TWI663165B - 非典型蛋白質激酶ｃ之氮雜喹唑啉抑制劑 - Google Patents
非典型蛋白質激酶ｃ之氮雜喹唑啉抑制劑 Download PDFInfo
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- TWI663165B TWI663165B TW102134928A TW102134928A TWI663165B TW I663165 B TWI663165 B TW I663165B TW 102134928 A TW102134928 A TW 102134928A TW 102134928 A TW102134928 A TW 102134928A TW I663165 B TWI663165 B TW I663165B
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- Prior art keywords
- pyridin
- pyrido
- cyclopropyl
- pyrimidin
- optionally substituted
- Prior art date
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- 101710082924 Atypical protein kinase C Proteins 0.000 title description 12
- 239000003112 inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 575
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 500
- 125000000217 alkyl group Chemical group 0.000 claims description 496
- 125000001424 substituent group Chemical group 0.000 claims description 352
- 125000003118 aryl group Chemical group 0.000 claims description 300
- 125000001072 heteroaryl group Chemical group 0.000 claims description 294
- MXFOQZLUCVHVRD-UHFFFAOYSA-N 2-methylsulfonyloxyethyl-[2,3,4,5-tetrahydroxy-6-(2-methylsulfonyloxyethylamino)hexyl]azanium;chloride Chemical compound [Cl-].CS(=O)(=O)OCCNCC(O)C(O)C(O)C(O)C[NH2+]CCOS(C)(=O)=O MXFOQZLUCVHVRD-UHFFFAOYSA-N 0.000 claims description 242
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 205
- -1 R 24 Chemical compound 0.000 claims description 193
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 183
- 229910052799 carbon Inorganic materials 0.000 claims description 182
- 229910052736 halogen Inorganic materials 0.000 claims description 182
- 150000002367 halogens Chemical class 0.000 claims description 180
- 229910052739 hydrogen Inorganic materials 0.000 claims description 174
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 169
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 160
- 125000004429 atom Chemical group 0.000 claims description 151
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 143
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 139
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 134
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 131
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 130
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 102
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 101
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 83
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 80
- 125000005843 halogen group Chemical group 0.000 claims description 78
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 70
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 68
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 55
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 50
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 45
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 44
- 125000004432 carbon atom Chemical group C* 0.000 claims description 41
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 36
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 32
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 25
- CYHOWEBNQPOWEI-UHFFFAOYSA-L calcium 3-carboxy-1-phenyldiazenylnaphthalen-2-olate Chemical compound OC=1C(=CC2=CC=CC=C2C1N=NC1=CC=CC=C1)C(=O)[O-].OC=1C(=CC2=CC=CC=C2C1N=NC1=CC=CC=C1)C(=O)[O-].[Ca+2] CYHOWEBNQPOWEI-UHFFFAOYSA-L 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 17
- 125000003107 substituted aryl group Chemical group 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 229910052698 phosphorus Inorganic materials 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000004437 phosphorous atom Chemical group 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 150000003254 radicals Chemical class 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 210000002307 prostate Anatomy 0.000 claims description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 11
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 6
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 5
- 241000009298 Trigla lyra Species 0.000 claims 4
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 3
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 claims 3
