CA2844058A1 - Quinazoline compounds as serine/threonine kinase inhibitors - Google Patents

Info

Publication number

CA2844058A1

CA2844058A1 CA2844058A CA2844058A CA2844058A1 CA 2844058 A1 CA2844058 A1 CA 2844058A1 CA 2844058 A CA2844058 A CA 2844058A CA 2844058 A CA2844058 A CA 2844058A CA 2844058 A1 CA2844058 A1 CA 2844058A1

Authority

CA

Canada

Prior art keywords

methyl

fluoro

quinazoline

ylamino

phenyl

Prior art date

2011-08-04

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 title description 3
• 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 title description 3
• 229940043355 kinase inhibitor Drugs 0.000 title description 3
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 3
• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 265
• 239000000203 mixture Substances 0.000 claims abstract description 92
• 238000000034 method Methods 0.000 claims abstract description 64
• 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 37
• 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 claims abstract description 21
• -1 tetrahydrofuranyl,2-oxabicyclo[2.2.1]heptan-5-yl Chemical group 0.000 claims description 318
• 229910052736 halogen Inorganic materials 0.000 claims description 130
• 150000002367 halogens Chemical group 0.000 claims description 130
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 89
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 88
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 85
• 125000000623 heterocyclic group Chemical group 0.000 claims description 81
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 70
• 125000003566 oxetanyl group Chemical group 0.000 claims description 69
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 54
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 52
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 49
• 125000001072 heteroaryl group Chemical group 0.000 claims description 46
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 37
• 208000035475 disorder Diseases 0.000 claims description 36
• WIVJYUYFVAZMMS-UHFFFAOYSA-N 2-(oxan-4-ylamino)quinazoline-7-carboxylic acid Chemical compound N=1C2=CC(C(=O)O)=CC=C2C=NC=1NC1CCOCC1 WIVJYUYFVAZMMS-UHFFFAOYSA-N 0.000 claims description 32
• TYHCBIKGTCZFTK-UHFFFAOYSA-N quinazoline-7-carboxamide Chemical compound C1=NC=NC2=CC(C(=O)N)=CC=C21 TYHCBIKGTCZFTK-UHFFFAOYSA-N 0.000 claims description 31
• 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 30
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
• 206010028980 Neoplasm Diseases 0.000 claims description 29
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
• HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 claims description 28
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 28
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 28
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
• 239000001257 hydrogen Substances 0.000 claims description 27
• 229910052739 hydrogen Inorganic materials 0.000 claims description 27
• 150000003839 salts Chemical class 0.000 claims description 24
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 19
• 238000011282 treatment Methods 0.000 claims description 19
• 201000011510 cancer Diseases 0.000 claims description 18
• 230000000694 effects Effects 0.000 claims description 17
• 125000001424 substituent group Chemical group 0.000 claims description 17
• 201000010099 disease Diseases 0.000 claims description 16
• 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 15
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 15
