GTLDJFMQUCVNBR-UHFFFAOYSA-N 0.000 claims description 6
- UCKPXDLBZLKNOP-UHFFFAOYSA-N 3-[[2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol;hydrochloride Chemical compound Cl.OC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 UCKPXDLBZLKNOP-UHFFFAOYSA-N 0.000 claims description 6
- FVPIDRYEXQKWJL-UHFFFAOYSA-N 3-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol;hydrochloride Chemical compound Cl.OC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 FVPIDRYEXQKWJL-UHFFFAOYSA-N 0.000 claims description 6
- QPTFHKROCNHDAI-UHFFFAOYSA-N 3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol;hydrochloride Chemical compound Cl.OC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1 QPTFHKROCNHDAI-UHFFFAOYSA-N 0.000 claims description 6
- OKEHEHUQVMWARG-UHFFFAOYSA-N 3-n,3-n-dimethyl-1-n-(6-methyl-2-pyridin-2-ylpyrimidin-4-yl)benzene-1,3-diamine Chemical compound CN(C)C1=CC=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 OKEHEHUQVMWARG-UHFFFAOYSA-N 0.000 claims description 6
- FERODZQLHAZVHK-UHFFFAOYSA-N 4,5-dimethoxy-2-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]benzonitrile Chemical compound C1=C(OC)C(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1C#N FERODZQLHAZVHK-UHFFFAOYSA-N 0.000 claims description 6
- LVFUMIJLYGPHPJ-UHFFFAOYSA-N 4-[(4-methylpiperazin-1-yl)methyl]-n-[4-methyl-3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]benzamide Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(N=C(C=3)C(F)(F)F)C=3C=CN=CC=3)C(C)=CC=2)C=C1 LVFUMIJLYGPHPJ-UHFFFAOYSA-N 0.000 claims description 6
- DLZROSDLEOULHK-UHFFFAOYSA-N 4-chloro-2-[[2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound OC1=CC=C(Cl)C=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=NC=2)=N1 DLZROSDLEOULHK-UHFFFAOYSA-N 0.000 claims description 6
- KNADHLLFTNUMBT-UHFFFAOYSA-N 4-chloro-3-[[2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound OC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1 KNADHLLFTNUMBT-UHFFFAOYSA-N 0.000 claims description 6
- IPEFIDKCWLEWKZ-UHFFFAOYSA-N 4-chloro-3-[[2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound OC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 IPEFIDKCWLEWKZ-UHFFFAOYSA-N 0.000 claims description 6
- YLNSBRKAZMZQOB-UHFFFAOYSA-N 4-chloro-3-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound OC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 YLNSBRKAZMZQOB-UHFFFAOYSA-N 0.000 claims description 6
- YRRJWQJFPYNRJW-UHFFFAOYSA-N 4-chloro-3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound OC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1 YRRJWQJFPYNRJW-UHFFFAOYSA-N 0.000 claims description 6
- TVHNIVSFKFFWTR-UHFFFAOYSA-N 4-methoxy-n-[4-methyl-3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]benzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=C(C)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1 TVHNIVSFKFFWTR-UHFFFAOYSA-N 0.000 claims description 6
- JCJMKKAQAILSMX-UHFFFAOYSA-N 4-methyl-2-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]benzonitrile Chemical compound CC1=CC=C(C#N)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 JCJMKKAQAILSMX-UHFFFAOYSA-N 0.000 claims description 6
- RJQNYHVBELHLLA-UHFFFAOYSA-N 4-methyl-3-[[2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound CC1=CC=C(O)C=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=CC=2)=N1 RJQNYHVBELHLLA-UHFFFAOYSA-N 0.000 claims description 6
- WFCJHEKNLOFCPH-UHFFFAOYSA-N 4-methyl-3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound CC1=CC=C(O)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=CN=CC=2)=N1 WFCJHEKNLOFCPH-UHFFFAOYSA-N 0.000 claims description 6
- KGCIIIAWCQBLFS-UHFFFAOYSA-N 4-methyl-3-n-[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]benzene-1,3-diamine;hydrochloride Chemical compound Cl.CC1=CC=C(N)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 KGCIIIAWCQBLFS-UHFFFAOYSA-N 0.000 claims description 6
- CRJZCANGJMWXMF-UHFFFAOYSA-N 4-methyl-n-[4-methyl-3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]benzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC1=CC=C(C)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1 CRJZCANGJMWXMF-UHFFFAOYSA-N 0.000 claims description 6
- QKQGRWOCUMFNSY-UHFFFAOYSA-N 5-methyl-6-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]-1h-pyrimidin-2-one Chemical compound CC1=CN=C(O)N=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 QKQGRWOCUMFNSY-UHFFFAOYSA-N 0.000 claims description 6
- GNXARXXPYFZUEF-UHFFFAOYSA-N 6-chloro-n-[4-methyl-3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]pyridine-3-carboxamide Chemical compound C1=C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)C(C)=CC=C1NC(=O)C1=CC=C(Cl)N=C1 GNXARXXPYFZUEF-UHFFFAOYSA-N 0.000 claims description 6
- YWIQFXQGLAQYBJ-UHFFFAOYSA-N 6-methyl-n-(3-methylphenyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound CC1=CC=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 YWIQFXQGLAQYBJ-UHFFFAOYSA-N 0.000 claims description 6
- NEOQUWIFJYUNMY-UHFFFAOYSA-N 6-methyl-n-(3-phenoxyphenyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C)=CC=1NC(C=1)=CC=CC=1OC1=CC=CC=C1 NEOQUWIFJYUNMY-UHFFFAOYSA-N 0.000 claims description 6
- DWPZTFMISSBVGK-UHFFFAOYSA-N 6-methyl-n-(3-propan-2-yloxyphenyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound CC(C)OC1=CC=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 DWPZTFMISSBVGK-UHFFFAOYSA-N 0.000 claims description 6
- TVUYEVPOCJDCQJ-UHFFFAOYSA-N 6-methyl-n-(3-propan-2-ylphenyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound CC(C)C1=CC=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 TVUYEVPOCJDCQJ-UHFFFAOYSA-N 0.000 claims description 6
- KJNQJGYQWZFPSO-UHFFFAOYSA-N 6-tert-butyl-n-(2-chloro-5-methoxyphenyl)-2-pyridin-3-ylpyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(C)(C)C)C=2C=NC=CC=2)=C1 KJNQJGYQWZFPSO-UHFFFAOYSA-N 0.000 claims description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 229940022353 herceptin Drugs 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 230000003211 malignant effect Effects 0.000 claims description 6
- NAXMYGNNHOHARB-UHFFFAOYSA-N n-(1,3-benzodioxol-5-yl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C(F)(F)F)=CC(NC=2C=C3OCOC3=CC=2)=NC=1C1=CN=CC=N1 NAXMYGNNHOHARB-UHFFFAOYSA-N 0.000 claims description 6
- FGYJZUPWTLEWBZ-UHFFFAOYSA-N n-(1,3-benzodioxol-5-yl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C(F)(F)F)=CC(NC=2C=C3OCOC3=CC=2)=NC=1C1=CC=CC=N1 FGYJZUPWTLEWBZ-UHFFFAOYSA-N 0.000 claims description 6
- RLOZOOKCCZWGQV-UHFFFAOYSA-N n-(2,5-diethoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CCOC1=CC=C(OCC)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 RLOZOOKCCZWGQV-UHFFFAOYSA-N 0.000 claims description 6
- NYJNMYXJHGUEDV-UHFFFAOYSA-N n-(2,5-dimethoxyphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(OC)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1 NYJNMYXJHGUEDV-UHFFFAOYSA-N 0.000 claims description 6
- BZMNTBUEVBNNDC-UHFFFAOYSA-N n-(2,5-dimethoxyphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(OC)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 BZMNTBUEVBNNDC-UHFFFAOYSA-N 0.000 claims description 6
- YENIAOLWKPDDOQ-UHFFFAOYSA-N n-(2,5-dimethoxyphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(OC)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1 YENIAOLWKPDDOQ-UHFFFAOYSA-N 0.000 claims description 6
- GKMABZJWMVNDIV-UHFFFAOYSA-N n-(2,5-dimethoxyphenyl)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=C(C)C=CC=2)=NC(COC)=CC=1NC1=CC(OC)=CC=C1OC GKMABZJWMVNDIV-UHFFFAOYSA-N 0.000 claims description 6
- ISHNIKMCGJJDSP-UHFFFAOYSA-N n-(2,5-dimethoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=C(OC)C(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 ISHNIKMCGJJDSP-UHFFFAOYSA-N 0.000 claims description 6
- GNEJIQJEFCDLAA-UHFFFAOYSA-N n-(2,5-dimethylphenyl)-2,6-dipyridin-2-ylpyrimidin-4-amine Chemical compound CC1=CC=C(C)C(NC=2N=C(N=C(C=2)C=2N=CC=CC=2)C=2N=CC=CC=2)=C1 GNEJIQJEFCDLAA-UHFFFAOYSA-N 0.000 claims description 6
- XKCKYTPIPFMYFM-UHFFFAOYSA-N n-(2,5-dimethylphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=CC=C(C)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1 XKCKYTPIPFMYFM-UHFFFAOYSA-N 0.000 claims description 6
- OBFLNRYNESDYRS-UHFFFAOYSA-N n-(2,6-dimethoxypyridin-3-yl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=NC(OC)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 OBFLNRYNESDYRS-UHFFFAOYSA-N 0.000 claims description 6
- VJUAYEDQEIBTOC-UHFFFAOYSA-N n-(2,6-dimethylphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C)=CC=1NC1=C(C)C=CC=C1C VJUAYEDQEIBTOC-UHFFFAOYSA-N 0.000 claims description 6
- GGCAWWYPAJSTCE-UHFFFAOYSA-N n-(2-bromo-5-methoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Br)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 GGCAWWYPAJSTCE-UHFFFAOYSA-N 0.000 claims description 6
- VEZJTTQMMOOCOS-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-2,6-dipyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C=2N=CC=CC=2)C=2N=CC=CC=2)=C1 VEZJTTQMMOOCOS-UHFFFAOYSA-N 0.000 claims description 6
- VYVGOWMMZYTOPD-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-2-phenyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CC=CC=2)=C1 VYVGOWMMZYTOPD-UHFFFAOYSA-N 0.000 claims description 6
- OUUPLSRKIMXCCG-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1 OUUPLSRKIMXCCG-UHFFFAOYSA-N 0.000 claims description 6
- DNSATAUGEAROES-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 DNSATAUGEAROES-UHFFFAOYSA-N 0.000 claims description 6
- KSSBTNVSVYHOBY-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=C(C)C=CC=2)=NC(COC)=CC=1NC1=CC(OC)=CC=C1Cl KSSBTNVSVYHOBY-UHFFFAOYSA-N 0.000 claims description 6
- HIWXLNWFVZBDKZ-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 HIWXLNWFVZBDKZ-UHFFFAOYSA-N 0.000 claims description 6
- STAQAMPDFYXRPX-UHFFFAOYSA-N n-(2-methoxy-5-methylphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(C)C=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=NC=2)=N1 STAQAMPDFYXRPX-UHFFFAOYSA-N 0.000 claims description 6
- RHLLJOJWNYRUNZ-UHFFFAOYSA-N n-(2-methoxy-5-methylphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(C)C=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=CC=2)=N1 RHLLJOJWNYRUNZ-UHFFFAOYSA-N 0.000 claims description 6
- YDJXUAZJYVSXPH-UHFFFAOYSA-N n-(2-methoxy-5-methylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(C)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 YDJXUAZJYVSXPH-UHFFFAOYSA-N 0.000 claims description 6
- FBORYBIMVUYFBF-UHFFFAOYSA-N n-(2-methoxy-5-methylphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(C)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=CN=CC=2)=N1 FBORYBIMVUYFBF-UHFFFAOYSA-N 0.000 claims description 6
- HXMSPHMJFABKFI-UHFFFAOYSA-N n-(2-methoxy-5-nitrophenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C([N+]([O-])=O)C=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=NC=2)=N1 HXMSPHMJFABKFI-UHFFFAOYSA-N 0.000 claims description 6
- XPKZEUYTQPGGFB-UHFFFAOYSA-N n-(2-methyl-5-nitrophenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=CC=C([N+]([O-])=O)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 XPKZEUYTQPGGFB-UHFFFAOYSA-N 0.000 claims description 6
- OGGFXWNPMOGQTK-UHFFFAOYSA-N n-(2-methyl-5-nitrophenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=CC=C([N+]([O-])=O)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=CN=CC=2)=N1 OGGFXWNPMOGQTK-UHFFFAOYSA-N 0.000 claims description 6
- VVBRCLDDLVAMDW-UHFFFAOYSA-N n-(3,4-dimethoxyphenyl)-2-phenyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=C(OC)C(OC)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2C=CC=CC=2)=N1 VVBRCLDDLVAMDW-UHFFFAOYSA-N 0.000 claims description 6
- XBYZMTGHUXTNQX-UHFFFAOYSA-N n-(3,4-dimethoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound C1=C(OC)C(OC)=CC=C1NC1=CC(C)=NC(C=2N=CC=CC=2)=N1 XBYZMTGHUXTNQX-UHFFFAOYSA-N 0.000 claims description 6
- VHRAKWHFLVBDAT-UHFFFAOYSA-N n-(3,5-dimethoxyphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1 VHRAKWHFLVBDAT-UHFFFAOYSA-N 0.000 claims description 6
- UWTSBOJYYYSHQO-UHFFFAOYSA-N n-(3,5-dimethoxyphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 UWTSBOJYYYSHQO-UHFFFAOYSA-N 0.000 claims description 6
- VXGOGWQYJSWHLF-UHFFFAOYSA-N n-(3,5-dimethoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.COC1=CC(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 VXGOGWQYJSWHLF-UHFFFAOYSA-N 0.000 claims description 6
- GYRLPTQRBCAZKW-UHFFFAOYSA-N n-(3-chlorophenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C)=CC=1NC1=CC=CC(Cl)=C1 GYRLPTQRBCAZKW-UHFFFAOYSA-N 0.000 claims description 6
- VFIYSZLVJMXQGH-UHFFFAOYSA-N n-(3-ethoxyphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CCOC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 VFIYSZLVJMXQGH-UHFFFAOYSA-N 0.000 claims description 6
- CVAQEZWZWFONDL-UHFFFAOYSA-N n-(3-methoxyphenyl)-2-piperidin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C2NCCCC2)=C1 CVAQEZWZWFONDL-UHFFFAOYSA-N 0.000 claims description 6
- NCJHUDMOVPNTQL-UHFFFAOYSA-N n-(3-methoxyphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1 NCJHUDMOVPNTQL-UHFFFAOYSA-N 0.000 claims description 6
- FBFNFYABLPAQGK-UHFFFAOYSA-N n-(3-methoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 FBFNFYABLPAQGK-UHFFFAOYSA-N 0.000 claims description 6
- WUHCPTLUDHTIFP-UHFFFAOYSA-N n-(3-methylsulfanylphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CSC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 WUHCPTLUDHTIFP-UHFFFAOYSA-N 0.000 claims description 6
- RSYWRJOLKLYJGG-UHFFFAOYSA-N n-(4,5-dimethoxy-2-methylphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC(C)=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=CC=2)=N1 RSYWRJOLKLYJGG-UHFFFAOYSA-N 0.000 claims description 6
- JNWTUXCDRXIWAE-UHFFFAOYSA-N n-(4,5-dimethoxy-2-methylphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.C1=C(OC)C(OC)=CC(C)=C1NC1=CC(C(F)(F)F)=NC(C=2C=CN=CC=2)=N1 JNWTUXCDRXIWAE-UHFFFAOYSA-N 0.000 claims description 6
- LQUWTVPMHXSVEP-UHFFFAOYSA-N n-(4,6-dimethoxypyrimidin-2-yl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC(OC)=NC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=N1 LQUWTVPMHXSVEP-UHFFFAOYSA-N 0.000 claims description 6
- DEHSPNSTQDGEHX-UHFFFAOYSA-N n-(4-chloro-2,5-dimethoxyphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.C1=C(Cl)C(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1OC DEHSPNSTQDGEHX-UHFFFAOYSA-N 0.000 claims description 6
- FZQPQOQRRNBQRD-UHFFFAOYSA-N n-(4-chloro-2,5-dimethoxyphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.C1=C(Cl)C(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1OC FZQPQOQRRNBQRD-UHFFFAOYSA-N 0.000 claims description 6
- UYKDAOSFWKZYMI-UHFFFAOYSA-N n-(4-fluoro-3-methoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound C1=C(F)C(OC)=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 UYKDAOSFWKZYMI-UHFFFAOYSA-N 0.000 claims description 6
- IFPDHXWVIVBFII-UHFFFAOYSA-N n-(5-bromo-2-methoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Br)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 IFPDHXWVIVBFII-UHFFFAOYSA-N 0.000 claims description 6
- LZASDYAGXLVTFJ-UHFFFAOYSA-N n-(5-chloro-2-methoxyphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=CN=CC=2)=N1 LZASDYAGXLVTFJ-UHFFFAOYSA-N 0.000 claims description 6
- HCFYXRVZUMXIGG-UHFFFAOYSA-N n-(5-methoxy-2-methylphenyl)-2,6-dipyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=C(C)C(NC=2N=C(N=C(C=2)C=2N=CC=CC=2)C=2N=CC=CC=2)=C1 HCFYXRVZUMXIGG-UHFFFAOYSA-N 0.000 claims description 6
- NIZXJGAQXLGFPJ-UHFFFAOYSA-N n-(5-methoxy-2-methylphenyl)-2-phenyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(C)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CC=CC=2)=C1 NIZXJGAQXLGFPJ-UHFFFAOYSA-N 0.000 claims description 6
- ZQUCXKHLYGKKGU-UHFFFAOYSA-N n-(5-methoxy-2-methylphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(C)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 ZQUCXKHLYGKKGU-UHFFFAOYSA-N 0.000 claims description 6
- JAFQOOQMLMCNTN-UHFFFAOYSA-N n-(5-methoxy-2-methylphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(C)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1 JAFQOOQMLMCNTN-UHFFFAOYSA-N 0.000 claims description 6
- LVXMZAKXGAZNIB-UHFFFAOYSA-N n-(6-methoxypyridin-3-yl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=NC(OC)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 LVXMZAKXGAZNIB-UHFFFAOYSA-N 0.000 claims description 6
- SWYXCCFDJNHZNB-UHFFFAOYSA-N n-[2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]-1h-indol-4-amine Chemical compound N=1C(C(F)(F)F)=CC(NC=2C=3C=CNC=3C=CC=2)=NC=1C1=CC=CC=N1 SWYXCCFDJNHZNB-UHFFFAOYSA-N 0.000 claims description 6
- AFBZMGCVCNOSSI-UHFFFAOYSA-N n-[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]-1h-indol-4-amine Chemical compound N=1C(C(F)(F)F)=CC(NC=2C=3C=CNC=3C=CC=2)=NC=1C1=CC=CN=C1 AFBZMGCVCNOSSI-UHFFFAOYSA-N 0.000 claims description 6
- OLTDSHWGDRSOKW-UHFFFAOYSA-N n-[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]-1h-indol-5-amine Chemical compound N=1C(C(F)(F)F)=CC(NC=2C=C3C=CNC3=CC=2)=NC=1C1=CC=CN=C1 OLTDSHWGDRSOKW-UHFFFAOYSA-N 0.000 claims description 6
- DZINHMDCVHVGME-UHFFFAOYSA-N n-[3-methoxy-5-(trifluoromethyl)phenyl]-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound FC(F)(F)C1=CC(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 DZINHMDCVHVGME-UHFFFAOYSA-N 0.000 claims description 6
- PZHRCNKLVQBEIZ-UHFFFAOYSA-N n-[4-methyl-3-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]benzamide Chemical compound C1=C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)C(C)=CC=C1NC(=O)C1=CC=CC=C1 PZHRCNKLVQBEIZ-UHFFFAOYSA-N 0.000 claims description 6