- NTGHSKOWQAWIKS-UHFFFAOYSA-N 1-[4-[[5-cyclopropyl-2-[2-(2,6-difluoroanilino)pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-yl]-methylamino]piperidin-1-yl]ethanone Chemical compound N=1C(C=2C=C(NC=3C(=CC=CC=3F)F)N=CC=2)=NC2=CN=CC(C3CC3)=C2C=1N(C)C1CCN(C(C)=O)CC1 NTGHSKOWQAWIKS-UHFFFAOYSA-N 0.000 claims 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- 125000005605 benzo group Chemical group 0.000 claims 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical group FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims 2
- CSOJWBCIKMHWMZ-FQEVSTJZSA-N (2S)-2-amino-6-[[5-cyclobutyl-2-(9H-pyrido[2,3-b]indol-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino]hexanoic acid Chemical compound N[C@@H](CCCCNc1nc(nc2cncc(C3CCC3)c12)-c1ccnc2[nH]c3ccccc3c12)C(O)=O CSOJWBCIKMHWMZ-FQEVSTJZSA-N 0.000 claims 1
- AZPCZTAAQBVGMR-FQSKIORSSA-N (3S)-1-[2-[2-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-cyclopropyl-1,4-dihydropyrido[3,4-d]pyrimidin-4-yl]piperidin-3-amine Chemical compound ClC1=C(C=CC=C1)C1=CC=2C(=NC=CC2C=2NC(C3=C(N2)C=NC=C3C3CC3)N3C[C@H](CCC3)N)N1 AZPCZTAAQBVGMR-FQSKIORSSA-N 0.000 claims 1
- AKHNLBKJGAXVHT-STFFIMJZSA-N (3S)-1-[5-cyclopropyl-2-[2-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1,4-dihydropyrido[3,4-d]pyrimidin-4-yl]piperidin-3-amine Chemical compound C1(CC1)C1=CN=CC=2N=C(NC(C21)N2C[C@H](CCC2)N)C2=C1C(=NC=C2)NC(=C1)C1=C(C=CC=C1)OC AKHNLBKJGAXVHT-STFFIMJZSA-N 0.000 claims 1
- GCMNJUJAKQGROZ-UHFFFAOYSA-N 1,2-Dihydroquinolin-2-imine Chemical compound C1=CC=CC2=NC(N)=CC=C21 GCMNJUJAKQGROZ-UHFFFAOYSA-N 0.000 claims 1
- DNHVFNDOHJKATM-UHFFFAOYSA-N 1-(2,2,2-trifluoroethyl)pyrazole Chemical compound FC(F)(F)CN1C=CC=N1 DNHVFNDOHJKATM-UHFFFAOYSA-N 0.000 claims 1
- ZCBSJPVMIHRQLD-UHFFFAOYSA-N 1-(5-cyclopropyl-2-spiro[1,3-dihydropyrrolo[2,3-b]pyridine-2,1'-cyclohexane]-4-ylpyrido[3,4-d]pyrimidin-4-yl)piperidin-3-amine Chemical compound C1(CC1)C1=CN=CC=2N=C(N=C(C21)N2CC(CCC2)N)C2=C1C(=NC=C2)NC2(C1)CCCCC2 ZCBSJPVMIHRQLD-UHFFFAOYSA-N 0.000 claims 1
- QANYVBDSGBIANY-UHFFFAOYSA-N 1-[4-[[5-cyclopropyl-2-[2-(2,6-difluoroanilino)pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-yl]amino]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1NC1=NC(C=2C=C(NC=3C(=CC=CC=3F)F)N=CC=2)=NC2=CN=CC(C3CC3)=C12 QANYVBDSGBIANY-UHFFFAOYSA-N 0.000 claims 1
- 125000006420 1-fluorocyclopropyl group Chemical group [H]C1([H])C([H])([H])C1(F)* 0.000 claims 1
- 125000006458 1-fluoromethyl cyclopropyl group Chemical group [H]C([H])(F)C1(*)C([H])([H])C1([H])[H] 0.000 claims 1
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 claims 1
- QGCRJRVFQZXCAZ-UHFFFAOYSA-N 1h-triazolo[1,5-a]pyridin-2-amine Chemical compound C1=CC=CC2=CN(N)NN21 QGCRJRVFQZXCAZ-UHFFFAOYSA-N 0.000 claims 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims 1
- ODUZJBKKYBQIBX-UHFFFAOYSA-N 2,6-difluoroaniline Chemical group NC1=C(F)C=CC=C1F ODUZJBKKYBQIBX-UHFFFAOYSA-N 0.000 claims 1
- FEPVUIPYLYGZNF-UHFFFAOYSA-N 2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrido[3,4-d]pyrimidine Chemical compound N1C=CC=2C1=NC=CC=2C=1N=CC2=C(N=1)C=NC=C2 FEPVUIPYLYGZNF-UHFFFAOYSA-N 0.000 claims 1
- UZQIDODZFWOSCQ-UHFFFAOYSA-N 2-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine Chemical compound ClC1=CC=CC=C1C1=CC2=CC=CN=C2N1 UZQIDODZFWOSCQ-UHFFFAOYSA-N 0.000 claims 1
- NXDRDACAFQCOHU-UHFFFAOYSA-N 2-[2-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-N-methylpyrido[3,4-d]pyrimidin-4-amine Chemical compound ClC1=C(C=CC=C1)C1=CC=2C(=NC=CC=2C=2N=C(C3=C(N=2)C=NC=C3C2CC2)N(C)C2C(CNCC2)(C)C)N1 NXDRDACAFQCOHU-UHFFFAOYSA-N 0.000 claims 1
- UTGOMLNXPOJUHC-UHFFFAOYSA-N 2-[2-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(C)CNCCC1Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc2[nH]c(cc12)-c1ccccc1Cl UTGOMLNXPOJUHC-UHFFFAOYSA-N 0.000 claims 1
- JONCORLVUSTPEJ-UHFFFAOYSA-N 2-[2-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-cyclopropyl-N-(4-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(CCNCC1)Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc2[nH]c(cc12)-c1ccccc1Cl JONCORLVUSTPEJ-UHFFFAOYSA-N 0.000 claims 1
- VPUPBQAVOYNXLU-UHFFFAOYSA-N 2-[2-(4-chloroanilino)pyridin-4-yl]-5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-N-methylpyrido[3,4-d]pyrimidin-4-amine Chemical compound ClC1=CC=C(C=C1)NC1=NC=CC(=C1)C=1N=C(C2=C(N1)C=NC=C2C2CC2)N(C)C2C(CNCC2)(C)C VPUPBQAVOYNXLU-UHFFFAOYSA-N 0.000 claims 1