• 125000004043 oxo group Chemical group O=* 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• 125000003386 piperidinyl group Chemical group 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• 125000004442 acylamino group Chemical group 0.000 claims description 10
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 10
• 239000003085 diluting agent Substances 0.000 claims description 9
• 238000004519 manufacturing process Methods 0.000 claims description 9
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
• 125000002971 oxazolyl group Chemical group 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 8
• 125000004076 pyridyl group Chemical group 0.000 claims description 8
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 7
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
• 208000026310 Breast neoplasm Diseases 0.000 claims description 7
• 206010009944 Colon cancer Diseases 0.000 claims description 7
• 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 claims description 7
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
• 208000024770 Thyroid neoplasm Diseases 0.000 claims description 7
• 239000002246 antineoplastic agent Substances 0.000 claims description 7
• 229940127089 cytotoxic agent Drugs 0.000 claims description 7
• 230000002401 inhibitory effect Effects 0.000 claims description 7
• 201000002528 pancreatic cancer Diseases 0.000 claims description 7
• 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 6
• 206010006187 Breast cancer Diseases 0.000 claims description 6
• 201000009030 Carcinoma Diseases 0.000 claims description 6
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
• 206010033128 Ovarian cancer Diseases 0.000 claims description 6
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
• 201000005202 lung cancer Diseases 0.000 claims description 6
• 208000020816 lung neoplasm Diseases 0.000 claims description 6
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
• 201000002510 thyroid cancer Diseases 0.000 claims description 6
• 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
• KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 5
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 5
• 201000001441 melanoma Diseases 0.000 claims description 5
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 4
• 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
• 206010038389 Renal cancer Diseases 0.000 claims description 4
• 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 4
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• 201000010982 kidney cancer Diseases 0.000 claims description 4
• 208000032839 leukemia Diseases 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
• 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 claims description 3
• UEOXRBXYKVEYEB-HXOBKFHXSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-[[(3r)-oxolan-3-yl]amino]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(N[C@H]2COCC2)=N2)C2=C1 UEOXRBXYKVEYEB-HXOBKFHXSA-N 0.000 claims description 3
• 206010005003 Bladder cancer Diseases 0.000 claims description 3
• KPKPKFXGSDXZJO-NEPJUHHUSA-N OC[C@@H]1C[C@@H](CCO1)Nc1ncc2ccc(cc2n1)C(O)=O Chemical compound OC[C@@H]1C[C@@H](CCO1)Nc1ncc2ccc(cc2n1)C(O)=O KPKPKFXGSDXZJO-NEPJUHHUSA-N 0.000 claims description 3
• 206010060862 Prostate cancer Diseases 0.000 claims description 3
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
• 208000015634 Rectal Neoplasms Diseases 0.000 claims description 3
• 206010039491 Sarcoma Diseases 0.000 claims description 3
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
