CN116354964A - 作为btk抑制剂的7(8h)-喋啶酮衍生物及其应用 - Google Patents
作为btk抑制剂的7(8h)-喋啶酮衍生物及其应用 Download PDFInfo
- Publication number
- CN116354964A CN116354964A CN202111573921.3A CN202111573921A CN116354964A CN 116354964 A CN116354964 A CN 116354964A CN 202111573921 A CN202111573921 A CN 202111573921A CN 116354964 A CN116354964 A CN 116354964A
- Authority
- CN
- China
- Prior art keywords
- substituted
- unsubstituted
- compound
- phenyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940124291 BTK inhibitor Drugs 0.000 title abstract description 16
- OOIPDYWPGUHUJW-UHFFFAOYSA-N 8h-pteridin-7-one Chemical class C1=NC=NC2=NC(O)=CN=C21 OOIPDYWPGUHUJW-UHFFFAOYSA-N 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- 239000003814 drug Substances 0.000 claims abstract description 23
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- -1 homopiperazinyl Chemical group 0.000 claims description 116
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 claims description 49
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
- 206010028980 Neoplasm Diseases 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 230000005764 inhibitory process Effects 0.000 claims description 26
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 230000000306 recurrent effect Effects 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 230000001404 mediated effect Effects 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 9
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 9
- 208000023275 Autoimmune disease Diseases 0.000 claims description 8
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 8
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 claims description 8
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 claims description 8
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 8
- 201000003444 follicular lymphoma Diseases 0.000 claims description 8
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 6
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 claims description 4
- 208000028622 Immune thrombocytopenia Diseases 0.000 claims description 4
- 208000028018 Lymphocytic leukaemia Diseases 0.000 claims description 4
- 241000721454 Pemphigus Species 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 4
- 208000024780 Urticaria Diseases 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 201000005787 hematologic cancer Diseases 0.000 claims description 4
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 claims description 4
- 208000021937 marginal zone lymphoma Diseases 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 3
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 201000000564 macroglobulinemia Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 16
- VWXIHLCLIOQWRA-UHFFFAOYSA-N 1h-pteridin-2-one Chemical class N1=CC=NC2=NC(O)=NC=C21 VWXIHLCLIOQWRA-UHFFFAOYSA-N 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000007787 solid Substances 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 46
- 238000005481 NMR spectroscopy Methods 0.000 description 40
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 36
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 33
- 210000004027 cell Anatomy 0.000 description 32
- 230000000694 effects Effects 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 239000011734 sodium Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 108091000080 Phosphotransferase Proteins 0.000 description 18
- 102000020233 phosphotransferase Human genes 0.000 description 18
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 17
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 16
- 230000026731 phosphorylation Effects 0.000 description 16
- 238000006366 phosphorylation reaction Methods 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 101001050476 Homo sapiens Tyrosine-protein kinase ITK/TSK Proteins 0.000 description 14
- 102100023345 Tyrosine-protein kinase ITK/TSK Human genes 0.000 description 14
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 229960001507 ibrutinib Drugs 0.000 description 7
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 5
- 206010012735 Diarrhoea Diseases 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 5
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- 208000032843 Hemorrhage Diseases 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- IEUIEMIRUXSXCL-UHFFFAOYSA-N tert-butyl n-(3-aminophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(N)=C1 IEUIEMIRUXSXCL-UHFFFAOYSA-N 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- AMSIAIRQIAPAPM-UHFFFAOYSA-N 1-(2-methoxyethoxy)-4-nitrobenzene Chemical compound COCCOC1=CC=C([N+]([O-])=O)C=C1 AMSIAIRQIAPAPM-UHFFFAOYSA-N 0.000 description 3
- INUSQTPGSHFGHM-UHFFFAOYSA-N 2,4-dichloro-5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1Cl INUSQTPGSHFGHM-UHFFFAOYSA-N 0.000 description 3
- 206010003658 Atrial Fibrillation Diseases 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 208000010201 Exanthema Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000003172 aldehyde group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 201000005884 exanthem Diseases 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- 206010037844 rash Diseases 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 2
- WZCQRUWWHSTZEM-UHFFFAOYSA-N 1,3-phenylenediamine Chemical compound NC1=CC=CC(N)=C1 WZCQRUWWHSTZEM-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000019260 B-Cell Antigen Receptors Human genes 0.000 description 2
- 108010012919 B-Cell Antigen Receptors Proteins 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- ICIBMWFVBWGWHU-UHFFFAOYSA-N N-[3-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-7-oxo-6-phenylpteridin-8-yl]phenyl]prop-2-enamide Chemical compound COC1=C(C=CC(=C1)N1CCN(CC1)C)NC1=NC=2N(C(C(=NC=2C=N1)C1=CC=CC=C1)=O)C=1C=C(C=CC=1)NC(C=C)=O ICIBMWFVBWGWHU-UHFFFAOYSA-N 0.000 description 2
- 201000011152 Pemphigus Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 201000001976 pemphigus vulgaris Diseases 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- UBMONMNZSGNXMV-UHFFFAOYSA-N (3-aminophenyl) carbamate Chemical compound NC(=O)OC1=CC=CC(N)=C1 UBMONMNZSGNXMV-UHFFFAOYSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- OKWUYBGGPXXFLS-UHFFFAOYSA-N 1-chlorobut-2-yne Chemical compound CC#CCCl OKWUYBGGPXXFLS-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 102100026205 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 Human genes 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 229940125814 BTK kinase inhibitor Drugs 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102100027907 Cytoplasmic tyrosine-protein kinase BMX Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102100023332 Dual specificity mitogen-activated protein kinase kinase 7 Human genes 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 101000691599 Homo sapiens 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 Proteins 0.000 description 1
- 101000935548 Homo sapiens Cytoplasmic tyrosine-protein kinase BMX Proteins 0.000 description 1
- 101000624594 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 7 Proteins 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000984551 Homo sapiens Tyrosine-protein kinase Blk Proteins 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- 101000606067 Homo sapiens Tyrosine-protein kinase TXK Proteins 0.000 description 1
- 101000889732 Homo sapiens Tyrosine-protein kinase Tec Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- HHAIXNHKPAADOF-UHFFFAOYSA-N ONC(CO)(CO)CO.[Na] Chemical compound ONC(CO)(CO)CO.[Na] HHAIXNHKPAADOF-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 102000042834 TEC family Human genes 0.000 description 1
- 108091082333 TEC family Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102100027053 Tyrosine-protein kinase Blk Human genes 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 102100039079 Tyrosine-protein kinase TXK Human genes 0.000 description 1
- 102100040177 Tyrosine-protein kinase Tec Human genes 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 description 1