- IJLXWULSFUOKLF-UHFFFAOYSA-N n-[4-methyl-3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]pyridine-3-carboxamide Chemical compound C1=C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)C(C)=CC=C1NC(=O)C1=CC=CN=C1 IJLXWULSFUOKLF-UHFFFAOYSA-N 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 229960004641 rituximab Drugs 0.000 claims description 6
- WEIFITABWFRJDL-UHFFFAOYSA-N 2,4-dichloro-5-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound C1=C(Cl)C(O)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1Cl WEIFITABWFRJDL-UHFFFAOYSA-N 0.000 claims description 5
- XWZSYTPGIUQOSQ-UHFFFAOYSA-N 2-pyridin-3-yl-6-(trifluoromethyl)-n-(2,4,5-trimethylphenyl)pyrimidin-4-amine Chemical compound C1=C(C)C(C)=CC(C)=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 XWZSYTPGIUQOSQ-UHFFFAOYSA-N 0.000 claims description 5
- RNPZASZEMJYBNV-UHFFFAOYSA-N 3-[[2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol;hydrochloride Chemical compound Cl.OC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1 RNPZASZEMJYBNV-UHFFFAOYSA-N 0.000 claims description 5
- ZMJJVZRAGPLFOT-UHFFFAOYSA-N 4-chloro-2-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound OC1=CC=C(Cl)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 ZMJJVZRAGPLFOT-UHFFFAOYSA-N 0.000 claims description 5
- HSXNSSFOMQTYRH-UHFFFAOYSA-N 4-chloro-n-[4-methyl-3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]benzamide Chemical compound C1=C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)C(C)=CC=C1NC(=O)C1=CC=C(Cl)C=C1 HSXNSSFOMQTYRH-UHFFFAOYSA-N 0.000 claims description 5
- OYFYANFPEUAZAB-UHFFFAOYSA-N 4-methoxy-3-[[2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]benzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=NC=2)=N1 OYFYANFPEUAZAB-UHFFFAOYSA-N 0.000 claims description 5
- IEMFLCMNPVLQBJ-UHFFFAOYSA-N 4-methyl-2-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound CC1=CC=C(O)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 IEMFLCMNPVLQBJ-UHFFFAOYSA-N 0.000 claims description 5
- DDAFEGVTPQQYPD-UHFFFAOYSA-N 4-methyl-3-[[2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound CC1=CC=C(O)C=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=NC=2)=N1 DDAFEGVTPQQYPD-UHFFFAOYSA-N 0.000 claims description 5
- VCWHCPYOUGCDSW-UHFFFAOYSA-N 4-propan-2-yl-2-[[2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound CC(C)C1=CC=C(O)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 VCWHCPYOUGCDSW-UHFFFAOYSA-N 0.000 claims description 5
- YCZHRINUSWZKPU-UHFFFAOYSA-N 6-(methoxymethyl)-n-(4-methoxyphenyl)-2-(3-methylphenyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=C(C)C=CC=2)=NC(COC)=CC=1NC1=CC=C(OC)C=C1 YCZHRINUSWZKPU-UHFFFAOYSA-N 0.000 claims description 5
- FKPKGNJMNUCJNM-UHFFFAOYSA-N 6-(methoxymethyl)-n-(5-methoxy-2-methylphenyl)-2-(3-methylphenyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=C(C)C=CC=2)=NC(COC)=CC=1NC1=CC(OC)=CC=C1C FKPKGNJMNUCJNM-UHFFFAOYSA-N 0.000 claims description 5
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 5
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 5
- 229930012538 Paclitaxel Natural products 0.000 claims description 5
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 5
- QJPJXOYCHIKWBH-UHFFFAOYSA-N n-(1,3-benzodioxol-5-yl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C(F)(F)F)=CC(NC=2C=C3OCOC3=CC=2)=NC=1C1=CC=NC=C1 QJPJXOYCHIKWBH-UHFFFAOYSA-N 0.000 claims description 5
- QNNSBAJECZKXPX-UHFFFAOYSA-N n-(2,4-dichloro-5-methoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=C(Cl)C(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1Cl QNNSBAJECZKXPX-UHFFFAOYSA-N 0.000 claims description 5
- NQAXCZJZVIJZHE-UHFFFAOYSA-N n-(2,4-dimethoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine;hydrochloride Chemical compound Cl.COC1=CC(OC)=CC=C1NC1=CC(C)=NC(C=2N=CC=CC=2)=N1 NQAXCZJZVIJZHE-UHFFFAOYSA-N 0.000 claims description 5
- FECLEAUHFKBHSF-UHFFFAOYSA-N n-(2,5-dimethoxyphenyl)-2-phenyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(OC)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CC=CC=2)=C1 FECLEAUHFKBHSF-UHFFFAOYSA-N 0.000 claims description 5
- NOYWKQYFMCVGMK-UHFFFAOYSA-N n-(2,5-dimethylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=CC=C(C)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 NOYWKQYFMCVGMK-UHFFFAOYSA-N 0.000 claims description 5
- VAAUTVXZYCKWAN-UHFFFAOYSA-N n-(2,5-dimethylphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.CC1=CC=C(C)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1 VAAUTVXZYCKWAN-UHFFFAOYSA-N 0.000 claims description 5
- YWDRORSEZINDPD-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 YWDRORSEZINDPD-UHFFFAOYSA-N 0.000 claims description 5
- IQDUNQUQCWGICF-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1 IQDUNQUQCWGICF-UHFFFAOYSA-N 0.000 claims description 5
- TZBZWDDUQNHTLN-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-6-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC(=CC=2)C(F)(F)F)=C1 TZBZWDDUQNHTLN-UHFFFAOYSA-N 0.000 claims description 5
- PLJSUUQGAJVCPK-UHFFFAOYSA-N n-(2-chloro-5-methylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 PLJSUUQGAJVCPK-UHFFFAOYSA-N 0.000 claims description 5
- LZONKNBQISQPPO-UHFFFAOYSA-N n-(2-methoxy-5-methylphenyl)-2,6-dipyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=C(C)C=C1NC1=CC(C=2N=CC=CC=2)=NC(C=2N=CC=CC=2)=N1 LZONKNBQISQPPO-UHFFFAOYSA-N 0.000 claims description 5
- AVFYCOFVNZBPDS-UHFFFAOYSA-N n-(2-methoxy-5-phenoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)C(OC)=CC=C1OC1=CC=CC=C1 AVFYCOFVNZBPDS-UHFFFAOYSA-N 0.000 claims description 5
- GDIYYTIBRMWVHO-UHFFFAOYSA-N n-(3,4-dimethoxyphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=C(OC)C(OC)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=NC=2)=N1 GDIYYTIBRMWVHO-UHFFFAOYSA-N 0.000 claims description 5
- WBXFFLIFVWZNTJ-UHFFFAOYSA-N n-(3,5-dimethoxyphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1 WBXFFLIFVWZNTJ-UHFFFAOYSA-N 0.000 claims description 5
- KJWXPQHKPFLYAE-UHFFFAOYSA-N n-(3,5-dimethoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine;hydrochloride Chemical compound Cl.COC1=CC(OC)=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 KJWXPQHKPFLYAE-UHFFFAOYSA-N 0.000 claims description 5
- NPYFGZJFCAMFIN-UHFFFAOYSA-N n-(3-chlorophenyl)-6-(methoxymethyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(COC)=CC=1NC1=CC=CC(Cl)=C1 NPYFGZJFCAMFIN-UHFFFAOYSA-N 0.000 claims description 5
- HQRALYJEOKSNDB-UHFFFAOYSA-N n-(3-ethylphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CCC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 HQRALYJEOKSNDB-UHFFFAOYSA-N 0.000 claims description 5
- CROPXVXORWPZNY-UHFFFAOYSA-N n-(3-methoxyphenyl)-2,6-dipyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C=2)C=2N=CC=CC=2)C=2N=CC=CC=2)=C1 CROPXVXORWPZNY-UHFFFAOYSA-N 0.000 claims description 5
- WDRNAEVAOMLYRK-UHFFFAOYSA-N n-(3-methoxyphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1 WDRNAEVAOMLYRK-UHFFFAOYSA-N 0.000 claims description 5
- QPFCIBIHIXZQIU-UHFFFAOYSA-N n-(4-chloro-2,5-dimethoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.C1=C(Cl)C(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1OC QPFCIBIHIXZQIU-UHFFFAOYSA-N 0.000 claims description 5
- KQFORHWNGKKWDG-UHFFFAOYSA-N n-(4-chloro-2-methoxy-5-methylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC(Cl)=C(C)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 KQFORHWNGKKWDG-UHFFFAOYSA-N 0.000 claims description 5
- SOGYMKNBQQMAKP-UHFFFAOYSA-N n-(5-chloro-2-methoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 SOGYMKNBQQMAKP-UHFFFAOYSA-N 0.000 claims description 5
- SYBUHLOALKCEON-UHFFFAOYSA-N n-(5-methoxy-2-methylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(C)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 SYBUHLOALKCEON-UHFFFAOYSA-N 0.000 claims description 5
- JHBKHLLCJXAMKT-UHFFFAOYSA-N n-(5-methoxy-2-methylphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=C(C)C(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 JHBKHLLCJXAMKT-UHFFFAOYSA-N 0.000 claims description 5
- SLBRVYYCHRQYCG-UHFFFAOYSA-N n-[2-methoxy-5-(trifluoromethyl)phenyl]-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(C(F)(F)F)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 SLBRVYYCHRQYCG-UHFFFAOYSA-N 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 229960001592 paclitaxel Drugs 0.000 claims description 5
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 5
- 208000016691 refractory malignant neoplasm Diseases 0.000 claims description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 5
- 229960003048 vinblastine Drugs 0.000 claims description 5
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 5
- 229960004528 vincristine Drugs 0.000 claims description 5
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 5
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 5
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 claims description 4
- ZGNLFUXWZJGETL-YUSKDDKASA-N (Z)-[(2S)-2-amino-2-carboxyethyl]-hydroxyimino-oxidoazanium Chemical compound N[C@@H](C\[N+]([O-])=N\O)C(O)=O ZGNLFUXWZJGETL-YUSKDDKASA-N 0.000 claims description 4
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 4
- OKWQFEIFJIRFNI-UHFFFAOYSA-N 2-pyridin-2-yl-n-[3-(trifluoromethoxy)phenyl]-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.FC(F)(F)OC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 OKWQFEIFJIRFNI-UHFFFAOYSA-N 0.000 claims description 4
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 4
- GZCPFYKIYVYKDF-UHFFFAOYSA-N 4-(chloromethyl)-n-[4-methyl-3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]benzamide Chemical compound C1=C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)C(C)=CC=C1NC(=O)C1=CC=C(CCl)C=C1 GZCPFYKIYVYKDF-UHFFFAOYSA-N 0.000 claims description 4
- PNWREFIMDWNZGY-UHFFFAOYSA-N 4-methoxy-3-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]benzoic acid;hydrochloride Chemical compound Cl.COC1=CC=C(C(O)=O)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 PNWREFIMDWNZGY-UHFFFAOYSA-N 0.000 claims description 4
- JEXGOACDMHYCFT-UHFFFAOYSA-N 4-methyl-3-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound CC1=CC=C(O)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 JEXGOACDMHYCFT-UHFFFAOYSA-N 0.000 claims description 4
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 claims description 4
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 claims description 4
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 4
- VEZHFENCAJHFSZ-UHFFFAOYSA-N 6-(methoxymethyl)-n-(5-methoxy-2-methylphenyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidin-4-amine Chemical compound N=1C(C=2N=C(C)SC=2)=NC(COC)=CC=1NC1=CC(OC)=CC=C1C VEZHFENCAJHFSZ-UHFFFAOYSA-N 0.000 claims description 4
- FOHUMFIQHBSPGD-UHFFFAOYSA-N 7-aminoisochromen-1-one Chemical compound C1=COC(=O)C2=CC(N)=CC=C21 FOHUMFIQHBSPGD-UHFFFAOYSA-N 0.000 claims description 4
- 108010006654 Bleomycin Proteins 0.000 claims description 4
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 4
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 4
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- MLFKVJCWGUZWNV-UHFFFAOYSA-N L-alanosine Natural products OC(=O)C(N)CN(O)N=O MLFKVJCWGUZWNV-UHFFFAOYSA-N 0.000 claims description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 4
- 206010029260 Neuroblastoma Diseases 0.000 claims description 4
- 108010016076 Octreotide Proteins 0.000 claims description 4
- 229950005033 alanosine Drugs 0.000 claims description 4
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 4
- 229960002756 azacitidine Drugs 0.000 claims description 4
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 229960001561 bleomycin Drugs 0.000 claims description 4
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 4
- 229960002092 busulfan Drugs 0.000 claims description 4
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 4
- 229940127093 camptothecin Drugs 0.000 claims description 4
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 4
- 229960004562 carboplatin Drugs 0.000 claims description 4
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 4
- 229960004630 chlorambucil Drugs 0.000 claims description 4
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 4
- 229960004316 cisplatin Drugs 0.000 claims description 4
- 229960001338 colchicine Drugs 0.000 claims description 4
- 229960004397 cyclophosphamide Drugs 0.000 claims description 4
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 4
- 229960003668 docetaxel Drugs 0.000 claims description 4
- YZQRAQOSAPWELU-UHFFFAOYSA-O elliptinium Chemical compound C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 YZQRAQOSAPWELU-UHFFFAOYSA-O 0.000 claims description 4
- 229950007539 elliptinium Drugs 0.000 claims description 4
- 229960001904 epirubicin Drugs 0.000 claims description 4
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 4
- 229960000390 fludarabine Drugs 0.000 claims description 4
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 4
- 229960002949 fluorouracil Drugs 0.000 claims description 4
- 125000003838 furazanyl group Chemical group 0.000 claims description 4
- 206010020718 hyperplasia Diseases 0.000 claims description 4
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 4
- 229960001101 ifosfamide Drugs 0.000 claims description 4
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 4
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 4
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 claims description 4
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 4
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 4
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 4
- 229960001924 melphalan Drugs 0.000 claims description 4
- 229960003539 mitoguazone Drugs 0.000 claims description 4
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 claims description 4
- 229960004857 mitomycin Drugs 0.000 claims description 4
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 4
- 229960001156 mitoxantrone Drugs 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- MXOADGILTSGYGT-UHFFFAOYSA-N n-(1,3-benzodioxol-5-yl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C(F)(F)F)=CC(NC=2C=C3OCOC3=CC=2)=NC=1C1=CC=CN=C1 MXOADGILTSGYGT-UHFFFAOYSA-N 0.000 claims description 4
- AQPHONCLYCUXLK-UHFFFAOYSA-N n-(3-fluorophenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound FC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 AQPHONCLYCUXLK-UHFFFAOYSA-N 0.000 claims description 4
- GVYXQWQTMUNYPR-UHFFFAOYSA-N n-(4-methoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1NC1=CC(C)=NC(C=2N=CC=CC=2)=N1 GVYXQWQTMUNYPR-UHFFFAOYSA-N 0.000 claims description 4
- DVZOXUVDYNAWDW-UHFFFAOYSA-N n-(5-chloro-2-methoxyphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=NC=2)=N1 DVZOXUVDYNAWDW-UHFFFAOYSA-N 0.000 claims description 4
- OKLRPRBOAKLPAT-UHFFFAOYSA-N n-(5-chloro-2-methylpyrimidin-4-yl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=NC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=N1 OKLRPRBOAKLPAT-UHFFFAOYSA-N 0.000 claims description 4
- KIFNPBJGHDXCIF-UHFFFAOYSA-N n-(5-fluoro-2-methylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=CC=C(F)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 KIFNPBJGHDXCIF-UHFFFAOYSA-N 0.000 claims description 4
- FDSULCRASXSBOK-UHFFFAOYSA-N n-(5-methoxy-2-methylphenyl)-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(C)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=NC=2)=C1 FDSULCRASXSBOK-UHFFFAOYSA-N 0.000 claims description 4
- GAZHZBZNTBDQLH-UHFFFAOYSA-N n-[4-methyl-3-[[2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]-4-morpholin-4-ylbenzamide Chemical compound C1=C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)C(C)=CC=C1NC(=O)C(C=C1)=CC=C1N1CCOCC1 GAZHZBZNTBDQLH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 4
- 229960002700 octreotide Drugs 0.000 claims description 4
- 125000005327 perimidinyl group Chemical group N1C(=NC2=CC=CC3=CC=CC1=C23)* 0.000 claims description 4
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 claims description 4
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 claims description 4
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 claims description 4
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims description 4
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 4
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 4
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 4
- 125000002755 pyrazolinyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims description 4
- 229930002330 retinoic acid Natural products 0.000 claims description 4
- 229960001603 tamoxifen Drugs 0.000 claims description 4
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 229960003087 tioguanine Drugs 0.000 claims description 4
- 229960000303 topotecan Drugs 0.000 claims description 4
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 4
- 229960001727 tretinoin Drugs 0.000 claims description 4
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 claims description 4
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 4
- OSTNJIZPFGTQJX-UHFFFAOYSA-N 1,5,6-trimethyl-n-[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]benzimidazol-4-amine Chemical compound CC=1C(C)=CC=2N(C)C=NC=2C=1NC(N=1)=CC(C(F)(F)F)=NC=1C1=CC=CN=C1 OSTNJIZPFGTQJX-UHFFFAOYSA-N 0.000 claims description 3
- MJRJEPPPHJGPET-UHFFFAOYSA-N 1-ethyl-2-phenyl-5-[3-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]pyrazol-3-one Chemical compound CCN1C(C=2C=C(NC=3N=C(N=C(C=3)C(F)(F)F)C=3C=NC=CC=3)C=CC=2)=CC(=O)N1C1=CC=CC=C1 MJRJEPPPHJGPET-UHFFFAOYSA-N 0.000 claims description 3
