CA2917735C - Protein tyrosine kinase modulators and methods of use - Google Patents

Info

Publication number

CA2917735C

CA2917735C CA2917735A CA2917735A CA2917735C CA 2917735 C CA2917735 C CA 2917735C CA 2917735 A CA2917735 A CA 2917735A CA 2917735 A CA2917735 A CA 2917735A CA 2917735 C CA2917735 C CA 2917735C

Authority

CA

Canada

Prior art keywords

pyrimidin

chloro

ylamino

phenyl

dimethylamino

Prior art date

2013-07-11

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Fee Related

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• 238000000034 method Methods 0.000 title abstract description 28
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 title description 5
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 title description 5
• -1 Heterocyclic pyrimidine compounds Chemical class 0.000 claims abstract description 73
• 102100033793 ALK tyrosine kinase receptor Human genes 0.000 claims abstract description 69
• 101710168331 ALK tyrosine kinase receptor Proteins 0.000 claims abstract description 60
• 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 33
• 102000020233 phosphotransferase Human genes 0.000 claims abstract description 33
• 150000003839 salts Chemical class 0.000 claims abstract description 31
• 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 27
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
• 201000010099 disease Diseases 0.000 claims abstract description 16
• 238000011282 treatment Methods 0.000 claims abstract description 15
• 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims abstract description 10
• 150000001875 compounds Chemical class 0.000 claims description 231
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 106
• HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 80
• 206010028980 Neoplasm Diseases 0.000 claims description 57
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
• 125000000623 heterocyclic group Chemical group 0.000 claims description 52
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 51
• 201000011510 cancer Diseases 0.000 claims description 42
• 125000000217 alkyl group Chemical group 0.000 claims description 41
• 229910052736 halogen Inorganic materials 0.000 claims description 39
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
• 230000035772 mutation Effects 0.000 claims description 27
• 150000002367 halogens Chemical class 0.000 claims description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
• 125000003342 alkenyl group Chemical group 0.000 claims description 20
• 125000005843 halogen group Chemical group 0.000 claims description 19
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
• 102000037865 fusion proteins Human genes 0.000 claims description 17
• 108020001507 fusion proteins Proteins 0.000 claims description 17
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• 125000003118 aryl group Chemical group 0.000 claims description 16
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 16
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 16
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 12
• 125000003545 alkoxy group Chemical group 0.000 claims description 12
• 125000001188 haloalkyl group Chemical group 0.000 claims description 12
• 125000005842 heteroatom Chemical group 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
• 125000001072 heteroaryl group Chemical group 0.000 claims description 11
• 239000001257 hydrogen Substances 0.000 claims description 11