• 208000029742 colonic neoplasm Diseases 0.000 claims description 3
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 208000005017 glioblastoma Diseases 0.000 claims description 3
• 201000010536 head and neck cancer Diseases 0.000 claims description 3
• 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
• 201000005249 lung adenocarcinoma Diseases 0.000 claims description 3
• 125000002757 morpholinyl group Chemical group 0.000 claims description 3
• 206010038038 rectal cancer Diseases 0.000 claims description 3
• 201000001275 rectum cancer Diseases 0.000 claims description 3
• 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
• 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
• 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 2
• 208000003200 Adenoma Diseases 0.000 claims description 2
• 206010001233 Adenoma benign Diseases 0.000 claims description 2
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 2
• 208000017604 Hodgkin disease Diseases 0.000 claims description 2
• 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
• 206010023347 Keratoacanthoma Diseases 0.000 claims description 2
• 208000034578 Multiple myelomas Diseases 0.000 claims description 2
• 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 2
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
• 206010029260 Neuroblastoma Diseases 0.000 claims description 2
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
• 208000024313 Testicular Neoplasms Diseases 0.000 claims description 2
• 206010057644 Testis cancer Diseases 0.000 claims description 2
• 125000002883 imidazolyl group Chemical group 0.000 claims description 2
• 208000003849 large cell carcinoma Diseases 0.000 claims description 2
• 208000025113 myeloid leukemia Diseases 0.000 claims description 2
• 201000010198 papillary carcinoma Diseases 0.000 claims description 2
• 201000000849 skin cancer Diseases 0.000 claims description 2
• 208000000649 small cell carcinoma Diseases 0.000 claims description 2
• 201000003120 testicular cancer Diseases 0.000 claims description 2
• 125000006300 thietan-3-yl group Chemical group [H]C1([H])SC([H])([H])C1([H])* 0.000 claims description 2
• 208000030901 thyroid gland follicular carcinoma Diseases 0.000 claims description 2
• 208000010576 undifferentiated carcinoma Diseases 0.000 claims description 2
• NGEZLEPIEDVAFP-XMMPIXPASA-N 5-fluoro-n-[(r)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NC2CCOCC2)=N2)C2=C1 NGEZLEPIEDVAFP-XMMPIXPASA-N 0.000 claims 2
• YHZOHYDIEKONRJ-IMSXRSKXSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-[[(3r,4r)-3-fluorooxan-4-yl]amino]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(N[C@H]2[C@H](COCC2)F)=N2)C2=C1 YHZOHYDIEKONRJ-IMSXRSKXSA-N 0.000 claims 2
• JPKBESGDPJRCBB-QHCPKHFHSA-N 5-fluoro-n-[(s)-(3-fluorophenyl)-(1-methylpyrazol-4-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=NN(C)C=C1[C@H](C=1C=C(F)C=CC=1)NC(=O)C1=CC(F)=C(C=NC(NC2CCOCC2)=N2)C2=C1 JPKBESGDPJRCBB-QHCPKHFHSA-N 0.000 claims 2
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
• NWUZPNZUNARLLZ-LBPRGKRZSA-N (s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methanamine Chemical compound C1=C(F)C(OC)=CC=C1[C@H](N)C1=CN(C)N=C1 NWUZPNZUNARLLZ-LBPRGKRZSA-N 0.000 claims 1
• NBXOSGJMUZEDBS-QFIPXVFZSA-N 2-(2-cyanoethylamino)-5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NCCC#N)=N2)C2=C1 NBXOSGJMUZEDBS-QFIPXVFZSA-N 0.000 claims 1
• NZDVPKKBUOHHIN-QHCPKHFHSA-N 2-(cyclopropylmethylamino)-5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NCC2CC2)=N2)C2=C1 NZDVPKKBUOHHIN-QHCPKHFHSA-N 0.000 claims 1