- COQDJTYAJYQAHD-UHFFFAOYSA-N 2-(2,6-dichloropyridin-4-yl)-n-(3,5-dimethoxyphenyl)-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=C(Cl)N=C(Cl)C=2)=C1 COQDJTYAJYQAHD-UHFFFAOYSA-N 0.000 claims description 3
- SOIRHGNNWNKTJO-UHFFFAOYSA-N 2-pyridin-2-yl-6-(trifluoromethyl)-n-[3-(trifluoromethyl)phenyl]pyrimidin-4-amine Chemical compound FC(F)(F)C1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 SOIRHGNNWNKTJO-UHFFFAOYSA-N 0.000 claims description 3
- KBCOBLXZPGSNKZ-UHFFFAOYSA-N 2-pyridin-2-yl-n-[4-(trifluoromethoxy)phenyl]-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=CC=2)=N1 KBCOBLXZPGSNKZ-UHFFFAOYSA-N 0.000 claims description 3
- KYVYJCRCBXMXPW-UHFFFAOYSA-N 2-pyridin-3-yl-4-(trifluoromethyl)-6-[3-(trifluoromethyl)pyrazol-1-yl]pyrimidine Chemical compound N1=C(C(F)(F)F)C=CN1C1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 KYVYJCRCBXMXPW-UHFFFAOYSA-N 0.000 claims description 3
- NMPFYVJKJJGNMC-UHFFFAOYSA-N 2-pyridin-3-yl-6-(trifluoromethyl)-n-[3-(trifluoromethyl)phenyl]pyrimidin-4-amine Chemical compound FC(F)(F)C1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 NMPFYVJKJJGNMC-UHFFFAOYSA-N 0.000 claims description 3
- YTUJOTPNZCFXTD-UHFFFAOYSA-N 2-pyridin-3-yl-n-(1,2,4-triazol-4-yl)-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=NC=CC=2)=NC(C(F)(F)F)=CC=1NN1C=NN=C1 YTUJOTPNZCFXTD-UHFFFAOYSA-N 0.000 claims description 3
- ITYILTLCTNDHRA-UHFFFAOYSA-N 2-pyridin-3-yl-n-(3,4,5-trichlorophenyl)-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=NC=CC=2)=NC(C(F)(F)F)=CC=1NC1=CC(Cl)=C(Cl)C(Cl)=C1 ITYILTLCTNDHRA-UHFFFAOYSA-N 0.000 claims description 3
- JGGZDMRAYYUKNY-UHFFFAOYSA-N 3-[(6-methyl-2-pyridin-2-ylpyrimidin-4-yl)amino]benzonitrile Chemical compound N=1C(C=2N=CC=CC=2)=NC(C)=CC=1NC1=CC=CC(C#N)=C1 JGGZDMRAYYUKNY-UHFFFAOYSA-N 0.000 claims description 3
- LWHJTZWXMRQMOR-UHFFFAOYSA-N 4-(3-methoxyphenoxy)-6-methyl-2-pyridin-2-ylpyrimidine Chemical compound COC1=CC=CC(OC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 LWHJTZWXMRQMOR-UHFFFAOYSA-N 0.000 claims description 3
- IIGGKPOORZWXHM-UHFFFAOYSA-N 4-ethylsulfonyl-3-[[2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound CCS(=O)(=O)C1=CC=C(O)C=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=NC=2)=N1 IIGGKPOORZWXHM-UHFFFAOYSA-N 0.000 claims description 3
- GIFBVUGNWKGXNY-UHFFFAOYSA-N 4-ethylsulfonyl-3-[[2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound CCS(=O)(=O)C1=CC=C(O)C=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=CC=2)=N1 GIFBVUGNWKGXNY-UHFFFAOYSA-N 0.000 claims description 3
- UWIFGUGUFJDIRQ-UHFFFAOYSA-N 4-hydroxy-3-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]benzoic acid Chemical compound OC(=O)C1=CC=C(O)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 UWIFGUGUFJDIRQ-UHFFFAOYSA-N 0.000 claims description 3
- MPNABAIJTQEHKW-UHFFFAOYSA-N 4-nitro-3-[[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenol Chemical compound OC1=CC=C([N+]([O-])=O)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 MPNABAIJTQEHKW-UHFFFAOYSA-N 0.000 claims description 3
- JVHJXIXSHMNVBF-UHFFFAOYSA-N 4-pyrazol-1-yl-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidine Chemical compound N=1C(C(F)(F)F)=CC(N2N=CC=C2)=NC=1C1=CC=CN=C1 JVHJXIXSHMNVBF-UHFFFAOYSA-N 0.000 claims description 3
- LVCUPQSTXJXEGQ-UHFFFAOYSA-N 6-(methoxymethyl)-n-(3-methoxyphenyl)-2-(3-methylphenyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=C(C)C=CC=2)=NC(COC)=CC=1NC1=CC=CC(OC)=C1 LVCUPQSTXJXEGQ-UHFFFAOYSA-N 0.000 claims description 3
- SDPHVBDDIOKZET-UHFFFAOYSA-N 6-(methoxymethyl)-n-(4-methoxyphenyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(COC)=CC=1NC1=CC=C(OC)C=C1 SDPHVBDDIOKZET-UHFFFAOYSA-N 0.000 claims description 3
- ZVPWZWZPQJHJDE-UHFFFAOYSA-N 6-chloro-n-(3-methoxyphenyl)-2-phenylpyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(Cl)C=2)C=2C=CC=CC=2)=C1 ZVPWZWZPQJHJDE-UHFFFAOYSA-N 0.000 claims description 3
- RLZLJMQMAXLJIV-UHFFFAOYSA-N 6-methyl-2-pyridin-2-yl-n-[3-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C)=CC=1NC1=CC=CC(OC(F)(F)F)=C1 RLZLJMQMAXLJIV-UHFFFAOYSA-N 0.000 claims description 3
- QRZCNVCLHSGMKS-UHFFFAOYSA-N 6-methyl-2-pyridin-2-yl-n-[3-(trifluoromethyl)phenyl]pyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C)=CC=1NC1=CC=CC(C(F)(F)F)=C1 QRZCNVCLHSGMKS-UHFFFAOYSA-N 0.000 claims description 3
- CWAMCCUJQLSFET-UHFFFAOYSA-N 6-methyl-n-(2-methylphenyl)-2-phenylpyrimidin-4-amine Chemical compound N=1C(C=2C=CC=CC=2)=NC(C)=CC=1NC1=CC=CC=C1C CWAMCCUJQLSFET-UHFFFAOYSA-N 0.000 claims description 3
- DNYDPCZQAYAJTN-UHFFFAOYSA-N 6-methyl-n-(3-methylsulfanylphenyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound CSC1=CC=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 DNYDPCZQAYAJTN-UHFFFAOYSA-N 0.000 claims description 3
- NTNFABUXTHNHPL-UHFFFAOYSA-N 6-methyl-n-(3-phenylmethoxyphenyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C)=CC=1NC(C=1)=CC=CC=1OCC1=CC=CC=C1 NTNFABUXTHNHPL-UHFFFAOYSA-N 0.000 claims description 3
- QJCPTOMQDGRLPY-UHFFFAOYSA-N 6-tert-butyl-2-pyridin-2-yl-n-[4-(trifluoromethoxy)phenyl]pyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C(C)(C)C)=CC=1NC1=CC=C(OC(F)(F)F)C=C1 QJCPTOMQDGRLPY-UHFFFAOYSA-N 0.000 claims description 3
- SGBSFSJHLYOWNM-UHFFFAOYSA-N 6-tert-butyl-n-(4-methoxyphenyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1NC1=CC(C(C)(C)C)=NC(C=2N=CC=CC=2)=N1 SGBSFSJHLYOWNM-UHFFFAOYSA-N 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 206010039491 Sarcoma Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 claims description 3
- 229960004176 aclarubicin Drugs 0.000 claims description 3
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 3
- 229960004679 doxorubicin Drugs 0.000 claims description 3
- 229960005420 etoposide Drugs 0.000 claims description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 3
- 230000006882 induction of apoptosis Effects 0.000 claims description 3
- GZPNBLAUFGNQKG-UHFFFAOYSA-N n-(1,3-benzodioxol-5-yl)-2-phenyl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C(F)(F)F)=CC(NC=2C=C3OCOC3=CC=2)=NC=1C1=CC=CC=C1 GZPNBLAUFGNQKG-UHFFFAOYSA-N 0.000 claims description 3
- FFNFBUPWXOYFIA-UHFFFAOYSA-N n-(1h-pyrazol-5-yl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=NC=CC=2)=NC(C(F)(F)F)=CC=1NC=1C=CNN=1 FFNFBUPWXOYFIA-UHFFFAOYSA-N 0.000 claims description 3
- BYIVRZHRZDIVDT-UHFFFAOYSA-N n-(2,4-difluorophenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2C=CN=CC=2)=N1 BYIVRZHRZDIVDT-UHFFFAOYSA-N 0.000 claims description 3
- JCNLESNEGXWHJY-UHFFFAOYSA-N n-(2,5-diethoxy-4-morpholin-4-ylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CCOC=1C=C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)C(OCC)=CC=1N1CCOCC1 JCNLESNEGXWHJY-UHFFFAOYSA-N 0.000 claims description 3
- HRZLBURNYNJSIA-UHFFFAOYSA-N n-(2,5-dimethoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(OC)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 HRZLBURNYNJSIA-UHFFFAOYSA-N 0.000 claims description 3
- ACEPSZHHXIXWQT-UHFFFAOYSA-N n-(2,5-dimethoxyphenyl)-5-methoxy-2-pyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=C(OC)C(NC=2C(=CN=C(N=2)C=2N=CC=CC=2)OC)=C1 ACEPSZHHXIXWQT-UHFFFAOYSA-N 0.000 claims description 3
- HYWPMOXQAVHCIT-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-2-(2,6-dichloropyridin-4-yl)-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=C(Cl)N=C(Cl)C=2)=C1 HYWPMOXQAVHCIT-UHFFFAOYSA-N 0.000 claims description 3
- QKVZUXITWGWXMQ-UHFFFAOYSA-N n-(2-fluorophenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound FC1=CC=CC=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=CC=2)=N1 QKVZUXITWGWXMQ-UHFFFAOYSA-N 0.000 claims description 3
- NYLBDAIOMRDIPN-UHFFFAOYSA-N n-(2-fluorophenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound FC1=CC=CC=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 NYLBDAIOMRDIPN-UHFFFAOYSA-N 0.000 claims description 3
- JDZMXSQILFGOHX-UHFFFAOYSA-N n-(2-fluorophenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound FC1=CC=CC=C1NC1=CC(C(F)(F)F)=NC(C=2C=CN=CC=2)=N1 JDZMXSQILFGOHX-UHFFFAOYSA-N 0.000 claims description 3
- RVZPIXYSHRMLPB-UHFFFAOYSA-N n-(3,4-dichlorophenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C(F)(F)F)=CC=1NC1=CC=C(Cl)C(Cl)=C1 RVZPIXYSHRMLPB-UHFFFAOYSA-N 0.000 claims description 3
- QLWMVZLYUJQZOE-UHFFFAOYSA-N n-(3,5-dichlorophenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=CN=CC=2)=NC(C(F)(F)F)=CC=1NC1=CC(Cl)=CC(Cl)=C1 QLWMVZLYUJQZOE-UHFFFAOYSA-N 0.000 claims description 3
- OFAPDWDAGFTNNJ-UHFFFAOYSA-N n-(3,5-dimethylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=CC(C)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 OFAPDWDAGFTNNJ-UHFFFAOYSA-N 0.000 claims description 3
- RVCHWLBKEUHHII-UHFFFAOYSA-N n-(3-chlorophenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C(F)(F)F)=CC=1NC1=CC=CC(Cl)=C1 RVCHWLBKEUHHII-UHFFFAOYSA-N 0.000 claims description 3
- KESJSHICUIWNCL-UHFFFAOYSA-N n-(3-chlorophenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=NC=CC=2)=NC(C(F)(F)F)=CC=1NC1=CC=CC(Cl)=C1 KESJSHICUIWNCL-UHFFFAOYSA-N 0.000 claims description 3
- LNLWDQCVFZVYPP-UHFFFAOYSA-N n-(3-ethoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound CCOC1=CC=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 LNLWDQCVFZVYPP-UHFFFAOYSA-N 0.000 claims description 3
- KHNLCIWRUDWXBM-UHFFFAOYSA-N n-(3-methoxyphenyl)-6-morpholin-4-yl-2-phenylpyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C=2)N2CCOCC2)C=2C=CC=CC=2)=C1 KHNLCIWRUDWXBM-UHFFFAOYSA-N 0.000 claims description 3
- YZCAHZWYHSBTRH-UHFFFAOYSA-N n-(3-methoxyphenyl)-n-methyl-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=CC(N(C)C=2N=C(N=C(C=2)C(F)(F)F)C=2N=CC=CC=2)=C1 YZCAHZWYHSBTRH-UHFFFAOYSA-N 0.000 claims description 3
- ISSCVKUPEZXZGN-UHFFFAOYSA-N n-(3-phenoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=NC=CC=2)=NC(C(F)(F)F)=CC=1NC(C=1)=CC=CC=1OC1=CC=CC=C1 ISSCVKUPEZXZGN-UHFFFAOYSA-N 0.000 claims description 3
- MIMUWBWKKGHTNW-UHFFFAOYSA-N n-(3-phenylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2C=NC=CC=2)=NC(C(F)(F)F)=CC=1NC(C=1)=CC=CC=1C1=CC=CC=C1 MIMUWBWKKGHTNW-UHFFFAOYSA-N 0.000 claims description 3
- GONAJKZPOUIDTD-UHFFFAOYSA-N n-(4-chlorophenyl)-6-(methoxymethyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(COC)=CC=1NC1=CC=C(Cl)C=C1 GONAJKZPOUIDTD-UHFFFAOYSA-N 0.000 claims description 3
- FUPBZSAPQSMZQM-UHFFFAOYSA-N n-(4-fluorophenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=CC(F)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=CC=2)=N1 FUPBZSAPQSMZQM-UHFFFAOYSA-N 0.000 claims description 3
- FYULZVQQTCITDC-UHFFFAOYSA-N n-(4-fluorophenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=CC(F)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 FYULZVQQTCITDC-UHFFFAOYSA-N 0.000 claims description 3
- BHAZZOZHGNERJO-UHFFFAOYSA-N n-(4-methoxyphenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=CC=2)=N1 BHAZZOZHGNERJO-UHFFFAOYSA-N 0.000 claims description 3
- NEVQSJQQHYHVFA-UHFFFAOYSA-N n-(4-methoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 NEVQSJQQHYHVFA-UHFFFAOYSA-N 0.000 claims description 3
- JCRQVNMYHADBMC-UHFFFAOYSA-N n-(4-methoxyphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2C=CN=CC=2)=N1 JCRQVNMYHADBMC-UHFFFAOYSA-N 0.000 claims description 3
- RCDWEVIKNQWNPL-UHFFFAOYSA-N n-(5-methoxy-2-methyl-4-nitrophenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=C([N+]([O-])=O)C(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1C RCDWEVIKNQWNPL-UHFFFAOYSA-N 0.000 claims description 3
- HZQJZTWTJHMFAX-UHFFFAOYSA-N n-(5-methoxy-2-piperidin-1-ylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C=1C(C(F)(F)F)=NC(C=2C=NC=CC=2)=NC=1NC1=CC(OC)=CC=C1N1CCCCC1 HZQJZTWTJHMFAX-UHFFFAOYSA-N 0.000 claims description 3
- BGEJXZOWRGHUOY-UHFFFAOYSA-N n-[2-(2,5-dimethoxyphenyl)ethyl]-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C(OC)C(CCNC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 BGEJXZOWRGHUOY-UHFFFAOYSA-N 0.000 claims description 3
- NQOWSXCHFQXQAX-UHFFFAOYSA-N n-[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]-4,5-dihydro-1,3-thiazol-2-amine Chemical compound N=1C(C=2C=NC=CC=2)=NC(C(F)(F)F)=CC=1NC1=NCCS1 NQOWSXCHFQXQAX-UHFFFAOYSA-N 0.000 claims description 3
- FEAGOFUJSOVSDS-UHFFFAOYSA-N n-[3-(2,3,4,5,6-pentafluorophenoxy)phenyl]-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1OC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 FEAGOFUJSOVSDS-UHFFFAOYSA-N 0.000 claims description 3
- RCELTGDKZATYCD-UHFFFAOYSA-N n-[3-(2-methylpyrimidin-4-yl)phenyl]-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=NC=CC(C=2C=C(NC=3N=C(N=C(C=3)C(F)(F)F)C=3C=NC=CC=3)C=CC=2)=N1 RCELTGDKZATYCD-UHFFFAOYSA-N 0.000 claims description 3
- YUTQHQKOTNAELI-UHFFFAOYSA-N n-[3-(3-nitrophenyl)phenyl]-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound [O-][N+](=O)C1=CC=CC(C=2C=C(NC=3N=C(N=C(C=3)C(F)(F)F)C=3C=NC=CC=3)C=CC=2)=C1 YUTQHQKOTNAELI-UHFFFAOYSA-N 0.000 claims description 3
- VOEALPHKGHOHOB-UHFFFAOYSA-N n-[3-(4-bromo-1-methylpyrazol-3-yl)phenyl]-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CN1C=C(Br)C(C=2C=C(NC=3N=C(N=C(C=3)C(F)(F)F)C=3C=NC=CC=3)C=CC=2)=N1 VOEALPHKGHOHOB-UHFFFAOYSA-N 0.000 claims description 3
- NKJGCAMSDXASOQ-UHFFFAOYSA-N n-[3-methyl-5-(trifluoromethyl)phenyl]-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound FC(F)(F)C1=CC(C)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 NKJGCAMSDXASOQ-UHFFFAOYSA-N 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- IDXKTTNFXPPXJY-UHFFFAOYSA-N pyrimidin-1-ium;chloride Chemical compound Cl.C1=CN=CN=C1 IDXKTTNFXPPXJY-UHFFFAOYSA-N 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- SOOYGPRHMUTZTE-UHFFFAOYSA-N 2-[4-(4-methoxyanilino)-6-methylpyrimidin-2-yl]phenol Chemical compound C1=CC(OC)=CC=C1NC1=CC(C)=NC(C=2C(=CC=CC=2)O)=N1 SOOYGPRHMUTZTE-UHFFFAOYSA-N 0.000 claims description 2
- LDEHJQHFLSAJIG-UHFFFAOYSA-N 2-pyridin-2-yl-6-(trifluoromethyl)-n-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine Chemical compound C1=CC(C(F)(F)F)=CC=C1NC1=CC(C(F)(F)F)=NC(C=2N=CC=CC=2)=N1 LDEHJQHFLSAJIG-UHFFFAOYSA-N 0.000 claims description 2
- OBQDCYHWOGJBHE-UHFFFAOYSA-N 2-pyridin-2-yl-6-(trifluoromethyl)-n-[[2-(trifluoromethyl)phenyl]methyl]pyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C(F)(F)F)=CC=1NCC1=CC=CC=C1C(F)(F)F OBQDCYHWOGJBHE-UHFFFAOYSA-N 0.000 claims description 2
- SYJXYRFLWREJGR-UHFFFAOYSA-N 4-n-(2-chloro-5-methoxyphenyl)-6-methylpyrimidine-2,4-diamine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N)N=C(C)C=2)=C1 SYJXYRFLWREJGR-UHFFFAOYSA-N 0.000 claims description 2
- DTYPNCHDBYWKHY-UHFFFAOYSA-N 4-pyrrol-1-yl-n-(3,4,5-trimethoxyphenyl)-1,3,5-triazin-2-amine Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C(N=CN=2)N2C=CC=C2)=C1 DTYPNCHDBYWKHY-UHFFFAOYSA-N 0.000 claims description 2
- YDFKQCSNBRBZAI-UHFFFAOYSA-N 6-methyl-n-(3-nitrophenyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C)=CC=1NC1=CC=CC([N+]([O-])=O)=C1 YDFKQCSNBRBZAI-UHFFFAOYSA-N 0.000 claims description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims description 2
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
- 208000032027 Essential Thrombocythemia Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 208000037147 Hypercalcaemia Diseases 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 2
- 208000008383 Wilms tumor Diseases 0.000 claims description 2
- 208000017733 acquired polycythemia vera Diseases 0.000 claims description 2
- 208000020990 adrenal cortex carcinoma Diseases 0.000 claims description 2
- 201000001531 bladder carcinoma Diseases 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 claims description 2
- 208000002458 carcinoid tumor Diseases 0.000 claims description 2
- 208000019065 cervical carcinoma Diseases 0.000 claims description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 201000005619 esophageal carcinoma Diseases 0.000 claims description 2
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000010749 gastric carcinoma Diseases 0.000 claims description 2
- 201000009277 hairy cell leukemia Diseases 0.000 claims description 2
- 201000003911 head and neck carcinoma Diseases 0.000 claims description 2
- 230000000148 hypercalcaemia Effects 0.000 claims description 2
- 208000030915 hypercalcemia disease Diseases 0.000 claims description 2
- 201000005296 lung carcinoma Diseases 0.000 claims description 2
- 201000000564 macroglobulinemia Diseases 0.000 claims description 2
- 201000005962 mycosis fungoides Diseases 0.000 claims description 2
- CQEOVUJQJZYQKD-UHFFFAOYSA-N n-(2,4-dichlorophenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C(F)(F)F)=CC=1NC1=CC=C(Cl)C=C1Cl CQEOVUJQJZYQKD-UHFFFAOYSA-N 0.000 claims description 2
- QPEHIFMXBFOXPR-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-6-methyl-2-morpholin-4-ylpyrimidin-4-amine Chemical compound COC1=CC=C(Cl)C(NC=2N=C(N=C(C)C=2)N2CCOCC2)=C1 QPEHIFMXBFOXPR-UHFFFAOYSA-N 0.000 claims description 2
- LZMMONIDZNTEDM-UHFFFAOYSA-N n-(2-methoxy-5-methyl-4-nitrophenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC([N+]([O-])=O)=C(C)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 LZMMONIDZNTEDM-UHFFFAOYSA-N 0.000 claims description 2
- QGPNGESOLHHEKV-UHFFFAOYSA-N n-(3-methoxydibenzofuran-4-yl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=C2C3=CC=CC=C3OC2=C1NC(N=1)=CC(C(F)(F)F)=NC=1C1=CC=CN=C1 QGPNGESOLHHEKV-UHFFFAOYSA-N 0.000 claims description 2
- LOKUFABRRHJEKM-UHFFFAOYSA-N n-(4-chlorophenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C(F)(F)F)=CC=1NC1=CC=C(Cl)C=C1 LOKUFABRRHJEKM-UHFFFAOYSA-N 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 208000021255 pancreatic insulinoma Diseases 0.000 claims description 2
- 208000037244 polycythemia vera Diseases 0.000 claims description 2