• 125000000304 alkynyl group Chemical group 0.000 claims description 10
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 10
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 10
• 208000009956 adenocarcinoma Diseases 0.000 claims description 9
• 208000014829 head and neck neoplasm Diseases 0.000 claims description 9
• 230000002401 inhibitory effect Effects 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• 206010006187 Breast cancer Diseases 0.000 claims description 8
• 208000026310 Breast neoplasm Diseases 0.000 claims description 8
• 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 8
• 125000002837 carbocyclic group Chemical group 0.000 claims description 8
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
• 208000005017 glioblastoma Diseases 0.000 claims description 7
• 201000010536 head and neck cancer Diseases 0.000 claims description 7
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 7
• 201000002528 pancreatic cancer Diseases 0.000 claims description 7
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 7
• 238000002360 preparation method Methods 0.000 claims description 7
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
• 206010009944 Colon cancer Diseases 0.000 claims description 6
• 101150069380 JAK3 gene Proteins 0.000 claims description 6
• 206010060862 Prostate cancer Diseases 0.000 claims description 6
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
• 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 claims description 6
• 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 claims description 6
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
• 201000009030 Carcinoma Diseases 0.000 claims description 5
• 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 5
• 206010033128 Ovarian cancer Diseases 0.000 claims description 5
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
• 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 5
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
• 125000004429 atom Chemical group 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
• 229920002554 vinyl polymer Polymers 0.000 claims description 4
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
• 206010027476 Metastases Diseases 0.000 claims description 3
• 208000022873 Ocular disease Diseases 0.000 claims description 3
• 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 3
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
• 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 3
• 208000026278 immune system disease Diseases 0.000 claims description 3
• 230000009401 metastasis Effects 0.000 claims description 3
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• 229910052760 oxygen Inorganic materials 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 3
• DADKXUOVSZYHMW-MDWZMJQESA-N (E)-N-[3-[[5-chloro-4-[2-[2-(dimethylamino)-2-oxoacetyl]anilino]pyrimidin-2-yl]amino]phenyl]-4-(dimethylamino)but-2-enamide Chemical compound ClC=1C(=NC(=NC=1)NC=1C=C(C=CC=1)NC(\C=C\CN(C)C)=O)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O DADKXUOVSZYHMW-MDWZMJQESA-N 0.000 claims description 2
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• MMCUGRPNLUIXRH-UHFFFAOYSA-N 1-[2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-2-morpholin-4-ylethane-1,2-dione Chemical compound COC1=CC(N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)N1CCOCC1 MMCUGRPNLUIXRH-UHFFFAOYSA-N 0.000 claims description 2