- XQKRPEDJRVOOAA-UHFFFAOYSA-J [Mg+2].[Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O Chemical compound [Mg+2].[Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XQKRPEDJRVOOAA-UHFFFAOYSA-J 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- WDENQIQQYWYTPO-IBGZPJMESA-N acalabrutinib Chemical compound CC#CC(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C(=O)NC=2N=CC=CC=2)=C2N1C=CN=C2N WDENQIQQYWYTPO-IBGZPJMESA-N 0.000 description 1
- 229950009821 acalabrutinib Drugs 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 108010021848 cyclosomatostatin Proteins 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- CKTYYUQUWFEUCO-UHFFFAOYSA-N ethyl 3-methyl-2-oxobutanoate Chemical compound CCOC(=O)C(=O)C(C)C CKTYYUQUWFEUCO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 231100000226 haematotoxicity Toxicity 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000003674 kinase activity assay Methods 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910000664 lithium aluminum titanium phosphates (LATP) Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 229940018564 m-phenylenediamine Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 150000003230 pyrimidines Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000026775 severe diarrhea Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 208000014680 small intestine neoplasm Diseases 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 208000021550 spleen neoplasm Diseases 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CMIBWIAICVBURI-UHFFFAOYSA-N tert-butyl 3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)C1 CMIBWIAICVBURI-UHFFFAOYSA-N 0.000 description 1
- NYFUZKMRSVRPBK-UHFFFAOYSA-N tert-butyl n-[3-[[5-amino-2-[4-(2-methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]carbamate Chemical compound C1=CC(OCCOC)=CC=C1NC1=NC=C(N)C(NC=2C=C(NC(=O)OC(C)(C)C)C=CC=2)=N1 NYFUZKMRSVRPBK-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及作为BTK抑制剂的7(8H)‑喋啶酮衍生物及其应用。具体而言,本发明涉及式I所示化合物、含有式I化合物的药物组合物及所述化合物在制备治疗BTK相关疾病或抑制BTK的药物中的用途:
Description
技术领域
本发明涉及药物化学领域。具体地说,本发明涉及新型的7(8H)-喋啶酮衍生物,其合成方法及其作为BTK抑制剂在制备肿瘤以及自身免疫相关疾病的药物中的应用。
背景技术
癌症是以体内细胞的异常增殖和转移的一类疾病,也是目前对人类的生命健康具有严重威胁的疾病之一。现在由于人们生活环境、饮食习惯等因素的影响,癌症已经成为世界范围内的疾病。而目前对于癌症的治疗有手术疗法、放射治疗、化学疗法等。手术疗法虽然是最常用的手段之一,但是很多的患者被确诊时已经处于癌症晚期,错过了手术切除的最佳时期,手术切除只能切除病灶部位,不可避免的产生术后复发、转移等对患者的后期治疗带来很大的影响。对于放射治疗来说。由于放疗原理以及机制的限制和,会对机体产生一系列不良反应,如免疫功能损伤,胃肠道反应等。而传统的化学疗法中所用的药物属于细胞毒素类,不能选择性杀死癌变细胞,它们会损伤正常细胞,使人体产生恶心、呕吐、脱发、免疫失调等毒副作用。因而寻找高效、高选择性、毒副作用低的新型抗肿瘤药物已经成为现在研究者的主要目标。
而近年来以蛋白激酶作为药物靶标,设计,研发一系列作用于特定靶标的靶向激酶抑制剂,已经成为药物研究的重要领域。Bruton’s tyrosine kinase(Btk,Bruton’s酪氨酸激酶)属于非受体蛋白激酶TEC家族的一员,主要表达于造血系统的细胞:B细胞、巨噬细胞、肥大细胞等。Bruton’s酪氨酸激酶是B细胞抗原受体(BCR)信号通路中一类关键的末端激酶,与B细胞的活化、增殖、信号转导、成熟和生存等密切相关,近年来发现由B细胞异常增殖引发的B细胞慢性淋巴细胞白血病,以及类风湿性关节炎等疾病都可以通过抑制Bruton’s酪氨酸激酶的活性来进行治疗,进而产生了BTK抑制剂。目前BTK抑制剂主要包括两类:一类是含有Michael受体与Bruton’s酪氨酸激酶的Cys481共价结合的抑制剂,但其使用过程中会发生Cys481突变为Ser使药物发生耐药,继而出现了另一类非共价结合的BTK抑制剂,其选择性作用于Bruton’s酪氨酸激酶疏水口袋。
目前上市的BTK抑制剂有Ibrutinib、Acalabrutinib和Zanubritinib,其中重磅炸弹药物Ibrutinib虽然是BTK抑制剂,但是它的选择性较差仍然会作用于其它激酶,其中作用于ITK和EGFR会产生腹泻、皮疹以及血液毒性,而这也是Ibrutinib的主要副作用。
因而,开发一类能够选择性作用于BTK而对于其它激酶具有较低抑制作用的新型抑制剂,对于治疗BTK相关的疾病在临床上具有重要意义和潜在的应用前景。
发明内容
本发明的目的在于提供一类新型的BTK抑制剂。这种BTK抑制剂对BTK具备优异的抑制活性,但对于其它激酶的抑制作用应该较低;即在BTK和其它激酶之间应该具备选择抑制性。
在第一方面,本发明提供式I所示的化合物或其药学上可接受的盐:
式中,A为取代或未取代的苯环、取代或未取代的吡啶环、取代或未取代嘧啶环、取代或未取代的含1-3个选自N、O或S的杂原子的五元或六元杂环、取代或未取代的C3-C8烷基以及取代或未取代C3-C8环烷基;
R1各自独立选自:氢、卤素、取代或未取代的C1-C8烷氧基、取代或未取代的C1-C3烷基、取代或未取代的哌嗪基、取代或未取代的高哌嗪基、取代或未取代的吗啉基、取代或未取代的硫代吗啉基、取代或未取代的4-N-甲基哌嗪基、取代或未取代的氨基酰基、取代或未取代的4-N-乙酰基哌嗪基、取代或未取代的4-N,N-二甲基哌啶基、取代或未取代的哌啶基、-NRaRb,其中,Ra和Rb可独立选自氢或C1-C3烷基;
R2各自独立选自以下基团:
R3选自下组:氢、取代或未取代的C1-C10烷基、取代或未取代的C2-C6链烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的芳基(取代或未取代的苯基)、取代或未取代的苯氧基、取代或未取代的苄基、取代或未取代的含1-3个选自N、O或S的杂原子的C5-C10杂环基或芳杂环基;
B选自下组:
m为0-7的整数。
在具体的实施方式中,所述化合物如式II所示:
式中,B、R1、R2、R3如权利要求1所限定;
m为0-5的整数。
在具体的实施方式中,所述化合物如式III所示:
式中,
R3选自C1-C6烷基、C3-C6环烷基、异丙基、环丙基、环戊基、环己基、取代的苯基、苄基;
R4、R5、R6、R7和R8独立选自下组:
卤素、C1-C5烷基、三氟甲基、三氟乙基、取代或未取代的C1-C5烷氧基、三氟甲氧基、三氟乙氧基、丙烯酰胺基、乙酰基、氨基甲酰基、乙酰基甲氧基、氨基甲酰基甲氧基、甲氧基乙氧基,及下面杂环:
在具体的实施方式中,本发明提供选自下组的化合物或其药学上可接受的盐:
在第二方面,本发明提供式IV所示化合物或其药学上可接受的盐:
式中,
R1为位于苯基间位或对位的取代基并且选自:取代或未取代的C1-C8烷氧基(优选甲氧基、甲氧基乙氧基)、取代或未取代的4-N-甲基哌嗪基、取代或未取代的氨基酰基;
R3选自下组:取代或未取代的C3-C5烷基(优选异丙基)、取代或未取代的C3-C8环烷基(优选环己基)。
在具体的实施方式中,所述化合物选自下组:
在第三方面,本发明提供一种药物组合物,所述药物组合物含有第一或第二方面所述的化合物或其药学上可接受的盐,以及药学上可接受的载体或赋形剂。
在优选的实施方式中,所述药物组合物是适于口服的剂型,包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。
在第四方面,本发明提供第一或第二方面所述的化合物在制备治疗或预防BTK介导的疾病,或抑制BTK的药物中的用途。
在具体的实施方式中,所述BTK介导的疾病为癌症或者自身免疫性疾病。
在具体的实施方式中,所述癌症选自下组:复发/难治性B细胞非霍奇金淋巴瘤、晚期复发性或难治性慢性淋巴细胞白血病、慢性淋巴细胞白血病(CLL)、小淋巴细胞淋巴瘤(SLL)、套细胞淋巴瘤(MCL)、外周T细胞淋巴瘤(PTCL)、弥漫性大B细胞淋巴瘤、边缘区淋巴瘤、B细胞性慢性淋巴细胞白血病、复发性淋巴细胞白血病、活化B细胞亚型弥漫性大B细胞淋巴瘤(ABC-DLBCL)、滤泡性淋巴瘤(FL)和、华氏巨球蛋白血症、多发性硬化症、类风湿性关节炎、系统性红斑狼疮、银屑病、荨麻疹、哮喘、急性干燥综合症、骨髓瘤、天疱疮、免疫性血小板减少性紫癜、自身免疫疾病和血液瘤等。
在第五方面,本发明提供利用第一或第二方面所述的化合物治疗或预防BTK介导的疾病方法。
在优选的实施方式中,所述BTK介导的疾病为癌症;优选地,所述癌症选自下组:复发/难治性B细胞非霍奇金淋巴瘤、晚期复发性或难治性慢性淋巴细胞白血病、慢性淋巴细胞白血病(CLL)、小淋巴细胞淋巴瘤(SLL)、套细胞淋巴瘤(MCL)、外周T细胞淋巴瘤(PTCL)、弥漫性大B细胞淋巴瘤、边缘区淋巴瘤、B细胞性慢性淋巴细胞白血病、复发性淋巴细胞白血病、活化B细胞亚型弥漫性大B细胞淋巴瘤(ABC-DLBCL)、滤泡性淋巴瘤(FL)、华氏巨球蛋白血症、多发性硬化症、类风湿性关节炎、系统性红斑狼疮、银屑病、寻常型天疱疮、荨麻疹、哮喘、急性干燥综合症、骨髓瘤、天疱疮、免疫性血小板减少性紫癜、自身免疫疾病和血液瘤等。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了本发明的代表性化合物024的磷酸化抑制效果;
图2显示了本发明的化合物002、016和024在U-937移植瘤模型鼠中显示出的肿瘤抑制效果以及对小鼠体重的影响。
具体实施方式
发明人经过广泛而深入的研究,出乎意料地发现一批结构全新的7(8H)-喋啶酮衍生物。这些衍生物能够选择性抑制BTK,对BTK激酶抑制活性的IC50值达到nM级别;对癌细胞(BTK依赖的细胞)增殖的抑制活性IC50值达到μM级别,从而为BTK抑制剂,特别是选择性BTK抑制剂的开发奠定了新的物质基础。在此基础上完成了本发明。
术语定义
本文所用的术语的含义与本领域技术人员常规理解的含义相同或相似。为清晰起见,对本文所用的术语定义如下。但应该知晓的是,对以下术语进行定义只是为了本领域技术人员能够更好地理解本发明,而非对本发明的范围进行限制。
本文中涉及到的一些基团定义如下:
本文中,“烷基”指碳链长度为1-10个碳原子的饱和的支链或直链烷基,优选的烷基包括长2-8个、1-6个、1-4个、3-8个、1-3个碳原子不等的烷基。烷基的例子包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基、庚基等。烷基可以被1个或多个取代基取代,例如被卤素或卤代烷基取代。例如,烷基可以是被1-4个氟原子取代的烷基,或者烷基可以是被氟代烷基取代的烷基。
本文中,“烷氧基”指被烷基取代的氧基。优选的烷氧基是长1-6个碳原子的烷氧基,更优选为长1-4个碳原子的烷氧基,更优选为长1-3个碳原子的烷氧基。烷氧基的例子包括但不限于:甲氧基、乙氧基、丙氧基等。烷氧基可以被1个或多个取代基取代,例如被卤素或卤代烷基取代。例如,烷氧基可以是被1-4个氟原子取代的烷基,或者烷基可以是被氟代烷基取代的烷基。
本文中,“链烯基”通常表示具有至少一个双键的单价烃基,通常含有2-8个碳原子,优选含有2-6个碳原子,可以是直链或支链。链烯基的例子包括但不限于乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、己烯基等等。
本文中,“炔基”通常表示具有至少一个三键的单价烃基,通常含有2-8个碳原子,优选含有2-6个碳原子,更通常含有2-4个碳原子,可以是直链或支链。链烯基的例子包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、己炔基等。
本文中,“卤素”指氟、氯、溴或碘。
本文中,“芳基”指含有6到14个碳原子的单环、双环或三环芳族基团,包括苯基、萘基、菲基、蒽基、茚基、茀基、四氢化萘基、二氢化茚基等。芳基可任选地被1-5个(例如,1、2、3、4或5个)选自以下的取代基取代:卤素、C1-4醛基、C1-6烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基等、杂环基或杂芳基等。
本文所用“杂环基”包括但不限于含有1-3个选自O、S或N的杂原子的5元或6元杂环基团,包括但不限于呋喃基、噻吩基、吡咯基、吡咯烷基、吡唑基、咪唑基、三唑基、噁唑基、吡喃基、吡啶基、嘧啶基、吡嗪基、哌啶基、吗啉基等。
本文所用“芳杂环基”是指含有5-14个环原子,并且有6个、10个或14个电子在环体系上共用。而且所含环原子是碳原子和从氧、氮、硫中任选的1-3个杂原子。有用的芳杂环基包括哌嗪基、吗啉基、哌啶基、吡咯烷基、噻吩基、呋喃基、吡喃基、吡咯基、咪唑基、吡唑基、吡啶基、包括但不限制于2-吡啶基、3-吡啶基和4-吡啶基、吡嗪基、嘧啶基等。
芳杂环基可任选地被1-5个(例如,1、2、3、4或5个)选自以下的取代基取代:卤素、C1-4醛基、C1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基。
本文中,“酰氧基”指结构式为“-O-C(O)-R”的基团,其中,R可选自烷基、链烯基和炔基。所述R可任选地被取代。
本文中,“酰氨基”指结构式为“-R’-NH-C(O)-R”的基团,其中,R’可选自氢或烷基,R可选自烷基、链烯基、炔基、被NRcRd取代的烷基、被NRcRd取代的链烯基和NRcRd取代的炔基、被卤素取代的烷基、被氰基取代的链烯基,其中,Rc和Rd可选自烷基和链烯基。
本文中,“任选取代的”指其所修饰的取代基可任选地被1-5个(例如,1、2、3、4或5个)选自以下的取代基取代:卤素、C1-4醛基、C1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基。
基于本发明的教导以及本领域的公知常识,本领域技术人员会理解,本发明化合物中的各基团可以作进一步的取代,从而得到能够具备与本发明具体公开的化合物活性相同或相似的衍生物。本发明化合物中的各基团可以被本领域常规的各种取代基取代,只要这种取代不违反化学合成规则或者化合价规则。
本文所用的术语“取代”是指特定基团上的一个或多个氢原子被特定的取代基所替代。特定的取代基可以是前文中相应描述的取代基,也可以是各实施例中出现的具体取代基或者本领域的常规取代基。因此,在本发明中,通式中的取代基也可以各自独立地为实施例中具体化合物中的相应基团;即,本发明既包括上述通式中各取代基的组合,也包括通式中所示部分取代基与实施例中出现的其它具体取代基的组合。制备具有这样的取代基组合的化合物并检测所得化合物是活性是本领域技术人员基于本领域的惯常技术手段不难做到的。换言之,基于本发明的教导,本领域技术人员能够合成落在本发明的保护范围内的各种化合物,这些化合物并不限于说明书实施例部分公开的具体化合物;本发明的化合物既包括实施例部分公开的具体化合物,也包括这些具体化合物中的某一取代位置的具体取代基与通式中其它取代位置的取代基构成的各种化合物,限于篇幅,不在此一一列举。
本发明的化合物
本发明人合成了具有BTK抑制活性的候选化合物。对得到的候选化合物进行结构优化,设计并合成了一系列未见文献报道的7(8H)-喋啶酮类化合物,并进行了结构表征。对此系列化合物进行了分子水平的活性测试,得到一批具有选择性抑制BTK的化合物。
在具体的实施方式中,本发明的化合物是下式I所示的化合物或其药学上可接受的盐:
式中,A、R1、R2、R3、B、m如上所述。
在优选的实施方式中,A环为苯环或者芳香杂环,从而本发明的化合物如下式II所示:
式中,B、R1、R2、R3如上所述;和m为0-5的整数。
在优选的实施方式中,本发明的化合物中的上述苯环或者芳香杂环可以是取代或未取代的,例如,本发明的化合物可以如下式III所示:
式中,R2、R3、R4、R5、R6、R7和R8如上所述。
在进一步的实施方式中,本发明的化合物中的上述苯环可以作邻位取代、间位取代和/或对位取代。在优选的实施方式中,本发明的化合物中的上述苯环是邻位取代和对位取代的。在另一优选的实施方式中,本发明的化合物中的上述苯环是邻位取代、间位取代和对位取代的。在具体的实施方式中,式III中的R7和R8为H;R5、R7和R8为H或者R4、R6、R7和R8为H等。
本发明人合成得到了一系列结构未见文献报道的7(8H)-喋啶酮类化合物,具体的化合物如下所示:
本发明人发现,本发明的某些化合物对BTK具备优异的抑制活性,但对于其它激酶的抑制作用较低;因此,本发明还提供了在BTK和其它激酶之间具备选择抑制性的化合物。
在具体的实施方式中,本发明提供式IV所示化合物或其药学上可接受的盐:
式中,