- NYJWYCAHJRGKMI-UHFFFAOYSA-N pyrido[1,2-a]pyrimidin-4-one Chemical compound C1=CC=CN2C(=O)C=CN=C21 NYJWYCAHJRGKMI-UHFFFAOYSA-N 0.000 claims description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 2
- 208000017520 skin disease Diseases 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 201000000498 stomach carcinoma Diseases 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- 230000002381 testicular Effects 0.000 claims description 2
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 6
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 4
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 claims 3
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 claims 2
- LLEUVJRFMCHBQF-UHFFFAOYSA-N N-(4-chloro-2,5-dimethoxyphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine N-(4,5-dimethoxy-2-methylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine hydrochloride Chemical compound Cl.ClC1=CC(=C(NC2=NC(=NC(=C2)C(F)(F)F)C2=CC=NC=C2)C=C1OC)OC.COC1=CC(=C(NC2=NC(=NC(=C2)C(F)(F)F)C=2C=NC=CC2)C=C1OC)C LLEUVJRFMCHBQF-UHFFFAOYSA-N 0.000 claims 2
- 201000008275 breast carcinoma Diseases 0.000 claims 2
- YIBURHHWUDXFSU-UHFFFAOYSA-N n-(3,5-dichlorophenyl)-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C(F)(F)F)=CC=1NC1=CC(Cl)=CC(Cl)=C1 YIBURHHWUDXFSU-UHFFFAOYSA-N 0.000 claims 2
- VZBIEXITABEFIS-UHFFFAOYSA-N 1-[2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-yl]-4,5,6,7-tetrahydroindazole Chemical compound N=1C(C(F)(F)F)=CC(N2C=3CCCCC=3C=N2)=NC=1C1=CC=CN=C1 VZBIEXITABEFIS-UHFFFAOYSA-N 0.000 claims 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims 1
- 206010014733 Endometrial cancer Diseases 0.000 claims 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 1
- OQHYTNFJMHVUCY-UHFFFAOYSA-N N-(2-chlorophenyl)-4-(1-pyrrolyl)-1,3,5-triazin-2-amine Chemical compound ClC1=CC=CC=C1NC1=NC=NC(N2C=CC=C2)=N1 OQHYTNFJMHVUCY-UHFFFAOYSA-N 0.000 claims 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims 1
- 208000033781 Thyroid carcinoma Diseases 0.000 claims 1
- 239000012830 cancer therapeutic Substances 0.000 claims 1
- 201000003914 endometrial carcinoma Diseases 0.000 claims 1
- QJNPBYANFDICQM-UHFFFAOYSA-N n-[2-methyl-5-(trifluoromethyl)phenyl]-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound CC1=CC=C(C(F)(F)F)C=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 QJNPBYANFDICQM-UHFFFAOYSA-N 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 201000002510 thyroid cancer Diseases 0.000 claims 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 225
- 238000005160 1H NMR spectroscopy Methods 0.000 description 222
- 239000007787 solid Substances 0.000 description 200
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 176
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 150
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 113
- 210000004027 cell Anatomy 0.000 description 98
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- JHVGKOOKRVOCKZ-UHFFFAOYSA-N 4-chloro-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC(Cl)=NC(C=2C=NC=CC=2)=N1 JHVGKOOKRVOCKZ-UHFFFAOYSA-N 0.000 description 67
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 66
- 235000019439 ethyl acetate Nutrition 0.000 description 60
- 239000000243 solution Substances 0.000 description 56
- 239000003921 oil Substances 0.000 description 34
- 235000019198 oils Nutrition 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- QXTIZJZQBKJJCB-UHFFFAOYSA-N 4-chloro-6-methyl-2-pyridin-2-ylpyrimidine Chemical compound CC1=CC(Cl)=NC(C=2N=CC=CC=2)=N1 QXTIZJZQBKJJCB-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- FXKIFMAMPPOOLJ-UHFFFAOYSA-N 4-chloro-2-pyrazin-2-yl-6-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC(Cl)=NC(C=2N=CC=NC=2)=N1 FXKIFMAMPPOOLJ-UHFFFAOYSA-N 0.000 description 22
- NPRHEFXGFBGECS-UHFFFAOYSA-N 4-chloro-2-pyridin-2-yl-6-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC(Cl)=NC(C=2N=CC=CC=2)=N1 NPRHEFXGFBGECS-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 17
- BXRCPVMQUNIGDK-UHFFFAOYSA-N 4-chloro-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC(Cl)=NC(C=2C=CN=CC=2)=N1 BXRCPVMQUNIGDK-UHFFFAOYSA-N 0.000 description 16
- GBOUQGUQUUPGLO-UHFFFAOYSA-N 2-chloro-5-methoxyaniline Chemical compound COC1=CC=C(Cl)C(N)=C1 GBOUQGUQUUPGLO-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 125000005843 halogen group Chemical group 0.000 description 13
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 201000010099 disease Diseases 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- NAZDVUBIEPVUKE-UHFFFAOYSA-N 2,5-dimethoxyaniline Chemical compound COC1=CC=C(OC)C(N)=C1 NAZDVUBIEPVUKE-UHFFFAOYSA-N 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- RPJXLEZOFUNGNZ-UHFFFAOYSA-N 5-methoxy-2-methylaniline Chemical compound COC1=CC=C(C)C(N)=C1 RPJXLEZOFUNGNZ-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 210000001744 T-lymphocyte Anatomy 0.000 description 9
- 150000002431 hydrogen Chemical group 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- VOWZNBNDMFLQGM-UHFFFAOYSA-N 2,5-dimethylaniline Chemical compound CC1=CC=C(C)C(N)=C1 VOWZNBNDMFLQGM-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 7
- 238000002835 absorbance Methods 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 125000004414 alkyl thio group Chemical group 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 210000002437 synoviocyte Anatomy 0.000 description 7
- WNRGWPVJGDABME-UHFFFAOYSA-N 3,5-Dimethoxyaniline Chemical compound COC1=CC(N)=CC(OC)=C1 WNRGWPVJGDABME-UHFFFAOYSA-N 0.000 description 6
- IGJZUIYZPXXSOR-UHFFFAOYSA-N 4-chloro-2,6-dipyridin-2-ylpyrimidine Chemical compound N=1C(Cl)=CC(C=2N=CC=CC=2)=NC=1C1=CC=CC=N1 IGJZUIYZPXXSOR-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 102220497176 Small vasohibin-binding protein_T47D_mutation Human genes 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 238000013019 agitation Methods 0.000 description 6
- 229940041181 antineoplastic drug Drugs 0.000 description 6
- 230000001640 apoptogenic effect Effects 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 6
- XGNXYCFREOZBOL-UHFFFAOYSA-N 1,3-benzodioxol-5-amine Chemical compound NC1=CC=C2OCOC2=C1 XGNXYCFREOZBOL-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 108010039471 Fas Ligand Protein Proteins 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000012980 RPMI-1640 medium Substances 0.000 description 5
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 5
- VEOXVBTXROWDAH-UHFFFAOYSA-N acetic acid;3-[1-(3-aminopropyl)indol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound CC(O)=O.C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=CC=C3N(CCCN)C=2)C(=O)NC1=O VEOXVBTXROWDAH-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 230000009826 neoplastic cell growth Effects 0.000 description 5
- WXWCDTXEKCVRRO-UHFFFAOYSA-N para-Cresidine Chemical compound COC1=CC=C(C)C=C1N WXWCDTXEKCVRRO-UHFFFAOYSA-N 0.000 description 5
- 239000012188 paraffin wax Substances 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- LGDHZCLREKIGKJ-UHFFFAOYSA-N 3,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C=C1OC LGDHZCLREKIGKJ-UHFFFAOYSA-N 0.000 description 4
- FWUALUHYKLDYAN-UHFFFAOYSA-N 3-amino-4-chlorophenol Chemical compound NC1=CC(O)=CC=C1Cl FWUALUHYKLDYAN-UHFFFAOYSA-N 0.000 description 4
- NUNAWQZKZVVELQ-UHFFFAOYSA-N 3-amino-4-methylphenol Chemical compound CC1=CC=C(O)C=C1N NUNAWQZKZVVELQ-UHFFFAOYSA-N 0.000 description 4
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical compound NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 description 4
- 229940018563 3-aminophenol Drugs 0.000 description 4
- BLAYBVPASDNLJM-UHFFFAOYSA-N 4,5-dimethoxy-2-methylaniline Chemical compound COC1=CC(C)=C(N)C=C1OC BLAYBVPASDNLJM-UHFFFAOYSA-N 0.000 description 4
- BKDUWMJFLCNPKP-UHFFFAOYSA-N 4-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC=NC=N1 BKDUWMJFLCNPKP-UHFFFAOYSA-N 0.000 description 4
- JSWVCUXQICMATE-UHFFFAOYSA-N 4-amino-2,5-dimethylphenol Chemical compound CC1=CC(O)=C(C)C=C1N JSWVCUXQICMATE-UHFFFAOYSA-N 0.000 description 4
- YGUFQYGSBVXPMC-UHFFFAOYSA-N 4-chloro-2,5-dimethoxyaniline Chemical compound COC1=CC(Cl)=C(OC)C=C1N YGUFQYGSBVXPMC-UHFFFAOYSA-N 0.000 description 4
- 235000019489 Almond oil Nutrition 0.000 description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004442 acylamino group Chemical group 0.000 description 4
- 125000005236 alkanoylamino group Chemical group 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 239000008168 almond oil Substances 0.000 description 4
- 230000000118 anti-neoplastic effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000003719 b-lymphocyte Anatomy 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
- 125000001589 carboacyl group Chemical group 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 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
- 230000007246 mechanism Effects 0.000 description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- LVGLWOPLFHFBMT-UHFFFAOYSA-N 4-(methoxymethyl)-2-(3-methylphenyl)pyrimidine Chemical compound COCC1=NC(=NC=C1)C1=CC(=CC=C1)C LVGLWOPLFHFBMT-UHFFFAOYSA-N 0.000 description 3
- SFPPMIWPSRZHFQ-UHFFFAOYSA-N 4-chloro-2-(2,6-dichloropyridin-4-yl)-6-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC(Cl)=NC(C=2C=C(Cl)N=C(Cl)C=2)=N1 SFPPMIWPSRZHFQ-UHFFFAOYSA-N 0.000 description 3
- CWZUWJRMFIDBRA-UHFFFAOYSA-N 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC(Cl)=NC(C=2C=CC=CC=2)=N1 CWZUWJRMFIDBRA-UHFFFAOYSA-N 0.000 description 3
- MZURRYBOMZXPPE-UHFFFAOYSA-N 4-chloro-2-pyrimidin-2-yl-6-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC(Cl)=NC(C=2N=CC=CN=2)=N1 MZURRYBOMZXPPE-UHFFFAOYSA-N 0.000 description 3
- VRKDKRBNQBEDQV-UHFFFAOYSA-N 4-chloro-6-methyl-2-(3-methylphenyl)pyrimidine Chemical compound CC1=CC=CC(C=2N=C(Cl)C=C(C)N=2)=C1 VRKDKRBNQBEDQV-UHFFFAOYSA-N 0.000 description 3
- WBSMIPLNPSCJFS-UHFFFAOYSA-N 5-chloro-2-methoxyaniline Chemical compound COC1=CC=C(Cl)C=C1N WBSMIPLNPSCJFS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound 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
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 150000005840 aryl radicals Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 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
- 238000000576 coating method Methods 0.000 description 3
- 239000013068 control sample Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- SFDRHPQGYUYYNX-UHFFFAOYSA-N ethyl 4,4,4-trifluorobut-2-ynoate Chemical compound CCOC(=O)C#CC(F)(F)F SFDRHPQGYUYYNX-UHFFFAOYSA-N 0.000 description 3
- 239000002024 ethyl acetate extract Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 239000012737 fresh medium Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- IMXNBQOMGJMSIT-UHFFFAOYSA-N n-(4,5-dimethoxy-2-methylphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound C1=C(OC)C(OC)=CC(C)=C1NC1=CC(C(F)(F)F)=NC(C=2C=NC=CC=2)=N1 IMXNBQOMGJMSIT-UHFFFAOYSA-N 0.000 description 3
- WFISYPWWCWVULV-UHFFFAOYSA-N n-(4-chloro-2,5-dimethoxyphenyl)-2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.C1=C(Cl)C(OC)=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=CN=CC=2)=C1OC WFISYPWWCWVULV-UHFFFAOYSA-N 0.000 description 3
- 230000001613 neoplastic effect Effects 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 125000003884 phenylalkyl group Chemical group 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- SZSKAHAHBFDQKN-UHFFFAOYSA-N pyrimidine-2-carboximidamide Chemical compound NC(=N)C1=NC=CC=N1 SZSKAHAHBFDQKN-UHFFFAOYSA-N 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 210000001685 thyroid gland Anatomy 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 2
- 150000008081 1H-pyrimidin-4-ones Chemical class 0.000 description 2
- BMIPMKQAAJKBKP-UHFFFAOYSA-N 2,4,5-Trimethylaniline Chemical compound CC1=CC(C)=C(N)C=C1C BMIPMKQAAJKBKP-UHFFFAOYSA-N 0.000 description 2
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 2
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 2
- SWFNPENEBHAHEB-UHFFFAOYSA-N 2-amino-4-chlorophenol Chemical compound NC1=CC(Cl)=CC=C1O SWFNPENEBHAHEB-UHFFFAOYSA-N 0.000 description 2
- PRQDMSJEMCRFMI-UHFFFAOYSA-N 2-bromo-5-methoxyaniline Chemical compound COC1=CC=C(Br)C(N)=C1 PRQDMSJEMCRFMI-UHFFFAOYSA-N 0.000 description 2
- RZQQQWUVWWVDCN-UHFFFAOYSA-N 2-pyridin-2-yl-6-(trifluoromethyl)-1h-pyrimidin-4-one Chemical compound N1C(C(F)(F)F)=CC(=O)N=C1C1=CC=CC=N1 RZQQQWUVWWVDCN-UHFFFAOYSA-N 0.000 description 2
- FAHNBQPDEIOEGI-UHFFFAOYSA-N 2-pyrimidin-2-yl-6-(trifluoromethyl)-1h-pyrimidin-4-one Chemical compound OC1=CC(C(F)(F)F)=NC(C=2N=CC=CN=2)=N1 FAHNBQPDEIOEGI-UHFFFAOYSA-N 0.000 description 2
- MKARNSWMMBGSHX-UHFFFAOYSA-N 3,5-dimethylaniline Chemical compound CC1=CC(C)=CC(N)=C1 MKARNSWMMBGSHX-UHFFFAOYSA-N 0.000 description 2
- SADHVOSOZBAAGL-UHFFFAOYSA-N 3-(trifluoromethoxy)aniline Chemical compound NC1=CC=CC(OC(F)(F)F)=C1 SADHVOSOZBAAGL-UHFFFAOYSA-N 0.000 description 2
- OQPALSCTMWORSH-UHFFFAOYSA-N 3-amino-4-ethylsulfonylphenol Chemical compound CCS(=O)(=O)C1=CC=C(O)C=C1N OQPALSCTMWORSH-UHFFFAOYSA-N 0.000 description 2
- FDGAEAYZQQCBRN-UHFFFAOYSA-N 3-amino-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1N FDGAEAYZQQCBRN-UHFFFAOYSA-N 0.000 description 2
- WEZAHYDFZNTGKE-UHFFFAOYSA-N 3-ethoxyaniline Chemical compound CCOC1=CC=CC(N)=C1 WEZAHYDFZNTGKE-UHFFFAOYSA-N 0.000 description 2
- AMKPQMFZCBTTAT-UHFFFAOYSA-N 3-ethylaniline Chemical compound CCC1=CC=CC(N)=C1 AMKPQMFZCBTTAT-UHFFFAOYSA-N 0.000 description 2
- ASHGTJPOSUFTGB-UHFFFAOYSA-N 3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1 ASHGTJPOSUFTGB-UHFFFAOYSA-N 0.000 description 2
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- KCHLDNLIJVSRPK-UHFFFAOYSA-N 3-methylsulfanylaniline Chemical compound CSC1=CC=CC(N)=C1 KCHLDNLIJVSRPK-UHFFFAOYSA-N 0.000 description 2
- BZJPIQKDEGXVFG-UHFFFAOYSA-N 3-n,3-n-dimethylbenzene-1,3-diamine;hydron;dichloride Chemical compound Cl.Cl.CN(C)C1=CC=CC(N)=C1 BZJPIQKDEGXVFG-UHFFFAOYSA-N 0.000 description 2
- UCSYVYFGMFODMY-UHFFFAOYSA-N 3-phenoxyaniline Chemical compound NC1=CC=CC(OC=2C=CC=CC=2)=C1 UCSYVYFGMFODMY-UHFFFAOYSA-N 0.000 description 2
- VXGRJERITKFWPL-UHFFFAOYSA-N 4',5'-Dihydropsoralen Natural products C1=C2OC(=O)C=CC2=CC2=C1OCC2 VXGRJERITKFWPL-UHFFFAOYSA-N 0.000 description 2
- LUNUNJFSHKSXGQ-UHFFFAOYSA-N 4-Aminoindole Chemical compound NC1=CC=CC2=C1C=CN2 LUNUNJFSHKSXGQ-UHFFFAOYSA-N 0.000 description 2
- BTHRCJACYHBCHX-UHFFFAOYSA-N 4-chloro-5-methoxy-2-pyridin-2-ylpyrimidine Chemical compound N1=C(Cl)C(OC)=CN=C1C1=CC=CC=N1 BTHRCJACYHBCHX-UHFFFAOYSA-N 0.000 description 2
- OWBBPBAWAUMHEO-UHFFFAOYSA-N 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine Chemical compound COCC1=CC(Cl)=NC(C=2C=C(C)C=CC=2)=N1 OWBBPBAWAUMHEO-UHFFFAOYSA-N 0.000 description 2
- UDKQAAACJWSKRF-UHFFFAOYSA-N 4-tert-butyl-6-chloro-2-pyridin-3-ylpyrimidine Chemical compound CC(C)(C)C1=CC(Cl)=NC(C=2C=NC=CC=2)=N1 UDKQAAACJWSKRF-UHFFFAOYSA-N 0.000 description 2
- OPGNSNDTPPIYPG-UHFFFAOYSA-N 5-bromo-2-methoxyaniline Chemical compound COC1=CC=C(Br)C=C1N OPGNSNDTPPIYPG-UHFFFAOYSA-N 0.000 description 2
- DSBIJCMXAIKKKI-UHFFFAOYSA-N 5-nitro-o-toluidine Chemical compound CC1=CC=C([N+]([O-])=O)C=C1N DSBIJCMXAIKKKI-UHFFFAOYSA-N 0.000 description 2
- WDJBSETZOSEBFA-UHFFFAOYSA-N 6-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]-1h-pyrimidin-4-one Chemical compound OC1=CC(C(F)(F)F)=NC(C=2C=NC(=CC=2)C(F)(F)F)=N1 WDJBSETZOSEBFA-UHFFFAOYSA-N 0.000 description 2
- LGAVGJGPOZMAKQ-UHFFFAOYSA-N 6-chloro-n-(4-methoxyphenyl)-2-phenylpyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1NC1=CC(Cl)=NC(C=2C=CC=CC=2)=N1 LGAVGJGPOZMAKQ-UHFFFAOYSA-N 0.000 description 2
- WXUAFQKJIZMNID-UHFFFAOYSA-N 6-methyl-n-phenyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound N=1C(C=2N=CC=CC=2)=NC(C)=CC=1NC1=CC=CC=C1 WXUAFQKJIZMNID-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 2
- 208000000659 Autoimmune lymphoproliferative syndrome Diseases 0.000 description 2
- 102100035904 Caspase-1 Human genes 0.000 description 2
- 108090000426 Caspase-1 Proteins 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 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
- 229940126062 Compound A Drugs 0.000 description 2
- 102000005927 Cysteine Proteases Human genes 0.000 description 2
- 108010005843 Cysteine Proteases Proteins 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 2
- 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 2
- 206010062049 Lymphocytic infiltration Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- 102000015439 Phospholipases Human genes 0.000 description 2
- 108010064785 Phospholipases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000018199 S phase Effects 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 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
- 230000009471 action Effects 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 108700000707 bcl-2-Associated X Proteins 0.000 description 2
- 102000055102 bcl-2-Associated X Human genes 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 239000012166 beeswax Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 101150055276 ced-3 gene Proteins 0.000 description 2
- 230000025084 cell cycle arrest Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000005025 clonogenic survival Effects 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 230000005427 lymphocyte apoptotic process Effects 0.000 description 2
- 210000002540 macrophage Anatomy 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
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- BQRLSUYPTOARBX-UHFFFAOYSA-N n-[(3-methoxyphenyl)methyl]-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=CC(CNC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 BQRLSUYPTOARBX-UHFFFAOYSA-N 0.000 description 2