• OHXBZRHYEDXUOR-UHFFFAOYSA-N 2-[2-[[5-chloro-2-(2-methoxy-4-piperidin-4-ylanilino)pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound COC1=CC(C2CCNCC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=C)C(N)=O OHXBZRHYEDXUOR-UHFFFAOYSA-N 0.000 claims description 2
• YPHMDPDDBHBKPH-UHFFFAOYSA-N 2-[2-[[5-chloro-2-(2-methoxy-4-piperidin-4-ylanilino)pyrimidin-4-yl]amino]phenyl]prop-2-enoic acid Chemical compound COC1=CC(C2CCNCC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=C)C(O)=O YPHMDPDDBHBKPH-UHFFFAOYSA-N 0.000 claims description 2
• VLQXKAVDAGQNTP-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound COC1=CC(C2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=C)C(N)=O VLQXKAVDAGQNTP-UHFFFAOYSA-N 0.000 claims description 2
• MVLGFIGPCZYXSX-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enoic acid Chemical compound COC1=CC(C2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=C)C(O)=O MVLGFIGPCZYXSX-UHFFFAOYSA-N 0.000 claims description 2
• ZYWWKSPNANEDRB-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-methoxypiperidin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound C1CC(OC)CCN1C(C=C1OC)=CC=C1NC1=NC=C(Cl)C(NC=2C(=CC=CC=2)C(=C)C(N)=O)=N1 ZYWWKSPNANEDRB-UHFFFAOYSA-N 0.000 claims description 2
• WMJNZVCMRZGYMH-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-n-methyl-2-oxoacetamide Chemical compound CNC(=O)C(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC(=CC=2)N2CCN(C)CC2)OC)=NC=C1Cl WMJNZVCMRZGYMH-UHFFFAOYSA-N 0.000 claims description 2
• BSOPHSCYRJAYIT-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound COC1=CC(N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=C)C(N)=O BSOPHSCYRJAYIT-UHFFFAOYSA-N 0.000 claims description 2
• XACHZVJBZTVCPK-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enoic acid Chemical compound COC1=CC(N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=C)C(O)=O XACHZVJBZTVCPK-UHFFFAOYSA-N 0.000 claims description 2
• UBPDOQYPGGLAJG-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[3-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-n-methyl-2-oxoacetamide Chemical compound CNC(=O)C(=O)C1=CC=CC=C1NC1=NC(NC=2C=C(OC)C(N3CCN(C)CC3)=CC=2)=NC=C1Cl UBPDOQYPGGLAJG-UHFFFAOYSA-N 0.000 claims description 2
• AYRRFTJVJJMHCH-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-[[1-(2-fluoroethyl)azetidin-3-yl]amino]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound C=1C=C(NC=2N=C(NC=3C(=CC=CC=3)C(=C)C(N)=O)C(Cl)=CN=2)C(OC)=CC=1NC1CN(CCF)C1 AYRRFTJVJJMHCH-UHFFFAOYSA-N 0.000 claims description 2
• PHGJBYINNNRCCL-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-[[1-(2-fluoroethyl)azetidin-3-yl]amino]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]prop-2-enoic acid Chemical compound C=1C=C(NC=2N=C(NC=3C(=CC=CC=3)C(=C)C(O)=O)C(Cl)=CN=2)C(OC)=CC=1NC1CN(CCF)C1 PHGJBYINNNRCCL-UHFFFAOYSA-N 0.000 claims description 2
• 125000001627 3 membered heterocyclic group Chemical group 0.000 claims description 2
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• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
• KLQNENPEPDBMGN-UHFFFAOYSA-N CCC(=O)Nc1cc(Nc2ncc(Cl)c(Nc3ccccc3C(=O)C(=O)N(C)C)n2)ccc1OCCN(C)C Chemical compound CCC(=O)Nc1cc(Nc2ncc(Cl)c(Nc3ccccc3C(=O)C(=O)N(C)C)n2)ccc1OCCN(C)C KLQNENPEPDBMGN-UHFFFAOYSA-N 0.000 claims description 2