R1为苯基间位或对位的取代基并且选自:取代或未取代的C1-C8烷氧基、取代或未取代的4-N-甲基哌嗪基、取代或未取代的氨基酰基;
R3选自下组:取代或未取代的C3-C5烷基(优选异丙基)、取代或未取代的C3-C8环烷基(优选环己基)。
在优选的实施方式中,在式IV所示化合物中,R1为甲氧基或甲氧基乙氧基、4-N-甲基哌嗪基、氨基酰基;R3为异丙基或环己基。
在具体的实施方式中,式IV所示化合物是以下化合物:
基于本发明的教导,本领域技术人员会了解本发明的化合物是具有药学活性的化合物,从而可以用作药物。作为药学活性的化合物,本发明化合物自然也应具备药物的各种固有特性,例如成药性、生物利用度、低毒副作用等等。本领域技术人员可以采用熟知的各种已有技术手段测试并获得本发明的化合物的上述种种特性,在此不一一赘述。
在本发明的化合物的基础上,本发明提供一种药物组合物,该组合物含有治疗有效量的本发明的化合物或其药学上可接受的盐,以及药学上可接受的载体或赋形剂。
本发明化合物的药学上可接受的盐的例子包括但不限于无机和有机酸盐,例如盐酸盐、甲酸盐、氢溴酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐;以及与碱例如钠羟基、三(羟基甲基)胺基甲烷(TRIS,胺丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。
虽然每个人的需求各不相同,本领域技术人员可确定本发明药物组合物中每种活性成分的最佳剂量。一般情况下,本发明的化合物或其药学上可接受的盐,对哺乳动物每天口服给药,药量按照约0.0025到50毫克/公斤体重。但最好是每公斤口服给药约0.01到10毫克。例如,单位口服剂量可以包括约0.01到50毫克,最好是约0.1到10毫克的本发明化合物。单位剂量可给予一次或多次,每天为一片或多片,每片含有约0.1到50毫克,合宜地约0.25到10毫克的本发明化合物或其溶剂化物。
本发明的药物组合物可被配制成适合各种给药途径的制剂形式,包括但不限于被配制成用于肠外,皮下,静脉,肌肉,腹腔内,透皮,口腔,鞘内,颅内,鼻腔或外用途径给药的形式,用于治疗肿瘤和其他疾病。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗,有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用,或者可依据有效的治疗方案给药。给药量也许可治愈疾病,但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。药的剂量将根据病人的年龄,健康与体重,并行治疗的种类,治疗的频率,以及所需治疗效益来决定。
本发明的药物制剂可以给予任何哺乳动物,只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人类。
本发明的化合物或其药物组合物可用于治疗各种由布鲁顿氏酪氨酸激酶(BTK)介导的疾病。本文中,由BTK介导的疾病为各种癌症以及自身免疫疾病。所述癌症以及自身免疫疾病包括但不限于:复发/难治性B细胞非霍奇金淋巴瘤、晚期复发性或难治性慢性淋巴细胞白血病、慢性淋巴细胞白血病(CLL)、小淋巴细胞淋巴瘤(SLL)、套细胞淋巴瘤(MCL)、外周T细胞淋巴瘤(PTCL)、弥漫性大B细胞淋巴瘤、边缘区淋巴瘤、B细胞性慢性淋巴细胞白血病、复发性淋巴细胞白血病、活化B细胞亚型弥漫性大B细胞淋巴瘤(ABC-DLBCL)、滤泡性淋巴瘤(FL)和、华氏巨球蛋白血症、多发性硬化症、类风湿性关节炎、系统性红斑狼疮、银屑病、寻常型天疱疮、荨麻疹、哮喘、急性干燥综合症、骨髓瘤、天疱疮、免疫性血小板减少性紫癜、自身免疫疾病和血液瘤等。
本发明的药物制剂可用已知的方式制造。例如,由传统的混合,制粒,制锭,溶解,或冷冻干燥过程制造。制造口服制剂时,可结合固体辅料和活性化合物,选择性研磨混合物。如果需要或必要时加入适量助剂后,加工颗粒混合物,获得片剂或锭剂芯。
合适的辅料特别是填料,例如糖类如乳糖或蔗糖,甘露醇或山梨醇;纤维素制剂或钙磷酸盐,例如磷酸三钙或磷酸氢钙;以及粘结剂,例如淀粉糊,包括玉米淀粉,小麦淀粉,大米淀粉,马铃薯淀粉,明胶,黄芪胶,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素钠,或聚乙烯吡咯烷酮。如果需要,可增加崩解剂,比如上面提到的淀粉,以及羧甲基淀粉,交联聚乙烯吡咯烷酮,琼脂,或褐藻酸或其盐,如海藻酸钠。辅助剂特别是流动调节剂和润滑剂,例如,硅石,滑石,硬脂酸盐类,如镁硬脂酸钙,硬脂酸或聚乙二醇。如果需要,可以給锭剂核芯提供可以抵抗胃液的合适包衣。为此,可以应用浓缩糖类溶液。这个溶液可以含有阿拉伯树胶,滑石,聚乙烯吡咯烷酮,聚乙二醇和/或二氧化钛,漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣,可使用适当的纤维素溶液,例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如,用于识别或为了表征活性成分剂量的组合。
基于上述化合物和药物组合物,本发明进一步提供一种治疗BTK介导的疾病的方法,该方法包括给予需要的对象以本发明的化合物或药物组合物。
给药方法包括但不限于本领域周知的各种给药方法,可根据患者的实际情况加以确定。这些方法包括但不限于肠外、皮下、静脉、肌肉、腹腔内、透皮、口腔、鞘内、颅内、鼻腔或外用途径给药。
本发明也包括本发明化合物在制备预防或治疗BTK、ITK、EGFR介导的疾病或抑制BTK、ITK、EGFR活性的药物中的用途。
本发明的优点:
1.本发明提供的化合物是一种结构全新的7(8H)-喋啶酮类化合物;
2.本发明提供的化合物对BTK介导的骨髓细胞、B细胞系细胞具有优异的抑制活性;
3.本发明提供的化合物为开发能抑制BTK激酶的活性,能克服临床上BTK抑制剂带来的腹泻、皮疹副作用,为BTK靶向药物奠定了基础,具备极大的产业化和商品化前景以及市场价值,经济效益显著。
以下结合具体实施案例对本发明的技术方案进一步描述,但以下实施案例不构成对本发明的限制,所有依据本发明的原理和技术手段采用的各种施用方法,均属于本发明范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
材料与方法
本发明的7(8H)-喋啶酮类化合物的合成如下所示:
试剂和条件:(a)(Boc)2O、CH2Cl2、0℃-室温;(b)2,4-二氯-5-硝基嘧啶、DIPEA、CH3CN、室温;(c)ArNH2,DIPEA,THF,室温;(d)10%Pd/C、H2、CH2Cl2、CH3OH、室温;(e)R2COCOOCH2CH3、EtOH、AcOH、回流;(f)三氟乙酸、CH2Cl2,室温;(g)酰氯、DIPEA、干燥CH2Cl2、0℃-室温。
实施例1
上述步骤a-g的具体合成方法如下:
1.N-(3-(2-((4-甲氧基苯基)氨基)-7-氧代-6-苯基-8(7H)-喋啶基)苯基)丙烯酰胺(2-2)的合成路线
称取间苯二胺(15.00g,138.89mmol)置于250mL三口烧瓶中,加入100mL二氯甲烷,在常温条件下搅拌溶解,另取二碳酸二叔丁酯(36.33g,166.67mmol)溶于20mL二氯甲烷并滴加到上述反应液中,滴加完成后,继续在室温下搅拌2h,TLC跟踪至原料基本完全转化(原料反应不完),然后在0℃条件下,滴加HCl溶液(浓盐酸/水=1/1)调节pH约等于5,有大量白色固体析出(注意酸性不能太强,不然Boc会掉),布氏漏斗抽滤,滤饼用50mL二氯甲烷洗涤,干燥。然后得到的白色固体置于800mL烧杯中,加入600mL去离子水,用饱和NaHCO3水溶液调节pH约等于9,有大量固体析出,布氏漏斗抽滤,200mL去离子水洗涤,真空干燥,即得到纯的(3-氨基苯基)氨基甲酸叔丁酯白色固体18.772g,产率约65%。减压回收二氯甲烷。
1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),6.84(t,J=8.0Hz,1H),6.80(s,1H),6.52(dd,J=8.0,1.0Hz,1H),6.18-6.14(m,1H),4.95(s,2H),1.45(s,9H).LC-MS(ESI)计算值C11H16N2O2[M+H]+:209.12,实验值209.20。
2.(3-(2-氯-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯(2-3)的合成路线
称取2,4-二氯-5-硝基嘧啶(2.99g,15.5mmol)置于250 mL圆底三口烧瓶中,加入50mL乙腈和N,N-二异丙基乙胺(3g,23.3mmol),在常温条件下搅拌,称取(3-氨基苯基)氨基甲酸叔丁酯(3.23g,15.5mmol)溶于30mL乙腈,滴加到上述反应液中,滴加完成后,继续在常温下拌约1h,有大量橙色固体析出,TLC跟踪至原料完全转化,直接抽滤,滤饼用30mL乙腈洗涤,真空干燥,得到纯的(3-(2-氯-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯橙色固体4.5g,产率约80%。减压回收乙腈。
1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.54(s,1H),9.14(s,1H),7.67(s,1H),7.31(d,J=5.1Hz,1H),7.26(d,J=4.2Hz,1H),7.14(d,J=2.9Hz,1H),1.48(s,9H).LC-MS:计算值C11H16N2O2[M+H]+:366.09,实验值366.15。
3.1-(2-甲氧基乙氧基)-4-硝基苯的合成路线
称取对硝基苯酚(5g,35.94mmol)于50mL的圆底烧瓶中,加入DMF 20mL,加入2-溴乙基甲基醚(6.39g,46.7mmol),碳酸钾(9.93g,71.88mmol),加热至90℃,TLC检测至反应结束,冷却至室温,黄白色浑浊,加入50mL水淬灭反应,加乙酸乙酯(40mL×3)萃取,合并有机相,无水硫酸钠干燥,饱和食盐水(50mL×2),无水硫酸钠干燥,浓缩,得到白色固体1-(2-甲氧基乙氧基)-4-硝基苯6.5g,产率91.7%。1H NMR(400MHz,DMSO-d6):δ8.21(d,J=9.2Hz,2H),7.00(d,J=9.2Hz,2H),4.22(t,J=4.4Hz,2H),3.79(t,J=4.4Hz,2H),3.46(s,3H).LC-MS:计算值C9H11NO4[M+H]+:198.07,实验值198.20.
4.1-(2-甲氧基乙氧基)-4-苯胺的合成路线
称取1-(2-甲氧基乙氧基)-4-硝基苯(5g,25.35mmol)于250mL的圆底烧瓶中,加入100mL(DCM:CH3OH=4:1)溶剂,加入10%的钯碳(0.8g),氢气保护下室温搅拌,TLC监测至反应结束。用硅藻土抽滤出去钯碳,二氯甲烷洗涤,减压蒸馏,得到1-(2-甲氧基乙氧基)-4-苯胺4.0g,产率95.23%,无需纯化直接用于下一步。
5.(3-((2-((4-甲氧基苯基)氨基)-5-硝基嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯的合成路线
称取(3-(2-氯-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯(9.27g,25.34mmol)置于250mL圆底烧瓶中,用120mL四氢呋喃溶解,再加入1-(2-甲氧基乙氧基)-4-苯胺(9.2g,25.34mmol)和N,N-二异丙基乙胺(4.9g,38.01mmol),室温搅拌,TLC跟踪至原料完全转化。有大量黄色固体析出,抽滤,滤饼用50mL去离子水洗涤,真空干燥,得(3-((2-((4-甲氧基苯基)氨基)-5-硝基嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯黄色固体10.8g(收率约85.7%)。
1H NMR(400MHz,DMSO-d6):δ10.36(s,1H),10.30(s,1H),9.52(s,1H),9.06(s,1H),7.69(s,1H),7.48(d,J=8Hz,2H),7.37-7.33(m,2H),7.11(d,J=6.4Hz,1H),6.71(d,J=8.4Hz,2H),4.01(s,2H),3.64(s,2H),3.33(s,3H),1.44(s,9H).LC-MS:计算值C24H29N6O6[M+H]+:497.21,实验值497.30.
6.(3-((5-氨基-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基氨基)苯基)氨基甲酸叔丁酯的合成路线
称取化合物(3-((2-((4-甲氧基苯基)氨基)-5-硝基嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯(3g,6.04mmol)于250mL的圆底烧瓶中,加入100mL(DCM:CH3OH=4:1)溶剂,加入10%的钯碳(0.5g),氢气保护下室温搅拌,TLC监测至反应结束。用硅藻土抽滤出去钯碳,二氯甲烷洗涤,减压蒸馏,得到(3-((5-氨基-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯2.82g(产率99.9%),无需纯化直接用于下一步。
7.(3-(6-异丙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-氧代喋呤-8(7H)-基)苯基)氨基甲酸叔丁酯的合成路线
称取化合物(3-((5-氨基-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯(650mg,1.4mmol)于50mL的圆底烧瓶中,加入二甲基丙酮酸乙酯(201mg,1.4mmol),加入无水乙醇15mL,冰醋酸1mL,加热回流5h,TLC监测至反应结束,产生黄绿色沉淀,冷却至室温,抽滤,乙醇洗涤,氨水洗涤,水洗,干燥,得到(3-(6-异丙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-氧代喋呤-8(7H)-基)苯基)氨基甲酸叔丁酯560mg,浅绿色固体(产率73.7%)。
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.65(s,1H),8.80(s,1H),7.61(s,1H),7.53(d,J=8.1Hz,1H),7.47(t,J=7.9Hz,1H),7.31(s,2H),7.00(d,J=7.6Hz,1H),6.62(s,2H),4.03-3.95(m,2H),3.67-3.60(m,2H),3.42(dd,J=13.6,6.8Hz,1H),3.30(s,3H),1.45(s,9H),1.25(d,J=6.8Hz,6H).LC-MS(ESI)计算值C29H35N6O5[M+H]+:547.27,实验值547.30。
8.8-(3-氨基苯基)-6-异丙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)蝶啶-7(8H)-酮的合成
称取化合物(3-(6-异丙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-氧代喋呤-8(7H)-基)苯基)氨基甲酸叔丁酯(0.55g,1.0mmol)置于100mL的圆底烧瓶中,加入24mL二氯甲烷使其溶解,冰浴冷却至0℃,将6mL三氟乙酸滴加到上述反应液中,室温搅拌,TLC监测至反应结束,减压蒸馏除去溶剂,得到棕黄色油状液体,在冰浴下加饱和碳酸氢钠调pH=7-9,二氯甲烷萃取,饱和食盐水萃取,无水硫酸钠干燥,合并有机相,减压蒸馏除去溶剂,得到8-(3-氨基苯基)-6-异丙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)蝶啶-7(8H)-酮黄色固体0.432g,产率96.5%,无需纯化直接用于下一步。
9.N-(3-(6-异丙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺的合成
取化合物8-(3-氨基苯基)-6-异丙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)蝶啶-7(8H)-酮(0.45g,1.0mmol)置于100mL的干燥两口圆底烧瓶中,加入转子,加入30mL无水二氯甲烷,氩气保护,冰浴冷却到0℃,加入N,N-二异丙基乙胺(0.2g,1.5mmol)搅拌3min;另取丙烯酰氯(0.12g,1.3mmol)滴加到上述反应液中,滴加完成后继续在冰浴下继续搅拌30min;然后室温搅拌3h。TLC监测至反应结束。减压蒸馏除去溶剂,加入乙酸乙酯和饱和碳酸氢钠萃取合并有机相,用饱和食盐水萃取,无水硫酸钠干燥。经硅胶柱层析得到N-(3-(6-异丙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺黄色固体0.32g,产率63.9%。
1H-NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.90(s,1H),8.80(s,1H),7.83(d,J=8.0Hz,1H),7.77(s,1H),7.56(t,J=8.0Hz,1H),7.31(s,2H),7.13(d,J=7.8Hz,1H),6.59(s,2H),6.45(dd,J=16.9,10.1Hz,1H),6.26(dd,J=16.9,1.5Hz,1H),5.77(d,J=10.6Hz,1H),3.96(s,2H),3.64–3.58(m,2H),3.42(dt,J=13.6,6.8Hz,1H),3.29(s,3H),1.25(d,J=6.8Hz,6H).13C NMR(101MHz,DMSO-d6)δ163.20,160.70,157.86,157.35,155.31,153.44,150.27,139.80,135.45,132.80,131.55,129.46,127.17,123.66,119.88,119.40,119.33,113.77,70.31,66.78,58.05,39.43,30.24,20.10.13C-NMR(100MHz,DMSO-d6)δ163.20,160.70,157.86,157.35,155.31,153.44,150.27,139.80,135.45,132.80,131.55,129.46,127.17,123.66,119.88,119.40,119.33,113.77,70.31,66.78,58.05,39.43,30.24,20.10.LC-MS(ESI)计算值C27H29N6O4[M+H]+:501.22,实验值501.30.HRMS(ESI)(M+H)+calculated for C27H29N6O4 +501.2245,found 501.2249.