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 125000005359 phenoxyalkyl group Chemical group 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000005522 programmed cell death Effects 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- FUADXEJBHCKVBN-UHFFFAOYSA-N (3-aminophenyl)-phenylmethanone Chemical compound NC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 FUADXEJBHCKVBN-UHFFFAOYSA-N 0.000 description 1
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 1
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 description 1
- WILMQVBUVCETSB-UHFFFAOYSA-N 1,2,4-trimethyl-5-nitrobenzene Chemical compound CC1=CC(C)=C([N+]([O-])=O)C=C1C WILMQVBUVCETSB-UHFFFAOYSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- KGKWXEGYKGTMAK-UHFFFAOYSA-N 1-(2-amino-4,5-dimethoxyphenyl)ethanone Chemical compound COC1=CC(N)=C(C(C)=O)C=C1OC KGKWXEGYKGTMAK-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- KCOBIBRGPCFIGF-UHFFFAOYSA-N 1-bromo-4-methoxy-2-nitrobenzene Chemical compound COC1=CC=C(Br)C([N+]([O-])=O)=C1 KCOBIBRGPCFIGF-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- LMOZMJRCHGZVMU-UHFFFAOYSA-N 1-n-[6-(methoxymethyl)-2-(3-methylphenyl)pyrimidin-4-yl]-4-n,4-n-dimethylbenzene-1,4-diamine Chemical compound N=1C(C=2C=C(C)C=CC=2)=NC(COC)=CC=1NC1=CC=C(N(C)C)C=C1 LMOZMJRCHGZVMU-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 1
- HMBHAQMOBKLWRX-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-3-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)COC2=C1 HMBHAQMOBKLWRX-UHFFFAOYSA-N 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- HEZIOZBMPKPOER-UHFFFAOYSA-N 2,3-dimethoxyaniline Chemical compound COC1=CC=CC(N)=C1OC HEZIOZBMPKPOER-UHFFFAOYSA-N 0.000 description 1
- AJROJTARXSATEB-UHFFFAOYSA-N 2,4-dichloro-5-methoxyaniline Chemical compound COC1=CC(N)=C(Cl)C=C1Cl AJROJTARXSATEB-UHFFFAOYSA-N 0.000 description 1
- MZVKNFPDQWHQKT-UHFFFAOYSA-N 2,4-difluoro-6-nitrophenol Chemical compound OC1=C(F)C=C(F)C=C1[N+]([O-])=O MZVKNFPDQWHQKT-UHFFFAOYSA-N 0.000 description 1
- GEQNZVKIDIPGCO-UHFFFAOYSA-N 2,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C(OC)=C1 GEQNZVKIDIPGCO-UHFFFAOYSA-N 0.000 description 1
- SFGWSUNUVDPPJG-UHFFFAOYSA-N 2,5-diethoxy-4-morpholin-4-ylaniline;dihydrochloride Chemical compound Cl.Cl.C1=C(N)C(OCC)=CC(N2CCOCC2)=C1OCC SFGWSUNUVDPPJG-UHFFFAOYSA-N 0.000 description 1
- XPKFTIYOZUJAGA-UHFFFAOYSA-N 2,5-diethoxyaniline Chemical compound CCOC1=CC=C(OCC)C(N)=C1 XPKFTIYOZUJAGA-UHFFFAOYSA-N 0.000 description 1
- PTBHRJOTANEONS-UHFFFAOYSA-N 2,6-dimethoxypyridin-3-amine Chemical compound COC1=CC=C(N)C(OC)=N1 PTBHRJOTANEONS-UHFFFAOYSA-N 0.000 description 1
- GBUQWAWFSGSYHK-UHFFFAOYSA-N 2-(2,6-dichloropyridin-4-yl)-6-(trifluoromethyl)-1h-pyrimidin-4-one Chemical compound OC1=CC(C(F)(F)F)=NC(C=2C=C(Cl)N=C(Cl)C=2)=N1 GBUQWAWFSGSYHK-UHFFFAOYSA-N 0.000 description 1
- WAMFIVMJCIVTIW-UHFFFAOYSA-N 2-(3-methylphenyl)pyrimidine Chemical compound CC1=CC=CC(C=2N=CC=CN=2)=C1 WAMFIVMJCIVTIW-UHFFFAOYSA-N 0.000 description 1
- ICNFOOJKOFXKIR-UHFFFAOYSA-N 2-(trifluoromethyl)pyrimidine;hydrochloride Chemical compound Cl.FC(F)(F)C1=NC=CC=N1 ICNFOOJKOFXKIR-UHFFFAOYSA-N 0.000 description 1
- BJAYMNUBIULRMF-UHFFFAOYSA-N 2-amino-4,5-dimethoxybenzonitrile Chemical compound COC1=CC(N)=C(C#N)C=C1OC BJAYMNUBIULRMF-UHFFFAOYSA-N 0.000 description 1
- LGNVAEIITHYWCG-UHFFFAOYSA-N 2-amino-4-methylbenzonitrile Chemical compound CC1=CC=C(C#N)C(N)=C1 LGNVAEIITHYWCG-UHFFFAOYSA-N 0.000 description 1
- WXULIANDWRYTKZ-UHFFFAOYSA-N 2-amino-4-propan-2-ylphenol Chemical compound CC(C)C1=CC=C(O)C(N)=C1 WXULIANDWRYTKZ-UHFFFAOYSA-N 0.000 description 1
- ZMXYNJXDULEQCK-UHFFFAOYSA-N 2-amino-p-cresol Chemical compound CC1=CC=C(O)C(N)=C1 ZMXYNJXDULEQCK-UHFFFAOYSA-N 0.000 description 1
- HPSCXFOQUFPEPE-UHFFFAOYSA-N 2-chloro-5-methylaniline Chemical compound CC1=CC=C(Cl)C(N)=C1 HPSCXFOQUFPEPE-UHFFFAOYSA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- FPWLTKFZPJGKSX-UHFFFAOYSA-N 2-methoxy-2-(3-methoxyphenyl)ethanamine Chemical compound COC(CN)C1=CC=CC(OC)=C1 FPWLTKFZPJGKSX-UHFFFAOYSA-N 0.000 description 1
- RKUSRLUGUVDNKP-UHFFFAOYSA-N 2-methoxy-5-(trifluoromethyl)aniline Chemical compound COC1=CC=C(C(F)(F)F)C=C1N RKUSRLUGUVDNKP-UHFFFAOYSA-N 0.000 description 1
- VXUMJWGCPAUKTB-UHFFFAOYSA-N 2-methoxy-5-methyl-4-nitroaniline Chemical compound COC1=CC([N+]([O-])=O)=C(C)C=C1N VXUMJWGCPAUKTB-UHFFFAOYSA-N 0.000 description 1
- NIPDVSLAMPAWTP-UHFFFAOYSA-N 2-methoxy-5-nitroaniline Chemical compound COC1=CC=C([N+]([O-])=O)C=C1N NIPDVSLAMPAWTP-UHFFFAOYSA-N 0.000 description 1
- SCDKUQBOSDILAR-UHFFFAOYSA-N 2-methoxy-5-phenoxyaniline Chemical compound C1=C(N)C(OC)=CC=C1OC1=CC=CC=C1 SCDKUQBOSDILAR-UHFFFAOYSA-N 0.000 description 1
- JQULCCZIXYRBSE-UHFFFAOYSA-N 2-methyl-1h-indol-5-amine Chemical compound NC1=CC=C2NC(C)=CC2=C1 JQULCCZIXYRBSE-UHFFFAOYSA-N 0.000 description 1
- VNJYQRKONYKZKV-UHFFFAOYSA-N 2-pyrazin-2-yl-6-(trifluoromethyl)-1h-pyrimidin-4-one Chemical compound N1C(C(F)(F)F)=CC(=O)N=C1C1=CN=CC=N1 VNJYQRKONYKZKV-UHFFFAOYSA-N 0.000 description 1
- KSSQDGWYRGRZLW-UHFFFAOYSA-N 2-pyridin-2-yl-4-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CC=NC(C=2N=CC=CC=2)=N1 KSSQDGWYRGRZLW-UHFFFAOYSA-N 0.000 description 1
- CKQHAYFOPRIUOM-UHFFFAOYSA-N 3'-Aminoacetophenone Chemical compound CC(=O)C1=CC=CC(N)=C1 CKQHAYFOPRIUOM-UHFFFAOYSA-N 0.000 description 1
- XOGYQVITULCUGU-UHFFFAOYSA-N 3,4,5-trichloroaniline Chemical compound NC1=CC(Cl)=C(Cl)C(Cl)=C1 XOGYQVITULCUGU-UHFFFAOYSA-N 0.000 description 1
- SDAARBLYPWZWOI-UHFFFAOYSA-N 3-(2,3,4,5,6-pentafluorophenoxy)aniline Chemical compound NC1=CC=CC(OC=2C(=C(F)C(F)=C(F)C=2F)F)=C1 SDAARBLYPWZWOI-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- DMWKPJRZFGLSAX-UHFFFAOYSA-N 3-(2-methylpyrimidin-4-yl)aniline Chemical compound CC1=NC=CC(C=2C=C(N)C=CC=2)=N1 DMWKPJRZFGLSAX-UHFFFAOYSA-N 0.000 description 1
- MFOBJFPOQKSSKE-UHFFFAOYSA-N 3-(3-nitrophenyl)aniline Chemical group NC1=CC=CC(C=2C=C(C=CC=2)[N+]([O-])=O)=C1 MFOBJFPOQKSSKE-UHFFFAOYSA-N 0.000 description 1
- PNSYPAPYJDCJFE-UHFFFAOYSA-N 3-(4-bromo-1-methylpyrazol-3-yl)aniline Chemical compound CN1C=C(Br)C(C=2C=C(N)C=CC=2)=N1 PNSYPAPYJDCJFE-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- RNDWVSUBNRMXMN-UHFFFAOYSA-N 3-(benzenesulfonyl)aniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=CC=CC=2)=C1 RNDWVSUBNRMXMN-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 1
- YGYGASJNJTYNOL-CQSZACIVSA-N 3-[(4r)-2,2-dimethyl-1,1-dioxothian-4-yl]-5-(4-fluorophenyl)-1h-indole-7-carboxamide Chemical compound C1CS(=O)(=O)C(C)(C)C[C@@H]1C1=CNC2=C(C(N)=O)C=C(C=3C=CC(F)=CC=3)C=C12 YGYGASJNJTYNOL-CQSZACIVSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- XKFIFYROMAAUDL-UHFFFAOYSA-N 3-amino-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1N XKFIFYROMAAUDL-UHFFFAOYSA-N 0.000 description 1
- WGEZJWMZNGUEHR-UHFFFAOYSA-N 3-amino-4-nitrophenol Chemical compound NC1=CC(O)=CC=C1[N+]([O-])=O WGEZJWMZNGUEHR-UHFFFAOYSA-N 0.000 description 1
- FOKAXXOSJFRRBQ-UHFFFAOYSA-N 3-amino-4-propan-2-ylphenol Chemical compound CC(C)C1=CC=C(O)C=C1N FOKAXXOSJFRRBQ-UHFFFAOYSA-N 0.000 description 1
- KPSPULPPMWHXGE-UHFFFAOYSA-N 3-amino-n-phenylbenzamide Chemical compound NC1=CC=CC(C(=O)NC=2C=CC=CC=2)=C1 KPSPULPPMWHXGE-UHFFFAOYSA-N 0.000 description 1
- NJXPYZHXZZCTNI-UHFFFAOYSA-N 3-aminobenzonitrile Chemical compound NC1=CC=CC(C#N)=C1 NJXPYZHXZZCTNI-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 description 1
- VTFGJEYZCUWSAM-UHFFFAOYSA-N 3-methoxy-5-(trifluoromethyl)aniline Chemical compound COC1=CC(N)=CC(C(F)(F)F)=C1 VTFGJEYZCUWSAM-UHFFFAOYSA-N 0.000 description 1
- ZFMZSZMUFWRAOG-UHFFFAOYSA-N 3-methoxy-n-methylaniline Chemical compound CNC1=CC=CC(OC)=C1 ZFMZSZMUFWRAOG-UHFFFAOYSA-N 0.000 description 1
- URYLDVBESOMXLR-UHFFFAOYSA-N 3-methoxydibenzofuran-4-amine Chemical compound C1=CC=C2C3=CC=C(OC)C(N)=C3OC2=C1 URYLDVBESOMXLR-UHFFFAOYSA-N 0.000 description 1
- WYDJMBLMXGCHOL-UHFFFAOYSA-N 3-methyl-5-(trifluoromethyl)aniline Chemical compound CC1=CC(N)=CC(C(F)(F)F)=C1 WYDJMBLMXGCHOL-UHFFFAOYSA-N 0.000 description 1
- HHSBHVJQXZLIRW-UHFFFAOYSA-N 3-n,3-n-dimethylbenzene-1,3-diamine Chemical compound CN(C)C1=CC=CC(N)=C1 HHSBHVJQXZLIRW-UHFFFAOYSA-N 0.000 description 1
- XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical compound NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 description 1
- MUNOBADFTHUUFG-UHFFFAOYSA-N 3-phenylaniline Chemical group NC1=CC=CC(C=2C=CC=CC=2)=C1 MUNOBADFTHUUFG-UHFFFAOYSA-N 0.000 description 1
- IGPFOKFDBICQMC-UHFFFAOYSA-N 3-phenylmethoxyaniline Chemical compound NC1=CC=CC(OCC=2C=CC=CC=2)=C1 IGPFOKFDBICQMC-UHFFFAOYSA-N 0.000 description 1
- XCCNRBCNYGWTQX-UHFFFAOYSA-N 3-propan-2-ylaniline Chemical compound CC(C)C1=CC=CC(N)=C1 XCCNRBCNYGWTQX-UHFFFAOYSA-N 0.000 description 1
- QMGBIPKOKCSUCL-UHFFFAOYSA-N 3-propan-2-yloxyaniline Chemical compound CC(C)OC1=CC=CC(N)=C1 QMGBIPKOKCSUCL-UHFFFAOYSA-N 0.000 description 1
- GDSQTWDUCDSZEY-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-indazole Chemical compound C1CCCC2=C1C=NN2 GDSQTWDUCDSZEY-UHFFFAOYSA-N 0.000 description 1
- REGFWZVTTFGQOJ-UHFFFAOYSA-N 4,5-dihydro-1,3-thiazol-2-amine Chemical compound NC1=NCCS1 REGFWZVTTFGQOJ-UHFFFAOYSA-N 0.000 description 1
- LVFRCHIUUKWBLR-UHFFFAOYSA-N 4,6-dimethoxypyrimidin-2-amine Chemical compound COC1=CC(OC)=NC(N)=N1 LVFRCHIUUKWBLR-UHFFFAOYSA-N 0.000 description 1
- RZJHEWQAORJNGN-UHFFFAOYSA-N 4-(4-chloro-6-methylpyrimidin-2-yl)morpholine Chemical compound CC1=CC(Cl)=NC(N2CCOCC2)=N1 RZJHEWQAORJNGN-UHFFFAOYSA-N 0.000 description 1
- RBZMQEYAQRKOQQ-UHFFFAOYSA-N 4-(4-chlorophenyl)-6-(4-methoxyanilino)-2-pyridin-2-ylpyrimidine-5-carbonitrile Chemical compound C1=CC(OC)=CC=C1NC1=NC(C=2N=CC=CC=2)=NC(C=2C=CC(Cl)=CC=2)=C1C#N RBZMQEYAQRKOQQ-UHFFFAOYSA-N 0.000 description 1
- BCZUTFTXOOUHBV-UHFFFAOYSA-N 4-(6-chloro-2-phenylpyrimidin-4-yl)morpholine Chemical compound N=1C(Cl)=CC(N2CCOCC2)=NC=1C1=CC=CC=C1 BCZUTFTXOOUHBV-UHFFFAOYSA-N 0.000 description 1
- RCOVTJVRTZGSBP-UHFFFAOYSA-N 4-(chloromethyl)benzoyl chloride Chemical compound ClCC1=CC=C(C(Cl)=O)C=C1 RCOVTJVRTZGSBP-UHFFFAOYSA-N 0.000 description 1
- VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- ORBHQHXVVMZIDP-UHFFFAOYSA-N 4-bromo-1-methoxy-2-nitrobenzene Chemical compound COC1=CC=C(Br)C=C1[N+]([O-])=O ORBHQHXVVMZIDP-UHFFFAOYSA-N 0.000 description 1
- XBAPOWUMJRIKAV-UHFFFAOYSA-N 4-chloro-2-methoxy-5-methylaniline Chemical compound COC1=CC(Cl)=C(C)C=C1N XBAPOWUMJRIKAV-UHFFFAOYSA-N 0.000 description 1
- OBHKONRNYCDRKM-UHFFFAOYSA-N 4-chloro-2-phenylquinazoline Chemical compound N=1C2=CC=CC=C2C(Cl)=NC=1C1=CC=CC=C1 OBHKONRNYCDRKM-UHFFFAOYSA-N 0.000 description 1
- JUIKCULGDIZNDI-UHFFFAOYSA-N 4-chloro-3-nitrophenol Chemical compound OC1=CC=C(Cl)C([N+]([O-])=O)=C1 JUIKCULGDIZNDI-UHFFFAOYSA-N 0.000 description 1
- ZTPMWAWOZJXEMH-UHFFFAOYSA-N 4-chloro-6-(trifluoromethyl)-2-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine Chemical compound C1=NC(C(F)(F)F)=CC=C1C1=NC(Cl)=CC(C(F)(F)F)=N1 ZTPMWAWOZJXEMH-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- XAACOEWSHBIFGJ-UHFFFAOYSA-N 4-fluoro-3-methoxyaniline Chemical compound COC1=CC(N)=CC=C1F XAACOEWSHBIFGJ-UHFFFAOYSA-N 0.000 description 1
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 1
- LVILGAOSPDLNRM-UHFFFAOYSA-N 4-methylpyrimidine Chemical compound CC1=CC=NC=N1 LVILGAOSPDLNRM-UHFFFAOYSA-N 0.000 description 1
- XVAJKPNTGSKZSQ-UHFFFAOYSA-N 4-morpholinobenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1N1CCOCC1 XVAJKPNTGSKZSQ-UHFFFAOYSA-N 0.000 description 1
- DCCYXIFZFBJLHE-UHFFFAOYSA-N 4-n,4-n-dimethyl-1-n-[6-methyl-2-(3-methylphenyl)pyrimidin-4-yl]benzene-1,4-diamine Chemical compound C1=CC(N(C)C)=CC=C1NC1=CC(C)=NC(C=2C=C(C)C=CC=2)=N1 DCCYXIFZFBJLHE-UHFFFAOYSA-N 0.000 description 1
- UIEQRHBRBYGBRC-UHFFFAOYSA-N 5-(3-aminophenyl)-1-ethyl-2-phenylpyrazol-3-one Chemical compound CCN1C(C=2C=C(N)C=CC=2)=CC(=O)N1C1=CC=CC=C1 UIEQRHBRBYGBRC-UHFFFAOYSA-N 0.000 description 1
- PYXNITNKYBLBMW-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrazole Chemical compound FC(F)(F)C1=CC=NN1 PYXNITNKYBLBMW-UHFFFAOYSA-N 0.000 description 1
- ANWMULVRPAUPJT-UHFFFAOYSA-N 5-Methylcytosine hydrochloride Chemical compound Cl.CC=1C=NC(=O)NC=1N ANWMULVRPAUPJT-UHFFFAOYSA-N 0.000 description 1
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- QPHMVRPABQUYGN-UHFFFAOYSA-N 5-amino-2,4-dichlorophenol Chemical compound NC1=CC(O)=C(Cl)C=C1Cl QPHMVRPABQUYGN-UHFFFAOYSA-N 0.000 description 1
- OJQYZICTUHBDSJ-UHFFFAOYSA-N 5-chloro-2-methylpyrimidin-4-amine Chemical compound CC1=NC=C(Cl)C(N)=N1 OJQYZICTUHBDSJ-UHFFFAOYSA-N 0.000 description 1
- JLCDTNNLXUMYFQ-UHFFFAOYSA-N 5-fluoro-2-methylaniline Chemical compound CC1=CC=C(F)C=C1N JLCDTNNLXUMYFQ-UHFFFAOYSA-N 0.000 description 1
- PEIGETRPPZVBHT-UHFFFAOYSA-N 5-methoxy-2-methyl-4-nitroaniline Chemical compound COC1=CC(N)=C(C)C=C1[N+]([O-])=O PEIGETRPPZVBHT-UHFFFAOYSA-N 0.000 description 1
- QEHVRGACCVLLNN-UHFFFAOYSA-N 5-methoxy-2-nitroaniline Chemical compound COC1=CC=C([N+]([O-])=O)C(N)=C1 QEHVRGACCVLLNN-UHFFFAOYSA-N 0.000 description 1
- ZURTUAPORLJXKN-UHFFFAOYSA-N 5-methoxy-n-(3-methoxyphenyl)-2-pyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2C(=CN=C(N=2)C=2N=CC=CC=2)OC)=C1 ZURTUAPORLJXKN-UHFFFAOYSA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- HEJHFZBJXIMGQF-UHFFFAOYSA-N 6-(trifluoromethyl)pyridine-3-carboximidamide Chemical compound NC(=N)C1=CC=C(C(F)(F)F)N=C1 HEJHFZBJXIMGQF-UHFFFAOYSA-N 0.000 description 1
- UUVDJIWRSIJEBS-UHFFFAOYSA-N 6-methoxypyridin-3-amine Chemical compound COC1=CC=C(N)C=N1 UUVDJIWRSIJEBS-UHFFFAOYSA-N 0.000 description 1
- YBYHRGZOBGFPDX-UHFFFAOYSA-N 6-tert-butyl-2-pyridin-3-yl-1h-pyrimidin-4-one Chemical compound CC(C)(C)C1=CC(O)=NC(C=2C=NC=CC=2)=N1 YBYHRGZOBGFPDX-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-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
- 229940027041 8-mop Drugs 0.000 description 1
- 244000215068 Acacia senegal Species 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
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- BWKDAAFSXYPQOS-UHFFFAOYSA-N Benzaldehyde glyceryl acetal Chemical compound O1CC(O)COC1C1=CC=CC=C1 BWKDAAFSXYPQOS-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 241000244203 Caenorhabditis elegans Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 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 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- 230000035519 G0 Phase Effects 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 208000019758 Hypergammaglobulinemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000008771 Lymphadenopathy Diseases 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical compound C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 239000007990 PIPES buffer Substances 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010041660 Splenomegaly Diseases 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000033540 T cell apoptotic process Effects 0.000 description 1
- 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 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- SMEGJBVQLJJKKX-HOTMZDKISA-N [(2R,3S,4S,5R,6R)-5-acetyloxy-3,4,6-trihydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@@H]1[C@H]([C@@H]([C@H]([C@@H](O1)O)OC(=O)C)O)O SMEGJBVQLJJKKX-HOTMZDKISA-N 0.000 description 1
- YKNZTUQUXUXTLE-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(C(F)(F)F)=C1 YKNZTUQUXUXTLE-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010398 acute inflammatory response Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 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
- 150000001447 alkali salts Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000005005 aminopyrimidines Chemical class 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 108700041737 bcl-2 Genes Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 244000309464 bull Species 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 101150112018 ced-4 gene Proteins 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- 229940075419 choline hydroxide Drugs 0.000 description 1
- 230000010428 chromatin condensation Effects 0.000 description 1
- 230000010405 clearance mechanism Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- LGLFFNDHMLKUMI-UHFFFAOYSA-N crystal violet cation Chemical compound C1=CC(N(C)C)=CC=C1C(C=1C=CC(=CC=1)N(C)C)=C1C=CC(=[N+](C)C)C=C1 LGLFFNDHMLKUMI-UHFFFAOYSA-N 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 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
- 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
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 230000008519 endogenous mechanism Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000036566 epidermal hyperplasia Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229960001235 gentian violet Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 1
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical class O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012092 media component Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- KZVPMNGUFGVZHA-UHFFFAOYSA-N n-(2,3-dimethoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1OC KZVPMNGUFGVZHA-UHFFFAOYSA-N 0.000 description 1
- CQFCGALYAPNPPM-UHFFFAOYSA-N n-(2-chloro-5-methoxyphenyl)-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidin-4-amine Chemical compound N=1C(C=2N=C(C)SC=2)=NC(COC)=CC=1NC1=CC(OC)=CC=C1Cl CQFCGALYAPNPPM-UHFFFAOYSA-N 0.000 description 1
- LVORAGJKVJIRLW-UHFFFAOYSA-N n-(2-methoxyphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound COC1=CC=CC=C1NC1=CC(C)=NC(C=2N=CC=CC=2)=N1 LVORAGJKVJIRLW-UHFFFAOYSA-N 0.000 description 1