- KWMUDIWBPBJDSR-UHFFFAOYSA-N 2-[2-(4-chloroanilino)pyridin-4-yl]-5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound ClC1=CC=C(C=C1)NC1=NC=CC(=C1)C=1N=C(C2=C(N1)C=NC=C2C2CC2)NC2C(CNCC2)(C)C KWMUDIWBPBJDSR-UHFFFAOYSA-N 0.000 claims 1
- LAXOLRMUBQRVMD-UHFFFAOYSA-N 2-[2-[(5-chloro-3-fluoropyridin-2-yl)amino]pyridin-4-yl]-5-cyclobutyl-N-methyl-N-piperidin-4-ylpyrido[3,4-d]pyrimidin-4-amine Chemical compound ClC=1C=C(C(=NC=1)NC1=NC=CC(=C1)C=1N=C(C2=C(N=1)C=NC=C2C1CCC1)N(C1CCNCC1)C)F LAXOLRMUBQRVMD-UHFFFAOYSA-N 0.000 claims 1
- OPXRILPQFLUAPK-UHFFFAOYSA-N 2-[2-[(5-chloro-3-fluoropyridin-2-yl)amino]pyridin-4-yl]-5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-N-methylpyrido[3,4-d]pyrimidin-4-amine Chemical compound CN(C1CCNCC1(C)C)c1nc(nc2cncc(C3CC3)c12)-c1ccnc(Nc2ncc(Cl)cc2F)c1 OPXRILPQFLUAPK-UHFFFAOYSA-N 0.000 claims 1
- AXQKQPAWXRUKRW-UHFFFAOYSA-N 2-[2-[(5-chloro-3-fluoropyridin-2-yl)amino]pyridin-4-yl]-5-cyclopropyl-n-methyl-n-piperidin-4-ylpyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=C(NC=3C(=CC(Cl)=CN=3)F)N=CC=2)=NC2=CN=CC(C3CC3)=C2C=1N(C)C1CCNCC1 AXQKQPAWXRUKRW-UHFFFAOYSA-N 0.000 claims 1
- SGTBHEUBUMWDKD-UHFFFAOYSA-N 2h-quinolin-1-amine Chemical compound C1=CC=C2N(N)CC=CC2=C1 SGTBHEUBUMWDKD-UHFFFAOYSA-N 0.000 claims 1
- JVLFMTZUPSBCNJ-UHFFFAOYSA-N 3,5-difluoropyridin-2-amine Chemical group NC1=NC=C(F)C=C1F JVLFMTZUPSBCNJ-UHFFFAOYSA-N 0.000 claims 1
- SVNCRRZKBNSMIV-UHFFFAOYSA-N 3-Aminoquinoline Chemical compound C1=CC=CC2=CC(N)=CN=C21 SVNCRRZKBNSMIV-UHFFFAOYSA-N 0.000 claims 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 1
- PFSNVRXTVPENKP-UHFFFAOYSA-N 4-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridin-1-yl)-5-cyclopropyl-2-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidine Chemical compound FC(F)(F)c1cc2c(ccnc2[nH]1)-c1nc(N2CCC3CNCCC23)c2c(cncc2n1)C1CC1 PFSNVRXTVPENKP-UHFFFAOYSA-N 0.000 claims 1
- RMCSIOVDLGKWLX-UHFFFAOYSA-N 4-[4-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridin-1-yl)-5-cyclobutylpyrido[3,4-d]pyrimidin-2-yl]-9H-pyrido[2,3-b]indole Chemical compound C1CC(C1)c1cncc2nc(nc(N3CCC4CNCCC34)c12)-c1ccnc2[nH]c3ccccc3c12 RMCSIOVDLGKWLX-UHFFFAOYSA-N 0.000 claims 1
- UKARJGSRBSMFOH-INIZCTEOSA-N 4-[4-[(3S)-3-aminopiperidin-1-yl]-5-(trifluoromethyl)pyrido[3,4-d]pyrimidin-2-yl]-N-phenylpyridin-2-amine Chemical compound N[C@@H]1CN(CCC1)C=1C2=C(N=C(N1)C1=CC(=NC=C1)NC1=CC=CC=C1)C=NC=C2C(F)(F)F UKARJGSRBSMFOH-INIZCTEOSA-N 0.000 claims 1
- RCWARRCDGCUFSE-UHFFFAOYSA-N 4-[5-cyclobutyl-2-(9H-pyrido[2,3-b]indol-4-yl)pyrido[3,4-d]pyrimidin-4-yl]morpholine Chemical compound C1(CCC1)C1=CN=CC=2N=C(N=C(C=21)N1CCOCC1)C1=CC=NC=2NC3=CC=CC=C3C=21 RCWARRCDGCUFSE-UHFFFAOYSA-N 0.000 claims 1
- WKJSPCMREUTPBI-UHFFFAOYSA-N 4-[5-cyclopropyl-4-(1-methylpiperidin-4-yl)sulfanylpyrido[3,4-d]pyrimidin-2-yl]-n-(2,6-difluorophenyl)pyridin-2-amine Chemical compound C1CN(C)CCC1SC1=NC(C=2C=C(NC=3C(=CC=CC=3F)F)N=CC=2)=NC2=CN=CC(C3CC3)=C12 WKJSPCMREUTPBI-UHFFFAOYSA-N 0.000 claims 1
- GHEFUEXFPLBHFL-UHFFFAOYSA-N 4-[[5-cyclopropyl-2-[2-(2,6-difluoroanilino)pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-yl]amino]piperidin-2-one Chemical compound FC1=CC=CC(F)=C1NC1=CC(C=2N=C3C=NC=C(C3=C(NC3CC(=O)NCC3)N=2)C2CC2)=CC=N1 GHEFUEXFPLBHFL-UHFFFAOYSA-N 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- BAHCGHPLGOEMEH-UHFFFAOYSA-N 4-n-[5-cyclopropyl-2-[2-[(3,5-difluoropyridin-2-yl)amino]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-yl]-1-n-methylbenzene-1,4-diamine Chemical compound C1=CC(NC)=CC=C1NC1=NC(C=2C=C(NC=3C(=CC(F)=CN=3)F)N=CC=2)=NC2=CN=CC(C3CC3)=C12 BAHCGHPLGOEMEH-UHFFFAOYSA-N 0.000 claims 1
- XYKWNCHCUQTYLF-UHFFFAOYSA-N 5-cyclobutyl-2-[2-(2,2-difluoro-1-methylcyclopropyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-N-methyl-N-piperidin-4-ylpyrido[3,4-d]pyrimidin-4-amine Chemical compound CN(C1CCNCC1)c1nc(nc2cncc(C3CCC3)c12)-c1ccnc2[nH]c(cc12)C1(C)CC1(F)F XYKWNCHCUQTYLF-UHFFFAOYSA-N 0.000 claims 1
- FUQZROGZCSBMKX-UHFFFAOYSA-N 5-cyclobutyl-2-[2-[(3,5-difluoropyridin-2-yl)amino]pyridin-4-yl]-n-methyl-n-piperidin-4-ylpyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=C(NC=3C(=CC(F)=CN=3)F)N=CC=2)=NC2=CN=CC(C3CCC3)=C2C=1N(C)C1CCNCC1 FUQZROGZCSBMKX-UHFFFAOYSA-N 0.000 claims 1