以下化合物(化合物001-010,014-028)均按照上述步骤a-g的方法合成得到,化合物011-013是按照步骤b-g的方法合成但是将(3-氨基苯基)氨基甲酸叔丁酯替换为3-氨基吡咯烷-1-羧酸叔丁酯,其中012和014将g中的丙烯酰氯替换为2-丁炔酰氯:
N-(3-(2-(((4-甲氧基苯基)氨基)-6-甲基-7-氧蝶呤-8(7H)-基)苯基)丙烯酰胺(化合物001)
黄色固体(产率65.6%)。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.93(br,1H),8.78(s,1H),7.83(d,J=8.0Hz,1H),7.77(s,1H),7.56(t,J=8.0Hz,1H),7.31(br,2H),7.11(d,J=8.0Hz,1H),6.58(br,2H),6.44(dd,J=17.0Hz,J=10.2Hz,1H),6.26(d,J=17.0Hz,1H),5.77(d,J=10.2Hz,1H),3.65(s,3H),2.42(s,3H).HRMS(ESI)计算值C23H21N6O3[M+H]+429.1675,实验值429.1675。HPLC purity:98.6%。
N-(3-(6-环己基-2-((4-甲氧基苯基)氨基)-7-喋啶酮-8(7H)-基)苯基)丙烯酰胺(化合物002)
黄色固体(产率62.2%)。1H-NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.85(s,1H),8.78(s,1H),7.83(d,J=8.4Hz,1H),7.76(s,1H),7.54(t,J=8Hz,1H),7.32(d,J=7.2Hz,2H),7.12(d,J=8Hz,1H),6.59(br,2H),6.48(dd,J1=10Hz,J2=17.2Hz,1H),6.28(dd,J1=2Hz,J2=17.2Hz,1H),5.77(dd,J1=2Hz,J2=10Hz,1H),3.65(s,3H),3.08-3.15(m,1H),1.93(d,J=8Hz,2H),1.83(d,J=8.4Hz,2H),1.73(d,J=12Hz,1H),1.50(dd,J1=24.3Hz,J2=12.0Hz,2H),1.37(dd,J1=25.2Hz,J2=12.4Hz,2H),1.30–1.22(m,1H).13C-NMR(100MHz,DMSO-d6)δ162.99,159.74,157.65,155.11,139.59,135.24,132.49,131.35,129.23,126.96,123.42,119.17,112.95,54.74,29.98,25.55.LC-MS:m/z:496.2,(M-H)-=495.3.HRMS(ESI)(M+H)+calculated for C28H29N6O3 497.2296,found 497.2297.
N-(-(2-((4-(2-甲氧基乙氧基)苯基)氨基)-6-甲基-7-喋啶酮-8(7H)-基)苯基)丙烯酰胺(化合物003)
黄色固体(产率33%)。1H-NMR(400MHz,DMSO-d6)δ10.42(S,1H),9.92(S,1H),8.77(S,1H),7.83(d,J=8.4Hz,1H),7.78(S,1H),7.56(t,J=8Hz,1H),7.31(br,2H),7.11(d,J=8Hz,1H),6.59(br,2H),6.45(dd,J1=10Hz,J2=10.4Hz,1H),6.26(d,J=16.8Hz,1H),5.77(d,J=10Hz,1H),3.96(br,2H),3.61(t,J=4.4Hz,2H),3.30(s,3H),3.24(s,3H).13C-NMR(100MHz,DMSO-d6)δ163.27,157.63,156.08,154.23,153.50,139.89,135.42,132.87,131.61,129.51,128.11,127.19,123.63,119.44,113.85,70.37,66.88,60.17,58.11,33.27,20.59.LC-MS:m/z:473.25,(M+H)+=473.19.HRMS(ESI)(M+H)+calculated forC25H25N6O4 473.1932,found 473.1855.
8-(3-氨基苯基)-2-((4-甲氧基苯基)氨基)-6-苯氧喋啶-7(8H)-酮(化合物004)
N-(3-(2-((4-甲氧基苯基)氨基)-7-氧代-6-苯基-8(7H)-喋啶基)苯基)丙烯酰胺的合成路线
称取间苯二胺(15.00g,138.89mmol)置于250mL三口烧瓶中,加入100mL二氯甲烷,在常温条件下搅拌,另取二碳酸二叔丁酯(36.33g,166.67mmol)溶于20mL二氯甲烷,并滴加到上述反应液中,滴加完成后,继续在室温下搅拌2h,TLC跟踪原料基本完全转化(原料反应不完),然后在0℃条件下,滴加HCl溶液(浓盐酸/水=1/1)调节pH约等于5,有大量白色固体析出(注意酸性不能太强,不然Boc会掉),布氏漏斗抽滤,滤饼用50mL二氯甲烷洗涤,干燥。然后得到的白色固体置于800mL烧杯中,加入600mL去离子水,用饱和NaHCO3水溶液调节pH约等于9,有大量固体析出,布氏漏斗抽滤,200mL去离子水洗涤,真空干燥,即得到纯的(3-氨基苯基)氨基甲酸叔丁酯白色固体18.772g,产率约65%。减压回收二氯甲烷。
1H NMR(400MHz,DMSO-d6):δ9.00(s,1H),6.84(t,J=7.6Hz,1H),6.80(s,1H),6.52(d,J=7.6Hz,1H),6.16(d,J=7.6Hz,1H),4.96(s,2H),1.45(s,9H).LC-MS(ESI)计算值C11H16N2O2[M+H]+:209.12,实验值209.10。
(3-(2-氯-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯的合成路线
称取2,4-二氯-5-硝基嘧啶(2.99g,15.5mmol)置于250mL圆底三口烧瓶中,加入50mL乙腈和N,N-二异丙基乙胺(3g,23.3mmol),在常温条件下搅拌,称取(3-氨基苯基)氨基甲酸叔丁酯(3.23g,15.5mmol)溶于30mL乙腈,滴加到上述反应液中,滴加完成后,继续在常温下拌约1h,有大量橙色固体析出,TLC跟踪至原料完全转化,直接抽滤,滤饼用30mL乙腈洗涤,真空干燥,得到纯的(3-(2-氯-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯橙色固体4.53g,产率约80%。减压回收乙腈。
1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),9.54(s,1H),9.14(s,1H),7.67(s,1H),7.32(s,1H),7.26(t,J=2.4Hz,1H),7.14(t,J=2.8Hz,1H),1.48(s,9H).LC MS计算值C11H16N2O2[M+H]+:367.08,实验值367.15。
(3-((2-((4-甲氧基苯基)氨基)-5-硝基嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯的合成路线
称取(3-(2-氯-5-硝基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯(2.3g,6.4mmol)置于250mL圆底烧瓶中,用60mL四氢呋喃溶解,再加入对甲氧基苯胺(0.79g,6.4mmol)和N,N-二异丙基乙胺(1.24g,9.6mmol),氩气保护,加热回流搅拌约3h,TLC跟踪至原料完全转化。冷却室温,有大量黄色固体析出,抽滤,滤饼用50mL去离子水洗涤,真空干燥,得(3-((2-((4-甲氧基苯基)氨基)-5-硝基嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯黄色固体2.5g,收率约86%。
1H NMR(400MHz,DMSO-d6):δ10.36(s,1H),10.30(s,1H),9.52(s,1H),9.06(s,1H),7.69(s,1H),7.48(d,J=8Hz,2H),7.35-7.27(m,2H),7.11(d,J=6.4Hz,1H),6.71(d,J=8.4Hz,2H),3.71(s,3H),1.44(s,9H).LC-MS:计算值C22H25N6O5[M+H]+:453.19,实验值453.20.
(3-(2-(4-甲氧基苯基氨基)-5-氨基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯的合成路线
称取化合物(3-((2-((4-甲氧基苯基)氨基)-5-硝基嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯(5g,11.1mmol)置于250mL的圆底烧瓶中,加入二氯甲烷50mL,甲醇100mL,黄色浑浊加入钯碳(600mg)(含10%Pd),用氢气球通入氢气,室温下搅拌10h,TLC跟踪至原料完全转化。反应结束后,经硅藻土抽滤,50mL乙醇洗涤,将滤液旋干,真空干燥,得到的产品(3-(2-(4-甲氧基苯基氨基)-5-氨基嘧啶-4-氨基)苯基)氨基甲酸叔丁酯,无需纯化直接用于下一步反应。
(3-(2-((4-甲氧基苯基)氨基)-6,7-二氧代-6,7-二氢蝶啶-8(5H)-基)苯基)氨基甲酸叔丁酯的合成路线
称取化合物(3-((5-氨基-2-((4-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯(4.4g,10.43mmol)于250mL的圆底烧瓶中,加入100mL乙醇使其溶解,加入三乙胺(2.1g,20.86mmol),草酸二乙酯(1.5g,12.17mmol),氩气保护,加热回流TLC监测至反应结束。产生绿色固体,冷却至室温,抽滤,用冷乙醇洗涤,干燥,得到(3-(2-((4-甲氧基苯基)氨基)-6,7-二氧代-6,7-二氢蝶啶-8(5H)-基)苯基)氨基甲酸叔丁酯绿色固体3.3g(产率66.5%)。
1H NMR(400MHz,DMSO-d6):δ11.98(s,1H),9.64(s,1H),9.32(s,1H),8.17(s,1H),7.62(s,1H),7.54(d,J=8.4Hz,1H),7.45(t,J=8.4Hz,1H),7.19(d,J=9.2Hz,2H),6.98(d,J=8Hz,1H),6.55(d,J=8.8Hz,2H),3.65(s,3H),1.44(s,9H).LC-MS:计算值C24H25N6O5[M+H]+:477.18,实验值477.30.
8-(3-氨基苯基)-6-氯-2-((4-甲氧基苯基)氨基)蝶啶-7(8H)-酮的合成路线
称取化合物(3-(2-((4-甲氧基苯基)氨基)-6,7-二氧代-6,7-二氢蝶啶-8(5H)-基)苯基)氨基甲酸叔丁酯(1g,2.1mmol)于50mL的圆底烧瓶中,加入甲苯50mL,三氯氧磷5mL,氩气保护,TLC监测至反应结束,红褐色浑浊,减压浓缩除去甲苯,用饱和碳酸氢钠溶液调pH=8-10,用乙酸乙酯萃取,合并有机相,饱和氯化钠萃取,无水硫酸钠干燥,粗产品经柱层析(DCM:CH3OH=100:1)分离纯化得到黄色固体8-(3-氨基苯基)-6-氯-2-((4-甲氧基苯基)氨基)蝶啶-7(8H)-酮289mg(产率35%)。
1H NMR(400MHz,DMSO-d6):δ10.12(s,1H),8.79(s,1H),7.38(d,J=6.4Hz,2H),7.22(t,J=8Hz,1H),6.7(d,J=6Hz,1H),6.65(d,J=2.4Hz,2H),6.56(s,1H),6.50(d,J=8Hz,1H),5.38(s,2H),3.68(s,3H).LC-MS:m/z:(M+H)+=395.1,found395.1.
8-(3-氨基苯基)-2-((4-甲氧基苯基)氨基)-6-苯氧喋啶-7(8H)-酮的合成路线
称取化合物8-(3-氨基苯基)-6-氯-2-((4-甲氧基苯基)氨基)蝶啶-7(8H)-酮(0.24g,0.62mmol)放入25mL的圆底烧瓶中,加入碳酸钾(85mg,0.62mmol)、苯酚(64mg,0.68mmol)、5mL的N,N-二甲基甲酰胺,油浴加热至85℃,氩气保护,TLC监测至反应结束,橙黄色浑浊,减压浓缩,除去溶剂,用水和二氯甲烷萃取,合并有机相,饱和食盐水(20mL×1)萃取,无水硫酸钠干燥,浓缩,粗品经硅胶柱层析(DCM:CH3OH=80:1)纯化,得到8-(3-氨基苯基)-2-((4-甲氧基苯基)氨基)-6-苯氧喋啶-7(8H)-酮,黄色固体0.22mg(产率80.4%)。
1H-NMR(400MHz,DMSO-d6)δ9.66(S,1H),8.44(S,1H),7.50(t,J=7.6Hz,2H),7.38(d,J=8.8Hz,2H),7.32(dd,J1=7.6Hz,J2=14.1Hz,3H),7.24(t,J=8Hz,1H),6.78(d,J=8.4Hz,1H),6.65(d,J=8.8Hz,2H),6.59(s,1H),6.55(d,J=7.6Hz,1H),5.38(s,2H),3.67(s,3H).LC-MS:m/z:452.15,(M+H)+=453.16.HRMS(ESI)(M+H)+calculated for C25H20N6O3453.16,found 453.16.
N-(3-(2-((4-甲氧基苯基)氨基)-7-氧代-6-喋啶酮-8(7H)-基)苯基)丙烯酰胺(化合物004)的合成路线
称取化合物8-(3-氨基苯基)-2-((4-甲氧基苯基)氨基)-6-苯氧喋啶-7(8H)-酮(275mg,0.608mmol)于50mL的干燥两口圆底烧瓶中,加入无水二氯甲烷20mL,形成黄色澄清溶液,加入磁子,N,N-二异丙基乙胺(117mg,0.912mmol),氩气保护,冰浴冷却至0℃,将丙烯酰氯(66mg,0.729mmol)在冰浴下滴加到上述反应液中,继续冰浴搅拌至室温,TLC监测至反应结束,减压浓缩除去溶剂,粗产品经柱层析(DCM:CH3OH=150:1)分离纯化得到黄色固体粗产品经柱层析(DCM:CH3OH=100:1)分离纯化得到黄色固体N-(3-(2-((4-甲氧基苯基)氨基)-7-氧代-6-喋啶酮-8(7H)-基)苯基)丙烯酰胺120mg(产率47.7%)。
1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.71(s,1H),8.48(s,1H),7.89(s,1H),7.86(d,J=8.5Hz,1H),7.60(t,J=8.0Hz,1H),7.51(t,J=7.8Hz,2H),7.34(d,J=8.1Hz,3H),7.29(t,J=6.4Hz,2H),7.19(d,J=7.8Hz,1H),6.58(d,J=7.1Hz,2H),6.48(dd,J1=16.9Hz,J2=10.2Hz,1H),6.28(dd,J1=17.0Hz,J2=1.6Hz,1H),5.79(dd,J1=10.0Hz,J2=1.6Hz,1H),3.65(s,3H).13C-NMR(100MHz,DMSO-d6):δ163.29,155.73,152.60,152.36,151.93,139.98,135.53,133.03,131.63,129.70,129.62,127.26,125.42,123.61,121.55,119.47,116.61,113.22,55.00.LC-MS m/z:507.18,(M+H)+=507.20.HRMS(ESI)(M+Na)+calculated for C28H22N6O4Na+529.1595,found 529.1602.HPLC purity:97.68%,retention time=9.43min.