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• BBYTXTSYJQMNME-UHFFFAOYSA-N n-[5-[[5-chloro-4-[2-[2-(methylamino)-2-oxoacetyl]anilino]pyrimidin-2-yl]amino]-4-methoxy-2-(3-morpholin-4-ylpropoxy)phenyl]prop-2-enamide Chemical compound CNC(=O)C(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=2)OC)=NC=C1Cl BBYTXTSYJQMNME-UHFFFAOYSA-N 0.000 claims description 2
• HKNYNUXSBRUGNV-UHFFFAOYSA-N n-[5-[[5-chloro-4-[2-[2-(methylamino)-2-oxoacetyl]anilino]pyrimidin-2-yl]amino]-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl]prop-2-enamide Chemical compound CNC(=O)C(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC(=C(NC(=O)C=C)C=2)N2CCN(C)CC2)OC)=NC=C1Cl HKNYNUXSBRUGNV-UHFFFAOYSA-N 0.000 claims description 2
• UJROFNGOCICAHD-UHFFFAOYSA-N n-[5-[[5-chloro-4-[2-[2-[2-(dimethylamino)ethyl-methylamino]-2-oxoacetyl]anilino]pyrimidin-2-yl]amino]-2-methoxyphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(OC)=CC=C1NC1=NC=C(Cl)C(NC=2C(=CC=CC=2)C(=O)C(=O)N(C)CCN(C)C)=N1 UJROFNGOCICAHD-UHFFFAOYSA-N 0.000 claims description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
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• AERYPYJUMMERSC-UHFFFAOYSA-N 2-[2-[[5-chloro-2-(2-methoxy-4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]phenyl]-n,n-dimethyl-2-oxoacetamide Chemical compound COC1=CC(N2CCOCC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)N(C)C AERYPYJUMMERSC-UHFFFAOYSA-N 0.000 claims 1
• RSIQSLXNWUEYCL-UHFFFAOYSA-N 2-[2-[[5-chloro-2-(2-methoxy-4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]phenyl]-n-cyclopropyl-2-oxoacetamide Chemical compound COC1=CC(N2CCOCC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)NC1CC1 RSIQSLXNWUEYCL-UHFFFAOYSA-N 0.000 claims 1
• NUMIRKOBHLNKEQ-UHFFFAOYSA-N 2-[2-[[5-chloro-2-(4-fluoro-3-methoxyanilino)pyrimidin-4-yl]amino]phenyl]-2-oxo-n-(1-prop-2-enoylpiperidin-4-yl)acetamide Chemical compound C1=C(F)C(OC)=CC(NC=2N=C(NC=3C(=CC=CC=3)C(=O)C(=O)NC3CCN(CC3)C(=O)C=C)C(Cl)=CN=2)=C1 NUMIRKOBHLNKEQ-UHFFFAOYSA-N 0.000 claims 1
• CUOFJQAAYKJYJM-UHFFFAOYSA-N 2-[2-[[5-chloro-2-(4-fluoro-3-methoxyanilino)pyrimidin-4-yl]amino]phenyl]-n,n-dimethyl-2-oxoacetamide Chemical compound C1=C(F)C(OC)=CC(NC=2N=C(NC=3C(=CC=CC=3)C(=O)C(=O)N(C)C)C(Cl)=CN=2)=C1 CUOFJQAAYKJYJM-UHFFFAOYSA-N 0.000 claims 1
• FWPFRLAKYIVTFY-UHFFFAOYSA-N 2-[2-[[5-chloro-2-(4-fluoro-3-methoxyanilino)pyrimidin-4-yl]amino]phenyl]-n-methyl-2-oxoacetamide Chemical compound CNC(=O)C(=O)C1=CC=CC=C1NC1=NC(NC=2C=C(OC)C(F)=CC=2)=NC=C1Cl FWPFRLAKYIVTFY-UHFFFAOYSA-N 0.000 claims 1
• DCYQQOSGSUVQOP-UHFFFAOYSA-N 2-[2-[[5-chloro-2-(5-methyl-4-piperidin-4-yl-2-propan-2-yloxyanilino)pyrimidin-4-yl]amino]phenyl]-2-oxoacetamide Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)C(=O)C(N)=O)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 DCYQQOSGSUVQOP-UHFFFAOYSA-N 0.000 claims 1
• KXPICMSXZCNILY-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[(4-prop-2-enoyl-2,3-dihydro-1,4-benzoxazin-6-yl)amino]pyrimidin-4-yl]amino]phenyl]-n,n-dimethyl-2-oxoacetamide Chemical compound CN(C)C(=O)C(=O)C1=CC=CC=C1NC1=NC(NC=2C=C3N(C(=O)C=C)CCOC3=CC=2)=NC=C1Cl KXPICMSXZCNILY-UHFFFAOYSA-N 0.000 claims 1
• JLWCHILGPBXURH-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-2-oxo-n-(1-prop-2-enoylazetidin-3-yl)acetamide Chemical compound COC1=CC(N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)NC1CN(C(=O)C=C)C1 JLWCHILGPBXURH-UHFFFAOYSA-N 0.000 claims 1
• WHAGLQJWJWUYFE-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-2-oxo-n-(1-prop-2-enoylpiperidin-4-yl)acetamide Chemical compound COC1=CC(N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)NC1CCN(C(=O)C=C)CC1 WHAGLQJWJWUYFE-UHFFFAOYSA-N 0.000 claims 1