• HNMQRKFRTUIPCB-DEOSSOPVSA-N 2-[(2,5-dimethylpyrazol-3-yl)amino]-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC=C(C=NC(NC=2N(N=C(C)C=2)C)=N2)C2=C1 HNMQRKFRTUIPCB-DEOSSOPVSA-N 0.000 claims 1
• KLXOIEADLOCBLO-OECQAKIHSA-N 2-[[(1R)-1-cyclopropylethyl]amino]-N-[(R)-(3-fluoro-4-methoxyphenyl)-[(2S)-pyrrolidin-2-yl]methyl]quinazoline-7-carboxamide Chemical compound FC=1C=C(C=CC1OC)[C@H]([C@H]1NCCC1)NC(=O)C1=CC=C2C=NC(=NC2=C1)N[C@H](C)C1CC1 KLXOIEADLOCBLO-OECQAKIHSA-N 0.000 claims 1
• VTPREKMEYVQFCQ-XUZZJYLKSA-N 5-fluoro-N-[(R)-(3-fluoro-4-methoxyphenyl)-[(2S)-pyrrolidin-2-yl]methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound FC=1C=C(C=CC1OC)[C@H]([C@H]1NCCC1)NC(=O)C1=CC(=C2C=NC(=NC2=C1)NC1CCOCC1)F VTPREKMEYVQFCQ-XUZZJYLKSA-N 0.000 claims 1
• ZNTSMVKYLVMTDD-UHFFFAOYSA-N 5-fluoro-n-[(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-(1,1,1-trifluoropropan-2-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1C(C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NC(C)C(F)(F)F)=N2)C2=C1 ZNTSMVKYLVMTDD-UHFFFAOYSA-N 0.000 claims 1
• VARWPWPSRPPVSW-UHFFFAOYSA-N 5-fluoro-n-[(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-(2-oxabicyclo[2.2.1]heptan-5-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1C(C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NC2C3CC(OC3)C2)=N2)C2=C1 VARWPWPSRPPVSW-UHFFFAOYSA-N 0.000 claims 1
• AEOHEXWDZQICMA-UHFFFAOYSA-N 5-fluoro-n-[(3-fluoro-4-methoxyphenyl)-(2-methyltriazol-4-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1C(C1=NN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NC2CCOCC2)=N2)C2=C1 AEOHEXWDZQICMA-UHFFFAOYSA-N 0.000 claims 1
• CSDQFRNGMDCUPO-UHFFFAOYSA-N 5-fluoro-n-[(4-methoxypyridin-2-yl)-(1-methylpyrazol-4-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound COC1=CC=NC(C(NC(=O)C=2C=C3N=C(NC4CCOCC4)N=CC3=C(F)C=2)C2=CN(C)N=C2)=C1 CSDQFRNGMDCUPO-UHFFFAOYSA-N 0.000 claims 1
• AEOHEXWDZQICMA-HSZRJFAPSA-N 5-fluoro-n-[(r)-(3-fluoro-4-methoxyphenyl)-(2-methyltriazol-4-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@H](C1=NN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NC2CCOCC2)=N2)C2=C1 AEOHEXWDZQICMA-HSZRJFAPSA-N 0.000 claims 1
• GRWXYVACNOJJLZ-HSZRJFAPSA-N 5-fluoro-n-[(r)-(5-methoxypyridin-2-yl)-(1-methylpyrazol-4-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound N1=CC(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NC2CCOCC2)=N2)C2=C1 GRWXYVACNOJJLZ-HSZRJFAPSA-N 0.000 claims 1
• JZHTYSFEKDXGAH-QHCPKHFHSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1,3-oxazol-5-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C=1OC=NC=1)NC(=O)C1=CC(F)=C(C=NC(NC2CCOCC2)=N2)C2=C1 JZHTYSFEKDXGAH-QHCPKHFHSA-N 0.000 claims 1
• BYDHXONIQCKCTI-QHCPKHFHSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylimidazol-2-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C=1N(C=CN=1)C)NC(=O)C1=CC(F)=C(C=NC(NC2CCOCC2)=N2)C2=C1 BYDHXONIQCKCTI-QHCPKHFHSA-N 0.000 claims 1
• KSKGTHMCOPFIGO-QFIPXVFZSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylimidazol-2-yl)methyl]-2-[(2-methylpyrazol-3-yl)amino]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C=1N(C=CN=1)C)NC(=O)C1=CC(F)=C(C=NC(NC=2N(N=CC=2)C)=N2)C2=C1 KSKGTHMCOPFIGO-QFIPXVFZSA-N 0.000 claims 1
• MCRVDNPGNVRSMQ-DEOSSOPVSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylimidazol-4-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C=1N=CN(C)C=1)NC(=O)C1=CC(F)=C(C=NC(NC2CCOCC2)=N2)C2=C1 MCRVDNPGNVRSMQ-DEOSSOPVSA-N 0.000 claims 1
• VSHUAFALZZSEGQ-QFIPXVFZSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-(2-methoxyethylamino)quinazoline-7-carboxamide Chemical compound C=1([C@@H](NC(=O)C=2C=C(F)C3=CN=C(N=C3C=2)NCCOC)C=2C=C(F)C(OC)=CC=2)C=NN(C)C=1 VSHUAFALZZSEGQ-QFIPXVFZSA-N 0.000 claims 1