N-3-(6-苄基-2-((4-甲氧基苯基)氨基)-7-喋啶酮-8(7H)-基)苯基)丙烯酰胺(化合物005)
黄色固体(产率35%)。1H-NMR(400MHz,DMSO-d6)δ10.42(S,1H),8.79(S,1H),7.84(d,J=8.4Hz,1H),7.75(s,1H),7.29-7.38(m,7H),7.22(d,J=6.8Hz,2H),7.11(d,J=7.6Hz,1H),6.57(br,2H),6.45(dd,J1=10Hz,J2=16.8Hz,1H),6.22(dd,J1=1.6Hz,J2=16.8Hz,1H),5.75(dd,J1=1.6Hz,J2=10Hz,1H),4.13(s,2H),3.64(s,3H)。LC-MS:m/z:473.25,(M+H)+=473.19.HRMS(ESI)(M+Na)+calculated for C29H24N6O3Na 527.1802,found527.1808.
N-(3-(2-((2,4-二甲氧基苯基)氨基)-7-氧代-6-苯基-8(7H)-喋啶基)苯基)丙烯酰胺(化合物006)
黄色固体355mg(产率44.2%)。1H NMR(400MHz,DMSO-d6):δ10.42(s,1H),8.87(s,1H),8.50(s,1H),8.20(dd,J=6.4,3.0Hz,2H),7.86–7.79(m,2H),7.55(t,J=8.0Hz,1H),7.50–7.47(m,3H),7.40(d,J=8.7Hz,1H),7.16(d,J=8.0Hz,1H),6.55(d,J=1.7Hz,1H),6.47(dd,J=17.0,10.1Hz,1H),6.27(dd,J=17.0,1.7Hz,1H),6.12(s,1H),5.77(dd,J=10.2,1.7Hz,1H),3.77(s,3H),3.70(s,3H).LC-MS:m/z:520.18,(M+H)+=521.25.HRMS(ESI)(M+H)+calculated for C29H25N6O4 521.1932,found 521.1859.
N-(3-(2-((3,4-二甲氧基苯基)氨基)-7-氧代-6-苯基-8(7H)-喋啶基)苯基)丙烯酰胺(化合物007)
黄色固体(产率44.2%)。1H NMR(400MHz,DMSO-d6):δ10.41(s,1H),9.95(s,1H),8.92(s,1H),8.21(dd,J=6.4,3.0Hz s,2H),7.86(d,J=8.2Hz,1H),7.81(s,1H),7.56(t,J=8.0Hz,1H),7.52–7.44(m,3H),7.18(d,J=7.9Hz,1H),7.07(br,2H),6.55(s,1H),6.47(dd,J=17.0,10.1Hz,1H),6.27(dd,J=17.0,1.7Hz,1H),5.77(dd,J=10.2,1.7Hz,1H),3.66(s,3H),3.55(s,3H).13C NMR(100MHz,DMSO-d6):δ162.59,158.04,155.13,149.77,148.85,147.72,143.74,139.23,134.95,134.90,132.23,130.96,129.15,128.87,128.28,127.19,126.53,123.04,119.69,118.84,118.78,110.91,54.97,54.76.
N-(3-(2-((3-甲基-4-甲氧基苯基)氨基)-7-氧代-6-苯基-8(7H)-喋啶基)苯基)丙烯酰胺(化合物008)
黄色固体(产率44.2%)。1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),10.01(s,1H),8.91(s,1H),8.21(dd,J=6.6,3.1Hz,2H),7.88(d,J=8.0Hz,1H),7.81(s,1H),7.57(t,J=8.0Hz,1H),7.51–7.47(m,3H),7.27–7.14(m,3H),6.60(s,1H),6.46(dd,J=17.0,10.1Hz,1H),6.27(dd,J=17.0,1.9Hz,1H),5.79–5.75(m,1H),3.68(s,3H),1.91(s,9H).13C NMR(100MHz,DMSO-d6):δ163.41,158.90,155.99,149.43,140.11,135.87,135.77,132.27,131.80,129.95,129.74,129.09,128.03,127.35,125.33,119.66,119.52,110.02,55.38,16.14.LC-MS:m/z:504.19,(M+H)+=505.25.HRMS(ESI)(M+Na)+calculated forC29H24N6O3Na 527.1892,found 527.1799.
N-(3-(2-((3-甲基-4-甲氧基苯基)氨基)-7-氧代-6-苯基-8(7H)-喋啶基)苯基)丙烯酰胺(化合物009)
黄色固体(产率44.2%)。1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),10.01(s,1H),8.91(s,1H),8.21(dd,J=6.6,3.1Hz,2H),7.88(d,J=8.0Hz,1H),7.81(s,1H),7.57(t,J=8.0Hz,1H),7.51–7.47(m,3H),7.27–7.14(m,3H),6.60(s,1H),6.46(dd,J=17.0,10.1Hz,1H),6.27(dd,J=17.0,1.9Hz,1H),5.79–5.75(m,1H),3.68(s,3H),1.91(s,9H).13C NMR(100MHz,DMSO-d6):δ163.41,158.90,155.99,149.43,140.11,135.87,135.77,132.27,131.80,129.95,129.74,129.09,128.03,127.35,125.33,119.66,119.52,110.02,55.38,16.14.LC-MS:m/z:504.19,(M+H)+=505.25.HRMS(ESI)(M+Na)+calculated forC29H24N6O3Na 527.1892,found 527.1799.
N-(3-(2-((4-(2-甲氧基乙氧基苯基)氨基)-7-氧代-6-苯基-8(7H)-喋啶基)苯基)丙烯酰胺(化合物010)
黄色固体(产率46.2%)。1H NMR(400MHz,DMSO-d6):δ10.44(s,1H),10.10(s,1H),8.92(s,1H),8.21(s,2H),7.85(d,J=7.0Hz,2H),7.65–7.55(m,1H),7.49(s,3H),7.33(s,2H),7.18(d,J=7.0Hz,1H),6.60(s,2H),6.46(dd,J=16.8,10.3Hz,1H),6.27(d,J=16.2Hz,1H),5.77(d,J=9.6Hz,1H),3.97(s,2H),3.62(s,2H),3.30(s,3H).13C NMR(100MHz,DMSO-d6):δ140.05,135.84,135.77,132.82,131.77,129.97,129.70,129.11,128.03,127.36,123.87,119.69,114.01,70.52,67.02,58.27.LC-MS:m/z:534.20,(M+H)+=535.30HRMS(ESI)(M+H)+calculated for C30H27N6O4 535.2088,found 535.2082.
8-(1-丙烯酰胺吡咯烷-3-基)-2-((4-甲氧基苯基)氨基)-6-苯基喋啶-7(8H)-酮(化合物011)
黄色固体(产率23.6%)。1H NMR(400MHz,DMSO-d6):δ10.08(s,1H),8.85(d,J=1.9Hz,1H),8.12(d,J=3.1Hz,2H),7.58(t,J=7.5Hz,2H),7.47(d,J=2.2Hz,3H),6.87(d,J=8.2Hz,2H),6.60(ddd,J=82.4,16.5,10.2Hz,1H),6.25–6.14(m,1H),5.69(dd,J=25.5,6.0Hz,1H),4.34–3.99(m,1H),3.98–3.65(m,6H),3.47(dd,J=19.9,8.4Hz,1H),2.86(ddd,J=21.7,15.2,6.5Hz,1H),2.29–2.05(m,1H).13CNMR(100MHz,DMSO-d6):δ163.52,163.18,157.86,156.80,156.05,155.13,141.84,135.52,132.25,132.06,129.75,129.42,128.99,127.81,126.91,121.65,113.79,113.75,55.15,55.06,54.88,50.82,49.50,45.85,45.36,44.55,44.38,27.13,25.20..LC-MS:m/z:468.19,(M+H)+=469.30.HRMS(ESI)(M+H)+calculated for C26H25N6O3 469.1983,found 469.1996.
8-(1-丙烯酰胺吡咯烷-3-基)-2-((4-(2-甲氧基乙氧基)苯基)氨基)-6-苯基喋啶-7(8H)-酮(化合物012)
黄色固体(产率36.3%)。1H NMR(400MHz,DMSO-d6):δ10.08(s,1H),8.86(d,J=2.9Hz,1H),8.19–8.06(m,2H),7.58(dd,J=8.8,4.2Hz,2H),7.51–7.44(m,3H),6.89(dd,J=9.0,2.8Hz,2H),6.60(ddd,J=81.1,16.7,10.3Hz,1H),6.25–6.12(m,1H),5.69(ddd,J=29.8,10.3,2.4Hz,1H),4.31–4.01(m,3H),3.99–3.68(m,3H),3.65(dd,J=8.9,4.1Hz,2H),3.53–3.42(m,1H),3.31(d,J=1.4Hz,3H),2.89(dd,J=21.0,8.5Hz,1H),2.30–2.08(m,1H).13C NMR(100MHz,DMSO-d6):δ163.39,160.46,156.30,154.36,135.49,129.00,127.83,126.92,121.56,114.39,114.33,70.40,66.90,58.13,54.29,45.11,27.27,24.71.LC-MS:m/z:512.21,(M+H)+=513.30.HRMS(ESI)(M+H)+calculated for C28H29N6O4:513.2245,found 513.2245.
8-(1(-(丁-2-炔酰基)吡咯烷-3-基)-2-((4-(2-甲氧基乙氧基)苯基)氨基)-6-苯基喋啶-7(8H)-酮(化合物013)
黄色固体0.15g(产率36.3%)。1H NMR(400MHz,DMSO-d6):δ10.07(s,1H),8.85(d,J=2.7Hz,1H),8.13(dd,J=5.7,2.9Hz,2H),7.59(t,J=8.4Hz,2H),7.47(dd,J=3.8,2.3Hz,3H),6.93(dd,J=8.8,7.7Hz,2H),6.06(dd,J=16.6,8.3Hz,1H),4.30–4.21(m,1H),4.12–4.03(m,2H),4.01–3.88(m,1H),3.72(dd,J=12.0,8.7Hz,1H),3.68–3.64(m,2H),3.51–3.40(m,1H),3.33(s,3H),2.81(dd,J=23.4,13.8Hz,1H),2.30–2.12(m,1H),2.01(d,J=42.6Hz,3H).13C NMR(100MHz,DMSO-d6)δ162.26,159.30,156.03,154.37,151.63,151.53,135.48,132.28,129.71,128.98,127.78,121.57,114.38,87.89,87.69,74.34,70.41,67.00,58.17,58.13,35.73,30.73,3.18,3.15.LC-MS:m/z:524.21,(M+H)+=525.30.HRMS(ESI)(M+H)+calculated for C29H29N6O4:525.2245,found 525.2249.
8-(1-丙烯酰胺吡咯烷-3-基)-2–((4-(2-甲氧基乙氧基)苯基)氨基)-6-苯基喋啶-7(8H)-酮(化合物014)
1H NMR(400MHz,CDCl3)δ8.84(d,J=4.7Hz,1H),8.21–8.14(m,2H),7.71(s,1H),7.50–7.39(m,5H),6.97–6.91(m,2H),6.09(dq,J=16.8,8.3Hz,1H),4.21(ddd,J=65.8,15.2,9.0Hz,2H),3.85(s,3H),3.77–3.48(m,1H),2.93–2.15(m,2H),1.99(d,J=38.9Hz,3H),1.83(s,1H).LC-MS:m/z:480.19,(M+H)+=480.30.HRMS(ESI)(M+H)+calculated forC27H25N6O3 481.1983,found 481.1087.
N-(3-(6-环戊基-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-氧代-8(7H)-喋啶基)苯基)丙烯酰胺(化合物015)
黄色固体(产率30.1%)。1H-NMR(400MHz,DMSO-d6)δ10.43(s,1H),9.96(d,J=48.1Hz,1H),8.79(d,J=7.6Hz,1H),7.88–7.81(m,1H),7.77(s,1H),7.56(td,J=8.0,3.0Hz,1H),7.31(s,2H),7.13(d,J=7.7Hz,1H),6.59(s,2H),6.46(dd,J=16.8,10.2Hz,1H),6.26(d,J=16.8Hz,1H),5.80–5.73(m,1H),3.96(s,2H),3.61(t,J=4.3Hz,2H),3.29(s,3H),2.84(s,1H),2.62(s,1H),1.96(s,2H),1.93–1.83(m,2H),1.69(dd,J=32.4,6.6Hz,2H),1.22(s,1H).13C-NMR(100MHz,DMSO-d6)δ163.87,160.02,140.60,132.35,129.91,127.35,124.06,119.87,114.32,70.86,67.38,58.61,42.10,34.00,30.79,25.91.LC-MS:计算值C29H30N6O4[M+H]+:527.24,实验值527.30.HRMS(ESI)(M+H)+calculatedfor C29H31N6O4 +527.2401,found 527.2412.