- JTFBMRNPRJVHQL-UHFFFAOYSA-N 5-cyclobutyl-N-(3,3-dimethylpiperidin-4-yl)-2-(9H-pyrido[2,3-b]indol-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1(CCC1)C1=CN=CC=2N=C(N=C(C21)NC2C(CNCC2)(C)C)C2=CC=NC=1NC3=CC=CC=C3C12 JTFBMRNPRJVHQL-UHFFFAOYSA-N 0.000 claims 1
- HDCNGVLKWMHREZ-UHFFFAOYSA-N 5-cyclobutyl-N-(3,3-dimethylpiperidin-4-yl)-N-methyl-2-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1(CCC1)C1=CN=CC=2N=C(N=C(C=21)N(C)C1C(CNCC1)(C)C)C1=C2C(=NC=C1)NC(=C2)C(F)(F)F HDCNGVLKWMHREZ-UHFFFAOYSA-N 0.000 claims 1
- KEPJBXVLIFFELE-UHFFFAOYSA-N 5-cyclobutyl-N-(4-methylpiperidin-4-yl)-2-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(CCNCC1)Nc1nc(nc2cncc(C3CCC3)c12)-c1ccnc2[nH]c(cc12)C(F)(F)F KEPJBXVLIFFELE-UHFFFAOYSA-N 0.000 claims 1
- KVTVIWGXLNMALZ-PKOBYXMFSA-N 5-cyclobutyl-N-[(3R,4S)-3-methoxypiperidin-4-yl]-2-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound CO[C@@H]1CNCC[C@@H]1Nc1nc(nc2cncc(C3CCC3)c12)-c1ccnc2[nH]c(cc12)C(F)(F)F KVTVIWGXLNMALZ-PKOBYXMFSA-N 0.000 claims 1
- RQDPVHRTORZGLY-UHFFFAOYSA-N 5-cyclobutyl-n-methyl-n-piperidin-4-yl-2-[2-[(3,5,6-trifluoropyridin-2-yl)amino]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=C(NC=3C(=CC(F)=C(F)N=3)F)N=CC=2)=NC2=CN=CC(C3CCC3)=C2C=1N(C)C1CCNCC1 RQDPVHRTORZGLY-UHFFFAOYSA-N 0.000 claims 1
- CTQRLMZRSSAVSA-CYBMUJFWSA-N 5-cyclopropyl-2-[1-methyl-2-(trifluoromethyl)pyrrolo[2,3-b]pyridin-4-yl]-n-[(3r)-pyrrolidin-3-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1=CN=C2N(C)C(C(F)(F)F)=CC2=C1C(N=C1C=NC=C(C1=1)C2CC2)=NC=1N[C@@H]1CCNC1 CTQRLMZRSSAVSA-CYBMUJFWSA-N 0.000 claims 1
- UKPQKOYDUUQFMQ-UHFFFAOYSA-N 5-cyclopropyl-2-[2-(2,6-difluoroanilino)pyridin-4-yl]-n-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1CN(C)CCC1NC1=NC(C=2C=C(NC=3C(=CC=CC=3F)F)N=CC=2)=NC2=CN=CC(C3CC3)=C12 UKPQKOYDUUQFMQ-UHFFFAOYSA-N 0.000 claims 1
- QRLJSYVYWROZLW-UHFFFAOYSA-N 5-cyclopropyl-2-[2-(2,6-difluoroanilino)pyridin-4-yl]-n-(2,2-dimethylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1CNC(C)(C)CC1NC1=NC(C=2C=C(NC=3C(=CC=CC=3F)F)N=CC=2)=NC2=CN=CC(C3CC3)=C12 QRLJSYVYWROZLW-UHFFFAOYSA-N 0.000 claims 1
- WJCLLMBVBQSNCA-MRXNPFEDSA-N 5-cyclopropyl-2-[2-(2,6-difluoroanilino)pyridin-4-yl]-n-[(3r)-pyrrolidin-3-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound FC1=CC=CC(F)=C1NC1=CC(C=2N=C3C=NC=C(C3=C(N[C@H]3CNCC3)N=2)C2CC2)=CC=N1 WJCLLMBVBQSNCA-MRXNPFEDSA-N 0.000 claims 1
- WJCLLMBVBQSNCA-INIZCTEOSA-N 5-cyclopropyl-2-[2-(2,6-difluoroanilino)pyridin-4-yl]-n-[(3s)-pyrrolidin-3-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound FC1=CC=CC(F)=C1NC1=CC(C=2N=C3C=NC=C(C3=C(N[C@@H]3CNCC3)N=2)C2CC2)=CC=N1 WJCLLMBVBQSNCA-INIZCTEOSA-N 0.000 claims 1
- VXUNSKWKSLBAPW-QGZVFWFLSA-N 5-cyclopropyl-2-[2-(2,6-difluoroanilino)pyridin-4-yl]-n-methyl-n-[(3r)-pyrrolidin-3-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=C(NC=3C(=CC=CC=3F)F)N=CC=2)=NC2=CN=CC(C3CC3)=C2C=1N(C)[C@@H]1CCNC1 VXUNSKWKSLBAPW-QGZVFWFLSA-N 0.000 claims 1
- VXUNSKWKSLBAPW-UHFFFAOYSA-N 5-cyclopropyl-2-[2-(2,6-difluoroanilino)pyridin-4-yl]-n-methyl-n-pyrrolidin-3-ylpyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=C(NC=3C(=CC=CC=3F)F)N=CC=2)=NC2=CN=CC(C3CC3)=C2C=1N(C)C1CCNC1 VXUNSKWKSLBAPW-UHFFFAOYSA-N 0.000 claims 1
- OQXNMJDKUCVQFV-UHFFFAOYSA-N 5-cyclopropyl-2-[2-[(3,5-difluoropyridin-2-yl)amino]pyridin-4-yl]-N-methyl-N-(3-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1(CC1)C1=CN=CC=2N=C(N=C(C21)N(C2C(CNCC2)C)C)C2=CC(=NC=C2)NC2=NC=C(C=C2F)F OQXNMJDKUCVQFV-UHFFFAOYSA-N 0.000 claims 1
- HYNASBOSMAGXII-UHFFFAOYSA-N 5-cyclopropyl-2-[2-[(3,5-difluoropyridin-2-yl)amino]pyridin-4-yl]-n-(3,3-dimethylpiperidin-4-yl)-n-methylpyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=C(NC=3C(=CC(F)=CN=3)F)N=CC=2)=NC2=CN=CC(C3CC3)=C2C=1N(C)C1CCNCC1(C)C HYNASBOSMAGXII-UHFFFAOYSA-N 0.000 claims 1
- YDRIXBYNJUHFTO-UHFFFAOYSA-N 5-cyclopropyl-2-[2-[(3,5-difluoropyridin-2-yl)amino]pyridin-4-yl]-n-(3,3-dimethylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(C)CNCCC1NC1=NC(C=2C=C(NC=3C(=CC(F)=CN=3)F)N=CC=2)=NC2=CN=CC(C3CC3)=C12 YDRIXBYNJUHFTO-UHFFFAOYSA-N 0.000 claims 1
- TWIWVLNWQPBMPD-UHFFFAOYSA-N 5-cyclopropyl-2-[2-[(3,5-difluoropyridin-2-yl)amino]pyridin-4-yl]-n-(3-fluoropiperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound FC1CNCCC1NC1=NC(C=2C=C(NC=3C(=CC(F)=CN=3)F)N=CC=2)=NC2=CN=CC(C3CC3)=C12 TWIWVLNWQPBMPD-UHFFFAOYSA-N 0.000 claims 1
- DCASDAZVWFEQSG-UHFFFAOYSA-N 5-cyclopropyl-2-[2-[(3,5-difluoropyridin-2-yl)amino]pyridin-4-yl]-n-methyl-n-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=C(NC=3C(=CC(F)=CN=3)F)N=CC=2)=NC2=CN=CC(C3CC3)=C2C=1N(C)C1CCN(C)CC1 DCASDAZVWFEQSG-UHFFFAOYSA-N 0.000 claims 1
- GDGJQTIXJQSPAK-UHFFFAOYSA-N 5-cyclopropyl-2-[2-[(3,5-difluoropyridin-2-yl)amino]pyridin-4-yl]-n-methyl-n-piperidin-4-ylpyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=C(NC=3C(=CC(F)=CN=3)F)N=CC=2)=NC2=CN=CC(C3CC3)=C2C=1N(C)C1CCNCC1 GDGJQTIXJQSPAK-UHFFFAOYSA-N 0.000 claims 1
- MSWDTFIOSASDTA-UHFFFAOYSA-N 5-cyclopropyl-2-[2-[(3,6-difluoropyridin-2-yl)amino]pyridin-4-yl]-N-(4-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(CCNCC1)Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc(Nc2nc(F)ccc2F)c1 MSWDTFIOSASDTA-UHFFFAOYSA-N 0.000 claims 1
- HMAAVWZOLMQNRU-UHFFFAOYSA-N 5-cyclopropyl-4-piperidin-4-ylsulfanyl-2-[2-(trifluoromethyl)-1h-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidine Chemical compound C1=CN=C2NC(C(F)(F)F)=CC2=C1C(N=C1C=NC=C(C1=1)C2CC2)=NC=1SC1CCNCC1 HMAAVWZOLMQNRU-UHFFFAOYSA-N 0.000 claims 1
- DFWABOLDRIDOTR-UHFFFAOYSA-N 5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-2-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(C)CNCCC1Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc2[nH]c(cc12)-c1ccccc1 DFWABOLDRIDOTR-UHFFFAOYSA-N 0.000 claims 1
- YDBANSJBGNOYAH-UHFFFAOYSA-N 5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-2-[2-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-N-methylpyrido[3,4-d]pyrimidin-4-amine Chemical compound C1(CC1)C1=CN=CC=2N=C(N=C(C=21)N(C)C1C(CNCC1)(C)C)C1=C2C(=NC=C1)NC(=C2)C1=C(C=CC=C1)F YDBANSJBGNOYAH-UHFFFAOYSA-N 0.000 claims 1
- WAFQVNDNHPRZMH-UHFFFAOYSA-N 5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-2-[2-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(C)CNCCC1Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc2[nH]c(cc12)-c1ccccc1F WAFQVNDNHPRZMH-UHFFFAOYSA-N 0.000 claims 1
- XBENQVHZNFEASU-UHFFFAOYSA-N 5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-2-[2-(3-fluoropyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(C)CNCCC1Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc2[nH]c(cc12)-c1ncccc1F XBENQVHZNFEASU-UHFFFAOYSA-N 0.000 claims 1
- MTBCSQXQHKKPGP-UHFFFAOYSA-N 5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-2-[2-(pyrazolo[1,5-a]pyridin-5-ylamino)pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(C)CNCCC1Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc(Nc2ccn3nccc3c2)c1 MTBCSQXQHKKPGP-UHFFFAOYSA-N 0.000 claims 1
- WVSSJGBGBYTXTQ-UHFFFAOYSA-N 5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-2-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(C)CNCCC1Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc2[nH]c(cc12)C(F)(F)F WVSSJGBGBYTXTQ-UHFFFAOYSA-N 0.000 claims 1
- OFERVUCDIMEMBJ-UHFFFAOYSA-N 5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-N-methyl-2-[2-(4-propan-2-ylanilino)pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1(CC1)C1=CN=CC=2N=C(N=C(C21)N(C)C2C(CNCC2)(C)C)C2=CC(=NC=C2)NC2=CC=C(C=C2)C(C)C OFERVUCDIMEMBJ-UHFFFAOYSA-N 0.000 claims 1
- JKUOZPFJJMFIQN-UHFFFAOYSA-N 5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-N-methyl-2-[2-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1(CC1)C1=CN=CC=2N=C(N=C(C21)N(C)C2C(CNCC2)(C)C)C2=CC(=NC=C2)NC2=NN1C(C=CC=C1)=N2 JKUOZPFJJMFIQN-UHFFFAOYSA-N 0.000 claims 1
- SECGZUHQEXTGKP-UHFFFAOYSA-N 5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-N-methyl-2-[2-(pyrazolo[1,5-a]pyridin-6-ylamino)pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1(CC1)C1=CN=CC=2N=C(N=C(C21)N(C)C2C(CNCC2)(C)C)C2=CC(=NC=C2)NC=2C=CC=1N(C2)N=CC1 SECGZUHQEXTGKP-UHFFFAOYSA-N 0.000 claims 1
- MBEUISDXDWYEAX-UHFFFAOYSA-N 5-cyclopropyl-N-(3,3-dimethylpiperidin-4-yl)-N-methyl-2-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1(CC1)C1=CN=CC=2N=C(N=C(C=21)N(C)C1C(CNCC1)(C)C)C1=C2C(=NC=C1)NC(=C2)C(F)(F)F MBEUISDXDWYEAX-UHFFFAOYSA-N 0.000 claims 1
- DEHLOSOOUGOTIC-UHFFFAOYSA-N 5-cyclopropyl-N-(4-methylpiperidin-4-yl)-2-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(CCNCC1)Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc2[nH]c(cc12)-c1ccccc1 DEHLOSOOUGOTIC-UHFFFAOYSA-N 0.000 claims 1
- FMNVCPHVHHUBGM-UHFFFAOYSA-N 5-cyclopropyl-N-(4-methylpiperidin-4-yl)-2-[2-(pyrazolo[1,5-a]pyridin-5-ylamino)pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(CCNCC1)Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc(Nc2ccn3nccc3c2)c1 FMNVCPHVHHUBGM-UHFFFAOYSA-N 0.000 claims 1
- LLRWWAOXTQQSHO-UHFFFAOYSA-N 5-cyclopropyl-N-(4-methylpiperidin-4-yl)-2-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(CCNCC1)Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc2[nH]c(cc12)C(F)(F)F LLRWWAOXTQQSHO-UHFFFAOYSA-N 0.000 claims 1
- LNTAHNNTEWBLDP-FUHWJXTLSA-N 5-cyclopropyl-N-[(3R,4S)-3-methoxypiperidin-4-yl]-2-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound CO[C@@H]1CNCC[C@@H]1Nc1nc(nc2cncc(C3CC3)c12)-c1ccnc2[nH]c(cc12)C(F)(F)F LNTAHNNTEWBLDP-FUHWJXTLSA-N 0.000 claims 1
- JKGNFSIWEWAZBD-LJQANCHMSA-N 5-cyclopropyl-N-methyl-2-[2-[[(1R)-1-phenylethyl]amino]pyridin-4-yl]-N-piperidin-4-ylpyrido[3,4-d]pyrimidin-4-amine Chemical compound C[C@@H](Nc1cc(ccn1)-c1nc(N(C)C2CCNCC2)c2c(cncc2n1)C1CC1)c1ccccc1 JKGNFSIWEWAZBD-LJQANCHMSA-N 0.000 claims 1
- OREAJDRTKODNRO-UHFFFAOYSA-N 5-cyclopropyl-n-(3,3-difluoropiperidin-4-yl)-2-[2-[(3,5-difluoropyridin-2-yl)amino]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound FC1=CC(F)=CN=C1NC1=CC(C=2N=C3C=NC=C(C3=C(NC3C(CNCC3)(F)F)N=2)C2CC2)=CC=N1 OREAJDRTKODNRO-UHFFFAOYSA-N 0.000 claims 1
- HIWCPCJZNTXVRU-UHFFFAOYSA-N 5-cyclopropyl-n-(3,3-dimethylpiperidin-4-yl)-2-[2-[(3,5,6-trifluoropyridin-2-yl)amino]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound CC1(C)CNCCC1NC1=NC(C=2C=C(NC=3C(=CC(F)=C(F)N=3)F)N=CC=2)=NC2=CN=CC(C3CC3)=C12 HIWCPCJZNTXVRU-UHFFFAOYSA-N 0.000 claims 1
- YBAFMKSROHMZDQ-GFCCVEGCSA-N 5-cyclopropyl-n-[(3r)-pyrrolidin-3-yl]-2-[2-(trifluoromethyl)-1h-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1=CN=C2NC(C(F)(F)F)=CC2=C1C(N=C1C=NC=C(C1=1)C2CC2)=NC=1N[C@@H]1CCNC1 YBAFMKSROHMZDQ-GFCCVEGCSA-N 0.000 claims 1
- QSVRYALPYJDUHT-CQSZACIVSA-N 5-cyclopropyl-n-[(3r)-pyrrolidin-3-yl]-2-[2-[(3,5,6-trifluoropyridin-2-yl)amino]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N1=C(F)C(F)=CC(F)=C1NC1=CC(C=2N=C3C=NC=C(C3=C(N[C@H]3CNCC3)N=2)C2CC2)=CC=N1 QSVRYALPYJDUHT-CQSZACIVSA-N 0.000 claims 1
- NXWMFAGLBOYQRX-UHFFFAOYSA-N 5-cyclopropyl-n-methyl-n-(1-methylpiperidin-4-yl)-2-[2-(trifluoromethyl)-1h-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=3C=C(NC=3N=CC=2)C(F)(F)F)=NC2=CN=CC(C3CC3)=C2C=1N(C)C1CCN(C)CC1 NXWMFAGLBOYQRX-UHFFFAOYSA-N 0.000 claims 1
- NJQXZHOPKNERBA-UHFFFAOYSA-N 5-cyclopropyl-n-methyl-n-(piperidin-4-ylmethyl)-2-[2-(trifluoromethyl)-1h-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=3C=C(NC=3N=CC=2)C(F)(F)F)=NC2=CN=CC(C3CC3)=C2C=1N(C)CC1CCNCC1 NJQXZHOPKNERBA-UHFFFAOYSA-N 0.000 claims 1
- PUQCTCBOOCZICW-CYBMUJFWSA-N 5-cyclopropyl-n-methyl-n-[(3r)-pyrrolidin-3-yl]-2-[2-(trifluoromethyl)-1h-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=3C=C(NC=3N=CC=2)C(F)(F)F)=NC2=CN=CC(C3CC3)=C2C=1N(C)[C@@H]1CCNC1 PUQCTCBOOCZICW-CYBMUJFWSA-N 0.000 claims 1
- QDKPEPADMOTCJG-UHFFFAOYSA-N 5-cyclopropyl-n-methyl-n-piperidin-4-yl-2-[2-(trifluoromethyl)-1h-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=3C=C(NC=3N=CC=2)C(F)(F)F)=NC2=CN=CC(C3CC3)=C2C=1N(C)C1CCNCC1 QDKPEPADMOTCJG-UHFFFAOYSA-N 0.000 claims 1
- SZGCPVJJLHWYLM-UHFFFAOYSA-N 5-cyclopropyl-n-methyl-n-piperidin-4-yl-2-[2-[(3,4,6-trifluoropyridin-2-yl)amino]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=C(NC=3C(=C(F)C=C(F)N=3)F)N=CC=2)=NC2=CN=CC(C3CC3)=C2C=1N(C)C1CCNCC1 SZGCPVJJLHWYLM-UHFFFAOYSA-N 0.000 claims 1
- RNKJVVXIDNWTIR-UHFFFAOYSA-N 5-cyclopropyl-n-methyl-n-piperidin-4-yl-2-[2-[(3,5,6-trifluoropyridin-2-yl)amino]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N=1C(C=2C=C(NC=3C(=CC(F)=C(F)N=3)F)N=CC=2)=NC2=CN=CC(C3CC3)=C2C=1N(C)C1CCNCC1 RNKJVVXIDNWTIR-UHFFFAOYSA-N 0.000 claims 1
- XPUAAAIRHHIVIL-UHFFFAOYSA-N 5-cyclopropyl-n-piperidin-4-yl-2-[2-(trifluoromethyl)-1h-pyrrolo[2,3-b]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound C1=CN=C2NC(C(F)(F)F)=CC2=C1C(N=C1C=NC=C(C1=1)C2CC2)=NC=1NC1CCNCC1 XPUAAAIRHHIVIL-UHFFFAOYSA-N 0.000 claims 1
- UJPFGPKASKZVJK-UHFFFAOYSA-N 5-cyclopropyl-n-piperidin-4-yl-2-[2-[(3,5,6-trifluoropyridin-2-yl)amino]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N1=C(F)C(F)=CC(F)=C1NC1=CC(C=2N=C3C=NC=C(C3=C(NC3CCNCC3)N=2)C2CC2)=CC=N1 UJPFGPKASKZVJK-UHFFFAOYSA-N 0.000 claims 1
- YIWMXUQOWVCXMS-UHFFFAOYSA-N 5-cyclopropyl-n-pyrrolidin-3-yl-2-[2-[(3,4,6-trifluoropyridin-2-yl)amino]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound FC1=CC(F)=C(F)C(NC=2N=CC=C(C=2)C=2N=C3C=NC=C(C3=C(NC3CNCC3)N=2)C2CC2)=N1 YIWMXUQOWVCXMS-UHFFFAOYSA-N 0.000 claims 1
- QSVRYALPYJDUHT-UHFFFAOYSA-N 5-cyclopropyl-n-pyrrolidin-3-yl-2-[2-[(3,5,6-trifluoropyridin-2-yl)amino]pyridin-4-yl]pyrido[3,4-d]pyrimidin-4-amine Chemical compound N1=C(F)C(F)=CC(F)=C1NC1=CC(C=2N=C3C=NC=C(C3=C(NC3CNCC3)N=2)C2CC2)=CC=N1 QSVRYALPYJDUHT-UHFFFAOYSA-N 0.000 claims 1
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- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
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- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
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- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 101150037186 pkc-1 gene Proteins 0.000 description 1
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- 230000000861 pro-apoptotic effect Effects 0.000 description 1
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- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
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- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
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- 235000009566 rice Nutrition 0.000 description 1
- 229910021481 rutherfordium Inorganic materials 0.000 description 1
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- 230000008313 sensitization Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| US201261707340P | 2012-09-28 | 2012-09-28 | |
| US61/707,340 | 2012-09-28 | ||
| US201361781364P | 2013-03-14 | 2013-03-14 | |
| US61/781,364 | 2013-03-14 |
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| TW201427978A TW201427978A (zh) | 2014-07-16 |
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| MX (1) | MX372736B (enExample) |
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| TW (1) | TWI663165B (enExample) |
| WO (1) | WO2014052699A1 (enExample) |
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| NZ706857A (en) * | 2012-09-28 | 2018-05-25 | Ignyta Inc | Azaquinazoline inhibitors of atypical protein kinase c |
| EP2938608B1 (en) | 2012-12-20 | 2021-08-04 | Sanford-Burnham Medical Research Institute | Small molecule agonists of neurotensin receptor 1 |
| DK2970283T3 (da) | 2013-03-14 | 2021-01-25 | Boehringer Ingelheim Int | Substituerede 2-aza-bicyclo[2.2.1]heptan-3-carboxylsyre-(benzyl-cyano-methyl)-amider som inhibitorer af cathepsin-c |
| AU2014308616B2 (en) | 2013-08-23 | 2018-12-06 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
| WO2015143376A1 (en) * | 2014-03-21 | 2015-09-24 | Nivalis Therapeutics, Inc. | Novel compounds for the treatment of cystic fibrosis |
| TWI675836B (zh) * | 2014-03-25 | 2019-11-01 | 美商伊格尼塔公司 | 非典型蛋白質激酶ｃ之氮雜喹唑啉抑制劑 |
| JP6599908B2 (ja) | 2014-06-25 | 2019-10-30 | サンフォード−バーンハム メディカル リサーチ インスティテュート | ニューロテンシン受容体１の小分子アゴニスト |
| WO2016004305A2 (en) | 2014-07-02 | 2016-01-07 | Pharmacyclics Llc | Inhibitors of bruton's tyrosine kinase |
| US10759792B2 (en) * | 2014-09-05 | 2020-09-01 | The Johns Hopkins University | CaMKII inhibitors and uses thereof |
| KR102510588B1 (ko) | 2014-09-12 | 2023-03-17 | 베링거 인겔하임 인터내셔날 게엠베하 | 카텝신 c의 스피로사이클릭 억제제 |
| MX2017005346A (es) * | 2014-10-29 | 2017-08-02 | Dong A St Co Ltd | Nuevos compuestos de piridopirimidinona para modular la actividad catalitica de histona lisina desmetilasas (kdm). |
| CN105288512A (zh) * | 2015-12-08 | 2016-02-03 | 李野林 | 一种治疗肥胖症的中药组合物 |
| CA3026226A1 (en) | 2016-06-13 | 2017-12-21 | Glaxosmithkline Intellectual Property Development Limited | Substituted pyridines as inhibitors of dnmt1 |
| EP4006035B1 (en) * | 2016-08-15 | 2023-11-22 | Neupharma, Inc. | Quinazoline derivatives as tyrosine kinase inhibitors for the treatment of cancer |
| JP6954994B2 (ja) * | 2016-08-16 | 2021-10-27 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | 可逆性ｂｔｋ阻害剤としてのオキソ−イミダゾピリジン及びその使用 |
| CA3037456A1 (en) | 2016-09-19 | 2018-03-22 | Novartis Ag | Therapeutic combinations comprising a raf inhibitor and a erk inhibitor |
| JOP20190257A1 (ar) * | 2017-04-28 | 2019-10-28 | Novartis Ag | مركبات أريل غير متجانسة ثنائية الحلقة مندمجة 6-6 واستخدامها كمثبطات lats |
| IL270224B1 (en) | 2017-05-02 | 2024-04-01 | Novartis Ag | Combination therapy employing trametinib and a defined raf inhibitor |
| JP7311228B2 (ja) | 2017-06-30 | 2023-07-19 | ベイジン タイド ファーマシューティカル カンパニー リミテッド | Ｒｈｏ－関連プロテインキナーゼ阻害剤、それを含む医薬組成物並びにその調製方法及び使用 |
| EP3421465B1 (en) | 2017-06-30 | 2022-10-26 | Beijing Tide Pharmaceutical Co., Ltd. | Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof |
| WO2019000683A1 (zh) | 2017-06-30 | 2019-01-03 | 北京泰德制药股份有限公司 | Rho相关蛋白激酶抑制剂、包含其的药物组合物及其制备方法和用途 |
| ES2929227T3 (es) * | 2018-07-25 | 2022-11-25 | Faes Farma Sa | Piridopirimidinas como inhibidores del receptor de histamina H4 |
| US20210347785A1 (en) * | 2018-08-01 | 2021-11-11 | Shanghai Ennovabio Pharmaceuticals Co., Ltd. | Preparation and application of aromatic compound having immunoregulatory function |
| CN111100063B (zh) * | 2018-10-25 | 2022-05-17 | 南京药石科技股份有限公司 | 一种合成2-氟甲基取代的吡咯烷、哌啶以及哌嗪衍生物的制备方法 |
| KR20220002930A (ko) * | 2019-03-28 | 2022-01-07 | 캔써 리서치 테크놀로지 리미티드 | 비정형 단백질 키나제 c의 억제제 및 헷지호그 경로 의존성 암의 치료에서 이의 용도 |
| EP4563150A3 (en) | 2019-05-13 | 2025-07-23 | Novartis AG | New crystalline forms of n-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methvlphenyl)-2(trifluoromethyl) isonicotinamide as raf inhibitors for the treatment of cancer |
| CN116120243B (zh) * | 2021-11-15 | 2025-07-29 | 都创(上海)医药科技股份有限公司 | aPKC抑制剂化合物中间体片段及其制备方法和应用 |
| CN114349711B (zh) * | 2022-02-28 | 2023-08-15 | 四川依维欣医药科技有限公司 | 一种（R）-1-Boc-3-羟甲基哌嗪的合成方法 |
| CN117088898A (zh) * | 2022-05-13 | 2023-11-21 | 中国药科大学 | 稠环嘧啶类化合物及其制备方法、药物组合物和应用 |
| IL321456A (en) * | 2022-12-13 | 2025-08-01 | Windtree Therapeutics Inc | Solid forms of {5-cyclopropyl-2-[2-(3,6-difluoro¬pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl }-( (s)-3,3-dimethyl-piperidin-4-yl)-amine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050038047A1 (en) * | 2003-08-14 | 2005-02-17 | Edwards Paul John | Azaquinazoline derivatives |
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| JPS4936700A (enExample) | 1972-08-16 | 1974-04-05 | ||
| US6184226B1 (en) * | 1998-08-28 | 2001-02-06 | Scios Inc. | Quinazoline derivatives as inhibitors of P-38 α |
| JP2002080423A (ja) * | 2000-09-06 | 2002-03-19 | Daikin Ind Ltd | トリフルオロ酢酸エチルの合成方法 |
| AU2001296871A1 (en) * | 2000-09-15 | 2002-03-26 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| FR2846657B1 (fr) | 2002-11-05 | 2004-12-24 | Servier Lab | Nouveaux composes pyridopyrimidinone, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| CA2520323C (en) * | 2003-04-09 | 2013-07-09 | Exelixis, Inc. | Tie-2 modulators and methods of use |
| US7582631B2 (en) * | 2004-01-14 | 2009-09-01 | Amgen Inc. | Substituted heterocyclic compounds and methods of use |
| KR20070113252A (ko) * | 2005-02-25 | 2007-11-28 | 쿠도스 파마슈티칼스 리미티드 | 2,4-디아미노-피리도피리미딘 유도체 및 이의 ｍＴＯＲ억제제로서의 용도 |
| AU2007287430B2 (en) * | 2006-08-23 | 2011-07-21 | Kudos Pharmaceuticals Limited | 2-methylmorpholine pyrido-, pyrazo- and pyrimido-pyrimidine derivatives as mTOR inhibitors |
| AU2007297286A1 (en) * | 2006-09-08 | 2008-03-20 | Pfizer Products Inc. | Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
| CA2773131C (en) * | 2009-09-04 | 2015-07-14 | The Regents Of The University Of Michigan | Compositions and methods for treatment of leukemia |
| NZ706857A (en) * | 2012-09-28 | 2018-05-25 | Ignyta Inc | Azaquinazoline inhibitors of atypical protein kinase c |
| BR112015022602A2 (pt) * | 2013-03-13 | 2017-07-18 | Univ Michigan Regents | composições compreendendo compostos de tienopirimidina e tienopiridina e métodos de uso dos mesmos |
| US10246464B2 (en) * | 2014-09-09 | 2019-04-02 | The Regents Of The University Of Michigan | Thienopyrimidine and thienopyridine compounds and methods of use thereof |
| RU2018126774A (ru) * | 2015-12-22 | 2020-01-23 | Витэ Фармасьютикалз, Инк. | Ингибиторы менин-mll взаимодействия |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050038047A1 (en) * | 2003-08-14 | 2005-02-17 | Edwards Paul John | Azaquinazoline derivatives |
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| Title |
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| Bioorganic & Medicinal Chemistry Letters 21 (2011) 7367-7372 * |
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