• XQPBZAHAMNIOAK-QFIPXVFZSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-(3-fluoropropylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NCCCF)=N2)C2=C1 XQPBZAHAMNIOAK-QFIPXVFZSA-N 0.000 claims 1
• NGEZLEPIEDVAFP-DEOSSOPVSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NC2CCOCC2)=N2)C2=C1 NGEZLEPIEDVAFP-DEOSSOPVSA-N 0.000 claims 1
• SNFVBUXXVRWLLK-QHCPKHFHSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-(oxetan-3-ylmethylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NCC2COC2)=N2)C2=C1 SNFVBUXXVRWLLK-QHCPKHFHSA-N 0.000 claims 1
• GRDYTJICKQLANR-QHCPKHFHSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-[(2-methylpyrazol-3-yl)amino]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NC=2N(N=CC=2)C)=N2)C2=C1 GRDYTJICKQLANR-QHCPKHFHSA-N 0.000 claims 1
• DRDRRDIMLWOPTP-QFIPXVFZSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-[(3-methyloxetan-3-yl)amino]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(NC2(C)COC2)=N2)C2=C1 DRDRRDIMLWOPTP-QFIPXVFZSA-N 0.000 claims 1
• YHZOHYDIEKONRJ-DPLHUUCSSA-N 5-fluoro-n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-[[(3s,4s)-3-fluorooxan-4-yl]amino]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC(F)=C(C=NC(N[C@@H]2[C@@H](COCC2)F)=N2)C2=C1 YHZOHYDIEKONRJ-DPLHUUCSSA-N 0.000 claims 1
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• VJKPZNVYHGYYIB-VVEXTSJTSA-N n-[(s)-(3-fluoro-4-methoxyphenyl)-(1-methylpyrazol-4-yl)methyl]-2-[[(1r,4s,5s)-2-oxabicyclo[2.2.1]heptan-5-yl]amino]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(C)N=C1)NC(=O)C1=CC=C(C=NC(N[C@@H]2[C@@H]3C[C@@H](OC3)C2)=N2)C2=C1 VJKPZNVYHGYYIB-VVEXTSJTSA-N 0.000 claims 1
• FRSNUMOBGJAMTC-DEOSSOPVSA-N n-[(s)-(3-fluoro-4-methoxyphenyl)-(2-methylpyrazol-3-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C=1N(N=CC=1)C)NC(=O)C1=CC=C(C=NC(NC2CCOCC2)=N2)C2=C1 FRSNUMOBGJAMTC-DEOSSOPVSA-N 0.000 claims 1
• CJULNEVOGJYRGP-QHCPKHFHSA-N n-[(s)-(3-fluoro-4-methoxyphenyl)-(2-methylpyrazol-3-yl)methyl]-2-[(2-methylpyrazol-3-yl)amino]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C=1N(N=CC=1)C)NC(=O)C1=CC=C(C=NC(NC=2N(N=CC=2)C)=N2)C2=C1 CJULNEVOGJYRGP-QHCPKHFHSA-N 0.000 claims 1
• XGVGQGFUQGCUNQ-NMMYMHLASA-N n-[(s)-(3-fluoro-4-methoxyphenyl)-(2-methylpyrazol-3-yl)methyl]-2-[[(3s,4s)-3-fluorooxan-4-yl]amino]quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C=1N(N=CC=1)C)NC(=O)C1=CC=C(C=NC(N[C@@H]2[C@@H](COCC2)F)=N2)C2=C1 XGVGQGFUQGCUNQ-NMMYMHLASA-N 0.000 claims 1
• WEZUSONGOXQEOY-ANJVHQHFSA-N n-[(s)-(3-fluoro-4-methoxyphenyl)-[(2r,4s)-4-fluoropyrrolidin-2-yl]methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H]([C@@H]1NC[C@@H](F)C1)NC(=O)C1=CC=C(C=NC(NC2CCOCC2)=N2)C2=C1 WEZUSONGOXQEOY-ANJVHQHFSA-N 0.000 claims 1
• CXWZVYVZRSIBCW-VWLOTQADSA-N n-[(s)-(3-fluoro-4-methoxyphenyl)-[1-(2-hydroxyethyl)pyrazol-4-yl]methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H](C1=CN(CCO)N=C1)NC(=O)C1=CC=C(C=NC(NC2CCOCC2)=N2)C2=C1 CXWZVYVZRSIBCW-VWLOTQADSA-N 0.000 claims 1
• RCDKWQHFIJMQDJ-QHCPKHFHSA-N n-[(s)-(4-chloro-3-fluorophenyl)-(1-methylpyrazol-3-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound CN1C=CC([C@@H](NC(=O)C=2C=C3N=C(NC4CCOCC4)N=CC3=CC=2)C=2C=C(F)C(Cl)=CC=2)=N1 RCDKWQHFIJMQDJ-QHCPKHFHSA-N 0.000 claims 1
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• OZPDXPIOCLPNAM-QHCPKHFHSA-N n-[(s)-(4-chloro-3-fluorophenyl)-(1-methylpyrazol-4-yl)methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=NN(C)C=C1[C@H](C=1C=C(F)C(Cl)=CC=1)NC(=O)C1=CC=C(C=NC(NC2CCOCC2)=N2)C2=C1 OZPDXPIOCLPNAM-QHCPKHFHSA-N 0.000 claims 1
• KAVNWTJUHVNYDE-QFIPXVFZSA-N n-[(s)-(4-chloro-3-fluorophenyl)-(1-methylpyrazol-4-yl)methyl]-2-[(2-methylpyrazol-3-yl)amino]quinazoline-7-carboxamide Chemical compound C1=NN(C)C=C1[C@H](C=1C=C(F)C(Cl)=CC=1)NC(=O)C1=CC=C(C=NC(NC=2N(N=CC=2)C)=N2)C2=C1 KAVNWTJUHVNYDE-QFIPXVFZSA-N 0.000 claims 1
• KJYWWRQXFYFUCA-ZSEKCTLFSA-N n-[(s)-(4-chloro-3-fluorophenyl)-(1-methylpyrazol-4-yl)methyl]-2-[[(2s)-1-hydroxypropan-2-yl]amino]quinazoline-7-carboxamide Chemical compound C=1([C@@H](NC(=O)C=2C=CC3=CN=C(N=C3C=2)N[C@H](CO)C)C=2C=C(F)C(Cl)=CC=2)C=NN(C)C=1 KJYWWRQXFYFUCA-ZSEKCTLFSA-N 0.000 claims 1
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• FWSWGJRTWXRQJN-SKPFHBQLSA-N n-[(s)-(4-chloro-3-fluorophenyl)-(1-methylpyrazol-4-yl)methyl]-2-[[(2s,4s)-2-(hydroxymethyl)oxan-4-yl]amino]quinazoline-7-carboxamide Chemical compound C1=NN(C)C=C1[C@H](C=1C=C(F)C(Cl)=CC=1)NC(=O)C1=CC=C(C=NC(N[C@@H]2C[C@@H](CO)OCC2)=N2)C2=C1 FWSWGJRTWXRQJN-SKPFHBQLSA-N 0.000 claims 1
• RYAVEUFXJVCQNW-XJUOHMSHSA-N n-[(s)-(4-chloro-3-fluorophenyl)-(1-methylpyrazol-4-yl)methyl]-2-[[(3r,4r)-3-fluorooxan-4-yl]amino]quinazoline-7-carboxamide Chemical compound C1=NN(C)C=C1[C@H](C=1C=C(F)C(Cl)=CC=1)NC(=O)C1=CC=C(C=NC(N[C@H]2[C@H](COCC2)F)=N2)C2=C1 RYAVEUFXJVCQNW-XJUOHMSHSA-N 0.000 claims 1
• RYAVEUFXJVCQNW-FUDKSRODSA-N n-[(s)-(4-chloro-3-fluorophenyl)-(1-methylpyrazol-4-yl)methyl]-2-[[(3r,4s)-3-fluorooxan-4-yl]amino]quinazoline-7-carboxamide Chemical compound C1=NN(C)C=C1[C@H](C=1C=C(F)C(Cl)=CC=1)NC(=O)C1=CC=C(C=NC(N[C@@H]2[C@H](COCC2)F)=N2)C2=C1 RYAVEUFXJVCQNW-FUDKSRODSA-N 0.000 claims 1
• RYAVEUFXJVCQNW-XPNTWCBSSA-N n-[(s)-(4-chloro-3-fluorophenyl)-(1-methylpyrazol-4-yl)methyl]-2-[[(3s,4r)-3-fluorooxan-4-yl]amino]quinazoline-7-carboxamide Chemical compound C1=NN(C)C=C1[C@H](C=1C=C(F)C(Cl)=CC=1)NC(=O)C1=CC=C(C=NC(N[C@H]2[C@@H](COCC2)F)=N2)C2=C1 RYAVEUFXJVCQNW-XPNTWCBSSA-N 0.000 claims 1
• RYAVEUFXJVCQNW-GIWBLDEGSA-N n-[(s)-(4-chloro-3-fluorophenyl)-(1-methylpyrazol-4-yl)methyl]-2-[[(3s,4s)-3-fluorooxan-4-yl]amino]quinazoline-7-carboxamide Chemical compound C1=NN(C)C=C1[C@H](C=1C=C(F)C(Cl)=CC=1)NC(=O)C1=CC=C(C=NC(N[C@@H]2[C@@H](COCC2)F)=N2)C2=C1 RYAVEUFXJVCQNW-GIWBLDEGSA-N 0.000 claims 1
• BJQJOYNOELTEHJ-CHVDNLQBSA-N n-[(s)-(4-chloro-3-fluorophenyl)-[(2r,5r)-5-methylpyrrolidin-2-yl]methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound N1[C@H](C)CC[C@@H]1[C@H](C=1C=C(F)C(Cl)=CC=1)NC(=O)C1=CC=C(C=NC(NC2CCOCC2)=N2)C2=C1 BJQJOYNOELTEHJ-CHVDNLQBSA-N 0.000 claims 1
• IOOCGMZCMZXLSH-OPURJYLOSA-N n-[(s)-(4-chloro-3-fluorophenyl)-[(2s)-pyrrolidin-2-yl]methyl]-2-[[(2s)-1,1,1-trifluoropropan-2-yl]amino]quinazoline-7-carboxamide Chemical compound C([C@H]1[C@@H](NC(=O)C=2C=CC3=CN=C(N=C3C=2)N[C@@H](C)C(F)(F)F)C=2C=C(F)C(Cl)=CC=2)CCN1 IOOCGMZCMZXLSH-OPURJYLOSA-N 0.000 claims 1
• AGMBQICWEXGDAI-PKTZIBPZSA-N n-[(s)-[3-fluoro-4-(trifluoromethoxy)phenyl]-[(2r)-morpholin-2-yl]methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound C1=C(OC(F)(F)F)C(F)=CC([C@H](NC(=O)C=2C=C3N=C(NC4CCOCC4)N=CC3=CC=2)[C@@H]2OCCNC2)=C1 AGMBQICWEXGDAI-PKTZIBPZSA-N 0.000 claims 1
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• ILXGLHJWTMZTDE-RPWUZVMVSA-N n-[(s)-[3-fluoro-4-(trifluoromethyl)phenyl]-[(2r)-1-methylpyrrolidin-2-yl]methyl]-2-(oxan-4-ylamino)quinazoline-7-carboxamide Chemical compound CN1CCC[C@@H]1[C@H](C=1C=C(F)C(=CC=1)C(F)(F)F)NC(=O)C1=CC=C(C=NC(NC2CCOCC2)=N2)C2=C1 ILXGLHJWTMZTDE-RPWUZVMVSA-N 0.000 claims 1
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