N-(3-(6-环己基-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-氧代-8(7H)-喋啶基)苯基)丙烯酰胺(化合物016)
黄色固体(产率30.1%)。1H-NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.90(s,1H),8.79(s,1H),7.82(d,J=8.3Hz,1H),7.77(s,1H),7.55(t,J=8.0Hz,1H),7.31(s,2H),7.12(d,J=8.6Hz,1H),6.59(s,2H),6.45(dd,J=17.0,10.1Hz,1H),6.26(dd,J=17.0,1.9Hz,1H),5.76(dd,J=10.1,1.9Hz,1H),3.96(s,2H),3.64–3.58(m,2H),3.29(s,3H),3.12(dd,J=12.8,9.9Hz,1H),1.92(d,J=11.7Hz,2H),1.82(d,J=12.5Hz,2H),1.72(d,J=12.1Hz,1H),1.49(dd,J=24.1,11.5Hz,2H),1.37(dd,J=25.2,12.4Hz,2H),1.30–1.22(m,1H).13C-NMR(100MHz,DMSO-d6)δ163.76,160.52,158.41,155.87,140.36,136.03,133.36,132.11,130.01,127.72,124.20,119.95,114.32,70.87,67.35,58.61,30.75,26.32,26.26.。LC-MS:计算值C30H32N6O4[M+H]+:541.26,实验值541.35.HRMS(ESI)(M+H)+calculated forC30H33N6O4 +541.2558,found541.2565.
N-(3-(6-(2-氟苯基)-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-氧代-8(7H)-喋啶基)苯基)丙烯酰胺(化合物017)
黄色固体(产率56.0%)。1H-NMR(400MHz,DMSO-d6)δ10.45(s,1H),10.18(s,1H),8.92(s,1H),7.85(d,J=6.2Hz,2H),7.68(td,J=7.6,1.6Hz,1H),7.63–7.51(m,2H),7.39–7.27(m,4H),7.19(d,J=8.0Hz,1H),6.60(s,2H),6.47(dd,J=17.0,10.1Hz,1H),6.27(dd,J=17.0,1.8Hz,1H),5.77(dd,J=10.1,1.8Hz,1H),3.98(s,2H),3.65–3.59(m,2H),3.30(s,3H).13C-NMR(100MHz,DMSO-d6)δ163.80,159.92,159.29,155.46,149.46,140.44,135.84,133.06,132.11,130.11,127.76,124.69,124.55,124.16,120.03,119.93,116.25,116.04,114.37,70.87,67.38.19F-NMR(376MHz,DMSO-d6)δ-112.11–-112.36(m).LC-MS:计算值C30H25FN6O4[M+H]+:553.20,实验值553.30.HRMS(ESI)(M+H)+calculated forC30H26FN6O4 +553.1994,found 553.1996.
N-(3-(6-异丙基-2-((4-甲氧基苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物018)
黄色固体(产率37.5%)。1H-NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.89(s,1H),8.80(s,1H),7.83(d,J=8.0Hz,1H),7.76(s,1H),7.55(t,J=8.0Hz,1H),7.31(s,2H),7.12(d,J=7.7Hz,1H),6.59(s,2H),6.45(dd,J=16.9,10.1Hz,1H),6.29–6.19(m,1H),5.77(d,J=10.5Hz,1H),3.65(s,3H),3.41(dt,J=13.7,6.8Hz,1H),1.25(d,J=6.8Hz,6H).13C-NMR(100MHz,DMSO-d6)δ168.51,166.00,160.62,145.11,140.75,138.00,136.86,134.75,132.49,128.96,124.70,118.47,60.26,45.36,45.15,44.94,44.74,44.53,44.32,44.11,35.54,25.41.LC-MS(ESI)计算值C25H25N6O3[M+H]+:457.20,实验值457.20.HRMS(ESI)(M+H)+calculated for C25H25N6O3 +457.1983,found 457.1989.
N-(3-(6-异丙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物019)
黄色固体(产率39.5%)。1H-NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.90(s,1H),8.80(s,1H),7.83(d,J=8.0Hz,1H),7.77(s,1H),7.56(t,J=8.0Hz,1H),7.31(s,2H),7.13(d,J=7.8Hz,1H),6.59(s,2H),6.45(dd,J=16.9,10.1Hz,1H),6.26(dd,J=16.9,1.5Hz,1H),5.77(d,J=10.6Hz,1H),3.96(s,2H),3.64–3.58(m,2H),3.42(dt,J=13.6,6.8Hz,1H),3.29(s,3H),1.25(d,J=6.8Hz,6H).13C-NMR(100MHz,DMSO-d6)δ163.20,160.70,157.86,157.35,155.31,153.44,150.27,139.80,135.45,132.80,131.55,129.46,127.17,123.66,119.88,119.40,119.33,113.77,70.31,66.78,58.05,39.43,30.24,20.10.LC-MS(ESI)计算值C27H29N6O4[M+H]+:501.22,实验值501.30.HRMS(ESI)(M+H)+calculated forC27H29N6O4 +501.2245,found 501.2249.
N-(3-(6-乙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-氧代喋啶-8(7H)-基)苯基)丙烯酰胺(化合物020)
黄色固体(产率56.0%)。1H-NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.92(s,1H),8.80(s,1H),7.85(d,J=8.0Hz,1H),7.79(s,1H),7.56(t,J=8.0Hz,1H),7.31(s,2H),7.12(d,J=7.8Hz,1H),6.59(s,2H),6.48(dd,J=16.9,10.2Hz,1H),6.26(dd,J=17.0,1.6Hz,1H),5.76(dd,J=10.2,1.6Hz,1H),3.96(s,2H),3.62–3.58(m,2H),3.29(s,3H),2.81(q,J=7.3Hz,2H),1.25(t,J=7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ163.28,157.78,157.68,155.76,153.48,150.43,139.92,135.43,132.87,131.65,129.49,127.16,123.65,119.44,113.81,70.37,66.85,58.11,40.11,39.90,39.69,39.48,39.28,39.07,38.86,26.13,10.36.LC-MS(ESI)计算值C26H27N6O4[M+H]+:487.21,实验值487.25.HRMS(ESI)(M+Na)+calculated for C26H27N6O4Na+510.1986,found 509.1991.
N-(3-(2-((2-甲氧基-4-(4-甲基-1-哌嗪基)苯基)氨基)-7-氧代-6-苯基-8(7H)-蝶啶基)苯基)丙烯酰胺(化合物021)
橙红色固体(产率30.1%)。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),10.02(s,1H),8.91(s,1H),8.21(dd,J=6.6,3.0Hz,2H),7.88(d,J=8.0Hz,1H),7.81(s,1H),7.57(t,J=8.0Hz,1H),7.53–7.46(m,3H),7.24(s,1H),7.18(d,J=7.8Hz,2H),6.60(s,1H),6.46(dd,J=16.9,10.1Hz,1H),6.27(dd,J=17.0,1.9Hz,1H),5.77(dd,J=10.1,1.8Hz,1H),3.97(s,2H),3.66-3.59(m,2H),3.31(s,3H),1.92(s,3H).13C-NMR(101MHz,DMSO-d6):δ163.22,158.73,155.82,149.31,139.92,135.58,132.31,131.59,129.78,129.59,128.91,127.86,127,23,125.67,123.62,119.51,119.29,111.39,70.48,67.49,58.27,40.05,39.85,39.64,39.43,39.22,39.01,38.80,15.94.LC-MS:计算值C31H29N6O4[M+H]+:549.22,实验值549.30.
N-(3-(6-环己基-2-((3-(4-甲基哌嗪-1-基)苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物022)
黄色固体0.23g(产率48.0%)。1H-NMR(400MHz,DMSO-d))δ10.48(s,1H),9.75(s,1H),8.81(s,1H),7.82(d,J=8.4Hz,1H),7.77(s,1H),7.52(t,J=8.0Hz,1H),7.13–7.08(m,1H),7.05(d,J=7.5Hz,1H),6.86(s,1H),6.77(s,1H),6.52–6.43(m,2H),6.28–6.21(m,1H),5.76(dd,J=10.1,1.9Hz,1H),3.64–3.46(m,1H),3.12(td,J=8.1,3.9Hz,1H),3.02(s,4H),2.54(s,4H),2.29(s,3H),1.91(d,J=11.6Hz,2H),1.82(d,J=12.4Hz,2H),1.71(d,J=11.7Hz,1H),1.49(dd,J=24.3,10.3Hz,2H),1.37(dd,J=25.1,12.5Hz,2H),1.22(d,J=1.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ163.24,160.36,157.86,157.63,155.42,150.88,150.22,140.15,139.88,135.37,131.67,130.53,129.58,129.40,129.37,128.51,127.13,123.67,119.79,119.32,110.00,54.06,47.65,45.08,40.11,39.90,39.69,39.48,39.27,39.07,38.86,30.22,25.80,25.74.LC-MS(ESI)计算值C32H37N8O2[M+H]+:565.30,实验值565.35.HRMS(ESI)(M+H)+calculated for C32H37N8O2 +565.3040,found 565.3040.
N-(3-(2-((3-乙酰基苯基)氨基)-6-环己基-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物023)
黄色固体(产率49.3%)。1H-NMR(400MHz,DMSO-d6)δ10.40(s,1H),10.14(s,1H),8.86(s,1H),7.81(dd,J=19.0,10.9Hz,4H),7.54(t,J=8.0Hz,1H),7.46(d,J=7.7Hz,1H),7.13(d,J=8.3Hz,1H),7.05(s,1H),6.44(dd,J=17.0,10.1Hz,1H),6.25(dd,J=17.0,1.9Hz,1H),5.76(dd,J=10.1,2.0Hz,1H),3.12(ddd,J=11.4,7.2,3.1Hz,1H),2.46(s,3H),1.92(d,J=11.8Hz,2H),1.82(d,J=12.5Hz,2H),1.72(d,J=12.0Hz,1H),1.50(dd,J=23.6,11.0Hz,2H),1.43–1.31(m,2H),1.22(s,1H).13C-NMR(100MHz,DMSO-d6)δ197.58,163.24,160.93,157.94,157.46,155.36,150.21,139.94,139.89,137.05,135.40,131.59,129.52,128.34,127.24,123.69,121.72,120.14,119.42,119.35,118.66,40.09,39.88,39.67,39.47,39.26,39.05,38.84,30.21,26.64,25.79,25.74.LC-MS:计算值C29H29N6O3[M+H]+:508.22,实验值508.25.HRMS(ESI)(M+Na)+calculated for C29H28N6O3Na+5531.2115,found 531.2120.
N-(3-(6-环己基-2-((3-(2-甲氧基乙氧基)苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物024)
黄色固体(产率49.3%)。1H-NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.92(s,1H),8.84(s,1H),7.80(d,J=8.3Hz,1H),7.75(s,1H),7.54(t,J=8.0Hz,1H),7.11(t,J=9.3Hz,2H),6.99(s,1H),6.87(t,J=7.9Hz,1H),6.50–6.40(m,2H),6.25(dd,J=16.0,4Hz,1H),5.78–5.74(m,1H),3.90(t,J=4.0Hz,2H),3.62(t,J=4.0Hz,2H),3.30(s,3H),3.12(ddd,J=11.4,7.3,3.1Hz,1H),1.92(d,J=11.5Hz,2H),1.82(d,J=12.4Hz,2H),1.72(d,J=11.9Hz,1H),1.50(dd,J=23.5,11.1Hz,2H),1.37(dd,J=25.2,12.4Hz,2H),1.30–1.21(m,1H).13C-NMR(100MHz,DMSO-d6)δ163.22,160.60,158.50,157.85,157.52,155.42,150.20,140.66,139.86,135.35,131.63,129.56,128.87,127.17,123.63,119.90,119.45,119.25,107.54,70.31,66.49,58.09,40.09,39.89,39.68,39.47,39.26,39.05,38.84,30.21,25.80.HRMS(ESI)(M+Na)+calculated for C30H32N6O4Na+563.2377,found 563.2380.
N-(3-(6-环己基-7-氧代-2-((3-(2-氧代丙氧基)苯基)氨基)-8(7H)-蝶啶基)苯基)丙烯酰胺(化合物025)
黄色固体(产率45.3%)。1H-NMR(400MHz,DMSO-d)δ10.66(s,1H),10.13(s,1H),8.84(s,1H),7.91(s,1H),7.85(s,1H),7.67(d,J=13.2Hz,1H),7.55(t,J=8.0Hz,2H),7.32(d,J=8.2Hz,1H),7.25(d,J=8.4Hz,1H),7.14(d,J=7.9Hz,1H),6.54(dd,J=17.0,10.2Hz,1H),6.23(dd,J=17.0,1.9Hz,1H),5.78–5.67(m,1H),3.19–3.08(m,1H),2.12(s,3H),1.93(d,J=11.4Hz,2H),1.83(d,J=12.5Hz,2H),1.72(d,J=11.8Hz,1H),1.50(dd,J=24.2,10.3Hz,2H),1.38(dd,J=25.5,12.1Hz,2H),1.30–1.22(m,1H).LC-MS:计算值C30H31N6O4[M+H]+:539.24,实验值539.30.HRMS(ESI)(M+Na)+calculated for C30H30N6O4Na+561.2221,found 561.2225.