- VLFHXTUERUHJPB-UHFFFAOYSA-N n-(3,5-dichlorophenyl)-4-pyrrol-1-yl-1,3,5-triazin-2-amine Chemical compound ClC1=CC(Cl)=CC(NC=2N=C(N=CN=2)N2C=CC=C2)=C1 VLFHXTUERUHJPB-UHFFFAOYSA-N 0.000 description 1
- XCFCRXIGDLMJLO-UHFFFAOYSA-N n-(3-ethylphenyl)-6-methyl-2-pyridin-2-ylpyrimidin-4-amine Chemical compound CCC1=CC=CC(NC=2N=C(N=C(C)C=2)C=2N=CC=CC=2)=C1 XCFCRXIGDLMJLO-UHFFFAOYSA-N 0.000 description 1
- UMOFCHDIDXZHIT-UHFFFAOYSA-N n-(3-methoxyphenyl)-2-pyridin-3-yl-6-(trifluoromethyl)pyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C=2)C(F)(F)F)C=2C=NC=CC=2)=C1 UMOFCHDIDXZHIT-UHFFFAOYSA-N 0.000 description 1
- HWATVKQODWAFEM-UHFFFAOYSA-N n-(3-methoxyphenyl)-6-methyl-2-(3-methylphenyl)pyrimidin-4-amine Chemical compound COC1=CC=CC(NC=2N=C(N=C(C)C=2)C=2C=C(C)C=CC=2)=C1 HWATVKQODWAFEM-UHFFFAOYSA-N 0.000 description 1
- QRAUYZNJQJFUOM-UHFFFAOYSA-N n-(4-methoxyphenyl)-2-phenylquinazolin-4-amine Chemical compound C1=CC(OC)=CC=C1NC1=NC(C=2C=CC=CC=2)=NC2=CC=CC=C12 QRAUYZNJQJFUOM-UHFFFAOYSA-N 0.000 description 1
- RETAGFDJWROGOY-UHFFFAOYSA-N n-(4-methoxyphenyl)-6-methyl-2-(3-methylphenyl)pyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1NC1=CC(C)=NC(C=2C=C(C)C=CC=2)=N1 RETAGFDJWROGOY-UHFFFAOYSA-N 0.000 description 1
- BDQAGVLMJNNPCS-UHFFFAOYSA-N n-(4-methoxyphenyl)-6-methyl-2-phenylpyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1NC1=CC(C)=NC(C=2C=CC=CC=2)=N1 BDQAGVLMJNNPCS-UHFFFAOYSA-N 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 230000006654 negative regulation of apoptotic process Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 210000000633 nuclear envelope Anatomy 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
- 125000002347 octyl group Chemical group [H]C([*])([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 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000002071 phenylalkoxy group Chemical group 0.000 description 1
- 125000004660 phenylalkylthio group Chemical group 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 230000009894 physiological stress Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- KNXKVYCVGXFLES-UHFFFAOYSA-N pyridine-2-carboximidamide Chemical compound NC(=N)C1=CC=CC=N1 KNXKVYCVGXFLES-UHFFFAOYSA-N 0.000 description 1
- GMHCEDDZKAYPLB-UHFFFAOYSA-N pyridine-2-carboximidamide;hydrochloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=CC=N1 GMHCEDDZKAYPLB-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- IIHQNAXFIODVDU-UHFFFAOYSA-N pyrimidine-2-carbonitrile Chemical compound N#CC1=NC=CC=N1 IIHQNAXFIODVDU-UHFFFAOYSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 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
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- 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
-
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- 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
- C07D417/14—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 three or more hetero rings
Definitions
- This invention is in the field of medicinal chemistry.
- the invention relates to substituted 2-aryl-4-arylaminopyrimidines and analogs, and the discovery that these compounds are activators of caspases and inducers of apoptosis.
- the invention also relates to the use of these compounds as therapeuticaUy effective anti-cancer agents.
- Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-431 (1965); Ellis, et al, Dev. 112:591-603 (1991); Vaux, et al., Cell 76:111-119 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721).
- Apoptosis is achieved through an endogenous mechanism of cellular suicide (Wyllie, A.H., in Cell Death in Biology and Pathology, Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34).
- a cell activates its internally encoded suicide program as a result of either internal or external signals.
- the suicide program is executed through the activation of a carefully regulated genetic program (Wyllie, et al, Int. Rev. Cyt. 68:251 (1980); Ellis, et al, Ann. Rev. Cell Bio. 7:663 (1991)).
- Apoptotic cells and bodies are usually recognized and cleared by neighboring cells or macrophages before lysis. Because of this clearance mechanism, inflammation is not induced despite the clearance of great numbers of cells (Orrenius, S., J. Internal Medicine 237:529-536 (1995)).
- caspase family of cysteine proteases comprises 14 different members, and more may be discovered in the future. All known caspases are synthesized as zymogens that require cleavage at an aspartyl residue prior to forming the active enzyme. Thus, caspases are capable of activating other caspases, in the manner of an amplifying cascade.
- Apoptosis and caspases are thought to be crucial in the development of cancer ⁇ Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds., Humana Press (1999)).
- cancer cells while containing caspases, lack parts of the molecular machinery that activates the caspase cascade. This makes the cancer cells lose their capacity to undergo cellular suicide and the cells become cancerous.
- control points are known to exist that represent points for intervention leading to activation.
- CED-9-BCL-like and CED-3-ICE-like gene family products are intrinsic proteins regulating the decision of a cell to survive or die and executing part of the cell death process itself, respectively (see, Schmitt, et al, Biochem. Cell. Biol. 75:301- 314 (1997)).
- BCL-like proteins include BCL-xL and BAX-alpha, which appear to function upstream of caspase activation.
- BCL-xL appears to prevent activation of the apoptotic protease cascade, whereas BAX-alpha accelerates activation of the apoptotic protease cascade.
- chemotherapeutic drugs can trigger cancer cells to undergo suicide by activating the dormant caspase cascade. This may be a crucial aspect of the mode of action of most, if not all, known anticancer drugs (Los, et al, Blood P0:3118-3129 (1997); Friesen, et al, Nat. Med. 2:514 (1996)).
- the mechanism of action of current antineoplastic drugs frequently involves an attack at specific phases of the cell cycle.
- the cell cycle refers to the stages through which cells normally progress during their lifetimes. Normally, cells exist in a resting phase termed G 0 . During multiplication, cells progress to a stage in which DNA synthesis occurs, termed S.
- Antineoplastic drugs such as cytosine arabinoside, hydroxyurea, 6-mercaptopurine, and methotrexate are S phase specific, whereas antineoplastic drugs such as vincristine, vinblastine, and paclitaxel are M phase specific.
- Many slow growing tumors for example colon cancers, exist primarily in the G 0 phase, whereas rapidly proliferating normal tissues, for example bone marrow, exist primarily in the S or M phase.
- a drug like 6-mercaptopurine can cause bone marrow toxicity while remaining ineffective for a slow growing tumor.
- Ri is H, alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, alkenyl, alkynyl, cycloalkyalkyl, substituted aminoalkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylmercaptoalkyl or phenoxyphenoxyalkyl, wherein the phenyl-portions are optionally substituted;
- R 2 , R 3 , R 4 independently are H, alkyl or optionally substituted phenyl;
- R 5 is H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkoxy, alkylthio, alkoxyalkyl, R 7 R 8 N-, alkylthioalkyl, R 7 R 8 -alkyl, halogen, alkenyl, alkynyl, phenyl, phenoxy, phenylalkyl, phenoxyalkyl, phenylmercaptoalkyl, phenylmercapto, phenylalkoxy or phenylalkylthio, wherein the phenyl- portions are optionally substituted;
- R ⁇ 5 is H, alkyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio, halogen or optionally substituted phenyl; or R 5 and R are taken together to form a polymethylene group;
- R 7 and R 8 independently are H, alkyl, alkoxyalkyl, hydroxyalkyl, alkylthioalkyl, alkenyl, substituted aminoalkyl, alkynyl, cycloalkyl, cycloalkylalkyl, which in the cycloalkyl-portion is optionally substituted, formyl, phenyl or phenylalkyl, which in the phenyl-portion is optionally substituted; or
- R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 5- to 7-member, saturated or unsaturated, heterocycle with 1 or 3 heteroatoms, which are the same or different; and the acid addition salts which are functional as fungicides.
- WO 0127089 patent application discloses pyrimidine derivatives for the treatment of diseases or medical conditions mediated by cytokines:
- each R 1 group which may be the same or different, is selected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulphamoyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, (1- 6C)alkylamino, di[(l-6C)alkyl]amino, (l-6C)alkoxy carbonyl, N-(l- 6C)alkycarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2- 6C)alkanoyloxy, (2-6C)alkanoylamino, N-(l -6C)
- X 1 is a direct bond or is selected from O, S, SO, SO 2 , N(R 4 ),CO, CH(OR 4 ), CON(R 4 ), N(R 4 )CO, SO 2 N(R 4 ), N(R 4 ), N(R 4 )SO 2 , OC(R 4 ) 2 , SC(R 4 ) 2 and N(R 4 )C(R 4 ) 2 , wherein each R 4 is hydrogen or (l-6C)alkyl, and Q 2 is aryl-(l-6C)alkyl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l- 6C)alkyl, or (R ⁇ m is (l-3C)alkylenedioxy, and wherein any aryl, heteroaryl or heterocyclyl group within a substituted on R 1 optionally bears 1, 2 or 3 substituents,
- R 3 is hydrogen, halogeno or (l-6C)alkyl; n is 0, 1 or 2 and each R 2 group, which may be the same or different is selected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, (l-6C)alkoxycarbonyl, (l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylamino and di[(l-6C)alkyl]amino; p is O, 1, 2, 3, or 4; and
- Q 1 is aryl or heteroaryl and Q 1 is optionally substituted with 1, 2, or 3 substituents, which may be the same of different, selected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylthio, (1-6C) alkylsulphinyl, (1- 6C)alkylsulphonyl, (l-6C)alkylamino, di[(l-6C)alkyl]amino, (1- 6C)alkoxycarbonyl, N-(l-6C)alkycarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(2-6C)alky
- X 3 is a direct a bond or is selected from 0 and N(R 8 ), wherein R 8 is hydrogen or (l-6C)alkyl
- Q 4 is aryl, aryl-(l-6C)alkyl, heteroaryl, heteroaryl-(l-6C)-alkyl, heterocyclyl or heterocyclyl(l-6C)alkyl, and any Q 4 group optionally bears 1 or 2 substituents, which may be the same of different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylamino and di-[(l-6C)alkyl]amino.
- WO 0027824 patent application discloses substituted pyrimidine compositions and methods of use. The compounds are said to have activity as inhibitors of phospholipase A 2 , and are useful in treating disorders mediated by phospholipase A 2 :
- R t represents a C ⁇ -C 6 alkyl, CpC ⁇ alkoxy or halogen atom.
- the symbol R 2 represents a phenyl group, substituted phenyl group, benzyl moiety, substituted benzyl moiety, C 3 -C 7 cycloalkyl, or substituted C 3 -C 7 cycloalkyl.
- the symbol R 3 represents a hydrogen or C ⁇ -C 6 alkyl group.
- the symbol j represents -H, -OH, -N 3 or -NHCOCH 3 .
- the symbol R 5 represents H or alkyl, preferably H.
- R 1 is hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, (C ⁇ -C 6 )-alkyl, (C ⁇ -C 6 )-hydroxyalkyl, (C ⁇ -C 6 )-alkoxy, (C 6 -C ⁇ 2 )-aryl, (C ⁇ -C 6 )-alkoxycarbonyl- (C ⁇ -C 6 )-alkyl, (C 1 -C 6 )-alkyl-S-(C ⁇ -C 6 )-alkyl, (C 1 -C 6 )-alkyl-SO-(C 1 -C 6 )-alkyl, (C ⁇ -C 6 )-alkyl-SO 2 -(C ⁇ -C 6 )-alkyl, dihydroxy- ⁇ C ⁇ -alkyl, aryl, heteroaryl, heteroaryl-(C ⁇ -C 6 )-alkyl, aryl-(C 1 -C 6 )-alkyl, aryl-
- R 4 and R 5 independently of one another are hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, (C ⁇ -C 6 )-alkyl, (CrC ⁇ -hydroxyalkyl, ( -C ⁇ -alkoxy, (C 6 -C ⁇ 2 )-aryl, naphthyl, furyl, where (C 6 -C 12 )-aryl, naphthyl and furyl can be substituted by one or two substituents selected from the group consisting of chlorine, bromine, trifluoromethyl, (Q-C ⁇ -alkyl, (C ⁇ -C 6 )-alkoxy, -S-(CrC 6 )- alkyl, -SO-(C ⁇ -C 6 )-alkyl, -SO 2 -(C ⁇ -C 6 )-alkyl, hydroxyl; and their physiologically tolerable salts.
- the present invention is related to the discovery that substituted 2-aryl-
- 4-arylaminopyrimidines and analogs, as represented in Formula I, are activators of the caspase cascade and inducers of apoptosis.
- an aspect of the present invention is directed to the use of compounds of Formula I as inducers of apoptosis.
- Compounds of the present invention are represented by Formula I:
- Ar AT] and Ar 2 are independently and optionally substituted aryl or heteroaryl;
- A is N or C-R 2 ;
- Ri and R are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol; and
- R 3 is hydrogen, an optionally substituted alkyl or cycloalkyl.
- a second aspect of the present invention is to provide a method for treating, preventing or ameliorating neoplasia and cancer by administering a compound of Formula I to a mammal in need of such treatment.
- a third aspect of the present invention is to provide novel compounds of Formula I, and to also provide for the use of these novel compounds for treating, preventing or ameliorating neoplasia and cancer.
- a fourth aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the induction of apoptosis, containing an effective amount of a compound of Formula I in admixture with one or more pharmaceutically acceptable carriers or diluents.
- a fifth aspect of the present invention is directed to methods for the preparation of novel compounds of Formula I.
- Figs. 1A-B are graphs showing drug induced cell cycle arrest and apoptosis in T47D cells.
- Fig. 1 A control cells showing most of the cells in GI phase of the cell cycle (M2).
- Fig. IB cells treated with 200 nM of 4-(3- methoxyamTino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine for 48 h showing a reduction in the GI population (M2), an increase in the G2 M population (M4) and the sub-diploid DNA population of cells (Ml).
- Fig. 2 is a graph showing inhibition of clonogenic survival of MX-1 and T47D cells treated for 48 h with different concentrations of 4-(3- methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine.
- Fig. 2 shows increasing inhibition of clonogenicity with increasing drug concentration, with IC50 of about 100 nM and 300 nM for T47D and MX-1 cells, respectively.
- the present invention arises out of the discovery that substituted 2- aryl-4-arylaminopyrimidines and analogs, as represented in Formula I, are potent and highly efficacious activators of the caspase cascade and inducers of apoptosis. Therefore compounds of Formula I are useful for treating disorders responsive to induction of apoptosis.
- Arr and Ar 2 are independently and optionally substituted aryl or heteroaryl;
- A is N or C-R 2 ;
- Ri and R 2 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol; and R 3 is hydrogen, an optionally substituted alkyl or cycloalkyl.
- Preferred compounds of Formula I include compounds wherein Ari or
- Ar 2 is optionally substituted phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, isoquinolyl, thienyl, furyl, or pyrrolyl.
- Preferred compounds of Formula I also include compounds wherein R 3 is hydrogen.
- Preferred compounds of Formula I also include compounds wherein A is C- R 2 .
- Especially preferred compounds of Formula I include compounds wherein Aii is optionally substituted pyridinyl, pyrimidinyl and pyrazinyl.
- Ar 2 is optionally substituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl.
- Ar 2 are as defined in Formula I;
- B is N or C-R ⁇
- D is N or C-R 5 ;
- E is N or C-R 6 ;
- F is N or C-R 7 ;
- G is N or C-R 8 ; and Rj-Rs are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol; provided that not more than three of B, D, E, F and G are N.
- Preferred compounds falling within the scope of Formula II include compounds wherein Ri is an optionally substituted alkyl, haloalkyl or phenyl. Preferred compounds of Formula II also include compounds wherein Ar 2 is an optionally substituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl and indolyl. Preferred compounds of Formula II also include compounds wherein B is nitrogen, D is C-R 5 , E is C-R 6 , F is C-R , and G is C-R 8 . Preferred compounds of Formula II also include compounds wherein D is nitrogen, B is C-R 4 , E is C-Re, F is C-R , and G is C-R 8 .
- Preferred compounds of Formula II also include compounds wherein E is nitrogen, D is C-R 5 , B is C-Ri, F is C-R 7 , and G is C-R 8 .
- Preferred compounds of Formula II also include compounds wherein two of B, D, E, F and G are N.
- RT-R 3 , and B, D, E, F and G are as defined in Formula I and II;
- R 9 -R 13 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, haloalkoxy, carboxy, carbonylamido or alkylthiol.
- Preferred compounds falling within the scope of Formula III include compounds wherein Ri is an optionally substituted alkyl, haloalkyl. Preferred compounds of Formula III also include compounds wherein R 2 is hydrogen. Preferred compounds of Formula III also include compounds wherein one of the B, D, E, F and G is nitrogen. Preferred compounds of Formula III also include compounds wherein two of the B, D, E, F and G is nitrogen. Preferred compounds of Formula III also include compounds wherein Rio or R ⁇ 2 are not hydrogen. Preferred compounds of Formula III also include compounds wherein R 9 and R ⁇ 2 are not hydrogen. Preferred compounds of Formula III also include compounds wherein Rio and R ⁇ 2 are not hydrogen. Preferred compounds of Formula III also include compounds wherein R 9 , R ⁇ and R ⁇ 2 are not hydrogen. Preferred compounds of Formula III also include compounds wherein R 9 , R ⁇ and R ⁇ 2 are not hydrogen. [0027] Exemplary preferred compounds that may be employed in the method of the invention include, without limitation:
- Useful alkyl groups include straight-chained and branched Cno alkyl groups, more preferably C ⁇ . 6 alkyl groups.