• NGVDIADNZJLPMD-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-2-oxoacetamide Chemical compound COC1=CC(N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(N)=O NGVDIADNZJLPMD-UHFFFAOYSA-N 0.000 claims 1
• HUSAFYCXYIUNPB-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-n,n-dimethyl-2-oxoacetamide Chemical compound COC1=CC(N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)N(C)C HUSAFYCXYIUNPB-UHFFFAOYSA-N 0.000 claims 1
• XINCMWVRVWORPO-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-n-cyclopropyl-2-oxoacetamide Chemical compound COC1=CC(N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)NC1CC1 XINCMWVRVWORPO-UHFFFAOYSA-N 0.000 claims 1
• XNFZIAAEOHTBMQ-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-prop-2-enoylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-n,n-dimethyl-2-oxoacetamide Chemical compound COC1=CC(N2CCN(CC2)C(=O)C=C)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)N(C)C XNFZIAAEOHTBMQ-UHFFFAOYSA-N 0.000 claims 1
• IQISRWVHSPSIIQ-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-propanoylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-n,n-dimethyl-2-oxoacetamide Chemical compound C1CN(C(=O)CC)CCN1C(C=C1OC)=CC=C1NC1=NC=C(Cl)C(NC=2C(=CC=CC=2)C(=O)C(=O)N(C)C)=N1 IQISRWVHSPSIIQ-UHFFFAOYSA-N 0.000 claims 1
• ACUPPRKZIQHZNP-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-(4-propanoylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-n-methyl-2-oxoacetamide Chemical compound C1CN(C(=O)CC)CCN1C(C=C1OC)=CC=C1NC1=NC=C(Cl)C(NC=2C(=CC=CC=2)C(=O)C(=O)NC)=N1 ACUPPRKZIQHZNP-UHFFFAOYSA-N 0.000 claims 1
• BJFDBMNLCPJVHU-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[2-methoxy-4-[4-(methylamino)piperidin-1-yl]anilino]pyrimidin-4-yl]amino]phenyl]-n-(2-hydroxyethyl)-2-oxoacetamide Chemical compound C1CC(NC)CCN1C(C=C1OC)=CC=C1NC1=NC=C(Cl)C(NC=2C(=CC=CC=2)C(=O)C(=O)NCCO)=N1 BJFDBMNLCPJVHU-UHFFFAOYSA-N 0.000 claims 1
• LCWFBNTYQSRCSA-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[3-methoxy-4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]phenyl]-N,N-dimethyl-2-oxoacetamide Chemical compound COc1cc(Nc2ncc(Cl)c(Nc3ccccc3C(=O)C(=O)N(C)C)n2)ccc1C1CCN(C)CC1 LCWFBNTYQSRCSA-UHFFFAOYSA-N 0.000 claims 1
• DIQHRPNVYBPCQW-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[3-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]-n,n-dimethyl-2-oxoacetamide Chemical compound C=1C=C(N2CCN(C)CC2)C(OC)=CC=1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)N(C)C DIQHRPNVYBPCQW-UHFFFAOYSA-N 0.000 claims 1
• PAAKHQWOTAMVCC-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-(4-fluoropiperidin-1-yl)-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound COC1=CC(N2CCC(F)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=C)C(N)=O PAAKHQWOTAMVCC-UHFFFAOYSA-N 0.000 claims 1
• GUKXDBLCVTYCCQ-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]-2-oxo-n-piperidin-4-ylacetamide Chemical compound COC1=CC(N2CCC(CC2)N(C)C)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)NC1CCNCC1 GUKXDBLCVTYCCQ-UHFFFAOYSA-N 0.000 claims 1
• CMMPIADXDBMMJX-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]-2-oxo-n-pyrrolidin-3-ylacetamide Chemical compound COC1=CC(N2CCC(CC2)N(C)C)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)NC1CCNC1 CMMPIADXDBMMJX-UHFFFAOYSA-N 0.000 claims 1
• AMSONZZHZCNUHV-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]-2-oxoacetamide Chemical compound COC1=CC(N2CCC(CC2)N(C)C)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(N)=O AMSONZZHZCNUHV-UHFFFAOYSA-N 0.000 claims 1
• KTONNTOWXWZRTD-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]-2-oxoacetic acid Chemical compound COC1=CC(N2CCC(CC2)N(C)C)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(O)=O KTONNTOWXWZRTD-UHFFFAOYSA-N 0.000 claims 1
• JLFPEHXJEYWJFT-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]-n-hydroxy-2-oxoacetamide Chemical compound COC1=CC(N2CCC(CC2)N(C)C)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=O)C(=O)NO JLFPEHXJEYWJFT-UHFFFAOYSA-N 0.000 claims 1
• NIRIQZRPPUKCOA-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]-n-methyl-2-oxoacetamide Chemical compound CNC(=O)C(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC(=CC=2)N2CCC(CC2)N(C)C)OC)=NC=C1Cl NIRIQZRPPUKCOA-UHFFFAOYSA-N 0.000 claims 1
• XSRRSOYHBRNXHZ-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound COC1=CC(N2CCC(CC2)N(C)C)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1C(=C)C(N)=O XSRRSOYHBRNXHZ-UHFFFAOYSA-N 0.000 claims 1
• YAJAQZIBHSVGQC-UHFFFAOYSA-N 2-[2-[[5-chloro-2-[4-[[1-(2-fluoroethyl)azetidin-3-yl]amino]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]-2-oxoacetamide Chemical compound C=1C=C(NC=2N=C(NC=3C(=CC=CC=3)C(=O)C(N)=O)C(Cl)=CN=2)C(OC)=CC=1NC1CN(CCF)C1 YAJAQZIBHSVGQC-UHFFFAOYSA-N 0.000 claims 1
• JLTWZPIRUVBNHA-UHFFFAOYSA-N C(C)(=O)N1CCN(CC1)C1=CC(=C(C=C1)NC1=NC=C(C(=N1)NC1=C(C=CC=C1)C(C(=O)N)=O)C(F)(F)F)OC Chemical compound C(C)(=O)N1CCN(CC1)C1=CC(=C(C=C1)NC1=NC=C(C(=N1)NC1=C(C=CC=C1)C(C(=O)N)=O)C(F)(F)F)OC JLTWZPIRUVBNHA-UHFFFAOYSA-N 0.000 claims 1
• OXZCJVZJWPZZON-UHFFFAOYSA-N CN(C(C(=O)C1=C(C=CC=C1)NC1=NC(=NC=C1C)NC=1C=C(C=CC1OC)NC(C(=C)CN(C)C)=O)=O)C Chemical compound CN(C(C(=O)C1=C(C=CC=C1)NC1=NC(=NC=C1C)NC=1C=C(C=CC1OC)NC(C(=C)CN(C)C)=O)=O)C OXZCJVZJWPZZON-UHFFFAOYSA-N 0.000 claims 1
• QNHPQJSREUJAPV-UHFFFAOYSA-N CN(C)C(=O)C(=O)c1ccccc1Nc1nc(Nc2ccc(N3CCN(C)CC3)c(NC(=O)C(=C)CN3CCCCC3)c2)ncc1Cl Chemical compound CN(C)C(=O)C(=O)c1ccccc1Nc1nc(Nc2ccc(N3CCN(C)CC3)c(NC(=O)C(=C)CN3CCCCC3)c2)ncc1Cl QNHPQJSREUJAPV-UHFFFAOYSA-N 0.000 claims 1
• BGUOCXLBRPRPMP-UHFFFAOYSA-N CN(C)C(=O)C(=O)c1ccccc1Nc1nc(Nc2cccc(NC(=O)C(=C)CN3CCOCC3)c2)ncc1Cl Chemical compound CN(C)C(=O)C(=O)c1ccccc1Nc1nc(Nc2cccc(NC(=O)C(=C)CN3CCOCC3)c2)ncc1Cl BGUOCXLBRPRPMP-UHFFFAOYSA-N 0.000 claims 1
• NRQVNQUQJQSTSL-UHFFFAOYSA-N CN(C)CCN(C)CC(=C)C(=O)Nc1cccc(Nc2ncc(Cl)c(Nc3ccccc3C(=O)C(=O)N(C)C)n2)c1 Chemical compound CN(C)CCN(C)CC(=C)C(=O)Nc1cccc(Nc2ncc(Cl)c(Nc3ccccc3C(=O)C(=O)N(C)C)n2)c1 NRQVNQUQJQSTSL-UHFFFAOYSA-N 0.000 claims 1
• WEQWIGHEOWGCOY-UHFFFAOYSA-N CN(C1CCN(CC1)C1=CC(=C(C=C1)NC1=NC=C(C(=N1)NC1=C(C=CC=C1)C(C(=O)N)=O)C(F)(F)F)OC)C Chemical compound CN(C1CCN(CC1)C1=CC(=C(C=C1)NC1=NC=C(C(=N1)NC1=C(C=CC=C1)C(C(=O)N)=O)C(F)(F)F)OC)C WEQWIGHEOWGCOY-UHFFFAOYSA-N 0.000 claims 1
• XYNBROWABUHURG-UHFFFAOYSA-N COc1cc(Nc2ncc(Cl)c(Nc3ccccc3C(=O)C(=O)N(C)C)n2)ccc1N1CCC(CC1)N(C)C Chemical compound COc1cc(Nc2ncc(Cl)c(Nc3ccccc3C(=O)C(=O)N(C)C)n2)ccc1N1CCC(CC1)N(C)C XYNBROWABUHURG-UHFFFAOYSA-N 0.000 claims 1
• KRMZCNDWFUVTTM-UHFFFAOYSA-N COc1ccc(NC(=O)C(=C)CN(C)CCN(C)C)cc1Nc1ncc(Cl)c(Nc2ccccc2C(=O)C(=O)N(C)C)n1 Chemical compound COc1ccc(NC(=O)C(=C)CN(C)CCN(C)C)cc1Nc1ncc(Cl)c(Nc2ccccc2C(=O)C(=O)N(C)C)n1 KRMZCNDWFUVTTM-UHFFFAOYSA-N 0.000 claims 1
• XIZKOPKJPXWYQT-UHFFFAOYSA-N ClC=1C(=NC(=NC1)NC1=CC=C(C=C1)N1CCN(CC1)C)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O Chemical compound ClC=1C(=NC(=NC1)NC1=CC=C(C=C1)N1CCN(CC1)C)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O XIZKOPKJPXWYQT-UHFFFAOYSA-N 0.000 claims 1
• PMQHMXASLNUVDG-UHFFFAOYSA-N ClC=1C(=NC(=NC=1)NC1=C(C=C(C(=C1)C)C1CCNCC1)OC(C)C)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O Chemical compound ClC=1C(=NC(=NC=1)NC1=C(C=C(C(=C1)C)C1CCNCC1)OC(C)C)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O PMQHMXASLNUVDG-UHFFFAOYSA-N 0.000 claims 1
• OQCCKAQJCBSTAD-UHFFFAOYSA-N ClC=1C(=NC(=NC=1)NC1=C(C=C(C=C1)N1CCC(CC1)N(C)C)OC)NC1=C(C=CC=C1)C(C(=O)NCCN(C)C)=O Chemical compound ClC=1C(=NC(=NC=1)NC1=C(C=C(C=C1)N1CCC(CC1)N(C)C)OC)NC1=C(C=CC=C1)C(C(=O)NCCN(C)C)=O OQCCKAQJCBSTAD-UHFFFAOYSA-N 0.000 claims 1
• ACSYBWWKVXRLAM-UHFFFAOYSA-N ClC=1C(=NC(=NC=1)NC1=C(C=C(C=C1)N1CCC(CC1)N(C)C)OC)NC1=C(C=CC=C1)C(C(=O)O)=C Chemical compound ClC=1C(=NC(=NC=1)NC1=C(C=C(C=C1)N1CCC(CC1)N(C)C)OC)NC1=C(C=CC=C1)C(C(=O)O)=C ACSYBWWKVXRLAM-UHFFFAOYSA-N 0.000 claims 1
• MZFLYNFLSFBMGV-UHFFFAOYSA-N ClC=1C(=NC(=NC=1)NC1=CC(=C(C=C1)C1CCN(CC1)C(C)C)OC)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O Chemical compound ClC=1C(=NC(=NC=1)NC1=CC(=C(C=C1)C1CCN(CC1)C(C)C)OC)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O MZFLYNFLSFBMGV-UHFFFAOYSA-N 0.000 claims 1
• TYQLJBLABKIDIY-UHFFFAOYSA-N ClC=1C(=NC(=NC=1)NC1=CC(=C(C=C1)N1CCOCC1)OC)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O Chemical compound ClC=1C(=NC(=NC=1)NC1=CC(=C(C=C1)N1CCOCC1)OC)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O TYQLJBLABKIDIY-UHFFFAOYSA-N 0.000 claims 1
• DUKRJKCPYLPIHS-UHFFFAOYSA-N ClC=1C(=NC(=NC=1)NC=1C=CC(=C(C=1)NC(C(=C)CN1CCCCC1)=O)N1CCOCC1)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O Chemical compound ClC=1C(=NC(=NC=1)NC=1C=CC(=C(C=1)NC(C(=C)CN1CCCCC1)=O)N1CCOCC1)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O DUKRJKCPYLPIHS-UHFFFAOYSA-N 0.000 claims 1
• LPGXRLSRVXWDEY-UHFFFAOYSA-N ClC=1C(=NC(=NC=1)NC=1C=CC(=C(C=1)NC(C=C)=O)N1CCOCC1)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O Chemical compound ClC=1C(=NC(=NC=1)NC=1C=CC(=C(C=1)NC(C=C)=O)N1CCOCC1)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O LPGXRLSRVXWDEY-UHFFFAOYSA-N 0.000 claims 1
• CDHPTZZAPQRQAT-UHFFFAOYSA-N ClC=1C(=NC(=NC=1)NC=1C=CC(=C(C=1)NC(CCN1CCOCC1)=O)F)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O Chemical compound ClC=1C(=NC(=NC=1)NC=1C=CC(=C(C=1)NC(CCN1CCOCC1)=O)F)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O CDHPTZZAPQRQAT-UHFFFAOYSA-N 0.000 claims 1
• CKJQQBPVTLJGQA-OUKQBFOZSA-N ClC=1C(=NC(=NC=1)NC=1C=CC(=C(C=1)NC(\C=C\N(C)C)=O)N1CCN(CC1)C)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O Chemical compound ClC=1C(=NC(=NC=1)NC=1C=CC(=C(C=1)NC(\C=C\N(C)C)=O)N1CCN(CC1)C)NC1=C(C=CC=C1)C(C(=O)N(C)C)=O CKJQQBPVTLJGQA-OUKQBFOZSA-N 0.000 claims 1
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
• YMAKLKBXEXREET-UHFFFAOYSA-N ethyl 2-[2-[[5-chloro-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]-2-oxoacetate Chemical compound CCOC(=O)C(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC(=CC=2)N2CCC(CC2)N(C)C)OC)=NC=C1Cl YMAKLKBXEXREET-UHFFFAOYSA-N 0.000 claims 1
• XOBKPQQVWGGIIJ-UHFFFAOYSA-N ethyl 2-[2-[[5-chloro-2-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]prop-2-enoate Chemical compound CCOC(=O)C(=C)C1=CC=CC=C1NC1=NC(NC=2C(=CC(=CC=2)N2CCC(CC2)N(C)C)OC)=NC=C1Cl XOBKPQQVWGGIIJ-UHFFFAOYSA-N 0.000 claims 1
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