N-(3-(2-((3-(2-氨基-2-氧代乙氧基)苯基)氨基)-6-环己基-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物026)
黄色固体(产率48.3%)。1H-NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.97(s,1H),8.84(s,1H),7.78(d,J=8.3Hz,2H),7.54(t,J=8.0Hz,1H),7.38(s,2H),7.14(t,J=9.3Hz,2H),7.00(s,1H),6.87(s,1H),6.48–6.39(m,2H),6.25(dd,J=17.0,1.9Hz,1H),5.78–5.73(m,1H),4.30(s,2H),3.12(ddd,J=11.4,7.3,3.1Hz,1H),1.92(d,J=11.5Hz,2H),1.82(d,J=12.4Hz,2H),1.72(d,J=11.8Hz,1H),1.50(dd,J=23.5,11.1Hz,2H),1.37(dd,J=25.2,12.4Hz,2H),1.30–1.23(m,1H).13C-NMR(100MHz,DMSO-d6)δ169.89,163.23,160.69,157.81,157.52,155.40,150.22,140.68,139.88,135.38,131.63,129.53,128.80,127.15,123.65,119.95,119.37,107.73,105.94,66.65,48.57,40.10,39.89,39.68,39.47,39.27,39.06,38.85,30.22,25.80.LC-MS(ESI)计算值C29H30N7O4[M+H]+:540.24,实验值540.30.HRMS(ESI)(M+Na)+calculated for C29H29N7O4Na+562.2173,found 562.2178.
3-(((8-(3-丙烯酰胺基苯基)-6-环己基-7-氧代-7,8-二氢蝶呤-2-基)氨基)苯甲酰胺(化合物027)
黄色固体(产率35.5%)。1H-NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.08(s,1H),8.85(s,1H),7.76(dt,J=20.3,8.4Hz,5H),7.55(t,J=8.0Hz,1H),7.35(d,J=7.6Hz,1H),7.28(s,1H),7.14(d,J=7.9Hz,1H),6.95(s,1H),6.47(dd,J=17.0,10.1Hz,1H),6.26(dd,J=17.0,1.8Hz,1H),5.79–5.73(m,1H),3.16–3.09(m,1H),1.93(d,J=12.0Hz,2H),1.83(d,J=12.4Hz,2H),1.72(d,J=11.8Hz,1H),1.51(dd,J=23.6,11.2Hz,2H),1.44–1.29(m,3H).13C-NMR(100MHz,DMSO-d6)δ167.95,163.27,160.78,157.92,157.53,155.37,150.21,139.87,139.58,135.39,134.80,131.64,129.50,127.74,127.16,123.70,120.63,120.05,119.39,118.93,48.56,40.12,39.91,39.70,39.49,39.29,39.08,38.87,30.23,28.98,25.80.LC-MS(ESI)计算值C28H26N7O3[M-H]-:508.21,实验值508.30.HRMS(ESI)(M+Na)+calculated for C28H27N7O3Na+532.2068,found 532.2065.
N-(3-(6-环丙基-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物028)
黄色固体0.23g(产率45.3%)。1H-NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.92(s,1H),8.80(s,1H),7.85(d,J=8.0Hz,1H),7.79(s,1H),7.56(t,J=8.0Hz,1H),7.31(s,2H),7.12(d,J=7.8Hz,1H),6.59(s,2H),6.48(dd,J=16.9,10.2Hz,1H),6.26(dd,J=17.0,1.6Hz,1H),5.76(dd,J=10.2,1.6Hz,1H),3.96(s,2H),3.62–3.58(m,2H),3.29(s,3H),2.81(q,J=7.3Hz,2H),1.25(t,J=7.4Hz,3H).13C-NMR(100MHz,DMSO-d6)δ163.28,157.78,157.68,155.76,153.48,150.43,139.92,135.43,132.87,131.65,129.49,127.16,123.65,119.44,113.81,70.37,66.85,58.11,40.11,39.90,39.69,39.48,39.28,39.07,38.86,26.13,10.36.LC-MS(ESI)计算值C27H27N6O4[M+H]+:499.21,实验值499.25.HRMS(ESI)(M+Na)+calculated for C27H26N6O4Na+521.2908,found 521.1910.
N-(3-(6-环己基-2-((5-(2-甲氧基乙氧基)吡啶-2-基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物029)
黄色固体0.13g(产率55.8%)。1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),10.11(s,1H),8.85(s,1H),7.94(d,J=3.0Hz,1H),7.82(d,J=8.3Hz,1H),7.76(s,1H),7.57(t,J=8.0Hz,1H),7.42(d,J=9.2Hz,1H),7.14(d,J=8.0Hz,1H),6.86(dd,J=9.3,2.8Hz,1H),6.44(dd,J=16.9,10.1Hz,1H),6.25(dd,J=17.0,1.8Hz,1H),5.77(dd,J=10.1,1.7Hz,1H),4.14–4.01(m,2H),3.69–3.58(m,2H),3.30(s,3H),3.14(t,J=11.3Hz,1H),1.93(d,J=11.4Hz,2H),1.83(d,J=12.8Hz,2H),1.73(d,J=13.6Hz,1H),1.51(dd,J=24.2,10.7Hz,2H),1.38(dd,J=25.3,12.7Hz,2H),1.27(ddd,J=7.2,5.0,3.1Hz,1H).13C NMR(151MHz,DMSO-d6)δ162.70,160.50,157.37,156.12,154.72,149.85,149.49,145.34,139.22,134.89,133.70,130.99,129.02,126.73,123.16,122.40,119.51,119.06,118.99,113.00,69.70,66.95,57.55,39.44,39.32,39.18,39.05,38.91,38.77,38.63,38.49,29.66,25.22,25.17.LC-MS(ESI)计算值C29H32N7O4[M+H]+:542.25,实验值542.25。
N-(3-(6-环己基-2-((5-(2-甲氧基乙氧基)吡啶-3-基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物030)
黄色固体0.34g(产率70.6%)。1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.98(s,1H),8.81(s,1H),8.09(s,1H),7.85–7.70(m,3H),7.53(t,J=8.0Hz,1H),7.13–7.07(m,1H),6.45(dd,J=17.0,10.1Hz,2H),6.25(dd,J=17.0,1.9Hz,1H),5.76(dd,J=10.1,1.9Hz,1H),4.29–4.23(m,2H),3.63–3.57(m,2H),3.27(s,3H),3.12(tt,J=11.3,2.9Hz,1H),1.91(d,J=11.7Hz,2H),1.82(d,J=12.4Hz,2H),1.71(d,J=12.1Hz,1H),1.49(dd,J=24.2,10.5Hz,2H),1.37(dd,J=25.2,12.4Hz,2H),1.30–1.22(m,1H).LC-MS(ESI)计算值C29H31N7O4[M+H]+:542.25,实验值542.20.HRMS(ESI)(M+H)+calculated for C29H31N7O4 +542.2510,found 542.2517.
N-(3-(6-环己基-2-((3-3-甲氧基-4-(2-甲氧基乙氧基)苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物031)
黄色固体0.41g(产率65.7%)。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.79(s,1H),8.79(s,1H),7.82(d,J=8.3Hz,1H),7.73(s,1H),7.53(t,J=8.1Hz,1H),7.13–7.08(m,1H),7.01(s,2H),6.53(s,1H),6.46(dd,J=17.0,10.1Hz,1H),6.26(dd,J=17.0,1.9Hz,1H),5.76(dd,J=10.1,1.9Hz,1H),4.00–3.86(m,2H),3.62–3.57(m,2H),3.54(s,3H),3.29(s,3H),3.11(tt,J=11.4,3.1Hz,1H),1.91(d,J=11.4Hz,2H),1.82(d,J=12.5Hz,2H),1.72(d,J=12.1Hz,1H),1.49(dd,J=24.2,10.6Hz,2H),1.42–1.31(m,2H),1.30–1.25(m,1H).LC-MS(ESI)计算值C31H35N6O5[M+H]+:571.27,实验值571.30.HRMS(ESI)(M+H)+calculated for C31H35N6O5 +571.2663,found 571.2667.
N-(3-(6-环己基-2-((4-甲氧基-3-(2-甲氧基乙氧基)苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物032)
黄色固体0.11g(产率35.3%)。1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.75(s,1H),8.79(s,1H),7.83(d,J=8.1Hz,1H),7.72(s,1H),7.53(t,J=8.0Hz,1H),7.16–6.90(m,3H),6.62–6.38(m,2H),6.26(dd,J=17.0,1.6Hz,1H),5.82–5.71(m,1H),3.81(s,2H),3.65(s,3H),3.61–3.56(m,2H),3.29(s,3H),3.11(t,J=11.3Hz,1H),1.91(d,J=11.6Hz,2H),1.82(d,J=12.2Hz,2H),1.72(d,J=11.9Hz,1H),1.49(dd,J=24.1,11.3Hz,2H),1.37(dd,J=25.1,12.5Hz,2H),1.25(dd,J=23.7,11.6Hz,1H).LC-MS(ESI)计算值C31H33N6O5[M-H]-:569.25,实验值569.20.HRMS(ESI)(M+H)+calculated for C31H35N6O5 +571.2663,found571.2671.
N-(3-(6-(2-氯苯基)-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物033)
黄色固体0.30g(产率63.5%)。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),10.20(s,1H),8.91(s,1H),7.85(d,J=6.5Hz,2H),7.63–7.56(m,3H),7.53–7.45(m,2H),7.34(s,2H),7.17(d,J=8.0Hz,1H),6.60(s,2H),6.46(dd,J=16.9,10.1Hz,1H),6.27(dd,J=17.0,1.8Hz,1H),5.77(dd,J=10.1,1.8Hz,1H),3.98(s,2H),3.64–3.60(m,2H),3.30(s,3H).LC-MS(ESI)计算值C30H25N6O5Cl[M+H]+:569.17,实验值569.10.HRMS(ESI)(M+H)+calculated for C30H25N6O5Cl+569.1699,found 569.1703.
N-(3-(6-(叔丁基)-2-((4-(2-甲氧基乙氧基)苯基)氨基)-7-喋啶-8(7H)-基)苯基)丙烯酰胺(化合物034)
黄色固体0.41g(产率54.8%)。1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.62(s,1H),8.78(s,1H),7.58(s,1H),7.53(d,J=8.4Hz,1H),7.46(t,J=8.0Hz,1H),7.31(d,J=7.3Hz,2H),6.97(d,J=7.8Hz,1H),6.61(d,J=4.5Hz,2H),4.01–3.96(m,2H),3.65–3.60(m,2H),3.30(s,3H),1.45(s,9H),1.41(s,9H).LC-MS(ESI)计算值C28H31N6O4[M+H]+:515.24,实验值515.20.HRMS(ESI)(M+H)+calculated for C28H31N6O4 +515.2401,found515.2398.
N-(3-(2-(((4-甲氧基苯基)氨基)-7-氧代-6-苯基蝶啶-8(7H)-基)苯基)丙烯酰胺(化合物035)
黄色固体0.11g(产率44.2%)。1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.10(s,1H),8.92(s,1H),8.25–8.16(m,2H),7.93–7.76(m,2H),7.57(dd,J=16.6,8.5Hz,1H),7.49(t,3H),7.34(s,J=0.8Hz,2H),7.18(d,J=7.9Hz,1H),6.59(s,2H),6.47(dd,J=16.9,10.2Hz,1H),6.27(dd,J=17.0,1.4Hz,1H),5.77(d,J=11.8Hz,1H),3.66(s,3H).LC-MS(ESI)计算值C28H23N6O3[M+H]+:491.18,实验值491.25.HRMS(ESI)(M+H)+calculated forC28H23N6O3 +491.1826,found 491.1838.
8-(1-(2-丁酰基)吡咯烷-3-基)-2-((4-甲氧基苯基)氨基)-6-苯基蝶啶-7(8H)-酮(化合物036)
黄色固体0.13g(产率45.7%)。1H NMR(400MHz,CDCl3)δ8.84(d,J=4.7Hz,1H),8.21–8.14(m,2H),7.70(s,1H),7.50–7.38(m,5H),6.97–6.91(m,2H),6.17–6.01(m,1H),4.41–3.94(m,2H),3.84(s,3H),3.77–3.48(m,1H),2.98–2.69(m,1H),2.35–2.14(m,1H),1.99(d,J=38.9Hz,3H),1.83(s,1H).HRMS(ESI)(M+H)+calculated for C27H25N6O3 +481.1983,found 481.1987.