- Typical CM O alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups, which may be optionally substituted.
- Useful alkoxy groups include oxygen substituted by one of the Ci-io alkyl groups mentioned above, which may be optionally substituted.
- Useful alkylthio groups include sulphur substituted by one of the Ci-io alkyl groups mentioned above, which may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.
- Useful amino groups include -NH 2 , -NHR 15 and -NR ⁇ 5 R ⁇ 6 , wherein
- R ⁇ 5 and R ⁇ 6 are C MO alkyl or cycloalkyl groups, or R ⁇ 5 and R ⁇ 6 are combined with the N to form a ring structure, such as a piperidine, or R ⁇ 5 and R ⁇ 6 are combined with the N and other group to form a ring, such as a piperazine.
- the alkyl group may be optionally substituted.
- Optional substituents on the alkyl and cycloalkyl groups include one or more halo, hydroxy, carboxyl, amino, nitro, cyano, C ⁇ -C 6 acylamino, C ⁇ -C 6 acyloxy, C ⁇ -C 6 alkoxy, aryloxy, alkylthio, C 6 -C ⁇ o aryl, C 4 -C cycloalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C ⁇ o aryl(C 2 -C 6 )alkenyl, C 6 -C ⁇ o aryl(C 2 - C 6 )alkynyl, saturated and unsaturated heterocyclic or heteroaryl.
- Optional substituents on the aryl, arylalkyl and heteroaryl groups include one or more halo, C ⁇ -C 6 haloalkyl, C 6 -C ⁇ o aryl, C 4 -C 7 cycloalkyl, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C ⁇ 0 aryl(C ⁇ -C 6 )alkyl, C 6 -C ⁇ 0 aryl(C 2 -C 6 )alkenyl, C 6 -C ⁇ o aryl(C 2 -C 6 )alkynyl, C ⁇ -C 6 hydroxyalkyl, nitro, amino, ureido, cyano, C ⁇ -C 6 acylamino, hydroxy, thiol, C ⁇ -C 6 acyloxy, azido, C ⁇ -C 6 alkoxy or carboxy.
- aryl as employed herein by itself or as part of another group refers to monocyclic, bicyclic or tricyclic aromatic groups containing from 6 to 14 carbons in the ring portion.
- Useful aryl groups include C 6 _ ⁇ 4 aryl, preferably C 6 - ⁇ o aryl. Typical
- C 6 . ⁇ 4 aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
- Useful cycloalkyl groups are C 3 . 8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. [0038] Useful saturated or partially saturated carbocyclic groups are cycloalkyl groups as described above, as well as cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.
- Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.
- Useful arylalkyl groups include any of the above-mentioned Ci-io alkyl groups substituted by any of the above-mentioned C 6 - ⁇ 4 aryl groups.
- the arylalkyl group is benzyl, phenylethyl or naphthylmethyl.
- Useful haloalkyl groups include Ci-io alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.
- acylamino (acylamido) groups are any C ⁇ - 6 acyl (alkanoyl) attached to an amino nitrogen, e.g., acetamido, chloroacetamido, propionamido, butanoylamido, pentanoylamido and hexanoylamido, as well as aryl-substituted C ⁇ . 6 acylamino groups, e.g., benzoylamido, and pentafluorobenzoylamido .
- Useful acyloxy groups are any C ⁇ . 6 acyl (alkanoyl) attached to an oxy
- (-O-) group e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy.
- heterocycle is used herein to mean a saturated or partially saturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms ' independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
- Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.
- heteroaryl refers to groups having 5 to
- Useful heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, ⁇ -carbolinyl
- heteroaryl group contains a nitrogen atom in a ring
- nitrogen atom may be in the form of an N-oxide, e.g., a pyridinyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
- Some of the compounds of the present invention may exist as stereoisomers including optical isomers.
- the invention includes all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
- Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base addition salts with bases such as sodium hydroxy, Tris(hydroxymethyl)aminomethane (TRIS, tromethane) and N-methyl-glucamine.
- inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate
- inorganic and organic base addition salts with bases such as sodium hydroxy, Tris(hydroxymethyl)aminomethane (TRIS, tromethane) and N-methyl-glucamine.
- prodrugs of the compounds of the invention include the simple esters of carboxylic acid containing compounds (e.g., those obtained by condensation with a C alcohol according to methods known in the art); esters of hydroxy containing compounds (e.g., those obtained by condensation with a Cm carboxylic acid, C 3 . 6 dioic acid or anhydride thereof such as succinic and fumaric anhydrides according to methods known in the art); phosphate of hydroxy containing compounds (e.g. combretastatin A-l phosphate prodrug, see Pettit G. R. and Lippert III, J.
- carboxylic acid containing compounds e.g., those obtained by condensation with a C alcohol according to methods known in the art
- esters of hydroxy containing compounds e.g., those obtained by condensation with a Cm carboxylic acid, C 3 . 6 dioic acid or anhydride thereof such as succinic and fumaric anhydrides according to methods known in the art
- the compounds of this invention may be prepared using methods known to those skilled in the art, or the novel methods of this invention. Specifically, the compounds of this invention with Formulae I-III may be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of 4- chloro-6-methyl-2-(2-pyridinyl)pyrimidine with aniline gave the product 4- anilino-6-methyl-2-(2-pyridinyl)pyrimidine.
- the 2-aryl-4-chloro-pyrimidine may be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of pyridine-2-carboxamidine with 4,4,4-trifluoro-but-2-ynoic acid ethyl ester in ethanol in the presence of base such as KOH produced the substituted 4-hydroxy-pyrimidine. Treatment of the hydroxy-pyrimidine with POCI 3 gave the product 4-chloro-2-(2-pyridinyl)- 6-trifluoromethylpyrimidine.
- the 2-aryl-4-chloro-pyrimidine may be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of pyrimidine-2- carboxamidine with ethyl 4,4,4-trifluoro-acetoacetate in ethanol in the presence of base such as EtONa produced the substituted 4-hydroxy- pyrimidine. Treatment of the hydroxy-pyrimidine with POCI3 gave the product 4-chloro-2-(2-pyrimidinyl)-6-trifluoromethylpyrimidine.
- An important aspect of the present invention is the discovery that compounds having Formula I-III are activators of caspases and inducers of apoptosis. Therefore, these compounds are useful in a variety of clinical conditions in which there is uncontrolled cell growth and spread of abnormal cells, such as in the case of cancer.
- Another important aspect of the present invention is the discovery that compounds having Formula I-III are potent and highly efficacious activators of caspases and inducers of apoptosis in drug resistant cancer cells, such as breast cancer cells (Examples 11-14), which enables these compounds to kill these drug resistant cancer cells.
- drug resistant cancer cells such as breast cancer cells (Examples 11-14)
- most standard anti-cancer drugs are not effective in killing drug resistant cancer cells under the same conditions. Therefore, compounds of this invention are useful for the treatment of drug resistant cancer such as breast cancer in animals.
- the present invention includes a therapeutic method useful to modulate in vivo apoptosis or in vivo neoplastic disease, comprising administering to a subject in need of such treatment an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis.
- the present invention also includes a therapeutic method comprising administering to an animal an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I- III, wherein said therapeutic method is useful to treat cancer, which is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells.
- Such diseases include, but are not limited to, Hodgkin's disease, non- Hodgkin's lymphomas, acute lymphatic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinomas, ovarian carcinomas, lung carcinomas, Wilms' tumor, cervical carcinomas, testicular carcinomas, soft-tissue sarcomas, primary macroglobulinemia, bladder carcinomas, chronic granulocytic leukemia, primary brain carcinomas, malignant melanoma, small-cell lung carcinomas, stomach carcinomas, colon carcinomas, malignant pancreatic insulinoma, malignant carcinoid carcinomas, malignant melanomas, choriocarcinomas, mycosis fungoides, head or neck carcinomas, osteogenic sarcoma, pancreatic carcinomas, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's
- compositions containing therapeuticaUy effective concentrations of the compounds formulated for oral, intravenous, local and topical application, for the treatment of neoplastic diseases and other diseases in which caspase cascade mediated physiological responses are implicated are administered to an individual exhibiting the symptoms of one or more of these disorders.
- the amounts are effective to ameliorate or eliminate one or more symptoms of the disorders.
- An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce, the symptoms associated with the disease.
- Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
- the amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms
- a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt of said compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis in combination with a pharmaceutically acceptable vehicle is provided.
- Another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I- III, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.
- cancer chemotherapeutic agents which may be used for combination therapy include, but not are limited to alkylating agents such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents such as colchicine, vinblastine, paclitaxel, and docetaxel; topo I inhibitors such as camptothecin and topotecan; topo II inhibitors such as doxorubicin and etoposide; RNA/DNA antimetabolites such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites such as 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea and thioguanine; antibodies such as Herceptin® and Rituxan®.
- alkylating agents such as busulfan, cis-platin, mitomycin C, and carboplatin
- antimitotic agents such as colchicine, vinblastine, paclitaxel, and docetaxel
- cancer chemotherapeutic agents which may be used for combination therapy include melphalan, chlorambucil, cyclophosphamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen and alanosine.
- the compound of the invention may be administered together with at least one known chemotherapeutic agent as part of a unitary pharmaceutical composition.
- the compound of the invention may be administered apart from at least one known cancer chemotherapeutic agent.
- the compound of the invention and at least one known cancer chemotherapeutic agent are administered substantially simultaneously, i.e. the compounds are administered at the same time or one after the other, so long as the compounds reach therapeutic levels in vivo at the same time.
- the compound of the invention and at least one known cancer chemotherapeutic agent are administered according to their individual dose schedule, so long as the compounds reach therapeutic levels in vivo.
- Another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a bioconjugates of said compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis, in bioconjugation with at least one known therapeuticaUy useful antibody, such as Herceptin® or Rituxan®, growth factors such as EGF, NGF, cytokines such as IL-2, IL-4, or any molecule that binds to the cell surface.
- the antibodies and other molecules will deliver the compound of Formulae I-III to its targets and make it an effective anticancer agent.
- the bioconjugates could also enhance the anticancer effect of therapeuticaUy useful antibodies, such as Herceptin® or Rituxan®.
- another embodiment of the present invention is directed to a composition effective in inhibiting neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I- III, which functions as a caspase cascade activator and inducer of apoptosis, in combination with radiation therapy.
- the compound of the invention may be administered at the same time as the radiation therapy is administered or at a different time.
- Yet another embodiment of the present invention is directed to a composition effective for post-surgical treatment of cancer, comprising a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis.
- the invention also relates to a method of treating cancer by surgically removing the cancer and then treating the animal with one of the pharmaceutical compositions described herein.
- a wide range of immune mechanisms operate rapidly following exposure to an infectious agent. Depending on the type of infection, rapid clonal expansion of the T and B lymphocytes occurs to combat the infection. The elimination of the effector cells following an infection is one of the major mechanisms for maintaining immune homeostasis.
- autoimmune diseases have lately been determined to occur as a consequence of deregulated cell death.
- the immune system directs its powerful cytotoxic effector mechanisms against specialized cells such as oligodendrocytes in multiple sclerosis, the beta cells of the pancreas in diabetes mellitus, and thyrocytes in Hashimoto's thyroiditis (Ohsako, S. & Elkon, K.B., Cell Death Differ. 6:13-21 (1999)).
- lymphocyte apoptosis receptor Fas/APO-l/CD95 are reported to be associated with defective lymphocyte apoptosis and autoimmune lymphoproliferative syndrome (ALPS), which is characterized by chronic, histologically benign splenomegaly, generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation.
- APS autoimmune lymphoproliferative syndrome
- Fas-Fas ligand (FasL) interaction is known to be required for the maintenance of immune homeostasis.
- Experimental autoimmune thyroiditis (EAT) characterized by autoreactive T and B cell responses and a marked lymphocytic infiltration of the thyroid, is a good model to study the therapeutic effects of FasL. Batteux, F., et al, (J. Immunol.
- FasL expression on thyrocytes may have a curative effect on ongoing EAT by inducing death of pathogenic autoreactive infiltrating T lymphocytes.
- Bisindolylmaleimide VIII is known to potentiate Fas-mediated apoptosis in human astrocytoma 1321N1 cells and in Molt-4T cells; both of which were resistant to apoptosis induced by anti-Fas antibody in the absence of bisindolylmaleimide VIII. Potentiation of Fas-mediated apoptosis by bisindolylmaleimide VIII was reported to be selective for activated, rather than non-activated, T cells, and was Fas-dependent. Zhou T., et al, (Nat. Med.
- Psoriasis is a chronic skin disease that is characterized by scaly red patches.
- Psoralen plus ultraviolet A (PUVA) is a widely used and effective treatment for psoriasis vulgaris and Coven, et al, Photodermatol. Photoimmunol Photomed. 15:22-21 (1999), reported that lymphocytes treated with psoralen 8-MOP or TMP and UVA, displayed DNA degradation patterns typical of apoptotic cell death.
- Ozawa, et al, J. Exp. Med. 189:111-118 (1999) reported that induction of T cell apoptosis could be the main mechanism by which 312-nm UVB resolves psoriasis skin lesions.
- methotrexate Low doses of methotrexate may be used to treat psoriasis to restore a clinically normal skin. Heenen, et al, Arch. Dermatol Res. 290:240-245 (1998), reported that low doses of methotrexate may induce apoptosis and that this mode of action could explain the reduction in epidermal hyperplasia during treatment of psoriasis with methotrexate. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis, should be an effective treatment for psoriasis.
- Synovial cell hyperplasia is a characteristic of patients with rheumatoid arthritis (RA). It is believed that excessive proliferation of RA synovial cells, as well as defects in synovial cell death, may be responsible for synovial cell hyperplasia. Wakisaka, et al, Clin. Exp. Immunol. 77 :119-128 (1998), found that although RA synovial cells could die via apoptosis through a Fas/FasL pathway, apoptosis of synovial cells was inhibited by proinflammatory cytokines present within the synovium.
- an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis should be an effective treatment for rheumatoid arthritis.
- an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-III, which functions as a caspase cascade activator and inducer of apoptosis, should be an effective treatment for inflammation.
- compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
- the compounds may be administered to animals, e.g., mammals, orally at a dose of 0.0025 to 50 mg/kg of body weight, per day, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a mammal being treated for apoptosis-mediated disorders.
- a dose 0.0025 to 50 mg/kg of body weight, per day, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a mammal being treated for apoptosis-mediated disorders.
- about 0.01 to about 10 mg/kg of body weight is orally administered to treat or prevent such disorders.
- the dose is generally about one-half of the oral dose.
- a suitable intramuscular dose would be about 0.0025 to about 25 mg/kg of body weight, and most preferably, from about 0.01 to about 5 mg/kg of body weight.
- a known cancer chemotherapeutic agent is also administered, it is administered in an amount that is effective to achieve its intended purpose.
- the amounts of such known cancer chemotherapeutic agents effective for cancer are well known to those of skill in the art.
- the unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0.1 to about 10 mg of the compound of the invention.
- the unit dose may be administered one or more times daily as one or more tablets each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.
- the compound in a topical formulation, may be present at a concentration of about 0.01 to 100 mg per gram of carrier.
- the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which may be used pharmaceutically.
- suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which may be used pharmaceutically.
- the preparations particularly those preparations which may be administered orally and which may be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which may be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound(s), together with the excipient.
- non- toxic pharmaceutically acceptable salts of the compounds of the present invention are included within the scope of the present invention.
- Acid addition salts are formed by mixing a solution of the particular apoptosis inducers of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like.
- Basic salts are formed by mixing a solution of the particular apoptosis inducers of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, N-methyl-glucamine and the like.
- a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, N-methyl-glucamine and the like.
- compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention.
- animals are mammals, e.g., humans and veterinary animals, although the invention is not intended to be so limited.
- compositions of the present invention may be administered by any means that achieve their intended purpose.
- administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
- administration may be by the oral route.
- the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
- compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
- pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
- Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
- fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
- disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
- Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
- Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
- concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
- suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used.
- Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
- Other pharmaceutical preparations which may be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
- the push-fit capsules may contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
- stabilizers may be added.
- Possible pharmaceutical preparations which may be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
- Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
- gelatin rectal capsules which consist of a combination of the active compounds with a base.
- Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
- Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts and alkaline solutions.
- suspensions of the active compounds as appropriate oily injection suspensions may be administered.
- Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400) or cremophor, or cyclodextrins.
- Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
- the suspension may also contain stabilizers.
- compounds of the invention are employed in topical and parenteral formulations and are used for the treatment of skin cancer.
- the topical compositions of this invention are formulated preferably as oils, creams, lotions, ointments and the like by choice of appropriate carriers.
- Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C ⁇ 2 ).
- the preferred carriers are those in which the active ingredient is soluble.
- Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
- transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers are found in U.S. Patent Nos. 3,989,816 and 4,444,762.
- Creams are preferably formulated from a mixture of mineral oil, self- emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil such as almond oil, is admixed.
- a typical example of such a cream is one which includes about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.
- Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool.
- a vegetable oil such as almond oil
- a typical example of such an ointment is one which includes about 30% almond oil and about 70% white soft paraffin by weight.
- the title compound was prepared from 4-chloro-6-methyl-2-(3- methylphenyl)pyrimidine (100 mg, 0.457 mmol) and N,N-dimethyl-l,3- phenylene-diamine dihydrochloride (96 mg, 0.457 mmol) similar to Example 13 as a yellow oil (9 mg, 6%).
- the title compound was prepared from 4-chloro-6-methyl-2-(2- pyridinyl)pyrimidine (100 mg, 0.486 mmol) and m-phenetidine (65 ⁇ l, 0.486 mmol) similar to Example 11 and isolated as a light tan solid (116 mg, 78%).
- the title compound was prepared from a mixture of 4-chloro-6- methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-isopropylaniline (33 ⁇ l, 0.243 mmol) similar to Example 13 and isolated as a gray oil (70 mg, 95%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (100 mg, 0.385 mmol) and 2,5- dimethoxyaniline (59 mg, 0.385 mmol) similar to Example 13 and isolated as a greenish-yellow solid (24 mg, 17%).
- the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5- dimethoxyaniline (32 mg, 0.193 mmol) similar to Example 13 and isolated as a light tan solid (15 mg, 21%).
- the title compound was prepared from a mixture of 4-chloro-5- methoxy-2-(2-pyridinyl)pyrimidine (50 mg, 0.226 mmol) and 2,5- dimethoxyaniline (35 mg, 0.226 mmol) similar to Example 11 and isolated as a gray solid (46 mg, 61%).
- the title compound was prepared from a mixture of 4-(6-chloro-2- phenyl-4-pyrimidyl)morpholine (50 mg, 0.181 mmol) and 2,5- dimethoxyaniline (28 mg, 0.181 mmol) similar to Example 46 and isolated as a brown oil (6 mg, 8%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5- methoxy aniline (37 mg, 0.193 mmol) similar to Example 13 and isolated as a white solid (10 mg, 14%).
- the title compound was prepared from a mixture of 4-chloro-6- methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 2-chloro-5- methoxyaniline (47 mg, 0.243 mmol) similar to Example 13 and isolated as a tan oil (35 mg, 44%).
- the title compound was prepared from a mixture of 4-chloro-6- methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 5-methoxy-2- methylaniline (33 mg, 0.243 mmol) similar to Example 13 and isolated as a tan oil (45 mg, 60%).
- the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5- methoxyaniline (38 mg, 0.193 mmol) similar to Example 13 and isolated as a pink solid (18 mg, 25%).
- the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5- methoxy-2-methylaniline (27 mg, 0.193 mmol) similar to Example 13 and isolated as a pink solid (23 mg, 33%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-(3- aminophenyl)-2-methylpyrimidine (71 mg, 0.386 mmol) similar to Example 58.
- the mixture was extracted with ethyl acetate (50 ml), washed with water (1x25 ml) and with aqueous 2N HCl (1x25 ml).
- the acidic aqueous solution was basified with aqueous 2N NaOH to pH 10-12.
- the resulting precipitate was filtered, washed with water and isolated as a light tan solid (18 mg, 23%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3- aminobiphenyl (65 mg, 0.386 mmol) similar to Example 58.
- the mixture was basified with aqueous 2N NaOH to pH 10-12.
- the resulting precipitate was collected by filtration, washed with excess wate ⁇ ethanol (1:1) and isolated as a light brown solid (64 mg, 85%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino- 3'-nitrobiphenyl (83 mg, 0.386 mmol) similar to Example 58 and isolated as a light tan solid (65 mg, 77%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3- (2,3,4,5,6-pentafluorophenoxy)aniline (106 mg, 0.386 mmol) similar to Example 58 and isolated as a yellow solid (65 mg, 68%).
- the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5- dimethoxyaniline (59 mg, 0.386 mmol) similar to Example 58 and isolated as a light brown solid (36 mg, 50%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-(3- aminophenyl)-2-ethyl-l-phenyl-3-pyrazolin-5-one (54 mg, 0.193 mmol) similar to Example 58 and isolated as a dark yellow solid (52 mg, 54%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3- aminodiphenylsulfone (90 mg, 0.386 mmol) similar to Example 58 and isolated as a yellow solid (44 mg, 50%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3- aminobenzanilide (41 mg, 0.193 mmol) similar to Example 58 and isolated as a dark pink solid (41 mg, 49%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5- dimethylaniline (48 ⁇ l, 0.386 mmol) similar to Example 58 and isolated as a light tan solid ( 14mg, 21%).
- the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (89 mg, 0.344 mmol) and 3- aminophenol (30 mg, 0.275 mmol) similar to Example 58 and isolated as a yellow solid (61 mg, 67%).
- the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4- methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a purple solid (24 mg, 35%).
- the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4- methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a dark brown solid (47 mg, 68%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl) ⁇ yrimidine (50 mg, 0.193 mmol) and 3,4- methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a light brown solid (37 mg, 53%).
- 6-(trifluoromethyl)pyrimidine 50 mg, 0.193 mmol
- 3,4-dimethoxyaniline 44 mg, 0.290 mmol
- the mixture was extracted with ethyl acetate (75 ml), washed with water (2 x 25 ml), washed with aqueous saturated NaCl (1 x 25 ml), and dried over anhydrous sodium sulfate.
- the ethyl acetate solution was rotary evaporated to dryness. The residual was purified by column chromatography and isolated as a yellow oil (35 mg, 48%).
- the title compound was prepared from a mixture of 4-chloro-2-(2- pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol), 3,4- dimethoxyaniline (44 mg, 0.288 mmol) similar to Example 76 and isolated as a yellow solid (52 mg, 72%).
- the title compound was prepared from a mixture of 4-chloro-2-(2- pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol) and 2-chloro- 5-methoxyaniline hydrochloride (56 mg, 0.288 mmol) similar to Example 76 and isolated as a tan solid (41 mg, 56%).
- the title compound was prepared from a mixture of 4-chloro-2-(2- pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol) and 3,4- methylenedioxyaniline (39 mg, 0.288 mmol) similar to Example 76 and isolated as a pink solid (21 mg, 30%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2- methoxy-5-phenoxyaniline (62 mg, 0.290 mmol) similar to Example 58 and isolated as a tan solid (46 mg, 54%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino-4- methylbenzoate (48 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (2 mg, 3%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2- methoxy-5-methylaniline (40 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (41 mg, 59%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-fluoro-2- methylaniline (36 mg, 0.290 mmol) similar to Example 58 and isolated as a tan solid (4 mg, 6%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino-4- methoxybenzotrifluoride (55 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (56 mg, 70%).
- the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 3- ethylaniline (18 ⁇ l, 0.144 mmol) similar to Example 92 and isolated as a yellow oil (12 mg, 36%).
- the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 5- methoxy-2-methylaniline (20 mg, 0.144 mmol) similar to Example 92 and isolated as a yellow solid (18 mg, 52%).
- the title compound was prepared from a mixture of 4-chloro-2-(2- pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol) and 2-chloro-5- methoxyaniline (23 mg, 0.144 mmol) similar to Example 92 and isolated as a white solid (11 mg, 48%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 3- aminophenol (32 mg, 0.290 mmol), and 2N HCl (150 ⁇ l) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and the resulting crystals was filtered, washed with water, with water:ethanol (2:1) and dried to give a tan crystals (22 mg, 30%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino-4- methoxybenzoic acid (48 mg, 0.290 mmol) similar to Example 92 and isolated as a white solid (50 mg, 64%).
- the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5- hydroxyaniline (42 mg, 0.290 mmol) similar to Example 108 and isolated as a brown solid (3 mg, 4%).
- the title compound was prepared from a mixture 4-chloro-2,6-di(2- pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2,5-dimethoxyaniline (21 mg, 0.140 mmol) similar to Example 111 and isolated as a yellow oil (2 mg, 6%).
- the title compound was prepared from a mixture 4-chloro-2,6-di(2- pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 5-methoxy-2-methylaniline (19 mg, 0.140 mmol) similar to Example 111 and isolated as a white solid (21 mg, 61%).
- the title compound was prepared from a mixture of 4-chloro-2,6-di(2- pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2-chloro-5-methoxyaniline (27 mg, 0.140 mmol) similar to Example 111 and isolated as a white solid (20 mg, 55%).
- the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2- methoxy-5-methylaniline (40 mg, 0.290 mmol) similar to Example 115 and isolated as a white solid (48 mg, 69%).
- the title compound was prepared from a mixture of 4-chloro-2-(4- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-hydroxy- 2-methylaniline (36 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (19 mg, 28%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methyl- 5-(trifluoromethyl)aniline (51 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (60 mg, 78%).
- the title compound was prepared from a mixture of 4-chloro-2-(3- pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-chloro-2- hydroxyaniline (42 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (38 mg, 54%).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25458100P | 2000-12-12 | 2000-12-12 | |
US254581P | 2000-12-12 | ||
PCT/US2001/047498 WO2002047690A1 (fr) | 2000-12-12 | 2001-12-12 | 2-aryl-4-arylaminopyrimidines substituees et analogues en tant qu'activateurs de caspases et qu'inducteurs d'apoptose, et utilisation associee |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1351691A1 true EP1351691A1 (fr) | 2003-10-15 |
EP1351691A4 EP1351691A4 (fr) | 2005-06-22 |
Family
ID=22964830
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01990048A Withdrawn EP1351691A4 (fr) | 2000-12-12 | 2001-12-12 | 2-aryl-4-arylaminopyrimidines substituees et analogues en tant qu'activateurs de caspases et qu'inducteurs d'apoptose, et utilisation associee |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1351691A4 (fr) |
AU (1) | AU2002228922A1 (fr) |
WO (1) | WO2002047690A1 (fr) |
Families Citing this family (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6660731B2 (en) | 2000-09-15 | 2003-12-09 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
US6638926B2 (en) | 2000-09-15 | 2003-10-28 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
US6716851B2 (en) | 2000-12-12 | 2004-04-06 | Cytovia, Inc. | Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators or caspases and inducers of apoptosis and the use thereof |
CN100436452C (zh) | 2000-12-21 | 2008-11-26 | 沃泰克斯药物股份有限公司 | 可用作蛋白激酶抑制剂的吡唑化合物 |
US6939874B2 (en) | 2001-08-22 | 2005-09-06 | Amgen Inc. | Substituted pyrimidinyl derivatives and methods of use |
US7115617B2 (en) | 2001-08-22 | 2006-10-03 | Amgen Inc. | Amino-substituted pyrimidinyl derivatives and methods of use |
CA2494367A1 (fr) * | 2002-07-25 | 2004-02-05 | Scios Inc. | Methodes pour ameliorer la fonction respiratoire au moyen d'inhibiteurs du tgf-.beta. |
CN101037438A (zh) | 2002-08-02 | 2007-09-19 | 沃泰克斯药物股份有限公司 | 用作gsk-3的抑制剂的吡唑组合物 |
CA2439440A1 (fr) | 2002-09-05 | 2004-03-05 | Emory University | Traitement de tumeurs associees a la sclerose tubereuse |
CN1694708A (zh) * | 2002-09-10 | 2005-11-09 | 西奥斯股份有限公司 | TGFβ的抑制剂 |
US20050014753A1 (en) * | 2003-04-04 | 2005-01-20 | Irm Llc | Novel compounds and compositions as protein kinase inhibitors |
AU2004230928B2 (en) * | 2003-04-09 | 2010-12-02 | Exelixis, Inc. | Tie-2 modulators and methods of use |
US8309562B2 (en) | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
AU2004253967B2 (en) | 2003-07-03 | 2010-02-18 | Cytovia, Inc. | 4-arylamino-quinazolines as activators of caspases and inducers of apoptosis |
US7122542B2 (en) | 2003-07-30 | 2006-10-17 | Rigel Pharmaceuticals, Inc. | Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds |
US6818631B1 (en) | 2003-08-15 | 2004-11-16 | Nippon Soda Co. Ltd. | Fungicidal pyrimidine derivatives |
WO2005040133A1 (fr) * | 2003-10-23 | 2005-05-06 | Pharmacia Corporation | Composes de pyrimidine utiles pour le traitement des inflammations |
WO2005047268A2 (fr) * | 2003-11-10 | 2005-05-26 | X-Ceptor Therapeutics, Inc. | Compositions de pyrimidine substituee et procedes d'utilisation associes |
CN102127056B (zh) * | 2003-12-03 | 2013-08-21 | Ym生物科学澳大利亚私人有限公司 | 微管蛋白抑制剂 |
BRPI0417478A (pt) * | 2003-12-15 | 2007-05-08 | Almirall Prodesfarma Ag | 2,6-bis-heteroaril-4-aminopirimidinas como antagonistas de receptor de adenosina |
JP2007532669A (ja) | 2004-04-13 | 2007-11-15 | イカジェン インコーポレイテッド | カリウムイオンチャネル調節剤としての多環式ピリミジン |
JP4602686B2 (ja) * | 2004-04-15 | 2010-12-22 | 広栄化学工業株式会社 | 2,6−ジハロゲノ−4−アリールピリジン類の製造法 |
US7872005B2 (en) * | 2004-07-01 | 2011-01-18 | Synta Pharmaceuticals Corporation | 2-substituted heteroaryl compounds |
EP1789044B1 (fr) | 2004-09-06 | 2010-10-27 | Basilea Pharmaceutica AG | Phenylaminopyridines et phenylaminopyrazines |
CA2581454A1 (fr) | 2004-09-23 | 2006-03-30 | Reddy Us Therapeutics, Inc. | Nouveaux composes de pyrimidine, leur procede de preparation, et compositions les contenant |
US8258145B2 (en) | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
CA2594708A1 (fr) * | 2005-01-25 | 2006-08-03 | Astrazeneca Ab | Composes chimiques |
EP1888565B1 (fr) * | 2005-04-11 | 2011-03-23 | Almirall, S.A. | 2,6-di-(hétéro)aryl-4-amido-pyrimidines utiles comme antagonistes des récepteurs de l'adénosine |
GB0520657D0 (en) | 2005-10-11 | 2005-11-16 | Ludwig Inst Cancer Res | Pharmaceutical compounds |
US7713987B2 (en) | 2005-12-06 | 2010-05-11 | Rigel Pharmaceuticals, Inc. | Pyrimidine-2,4-diamines and their uses |
EP1878733A1 (fr) * | 2006-07-14 | 2008-01-16 | Novartis AG | Dérivés de pyrimidine comme inhibiteurs de ALK-5 |
MX2009000310A (es) | 2006-07-14 | 2009-01-26 | Novartis Ag | Derivados de pirimidina como inhibidores de alk-5. |
JP2010502674A (ja) * | 2006-09-07 | 2010-01-28 | ノイロサーチ アクティーゼルスカブ | カリウムチャンネル調節剤として有用なピリジニル−ピリミジン誘導体 |
EP3912973A3 (fr) * | 2007-11-28 | 2022-02-16 | Dana-Farber Cancer Institute, Inc. | Inhibiteurs de myristate de bcr-abl à petite molécule et procédés d'utilisation |
EP2649050A4 (fr) * | 2010-12-06 | 2014-04-23 | Glaxo Group Ltd | Composés |
US20130252963A1 (en) * | 2010-12-06 | 2013-09-26 | Yun Jin | Pyrimidinone compounds for use in the treatment of disease or conditions mediated by lp-pla2 |
CA2840883C (fr) * | 2011-07-07 | 2019-07-16 | Merck Patent Gmbh | Azaheterocycles substitues |
JP2014237590A (ja) * | 2011-09-30 | 2014-12-18 | アステラス製薬株式会社 | 2−(ピリジン−2−イル)ピリミジン−4−アミン化合物又はその塩 |
US20150141372A1 (en) * | 2012-05-11 | 2015-05-21 | Bayer Pharma Aktiengesellschaft | Substituted cycloalkenopyrazoles as bub1 inhibitors for the treatment of cancer |
JP2015525775A (ja) * | 2012-07-23 | 2015-09-07 | メルク パテント ゲーエムベーハー | リガンドおよびその製造方法 |
CN102887860B (zh) * | 2012-09-29 | 2015-07-01 | 上海泰坦科技有限公司 | 4-氯-6-三氟甲基嘧啶类化合物的制备方法 |
KR102275676B1 (ko) * | 2012-11-21 | 2021-07-12 | 피티씨 테라퓨틱스, 인크. | 치환된 리버스 피리미딘 bmi-1 저해제 |
CN103896856B (zh) * | 2012-12-25 | 2016-06-08 | 叶龙 | 一种多取代单环嘧啶类jnk激酶抑制剂及其制备方法和用途 |
CN108976172B (zh) * | 2017-05-31 | 2021-12-07 | 华东师范大学 | 一类4-嘧啶二胺类小分子有机化合物及其衍生物及其应用 |
CN108715589B (zh) * | 2018-06-19 | 2021-04-20 | 华侨大学 | 一种用作caspase-3激活剂的香豆素类衍生物及其应用 |
EP3836932A2 (fr) | 2018-08-17 | 2021-06-23 | PTC Therapeutics, Inc. | Méthode de traitement du cancer du pancréas |
SG11202104017VA (en) | 2018-10-22 | 2021-05-28 | Esker Therapeutics Inc | Tyk2 inhibitors and uses thereof |
EA202192117A1 (ru) * | 2019-02-28 | 2021-11-23 | ПиТиСи ТЕРАПЬЮТИКС, ИНК. | Способ лечения множественной миеломы |
CN114096537A (zh) * | 2019-03-27 | 2022-02-25 | Ptc医疗公司 | 肉瘤治疗方法的有用组合 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4041030A (en) * | 1973-09-20 | 1977-08-09 | Delalande S.A. | Arylamino pyrimidinic derivatives |
EP0629622A1 (fr) * | 1992-02-28 | 1994-12-21 | Zenyaku Kogyo Kabushikikaisha | DERIVE DE s-TRIAZINE ET REMEDE CONTRE DES MALADIES DEPENDENTES DE L' STROGENE LE CONTENANT COMME INGREDIENT ACTIF |
EP0640599A1 (fr) * | 1993-08-26 | 1995-03-01 | Ono Pharmaceutical Co., Ltd. | Dérivés de la 4-aminopyrimidine |
WO1997009315A1 (fr) * | 1995-09-01 | 1997-03-13 | Signal Pharmaceuticals, Inc. | Carboxamides de pyrimidine et composes associes, et methodes de traitement d'etats inflammatoires |
US6103737A (en) * | 1997-07-03 | 2000-08-15 | Dupont Pharmaceuticals Company | Aryl- and arylamino- substituted heterocycles as corticotropin releasing hormone antagonists |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995006473A2 (fr) * | 1993-09-01 | 1995-03-09 | Nippon Kayaku Kabushiki Kaisha | Utilisation medicale d'un compose d'acide polysulfonique |
US5935966A (en) * | 1995-09-01 | 1999-08-10 | Signal Pharmaceuticals, Inc. | Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions |
-
2001
- 2001-12-12 AU AU2002228922A patent/AU2002228922A1/en not_active Abandoned
- 2001-12-12 WO PCT/US2001/047498 patent/WO2002047690A1/fr not_active Application Discontinuation
- 2001-12-12 EP EP01990048A patent/EP1351691A4/fr not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4041030A (en) * | 1973-09-20 | 1977-08-09 | Delalande S.A. | Arylamino pyrimidinic derivatives |
EP0629622A1 (fr) * | 1992-02-28 | 1994-12-21 | Zenyaku Kogyo Kabushikikaisha | DERIVE DE s-TRIAZINE ET REMEDE CONTRE DES MALADIES DEPENDENTES DE L' STROGENE LE CONTENANT COMME INGREDIENT ACTIF |
EP0640599A1 (fr) * | 1993-08-26 | 1995-03-01 | Ono Pharmaceutical Co., Ltd. | Dérivés de la 4-aminopyrimidine |
WO1997009315A1 (fr) * | 1995-09-01 | 1997-03-13 | Signal Pharmaceuticals, Inc. | Carboxamides de pyrimidine et composes associes, et methodes de traitement d'etats inflammatoires |
US6103737A (en) * | 1997-07-03 | 2000-08-15 | Dupont Pharmaceuticals Company | Aryl- and arylamino- substituted heterocycles as corticotropin releasing hormone antagonists |
Non-Patent Citations (2)
Title |
---|
CHEMICAL ABSTRACTS, vol. 134, 10 May 2001 (2001-05-10), Columbus, Ohio, US; abstract no.: 295842, * |
See also references of WO0247690A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO2002047690A1 (fr) | 2002-06-20 |
EP1351691A4 (fr) | 2005-06-22 |
AU2002228922A1 (en) | 2002-06-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6716851B2 (en) | Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators or caspases and inducers of apoptosis and the use thereof | |
EP1351691A1 (fr) | 2-aryl-4-arylaminopyrimidines substituees et analogues en tant qu'activateurs de caspases et qu'inducteurs d'apoptose, et utilisation associee | |
US6794397B2 (en) | Substituted nicotinamides and analogs as activators of caspases and inducers of apoptosis and the use thereof | |
US7041685B2 (en) | Substituted 3-aryl-5-aryl-[1,2,4]-oxadiazoles and analogs as activators of caspases and inducers of apoptosis and the use thereof | |
US7144876B2 (en) | 3,5-Disubstituted-[1,2,4]-oxadiazoles and analogs as activators of caspases and inducers of apoptosis and the use thereof | |
US20070099941A1 (en) | N-arylalkyl-thienopyrimidin-4-amines and analogs as activators of caspases and inducers of apoptosis and the use thereof | |
AU2002313633A1 (en) | Substituted 3-aryl-5-aryl-[1,2,4]-oxadiazoles and analogs | |
US20070099877A1 (en) | N-aryl-thienopyrimidin-4-amines and analogs as activators of caspases and inducers of apoptosis and the use thereof | |
US20070213305A1 (en) | N-alkyl-N-aryl-thienopyrimidin-4-amines and analogs as activators of caspases and inducers of apoptosis and the use thereof | |
US7732468B2 (en) | 3-aryl-6-aryl-[ 1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and related compounds as activators of caspases and inducers of apoptosis and the use thereof | |
US6716859B2 (en) | Substituted N′-(Arylcarbonyl)-benzhydrazides, N′(Arylcarbonyl)-benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof | |
US20080096848A1 (en) | Substituted N-Aryl-9-Oxo-9H-Fluorene-1-Carboxamides and Analogs as Activators of Caspases and Inducers of Apoptosis | |
US20050014759A1 (en) | Substituted 1-benzoyl-3-cyano-pyrrolo [1,2-a] quinolines and analogs as activators of caspases and inducers of apoptosis | |
US20220259199A1 (en) | Novel heterocycle derivative | |
MX2008012971A (es) | Combinacion que comprende a) un compuesto de pirimidil-amino-benza mida, y b) un inhibidor de cinasa thr315lle. | |
WO2002098420A1 (fr) | 4-substitute-1-(arylmethylidene)thiosemicarbazide, 4-substitue-1-(arylcarbonyl)thiosemicarbazide et analogues en tant qu'activateurs de capsases et declencheurs d'apoptose, et leur utilisation | |
JP2008526704A (ja) | ピリド(3,2−d)ピリミジンおよび医療処置に有用な医薬組成物 | |
WO2005037196A2 (fr) | Malonamides 2-arylmethylene-n-aryl-n'-aryl substitues et leurs analogues utiles comme activateurs des caspases et inducteurs de l'apoptose |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20030710 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK RO SI |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20050506 |
|
17Q | First examination report despatched |
Effective date: 20051117 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61P 35/00 20060101ALI20070712BHEP Ipc: C07D 401/14 20060101ALI20070712BHEP Ipc: C07D 401/04 20060101ALI20070712BHEP Ipc: C07D 239/48 20060101ALI20070712BHEP Ipc: C07D 239/42 20060101ALI20070712BHEP Ipc: A61K 31/506 20060101ALI20070712BHEP Ipc: A61K 31/505 20060101ALI20070712BHEP Ipc: A61K 31/53 20060101ALI20070712BHEP Ipc: A61K 31/50 20060101AFI20070712BHEP |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20080111 |