实施例2.生物活性测试
本发明提供的化合物对BTK激酶活性的体外抑制效果实验如下进行:
体外酶活性分析:野生型EGFR蛋白和ITK蛋白均购自于Invitrogen,野生型BTK购自于Eurofins(Brussels,Belgium)。为所有的待测试化合物设置了从5.1×10-11mol/L到1.0×10-6mol/L的10个浓度梯度。
不同激酶的浓度由优化实验决定,使用酶联免疫吸附测定(ELISA)评估激酶活力测定。将总共20μg mL-1的Poly(Glu,Tyr)4:1(Sigma,St Louis,MO)预涂在96孔的ELISA板上作为底物。将活性激酶与指定药物在1X反应缓冲液(50mmol/L HEPES pH 7.4、20mmol/LMgCl2、0.1mmol/L MnCl2、0.2mmol/L Na3VO4、1mmol/L DTT)在37℃下含有5μmol/LATP的溶液中孵育1小时。孵育后,用PBS洗涤孔板,然后与抗磷酸酪氨酸(PY99)抗体(Santa CruzBiotechnology,Santa Cruz,CA)温育,然后与辣根过氧化物酶(HRP)缀合的第二抗体孵育。使用邻苯二胺(OPD)观察孔,并用多孔分光光度计(VERSAmaxTM,Molecular Devices,Sunnyvale,CA,USA)在492nm处读取吸光度。实验数据使用GraphPad Prism version 4.0进行计算。每次实验均重复3次以上。
BTK(Eurofins,Brussels,Belgium)或者ITK或者EGFR(PV3872,Invitrogen)0.287μg/μL,化合物在DMSO中从5.1×10-9M到1×10-4M稀释三倍。4μL化合物溶于96μL水,得到4x的化合物溶液。40μM ATP溶于1.33x激酶缓冲液,激酶/肽混合物包含2×激酶、4μM酪氨酸4肽准备好待用。10μL激酶反应包括2.5μL化合物溶液,5μL激酶/肽混合物,2.5μL ATP溶液。5μL磷酸化肽溶液代替激酶/肽混合物用作100%磷酸化对照。2.5μL 1.33×激酶缓冲液代替ATP溶液用作100%抑制对照,2.5μL 4%DMSO代替化合物溶液用作0%抑制对照。板内溶液充分混合后在室温下培养1.5小时。每孔加入5μL Development Solution后继续在室温下培养1小时,非磷酸化肽在此时间内被裂解。最后,加入5μL终止制剂(Stop Reagent)结束反应。孔板用EnVisionMultilabel Reader(Perkin Elmer)进行测量。实验数据使用GraphPadPrism version 4.0进行计算。每次实验均重复3次以上。
测试结果如下表1所示。
表1
*:>1000表示基本上检测不到对激酶的抑制作用。
体外细胞活性分析:
实验方法:
将U-937或者Ramos细胞配置成50000个/mL或者10000个/mL的细胞悬浮液种植在96孔板中,每孔100μL,在5%的二氧化碳培养箱中培养2h。将待测药物配置成20mM母液,进行三倍稀释,取10ul加入96孔板中(药物终浓度为18181.82nM,6060.6nM,2020.2nM,673.4nM,224.5nM,74.8nM,24.9nM,8.3nM),将不同浓度梯度的化合物加入培养液中,孵育48h后,在避光条件下每孔加入10μL CCK-8溶液,放入5%CO2恒温培养箱中反应3h,使用可调波长式微孔板酶标仪,37℃、450nm波长下测定OD值,计算抑制率。抑制率=(OD对照组平均值-OD加药组)÷OD对照组×100%,OD对照组平均值=(OD未加药-OD空白)÷未加药孔数。
实验结果:
表2.化合物的细胞活性
细胞水平选择性分析:
实验方法:
将Jurkat细胞(50w/孔)种于六孔板种后饥饿1h,然后加入待测试的化合物在培养箱中孵育4h,随后加入CD3/CD28磁珠刺激30min后用western blot检测化合物在Jurkat细胞中的PLCγ1和p-PLCγ1(Y783)的表达情况,最后用ImageJ进行谱带密度分析即灰度分析。
将U937细胞(100w/孔)种于六孔板种,饥饿过夜。然后加入待测试的化合物在培养箱中孵育4h,随后加入anti-IgM刺激15min,后用western blot检测化合物在U-937细胞中的BTK和p-BTK(Y223)的表达情况,最后用ImageJ进行谱带密度分析即灰度分析。
将A549细胞(50w/孔)种于六孔板种,饥饿过夜。然后加入待测试的化合物在培养箱中孵育4h,随后加入EGF刺激5min,后用western blot检测化合物在A549细胞中的EGFR和p-EGFR(Y1068)的表达情况,最后用ImageJ进行谱带密度分析即灰度分析。
实验结果:
由于部分化合物在激酶水平上对于ITK和EGFR显示出了激酶选择性,为了进一步验证喋啶酮类化合物在细胞水平上也对于ITK和EGFR具有较高的选择性,我们选取了在激酶水平上选择性较好的化合物015,016,018,022,024和027测试了它们在BTK表达量较高的U-937细胞中对于BTK磷酸化抑制的IC50值,Jurkat细胞中对于PLCγ1的磷酸化抑制IC50值和A549细胞中对于EGFR的磷酸化抑制IC50值。具体的测试结果如表3所示,这些化合物对于U-937细胞中BTK的磷酸化抑制活性的IC50值均在3.12-18.08nM之间,显示出了较优的磷酸化抑制效果。在ITK高表达的Jurkat细胞中对于PLCγ1的磷酸化抑制IC50值在952nM以上,而依鲁替尼在Jurkat细胞对于PLCγ1的磷酸化抑制IC50值为178nM,表明化合物015,016,018,022,024和027对于ITK的选择性均优于依鲁替尼。在EGFR高表达的A549细胞中化合物015,016,018,022,024和027对于EGFR的磷酸化抑制IC50值为35.96-150.88nM之间,而依鲁替尼为16.61nM抑制效果强于上述的化合物,综上所述,化合物015,016,018,022,024和027在细胞水平上对于BTK高表达的U-937细胞的BTK有较好的磷酸化抑制效果,对于ITK高表达的Jurkat细胞中PLCγ1的磷酸化和EGFR高表达的A549细胞中EGFR的磷酸化抑制活性较差,证实了它们在细胞水平上也有较好的选择性。
表3.化合物在细胞中的磷酸化抑制活性
上述化合物中代表性的化合物024的磷酸化抑制效果如图1所示,024在1000nM时对于ITK高表达的Jurkat细胞中PLCγ1的磷酸化无明显的抑制效果,而在相同浓度下Ibrutinib可以显著的抑制PLCγ1的磷酸化。024在1000nM时对于EGFR高表达的A549细胞中EGFR的磷酸化只有微弱的抑制效果,而Ibrutinib在100nM时可以显著的抑制EGFR的磷酸化。进而证明了024在细胞水平上也有较高的选择性。
体内肿瘤抑制活性分析:
实验方法:
收集培养好的U-937细胞,1000rpm离心除去培养基,用RPMI-1640重悬后离心除去上清(洗涤3次),用基质胶:RPMI-1640=1:1的混合溶液重悬U-937细胞,细胞密度为1000w/mL。采用皮下注射的方式给每只小鼠注射0.1mL的U-937细胞悬液(100W/只)待小鼠肿瘤体积长至50-150mm3时,称重并随机分笼。按照组别设置给药,待14天时,通过脊椎脱臼法处死小鼠,并取小鼠的心肝脾肺肾小肠肿瘤于组织固定液中。整个实验过程中,隔天测量移植瘤的长和宽,同时称量小鼠体重。量瘤:隔天通过游标卡尺记录肿瘤的长和宽,肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×L×W2,其中L、W分别表示长、宽,单位mm。根据测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为:RTV=TVt/TV0。其中V0为分笼给药时(即d0)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。将所有数据用GraphPad Prism 8处理。
实验结果:
如图2所示:化合物002,016和024在U-937移植瘤模型鼠中显示出显著的肿瘤抑制效果,并且小鼠体重无明显的变化,证明药物无明显的毒性,具有一定的安全性。
讨论:
发明人经过广泛而深入的研究,设计并合成得到了一系列未见文献报道的7(8H)-喋啶酮类化合物,对得到的化合物进行了分子水平的活性测试,得到一批能够选择性抑制BTK的化合物。本发明人进一步发现,本发明的化合物对BTK激酶有较好的活性抑制能力,从而提示本发明的化合物在体内有更好的差异毒性,有可能成为选择性抑制BTK,克服临床BTK靶向药物的毒副作用,或者作为经进一步修饰得到活性更佳和/或差异毒性更佳的化合物的基础。
目前,BTK激酶抑制剂上市药物依鲁替尼选择性较差,它的丙烯酰胺弹头,可以与BTK的半胱氨酸481形成共价键。但是除了BTK以,其他十种激酶BLK,BMX,EGFR,ERBB2,ERBB4,ITK,JAK3,TEC,MKK7和TXK也在他们的ATP结合位点附近存在可以与丙烯酰胺形成共价键的半胱氨酸,这就使得共价的BTK抑制剂如果选择性不高的话,可以潜在的共价抑制这些含有半胱氨酸的激酶以及非共价抑制其他结构相似的激酶,从而造成脱靶毒性。文献中报道,依鲁替尼脱靶于ITK,EGFR和SRC家族激酶会产生严重的腹泻,皮疹,出血和心房颤动等毒副作用,其中最常见的不良反应是腹泻和出血,约有一半的患者会发生腹泻和出血,其中有超过5%的患者会发生三级腹泻,6.6%的套细胞淋巴瘤患者会发生心房颤动,约有9%和12.3%的依鲁替尼患者会因为不可耐受的出血和心房颤动而中断用药。本发明为高选择性BTK抑制剂,对ITK、EGFR等具备高选择性、可降低脱靶带来的毒副作用。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.式I所示的化合物或其药学上可接受的盐:
式中,A为取代或未取代的苯环、取代或未取代的吡啶环、取代或未取代嘧啶环、取代或未取代的含1-3个选自N、O或S的杂原子的五元或六元杂环、取代或未取代的C3-C8烷基以及取代或未取代C3-C8环烷基;
R1各自独立选自:氢、卤素、取代或未取代的C1-C8烷氧基、取代或未取代的C1-C3烷基、取代或未取代的哌嗪基、取代或未取代的高哌嗪基、取代或未取代的吗啉基、取代或未取代的硫代吗啉基、取代或未取代的4-N-甲基哌嗪基、取代或未取代的氨基酰基、取代或未取代的4-N-乙酰基哌嗪基、取代或未取代的4-N,N-二甲基哌啶基、取代或未取代的哌啶基、-NRaRb,其中,Ra和Rb可独立选自氢或C1-C3烷基;
R2各自独立选自以下基团:
R3选自下组:氢、取代或未取代的C1-C10烷基、取代或未取代的C2-C6链烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的芳基(取代或未取代的苯基)、取代或未取代的苯氧基、取代或未取代的苄基、取代或未取代的含1-3个选自N、O或S的杂原子的C5-C10杂环基或芳杂环基;
B选自下组:
m为0-7的整数。
7.一种药物组合物,所述药物组合物含有权利要求1-6中任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的载体或赋形剂。
8.权利要求1-6中任一项所述的化合物在制备治疗或预防BTK介导的疾病,或抑制BTK的药物中的用途。
9.如权利要求8所述的用途,其特征在于,所述BTK介导的疾病为癌症或者自身免疫性疾病。
10.如权利要求9所述的用途,其特征在于,所述癌症选自下组:复发/难治性B细胞非霍奇金淋巴瘤、晚期复发性或难治性慢性淋巴细胞白血病、慢性淋巴细胞白血病(CLL)、小淋巴细胞淋巴瘤(SLL)、套细胞淋巴瘤(MCL)、外周T细胞淋巴瘤(PTCL)、弥漫性大B细胞淋巴瘤、边缘区淋巴瘤、B细胞性慢性淋巴细胞白血病、复发性淋巴细胞白血病、活化B细胞亚型弥漫性大B细胞淋巴瘤(ABC-DLBCL)、滤泡性淋巴瘤(FL)、华氏巨球蛋白血症、多发性硬化症、类风湿性关节炎、系统性红斑狼疮、银屑病、荨麻疹、哮喘、急性干燥综合症、骨髓瘤、天疱疮、免疫性血小板减少性紫癜、自身免疫疾病和血液瘤等。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111573921.3A CN116354964A (zh) | 2021-12-21 | 2021-12-21 | 作为btk抑制剂的7(8h)-喋啶酮衍生物及其应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111573921.3A CN116354964A (zh) | 2021-12-21 | 2021-12-21 | 作为btk抑制剂的7(8h)-喋啶酮衍生物及其应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116354964A true CN116354964A (zh) | 2023-06-30 |
Family
ID=86938942
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111573921.3A Pending CN116354964A (zh) | 2021-12-21 | 2021-12-21 | 作为btk抑制剂的7(8h)-喋啶酮衍生物及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116354964A (zh) |
-
2021
- 2021-12-21 CN CN202111573921.3A patent/CN116354964A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107922417B (zh) | 蝶啶酮衍生物作为egfr抑制剂的应用 | |
CN107428763B (zh) | 作为egfr抑制剂的嘧啶并嘧啶二酮衍生物及其应用 | |
US9670213B2 (en) | Pteridine ketone derivative and applications thereof as EGFR, BLK, and FLT3 inhibitor | |
CN109983016B (zh) | 嘧啶并[5,4-b]吲嗪或嘧啶并[5,4-b]吡呤化合物、其制备方法及用途 | |
CN108727382B (zh) | 作为btk抑制剂的杂环化合物及其应用 | |
CN107151249B (zh) | 作为flt3抑制剂的蝶啶酮衍生物及应用 | |
KR20190099209A (ko) | 8,9-디하이드로이미다졸[1,2-a]피리미도[5,4-e]피리미딘-5(6H)-케톤계 화합물 | |
KR20180083421A (ko) | 단백질 키나아제 억제제 및 이의 제조방법과 의학적 용도 | |
CN114656482A (zh) | 作为egfr抑制剂的大环杂环类化合物及其应用 | |
CN103421010A (zh) | 作为egfr抑制剂的蝶啶酮衍生物及其应用 | |
KR20190098266A (ko) | 치환된 축합 헤테로아릴기 화합물인 키나제 억제제 및 이의 응용 | |
WO2017144025A1 (zh) | 作为EGFR抑制剂的嘧啶并[4,5-d][1,3]噁嗪-2-酮衍生物及其应用 | |
JP2018135268A (ja) | 新規ヘテロアリールアミノ−3−ピラゾール誘導体およびその薬理学上許容される塩 | |
WO2017101862A1 (zh) | 作为egfr抑制剂的5,8-二氢蝶啶-6,7-二酮衍生物及其应用 | |
CN106467540B (zh) | 蝶啶酮衍生物作为flt3抑制剂的应用 | |
WO2023024545A1 (zh) | Fgfr4抑制剂、组合物及其在药物制备中的用途 | |
CN116354964A (zh) | 作为btk抑制剂的7(8h)-喋啶酮衍生物及其应用 | |
CN114853672A (zh) | 作为CDKs抑制剂的他克林衍生物及其应用 | |
KR20230026445A (ko) | 산화아릴인 화합물 및 이의 용도 | |
CN113801118A (zh) | 作为rsk抑制剂的蝶啶酮衍生物及其应用 | |
CN111072640A (zh) | 喹唑啉类衍生物及其制备方法和应用 | |
US20180244695A1 (en) | Quinoline derivative, and pharmaceutical composition, preparation method and use thereof | |
CN112209933B (zh) | 含有4-氮杂螺庚烷的btk抑制剂 | |
CN113493436B (zh) | 胺基取代吡啶衍生物及其制法和药物组合物与用途 | |
KR20220159457A (ko) | Fgfr4 억제제의 염 형태, 결정 형태 및 그 용도 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication |