CN115073468B - Preparation and application of imidazopyrazines BTK inhibitor - Google Patents
Preparation and application of imidazopyrazines BTK inhibitor Download PDFInfo
- Publication number
- CN115073468B CN115073468B CN202110277574.3A CN202110277574A CN115073468B CN 115073468 B CN115073468 B CN 115073468B CN 202110277574 A CN202110277574 A CN 202110277574A CN 115073468 B CN115073468 B CN 115073468B
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- preparation
- tyrosine kinase
- bruton
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 229940124291 BTK inhibitor Drugs 0.000 title claims description 6
- 150000005235 imidazopyrazines Chemical class 0.000 title description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 201000010099 disease Diseases 0.000 claims abstract description 20
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 claims abstract description 12
- 229940125814 BTK kinase inhibitor Drugs 0.000 claims abstract description 10
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims abstract description 9
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims abstract description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims abstract description 4
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 3
- 206010052779 Transplant rejections Diseases 0.000 claims abstract description 3
- 206010025135 lupus erythematosus Diseases 0.000 claims abstract description 3
- 210000000056 organ Anatomy 0.000 claims abstract description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 3
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 claims abstract 3
- 239000000203 mixture Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 2
- ZKAMEFMDQNTDFK-UHFFFAOYSA-N 1h-imidazo[4,5-b]pyrazine Chemical compound C1=CN=C2NC=NC2=N1 ZKAMEFMDQNTDFK-UHFFFAOYSA-N 0.000 claims 4
- 230000002265 prevention Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 63
- 238000000034 method Methods 0.000 abstract description 35
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 31
- 239000012453 solvate Substances 0.000 abstract description 10
- 206010009944 Colon cancer Diseases 0.000 abstract description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 abstract 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 abstract 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 abstract 1
- -1 spiroheterocyclyl Chemical group 0.000 description 95
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 36
- 239000007787 solid Substances 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- 125000000217 alkyl group Chemical group 0.000 description 22
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 125000000753 cycloalkyl group Chemical group 0.000 description 16
- 125000001072 heteroaryl group Chemical group 0.000 description 16
- 125000005842 heteroatom Chemical group 0.000 description 15
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 12
- 125000004093 cyano group Chemical group *C#N 0.000 description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 239000001301 oxygen Chemical group 0.000 description 11
- 229910052736 halogen Inorganic materials 0.000 description 10
- 150000002367 halogens Chemical class 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 229910052717 sulfur Chemical group 0.000 description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000011593 sulfur Chemical group 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 5
- 101000864342 Homo sapiens Tyrosine-protein kinase BTK Proteins 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 3
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001412 amines Chemical group 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229960001507 ibrutinib Drugs 0.000 description 3
- 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 3
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ZSBDGXGICLIJGD-UHFFFAOYSA-N 4-phenoxyphenol Chemical compound C1=CC(O)=CC=C1OC1=CC=CC=C1 ZSBDGXGICLIJGD-UHFFFAOYSA-N 0.000 description 2
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- MXZNUGFCDVAXLG-CHWSQXEVSA-N [(2S)-1-[(2R)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@@H](NC(=O)c1ccncc1)C(=O)N1CCC[C@@H]1B(O)O MXZNUGFCDVAXLG-CHWSQXEVSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 108020001756 ligand binding domains Proteins 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000000196 1,4-pentadienyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 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
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- LMGQTPMLPMDDOL-UHFFFAOYSA-N 2-chloro-4-phenoxybenzaldehyde Chemical compound C1=C(C=O)C(Cl)=CC(OC=2C=CC=CC=2)=C1 LMGQTPMLPMDDOL-UHFFFAOYSA-N 0.000 description 1
- OEHWUFIZHYKWIG-UHFFFAOYSA-N 2-chloro-4-phenoxyphenol Chemical compound C1=C(Cl)C(O)=CC=C1OC1=CC=CC=C1 OEHWUFIZHYKWIG-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- KDRNOBUWMVLVFH-UHFFFAOYSA-N 2-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)prop-2-enamide Chemical compound CC(=C)C(=O)NC1CC(C)(C)NC(C)(C)C1 KDRNOBUWMVLVFH-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CERUGSPISHDSHQ-UHFFFAOYSA-N 4-anilino-2-chlorobenzaldehyde Chemical compound C1=C(C=O)C(Cl)=CC(NC=2C=CC=CC=2)=C1 CERUGSPISHDSHQ-UHFFFAOYSA-N 0.000 description 1
- XXWHZIJHYNPASE-UHFFFAOYSA-N 4-anilinobenzaldehyde Chemical compound C1=CC(C=O)=CC=C1NC1=CC=CC=C1 XXWHZIJHYNPASE-UHFFFAOYSA-N 0.000 description 1
- JTTMYKSFKOOQLP-UHFFFAOYSA-N 4-hydroxydiphenylamine Chemical compound C1=CC(O)=CC=C1NC1=CC=CC=C1 JTTMYKSFKOOQLP-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- KRVLUHVEHIOJFK-UHFFFAOYSA-N BrC1=C(C(=O)OC)C=CC(=C1)OC1=CC=CC=C1 Chemical compound BrC1=C(C(=O)OC)C=CC(=C1)OC1=CC=CC=C1 KRVLUHVEHIOJFK-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 201000010717 Bruton-type agammaglobulinemia Diseases 0.000 description 1
- DKVQCTOEERBUPW-UHFFFAOYSA-N COC(=O)C1=C(C=C(C=C1)OC2=CC=CC=C2)F Chemical compound COC(=O)C1=C(C=C(C=C1)OC2=CC=CC=C2)F DKVQCTOEERBUPW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000740112 Homo sapiens Membrane-associated transporter protein Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102100037258 Membrane-associated transporter protein Human genes 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000016349 X-linked agammaglobulinemia Diseases 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005870 benzindolyl group Chemical group 0.000 description 1
- 125000000928 benzodioxinyl group Chemical group O1C(=COC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical group C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Chemical group 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 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
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 125000005507 decahydroisoquinolyl group Chemical group 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000000925 erythroid effect Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 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
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NFNHUSHZPUULHM-UHFFFAOYSA-N methyl 2-methyl-4-phenoxybenzoate Chemical compound C1=C(C)C(C(=O)OC)=CC=C1OC1=CC=CC=C1 NFNHUSHZPUULHM-UHFFFAOYSA-N 0.000 description 1
- VMJKRVJXYJHTCM-UHFFFAOYSA-N methyl 4-anilinobenzoate Chemical compound C1=CC(C(=O)OC)=CC=C1NC1=CC=CC=C1 VMJKRVJXYJHTCM-UHFFFAOYSA-N 0.000 description 1
- IVRIBXUIWOFCRP-UHFFFAOYSA-N methyl 4-phenoxy-2-(trifluoromethyl)benzoate Chemical compound C1=C(C(F)(F)F)C(C(=O)OC)=CC=C1OC1=CC=CC=C1 IVRIBXUIWOFCRP-UHFFFAOYSA-N 0.000 description 1
- XMXLYEKPSHVLKD-UHFFFAOYSA-N methyl 4-phenoxybenzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OC1=CC=CC=C1 XMXLYEKPSHVLKD-UHFFFAOYSA-N 0.000 description 1
- MTZVYWMZXMQCKF-UHFFFAOYSA-N methyl 4-pyridin-2-yloxybenzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OC1=CC=CC=N1 MTZVYWMZXMQCKF-UHFFFAOYSA-N 0.000 description 1
- NCGXAKPNWPIEJG-UHFFFAOYSA-N methyl 4-pyridin-3-yloxybenzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OC1=CC=CN=C1 NCGXAKPNWPIEJG-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([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
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 210000001948 pro-b lymphocyte Anatomy 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000003410 quininyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 102200162820 rs128620185 Human genes 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Abstract
The invention relates to a novel Bruton's tyrosine kinase inhibitor, which is a compound containing a polyaromatic heterocyclic structure, comprising a compound shown in a formula (I) or an isomer, a hydrate, a solvate, a polymorph and pharmaceutically acceptable salts thereof, and simultaneously discloses a preparation method of the compound and a method for using the novel compound to treat or prevent Bruton's tyrosine kinase related diseases such as Acute Lymphoblastic Leukemia (ALL), chronic granulocytic leukemia (CML), mantle Cell Lymphoma (MCL), colorectal cancer, rheumatoid arthritis, organ transplant rejection resistance, psoriasis resistance, lupus erythematosus and the like.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a novel Bruton's tyrosine kinase inhibitor, and a preparation method and application thereof.
Background
Bruton's tyrosine kinase is a member of the Tec family of non-receptor protein tyrosine kinases. The Tec family is the 2 nd largest family of human non-receptor kinases next to the Src family, the major members of which include Bruton's tyrosine kinase, BMX (etk), ITK, tec, and TXK (PLK). Bruton's tyrosine kinase was identified in 1993 as a defective protein in human X-linked agaropectinemia (X-linked agammaglobulinemia, XLA). This protein is expressed at various stages of B cell development (except for terminally differentiated plasma cells), and Bruton's tyrosine kinase is an essential gene for cell differentiation and proliferation during the transition from pre-B lymphocytes to post-B cells, and is expressed in B cell lymphomas, acute Lymphoblastic Leukemia (ALL) and plasmacytomas. In addition, there is also a small expression in bone marrow cells and erythroid progenitors.
Currently, small molecule inhibitors of Bruton's tyrosine kinase such as ibrutinib (ibrutinib, US751444B 2), acartinib (acalabruib, WO 2013010868), and zebutinib (zaubrutinib, WO 2014173289) are approved by the FDA in the united states for the treatment of Mantle Cell Lymphoma (MCL) and CLL.
Although ibrutinib, acartinib and zebutinib are therapeutically effective, a significant proportion of clinical B-cell lymphoma patients are not susceptible to their treatment, except for a proportion of patients who develop resistance later, such as approximately 1/3 of the patients in MCL do not respond to their treatment, nor do the response rates in DLBCL. In view of the above, there remains a need in the art to develop highly active, specific inhibitors of Bruton's tyrosine kinase.
Disclosure of Invention
In order to solve the problems, the invention provides a novel compound of Bruton's tyrosine kinase inhibitor shown in a formula (I) or a stereoisomer, a stable isotope derivative, a hydrate, a solvate and a pharmaceutically acceptable salt thereof:
x1 may be independently selected from N, CR 1 ;
Ar 1 And Ar is a group 2 Independently selected from benzene rings or 5-6 membered heteroaromatic rings, wherein said benzene rings and heteroaromatic rings are optionally substituted with one or more G 1 Substituted;
R 1 Independently selected from H, D, cyano, halogen, C 1-6 Alkyl, COOH, CONH2, NHCOH, CONHR2, OR 2 or-NHR 2 ;
R 2 Independently selected from H, D, cyano, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -OR 3 、-NR 3 R 4 、-C(O)NR 3 R 4 Wherein said alkyl, cycloalkyl OR heterocycloalkyl is optionally substituted with cyano, halogen, -OR 5 、-NR 5 R 6 、C 1-6 Alkyl group,C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;
L 1 and L 2 Independently selected from-C 1-4 Alkyl-, -CR 7 R 8 -、-C 1-2 Alkyl (R) 7 )(OH)-、-C(O)-、-CR 7 R 8 O-、-OCR 7 R 8 -、-SCR 7 R 8 -、-CR 7 R 8 S-、-NR 7 -、-NR 7 C(O)-、-C(O)NR 7 -、-NR 7 C(O)NR 8 -、-CF 2 -、-O-、-S-、-S(O) m -、-NR 7 S(O) 2 -、-S(O) 2 NR 7 -;
Y is absent or C is selected 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spiroheterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocycloalkyl, spiroheterocyclyl, fused ring, fused heterocyclyl, spiroheterocyclyl, aryl or heteroaryl is optionally substituted with one or more G 1 Substituted;
z is independently selected from cyano, -NR 12 CN、Bond a is a double bond or a triple bond;
when a is a double bond, R a 、R b And R is c Each independently selected from H, D, cyano, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl. Wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1 or more G 2 Substituted;
R a and R is b Or R is b And R is c Optionally together with the carbon atoms to which they are attached form a 3-6 membered ring optionally containing heteroatoms;
When bond a is a triple bond, R a And R is c Absent, R b Independently selected from H, D, cyano, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl groups substituted by one or more G 3 Substituted;
R 12 independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are optionally substituted with 1 or more G 4 Substituted;
G 1 、G 2 、G 3 and G 4 Each independently selected from D, cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 13 、-OC(O)NR 13 R 14 、-C(O)OR 13 、-C(O)NR 13 R 14 、-C(O)R 13 、-NR 13 R 14 、-NR 13 C(O)R 14 、-NR 13 C(O)NR 14 R 15 、-S(O) m R 13 or-NR 13 S(O) m R 14 Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1 or more cyano, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR 16 、-OC(O)NR 16 R 17 、-C(O)OR 16 、-C(O)NR 16 R 17 、-C(O)R 16 、-NR 16 R 17 、-NR 16 C(O)R 17 、-NR 16 C(O)NR 17 R 18 、-S(O) m R 16 or-NR 16 S(O) i R 17 Is substituted by a substituent of (2);
R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 13 、R 14 、R 15 、R 16 、R 17 and R is 18 Each independently selected from H, D, cyano, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl; and m is 1 or 2.
Typical compounds of the present invention include, but are not limited to, the following:
the invention provides a novel Bruton's tyrosine kinase inhibitor or an isomer, a hydrate, a solvate, a polymorph and a pharmaceutically acceptable salt thereof, and application of a pharmaceutically acceptable carrier in preparing the novel Bruton's tyrosine kinase inhibitor.
The pharmaceutical composition is in the form of a tablet, capsule, granule, spray or injection.
The pharmaceutically acceptable carrier is selected from one or more of filler, disintegrant, binder and lubricant. Including but not limited to any and all solvents, dispersion media, coatings, absorption retarders, and the like, such media and agents being used in the art for pharmaceutically active substances.
The invention also provides application of the novel Bruton's tyrosine kinase inhibitor or isomers, hydrates, solvates, polymorphs and pharmaceutically acceptable salts thereof as the Bruton's tyrosine kinase inhibitor.
Further, the protein tyrosine kinase inhibitor is a Bruton's tyrosine kinase inhibitor.
Use of a novel Bruton's tyrosine kinase inhibitor or an isomer, hydrate, solvate, polymorph, pharmaceutically acceptable salt or pharmaceutical composition thereof in the manufacture of a medicament for the treatment or prophylaxis of Bruton's tyrosine kinase associated disorders.
Further, the Bruton's tyrosine kinase related disease is selected from the group consisting of: acute Lymphoblastic Leukemia (ALL), chronic Myelogenous Leukemia (CML), mantle Cell Lymphoma (MCL), carcinoma of large intestine, rheumatoid arthritis, organ transplant rejection, psoriasis, lupus erythematosus, etc.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments. It should not be understood that the scope of the above subject matter of the present invention is only the following examples. All techniques based on the above are within the scope of the present invention.
Certain chemical terms
Unless stated to the contrary, the following terms used in the specification and claims.
The expression "C" as used herein has the following meaning x-y "means a range of carbon number wherein x and y are integers, e.g. C 3-8 Cycloalkyl means cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also to be understood that "C 3-8 "also includes any subrange therein, e.g. C 3-7 、C 3-6 、C 4-7 、C 4-6 、C 5-6 Etc.
"alkyl" refers to a straight or branched hydrocarbon group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.
"alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1, 4-pentadienyl and 1, 4-butadienyl. The alkenyl group may be substituted or unsubstituted.
"alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and typically from 2 to 20 carbon atoms, for example from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. The alkynyl group may be substituted or unsubstituted.
"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decalin, which cycloalkyl groups may be substituted or unsubstituted.
"heterocyclyl", "heterocycloalkyl", "heterocycle" refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spiro or bridged ring systems, a nitrogen, carbon or sulfur atom on a heterocyclyl group may be optionally oxidized, a nitrogen atom may be optionally quaternized, and a heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule by a single bond through a carbon atom or heteroatom in the ring. The heterocyclic group containing a condensed ring may contain one or more aromatic or heteroaromatic rings as long as the atom attached to the remainder of the molecule is a non-aromatic ring. For the purposes of this application, heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic monocyclic ring or bicyclic ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
"spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but the electronic system in which none of the rings has complete conjugation is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, with single spirocycloalkyl groups and double spirocycloalkyl groups being preferred. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro-cyclic group. Non-limiting examples of spiroheterocyclyl groups include:
"fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which hasCompletely conjugated pi-electron systems in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
"aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
"heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. Unless otherwise indicated, heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems, so long as the point of attachment to the rest of the molecule is an aromatic ring atom, the nitrogen, carbon, and sulfur atoms of the heteroaromatic ring may be selectively oxidized, and the nitrogen atom may be selectively quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 4-11 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxanyl, benzofuranonyl, benzofuranyl, benzonaphtofuranyl, benzopyronyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazole, furyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In this application, heteroaryl is preferably a 5-8 membered heteroaryl group comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridinyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.
"halogen" means fluorine, chlorine, bromine or iodine.
"hydroxy" means-OH, "amino" means-NH 2 "amido" means-NHCO-, -cyano "means-CN," nitro "means-CN," Isocyano "means-NC," trifluoromethyl "means-CF 3 。
The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to an atom other than carbon and hydrogen, the heteroatom being independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited to these atoms, in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different.
The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
"optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur, e.g., an "optionally alkyl-substituted heterocyclic group" means that alkyl may but need not be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.
"substituted" means that one or more atoms, preferably 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. It goes without saying that instead ofThe person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort, at their possible chemical positions. For example, a carbon atom having a free amine or hydroxyl group bonded to an unsaturated (e.g., olefinic) bond may be unstable. The substituents include, but are not limited to, hydroxy, amino, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl groups, and the like.
"pharmaceutical composition" refers to a composition comprising one or more of the compounds described herein or a pharmaceutically acceptable salt or prodrug thereof, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and further exert biological activity.
"isomer" refers to a compound having the same molecular formula but differing in the nature or sequence of their atoms bonded or the spatial arrangement of their atoms, and is referred to as an "isomer" and an isomer differing in the spatial arrangement of its atoms is referred to as a "stereoisomer". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers, and methods for preparing and separating optical isomers are known in the art.
The compounds of the invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configuration, and substituents around cycloalkyl or heterocycle are designated as cis or trans configuration.
The compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.
It is to be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming or chemical formulae of the compounds.
"isotopes" are all isotopes of atoms that are present in compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, each such as, but not limited to 2 H、 3 H、 13 C、 14 C、 15 N、 18 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in assaying biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
By "prodrug" is meant that the compounds of the invention may be administered in the form of a prodrug. Prodrugs refer to derivatives of the biologically active compounds of the present invention which are converted under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, etc. (each of which is performed with or without the aid of an enzyme). Examples of prodrugs are the following compounds: wherein the amine groups in the compounds of the invention are acylated, alkylated or phosphorylated, such as eicosanoylamino, propylamino, pivaloyloxymethylamino, or wherein the hydroxyl groups are acylated, alkylated, phosphorylated or converted to borates, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, propylaminooxy, or wherein the carboxyl groups are esterified or amidated, or wherein the sulfhydryl groups form disulfide bridges with carrier molecules, such as peptides, that selectively deliver the drug to the target and/or cytosol of the cell, these compounds may be prepared from the compounds of the invention according to well known methods.
"pharmaceutically acceptable salts" or "pharmaceutically acceptable" refer to those prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also encompasses their corresponding pharmaceutically acceptable salts. Thus, the compounds according to the invention containing acidic groups may be present in salt form and may be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium salts or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, etc., for example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, and particularly preferred organic bases are salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the invention containing basic groups may be present in salt form and may be used according to the invention in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, also internal salts or betaines. The individual salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.
Thus, references in the present application to "a compound", "a compound of the invention" or "a compound of the invention" include all such compound forms, e.g., prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, meso, racemates, enantiomers, diastereomers, and mixtures thereof.
Herein, the term "tumor" includes benign tumors and malignant tumors (e.g., cancers).
As used herein, the term "cancer" includes various malignant tumors that Bruton's tyrosine kinase participates in, including but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyodur, cellular cancer, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (e.g., hepatocellular cancer), more particularly liver cancer, gastric cancer and bladder cancer.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The term "polymorph" or "polymorphic form" as used herein means that a compound of the present invention has a plurality of crystalline forms, some compounds of the present invention may have more than one crystalline form, and the present invention encompasses all polymorphic forms or mixtures thereof.
Intermediate compounds of the invention and polymorphs thereof are also within the scope of the present invention.
Crystallization often yields solvates of the compounds of the present invention, and the term "solvate" as used herein refers to a complex composed of one or more molecules of the compounds of the present invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may simply accidentally retain water or a mixture of water with some other solvent, the compounds of the invention may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizer isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.
The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, including
(i) Preventing the occurrence of a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition;
(ii) Inhibiting the disease or disorder, i.e., controlling its progression;
(iii) Alleviating the disease or condition, i.e., slowing the regression of the disease or condition;
(iv) Relieving symptoms caused by diseases or symptoms.
The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.
The terms "administering," "administering," and the like as used herein refer to methods that enable delivery of a compound or composition to a desired site for biological action. Including, but not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
Synthesis method
The invention also provides a method for preparing the compound. The preparation of the compounds of formula I of the present invention may be accomplished by the following exemplary methods and examples, which should not be construed as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and methods described herein. The product obtained in each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis can be synthesized conventionally according to the literature (reaxys) or purchased.
The imidazopyrazine compound shown in the general formula I can be synthesized according to the following route:
the method comprises the following steps: 1. the initiator A1 is subjected to Friedel-crafts acylation reaction to obtain A2; 2. a2 generates aromatic nucleophilic substitution reaction under the action of ammonia gas to generate A3; 3. removing protection of amine groups in A3 to obtain A4; 4. the amine group in A4 is derivatized with a chemical reagent (e.g., allylic chloride, etc.) containing a functional group that is reactive with a cysteine residue within the kinase ligand binding domain to provide a compound of formula I.
The second method is as follows: 1. obtaining carbanion from the initiator B1 under the action of n-butyllithium, and then reacting with corresponding acyl chloride or ester to obtain A3; 2. removing protection of amine groups in A3 to obtain A4; 4. the amine group in A4 is derivatized with a chemical reagent (e.g., allylic chloride, etc.) containing a functional group that is reactive with a cysteine residue within the kinase ligand binding domain to provide a compound of formula I.
Unless otherwise indicated, temperatures are degrees celsius. Reagents were purchased from commercial suppliers such as chemlocks Inc, astatech Inc or michelin and these reagents were used directly without further purification unless otherwise indicated.
Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using dry tubes; glassware drying and/or heat drying.
Column chromatography purification uses 200-300 mesh silica gel from the Qingdao marine chemical plant unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.; MS was determined using a Thermo LCD jet type (ESI) liquid chromatograph-mass spectrometer.
Nuclear magnetic data [ ] 1 H NMR) using Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instrument, and CDCl is used as solvent for nuclear magnetic data 3 、CD 3 OD、D 2 O、DMSO-d 6 Etc., based on tetramethylsilane (0.000 ppm) or on residual solvent (CDCl) 3: 7.26ppm;CD 3 OD:3.31ppm;D 2 O4.79 ppm; d6-DMSO:2.50 ppm) when peak shape diversity is indicated, the following abbreviations indicate the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).
Example 1: preparation of (S) -1- (2- (8-amino-1- (4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 1)
Step 1: synthesis of Compound 1b
(S) -phenyl 2- (8-amino-1-bromoimidazole [1, 5-a) was reacted under nitrogen at-78deg.C]Pyrazin-3-yl) pyrrolidine-1-carboxylic acid ester 1a (4.16 g,10 mmol) was dissolved in dry THF (50 mL) and n-BuLi (2.0M in hexanes, 10.5mL,21 mmol) was added dropwise. After the completion of the dropwise addition, the reaction was continued for 1 hour, and methyl 4-phenoxybenzoate (2.40 g,10.5 mmol) was added at this temperature. The reaction was stirred at-78deg.C for 1 hour, quenched with saturated ammonium chloride solution, warmed to room temperature and extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure. The residue was purified by column chromatography to give compound 1b (1.87 g, yield 35%). LC/MS (ESI) m/z=534.2 [ M+H ] ] + .
Step 2: synthesis of Compound 1c
To the reaction flask was added compound 1b (1.60 g,3.0 mmol), 33% hydrobromic acid/acetic acid solution (15 mL). The reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with dichloromethane. The aqueous phase was neutralized with 2n naoh aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure to give compound 1c (0.78 g, yield 65%). LC/MS (ESI): m/z =400.2[M+H] + .
Step 3: synthesis of Compound 1
To the reaction flask was added compound 1c (400 mg,1.0 mmol), triethylamine (152 mg,1.5 mmol), 4mL of methylene chloride, and after cooling in an ice-water bath, a solution of acryloyl chloride (136 mg,1.5 mmol) in 0.5mL of methylene chloride was slowly added dropwise. After the addition was completed, stirring was continued for 2 hours, and the reaction solution was quenched with methanol and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 1 (204 mg, yield 45%) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.90(d,2H),7.78(d,1H),7.49(t,2H),7.27(t,1H),7.17(d,2H),7.12-7.10(m,3H),6.28(dd,1H),6.13(br s,2H),6.05(dd,1H),5.45-5.41(m,2H),3.79(t,2H),2.38-2.23(m,2H),2.16-2.08(m,1H),2.01-1.97(m,1H);LC/MS(ESI):m/z=454.2[M+H] + .
Example 2: preparation of (S) -1- (2- (8-amino-1- (4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 2)
Using a method similar to example 1 (intermediate changed to methyl 4-anilinobenzoate), compound 2 (176 mg, 39% yield, final step yield, the same below) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.83(d,2H),7.78(d,1H),7.43(t,2H),7.23(t,1H),7.13(d,2H),7.10-6.91(m,3H),6.27(dd,1H),6.13(br s,2H),6.05(dd,1H),5.45-5.41(m,2H),5.13(s,1H),3.79(t,2H),2.38-2.23(m,2H),2.17-2.09(m,1H),2.02-1.97(m,1H);LC/MS(ESI):m/z=453.2[M+H] + .
Example 3: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 3)
In a similar manner to example 1 (intermediate was changed to 2-chloro-4-benzeneMethyl oxybenzoate) gave compound 3 (165 mg, 34% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.67(d,1H),7.49-7.47(m,2H),7.27-7.24(m,1H),7.20-7.17(m,3H),7.11(d,1H),7.03-6.99(m,1H),6.29(dd,1H),6.11(br s,2H),6.05(dd,1H),5.44-5.39(m,2H),3.79(t,2H),2.38-2.23(m,2H),2.16-2.08(m,1H),2.01-1.96(m,1H);LC/MS(ESI):m/z=488.1[M+H] + .
Example 4: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (Compound 4)
Using a method similar to example 1 (intermediate changed to methyl 2-chloro-4-anilinobenzoate), compound 4 (199 mg, 41% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.43-7.41(m,2H),7.23-7.20(m,2H),7.15-7.10(m,4H),6.93-6.91(m,1H),6.28(dd,1H),6.12(br s,2H),6.05(dd,1H),5.44-5.39(m,2H),5.11(s,1H),3.81(t,2H),2.39-2.23(m,2H),2.16-2.08(m,1H),2.01-1.97(m,1H);LC/MS(ESI):m/z=487.2[M+H] + .
Example 5: preparation of (S) -1- (2- (8-amino-1- (4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 5)
Reaction of intermediate 1c and but-2-ynyl chloride in example 1 gave compound 5 (162 mg, 35% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.90(d,2H),7.78(d,1H),7.49(t,2H),7.27(t,1H),7.17(d,2H),7.12-7.10(m,3H),6.13(br s,2H),5.42(dd,1H),3.79(t,2H),2.38-2.24(m,2H),2.16-2.08(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=466.2[M+H] + .
Example 6: preparation of (S) -1- (2- (8-amino-1- (4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 6)
Reaction of intermediate 2c and but-2-ynyl chloride in example 2 gave compound 6 (176 mg, 38% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.83(d,2H),7.78(d,1H),7.43(t,2H),7.23(t,1H),7.13(d,2H),7.10-6.91(m,3H),6.13(br s,2H),5.39(dd,2H),5.13(s,1H),3.78(t,2H),2.39-2.23(m,2H),2.17-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=465.2[M+H] + .
Example 7: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 7)
Reaction of intermediate 3c and but-2-ynyl chloride in example 3 gave compound 7 (154 mg, 31% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.67(d,1H),7.49-7.47(m,2H),7.27-7.24(m,1H),7.20-7.17(m,3H),7.10(d,1H),7.03-6.99(m,1H),6.11(br s,2H),5.39(dd,1H),3.78(t,2H),2.38-2.25(m,2H),2.16-2.09(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=500.1[M+H] + .
Example 8: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 8)
Reaction of intermediate 4c and but-2-ynyl chloride in example 4 gave compound 8 (179 mg, 36% yield) as a yellow solid. 1 HNMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.43-7.41(m,2H),7.23-7.20(m,2H),7.15-7.10(m,4H),6.93-6.91(m,1H),6.12(br s,2H),5.40(dd,2H),5.09(s,1H),3.81(t,2H),2.39-2.25(m,2H),2.16-2.09(m,1H),2.01-1.97(m,4H);LC/MS(ESI):m/z=499.2[M+H] + .
Example 9: preparation of (S) -1- (2- (8-amino-1- (2-methyl-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 9)
Using a method similar to example 1 (intermediate changed to methyl 2-methyl-4-phenoxybenzoate and but-2-ynyl chloride), compound 9 (196 mg, 41% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.54(d,1H),7.44-7.38(m,2H),7.25-7.22(m,1H),7.19-7.12(m,3H),7.10(d,1H),7.03-6.99(m,1H),6.11(br s,2H),5.37-5.35(m,1H),3.78(t,2H),2.38-2.24(m,5H),2.16-2.09(m,1H),2.03-1.96(m,4H);LC/MS(ESI):m/z=480.2[M+H] + .
Example 10: preparation of (S) -1- (2- (8-amino-1- (2-methyl-4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 10)
Using a method similar to example 1 (intermediate changed to methyl 2-methyl-4-anilinobenzoate and but-2-ynyl chloride), compound 10 (162 mg, 34% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.38-7.31(m,2H),7.21-7.17(m,2H),7.12-7.05(m,4H),6.93-6.91(m,1H),6.09(br s,2H),5.37-5.35(m,1H),5.09(s,1H),3.81(t,2H),2.39-2.26(m,5H),2.15-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=479.2[M+H] + .
Example 11: preparation of (S) -1- (2- (8-amino-1- (2-fluoro-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 11)
Using a method similar to example 1 (intermediate changed to methyl 2-fluoro-4-phenoxybenzoate and but-2-ynyl chloride), compound 11 (183 mg, 38% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.83(d,1H),7.78(d,1H),7.42-7.36(m,2H),7.27-7.24(m,1H),7.20-7.15(m,3H),7.10(d,1H),7.03-6.99(m,1H),6.11(br s,2H),5.38(dd,1H),3.78(t,2H),2.38-2.24(m,2H),2.15-2.08(m,1H),2.02-1.95(m,4H);LC/MS(ESI):m/z=484.2[M+H] + .
Example 12: preparation of (S) -1- (2- (8-amino-1- (2-fluoro-4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 12)
Using a method similar to example 1 (intermediate changed to methyl 2-fluoro-4-anilinobenzoate and but-2-ynyl chloride), compound 12 (158 mg, 33% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.79(d,1H),7.49-7.42(m,2H),7.22-7.19(m,2H),7.13-7.07(m,4H),6.93-6.91(m,1H),6.12(br s,2H),5.40(dd,2H),5.13(s,1H),3.81(t,2H),2.39-2.25(m,2H),2.16-2.09(m,1H),2.01-1.97(m,4H);LC/MS(ESI):m/z=483.2[M+H] + .
Example 13: preparation of (S) -1- (2- (8-amino-1- (2-bromo-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 13)
Using a method similar to example 1 (intermediate changed to methyl 2-bromo-4-phenoxybenzoate and but-2-ynyl chloride), compound 13 (232 mg, 43% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.63(d,1H),7.44-7.40(m,2H),7.27-7.24(m,1H),7.20-7.15(m,3H),7.11(d,1H),7.02-6.98(m,1H),6.14(br s,2H),5.39-5.37(m,1H),3.78(t,2H),2.38-2.25(m,2H),2.16-2.09(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=544.1[M+H] + .
Example 14: preparation of (S) -1- (2- (8-amino-1- (2-bromo-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 14)
Using a method similar to example 1 (intermediate changed to methyl 2-bromo-4-anilinobenzoate and but-2-ynyl chloride), compound 14 (215 mg, 40% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.42-7.38(m,2H),7.25-7.19(m,2H),7.15-7.10(m,4H),6.93-6.91(m,1H),6.13(br s,2H),5.39-5.37(m,1H),5.12(s,1H),3.82(t,2H),2.38-2.24(m,2H),2.16-2.09(m,1H),2.01-1.97(m,4H);LC/MS(ESI):m/z=543.1[M+H] + .
Example 15: preparation of (S) -1- (2- (8-amino-1- (2-trifluoromethyl-4-phenoxybenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 15)
Using a method similar to example 1 (intermediate changed to methyl 2-trifluoromethyl-4-phenoxybenzoate and but-2-ynyl chloride), compound 15 (153 mg, 29% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.85-7.76(m,3H),7.42-7.38(m,2H),7.29-7.26(m,1H),7.19-7.15(m,2H),7.10(d,1H),7.03-6.99(m,1H),6.16(br s,2H),5.38(dd,1H),3.78(t,2H),2.38-2.24(m,2H),2.15-2.08(m,1H),2.02-1.95(m,4H);LC/MS(ESI):m/z=534.2[M+H] + .
Example 16: preparation of (S) -1- (2- (8-amino-1- (2-trifluoromethyl-4-anilinobenzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 16)
Using a method similar to example 1 (intermediate changed to methyl 2-trifluoromethyl-4-anilinobenzoate and but-2-ynyl chloride), compound 16 (167 mg, 32% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.79(d,1H),7.53-7.48(m,2H),7.24-7.20(m,2H),7.14-7.07(m,4H),6.93-6.90(m,1H),6.12(br s,2H),5.40(dd,2H),5.17(s,1H),3.81(t,2H),2.39-2.25(m,2H),2.17-2.11(m,1H),2.01-1.97(m,4H);LC/MS(ESI):m/z=533.2[M+H] + .
Example 17: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4- (pyridin-2-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 17)
Using a method similar to example 1 (intermediate changed to methyl 2-chloro-4- (pyridin-2-yloxy) benzoate and but-2-ynyl chloride), compound 17 (181 mg, 37% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:8.21(dd,1H),7.78(d,1H),7.65-7.63(m,1H),7.46-7.37(m,1H),7.27-7.24(m,1H),7.20-7.17(m,2H),7.10(d,1H),7.01-6.99(m,1H),6.12(br s,2H),5.39-5.37(m,1H),3.79(t,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=501.1[M+H] + .
Example 18: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4- (pyridin-3-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 18)
In a similar manner to example 1 (intermediate was changed to methyl 2-chloro-4- (pyridin-3-yloxy) benzoate and butyl2-alkynoyl chloride) gave compound 18 (166 mg, 34% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.79(d,1H),7.62-7.53(m,2H),7.46-7.31(m,3H),7.15-7.10(m,2H),7.00-6.97(m,1H),6.17(br s,2H),5.39-5.37(m,1H),3.79(t,2H),2.38-2.25(m,2H),2.14-2.09(m,1H),2.01-1.96(m,4H);LC/MS(ESI):m/z=501.1[M+H] + .
Example 19: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4- (pyridin-4-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 19)
Using a method similar to example 1 (intermediate changed to methyl 2-chloro-4- (pyridin-4-yloxy) benzoate and but-2-ynyl chloride), compound 19 (195 mg, 40% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:8.23(d,2H),7.78(d,1H),7.65-7.63(m,1H),7.45-7.38(m,1H),7.24-7.17(m,3H),7.11(d,1H),6.15(br s,2H),5.39-5.37(m,1H),3.81(t,2H),2.40-2.25(m,2H),2.16-2.11(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=501.1[M+H] + .
Example 20: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4- (pyrazin-2-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 20)
/>
Using a method similar to example 1 (intermediate changed to methyl 2-chloro-4- (pyrazin-2-yloxy) benzoate and but-2-ynyl chloride), compound 20 (151 mg, 31% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.91(s,1H),7.78(d,1H),7.65-7.63(m,1H),7.53-7.41(m,3H),7.33-7.29(m,1H),7.23-7.19(m,1H),7.10(d,1H),6.13(br s,2H),5.39-5.37(m,1H),3.79(t,2H),2.38-2.26(m,2H),2.16-2.10(m,1H),2.01-1.96(m,4H);LC/MS(ESI):m/z=502.1[M+H] + .
Example 21: preparation of (S) -1- (2- (8-amino-1- (4- (pyridin-2-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 21)
Using a method similar to example 1 (intermediate changed to methyl 4- (pyridin-2-yloxy) benzoate and but-2-ynyl chloride), compound 21 (128 mg, 34% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:8.21(dd,1H),7.78(d,1H),7.68-7.61(m,3H),7.46-7.39(m,1H),7.20-7.17(m,2H),7.11(d,1H),7.01-6.99(m,1H),6.12(br s,2H),5.41-5.38(m,1H),3.79(t,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=467.2[M+H] + .
Example 22: preparation of (S) -1- (2- (8-amino-1- (4- (pyridin-3-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 22)
Using a method similar to example 1 (intermediate changed to methyl 4- (pyridin-3-yloxy) benzoate and but-2-ynyl chloride), compound 22 (143 mg, 38% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.79(d,1H),7.63-7.52(m,2H),7.46-7.32(m,3H),7.17-7.10(m,3H),7.01-6.97(m,1H),6.15(br s,2H),5.39-5.37(m,1H),3.79(t,2H),2.38-2.25(m,2H),2.14-2.09(m,1H),2.01-1.96(m,4H);LC/MS(ESI):m/z=467.2[M+H] + .
Example 23: preparation of (S) -1- (2- (8-amino-1- (4- (pyridin-4-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 23)
Using a method similar to example 1 (intermediate changed to methyl 4- (pyridin-4-yloxy) benzoate and but-2-ynyl chloride), compound 23 (132 mg, 35% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:8.24(d,2H),7.78(d,1H),7.65-7.63(m,2H),7.45-7.38(m,2H),7.25-7.18(m,2H),7.11(d,1H),6.15(br s,2H),5.39-5.37(m,1H),3.81(t,2H),2.40-2.25(m,2H),2.16-2.11(m,1H),2.02-1.96(m,4H);LC/MS(ESI):m/z=467.2[M+H] + .
Example 24: preparation of (S) -1- (2- (8-amino-1- (4- (pyrazin-2-yloxy) benzoyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 24)
Using a method similar to example 1 (intermediate changed to methyl 4- (pyrazin-2-yloxy) benzoate and but-2-ynyl chloride), compound 24 (148 mg, 39% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.90(s,1H),7.78(d,1H),7.65-7.60(m,2H),7.53-7.41(m,3H),7.25-7.21(m,1H),7.10(d,1H),6.13(br s,2H),5.39-5.37(m,1H),3.79(t,2H),2.38-2.26(m,2H),2.16-2.10(m,1H),2.01-1.96(m,4H);LC/MS(ESI):m/z=468.2[M+H] + .
Example 25: preparation of (S) -1- (2- (8-amino-1- (4-phenoxybenzyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 25)
Step 1: synthesis of Compound 1d
Intermediate 1c (1.08 g,2.7 mmol), naBH, was added under nitrogen atmosphere 4 (0.5 g,13.2 mmol), anhydrous AlCl 3 (1 g,7.4 mmol) was dissolved in dry THF (25 mL), warmed to reflux and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure. Residue (C)The residue was purified by column chromatography to give compound 1d (0.90 g, yield 87%). LC/MS (ESI) m/z=386.2 [ M+H ]] + .
The subsequent step was conducted in a similar manner to example 1 (intermediate was changed to but-2-ynyl chloride) to give compound 25 (125 mg, yield 34%) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.29-7.24(m,4H),7.18-7.14(m,4H),7.10(d,1H),7.02-6.98(m,1H),6.09(br s,2H),5.41(dd,1H),3.80(t,2H),3.53(s,2H),2.38-2.24(m,2H),2.16-2.08(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=452.2[M+H] + .
Example 26: preparation of (S) -1- (2- (8-amino-1- (4-anilinobenzyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 26)
In a similar manner to example 25 (starting material was changed to (S) - (8-amino-3- (pyrrolidin-2-yl) imidazo [1, 5-a)]Pyrazin-1-yl) (4-anilinophenyl) methanone gives compound 26 (139 mg, 38% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.27-7.23(m,4H),7.16-7.10(m,5H),6.98-6.95(m,1H),6.12(br s,2H),5.41-5.39(m,1H),5.23(s,1H),3.81(t,2H),3.51(s,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=451.2[M+H] + .
Example 27: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-phenoxybenzyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 27)
In a similar manner to example 25 (starting material was changed to (S) - (8-amino-3- (pyrrolidin-2-yl) imidazo [1, 5-a)]Pyrazin-1-yl) (2-chloro-4-phenoxyphenyl) methanone gave compound 27 (134 mg, 34% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.54(d,1H),7.29-7.24(m,2H),7.21-7.15(m,4H),7.10(d,1H),7.02-6.98(m,1H),6.10(br s,2H),5.41(dd,1H),3.80(t,2H),3.55(s,2H),2.39-2.24(m,2H),2.16-2.08(m,1H),2.01-1.97(m,4H);LC/MS(ESI):m/z=486.2[M+H] + .
Example 28: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-anilinobenzyl) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 28)
In a similar manner to example 25 (starting material was changed to (S) - (8-amino-3- (pyrrolidin-2-yl) imidazo [1, 5-a)]Pyrazin-1-yl) (2-chloro-4-anilinophenyl) methanone gives compound 28 (160 mg, 41% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.56(d,1H),7.27-7.23(m,2H),7.18-7.13(m,4H),7.10(d,1H),6.99-6.97(m,1H),6.12(br s,2H),5.41-5.39(m,1H),5.22(s,1H),3.81(t,2H),3.55(s,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=485.2[M+H] + .
Example 29: preparation of (S) -1- (2- (8-amino-1- (4-phenoxyphenoxy) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 29)
Step 1: synthesis of Compound 1b
Raw material 1a (2.08 g,5.0 mmol), 4-phenoxyphenol (1.12 g,6.0 mmol), potassium carbonate (0.83 g,6.0 mmol) was dissolved in 15ml of N, N-dimethylformamide, and the temperature was raised to 100℃and the reaction was stirred overnight. Cooled to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 1b' (2.14 g, yield 82%) as a yellow solid. LC/MS (ESI) m/z=522.2 [ M+H ] ] + .
Subsequent steps were carried out in a similar manner to example 1 (intermediate exchangeAs but-2-ynyl chloride) gave compound 29 (140 mg, 38% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.31-7.22(m,4H),7.15-7.10(m,4H),6.99-6.97(m,2H),6.13(br s,2H),5.42(dd,1H),3.79(t,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=454.2[M+H] + .
Example 30: preparation of (S) -1- (2- (8-amino-1- (4-anilinophenoxy) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 30)
Using a method similar to example 29 (intermediate changed to 4-anilinophenol), compound 30 (154 mg, 42% yield) was obtained as a yellow solid. 1 HNMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.27-7.20(m,4H),7.12-7.01(m,4H),6.93-6.90(m,2H),6.13(br s,2H),5.42(dd,1H),5.31(s,1H),3.81(t,2H),2.39-2.26(m,2H),2.16-2.11(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=453.2[M+H] + .
Example 31: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-phenoxyphenoxy) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 31)
Using a method similar to example 29 (intermediate changed to 2-chloro-4-phenoxyphenol), compound 31 (135 mg, 34% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.43(d,1H),7.31-7.22(m,2H),7.15-7.10(m,4H),6.99-6.97(m,2H),6.12(br s,2H),5.42(dd,1H),3.79(t,2H),2.38-2.25(m,2H),2.16-2.10(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=488.1[M+H] + .
Example 32: preparation of (S) -1- (2- (8-amino-1- (2-chloro-4-anilinophenoxy) imidazo [1,5-a ] pyrazin-3-yl) pyrrolidin-1-yl) but-2-yn-1-one (Compound 32)
Using a method similar to example 29 ((intermediate changed to 2-chloro-4-anilinophenol) compound 32 (158 mg, 40% yield) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ:7.78(d,1H),7.53(d,1H),7.27-7.23(m,2H),7.15-7.08(m,5H),6.96-6.93(m,1H),6.12(br s,2H),5.41-5.39(m,1H),5.28(s,1H),3.81(t,2H),2.38-2.25(m,2H),2.16-2.11(m,1H),2.02-1.97(m,4H);LC/MS(ESI):m/z=485.2[M+H] + .
Example 33: inhibition test of in vitro Activity of kinases BTK, BTK (R28H)
1.1 screening for BTK inhibitory Activity
With kinase buffer (50 mM HEPES, 10mM MgCl) 2 2mM DTT, 1mM EGTA, 0.01% Tween 20) was diluted with 350ng/uL of BTK stock, 6. Mu.L of 1.67 X0.134 ng/. Mu.L of working solution (final concentration 0.08 ng/. Mu.L) was added to each well, 1-32 of the various DMSO-dissolved compounds were added to the wells with a nanoliter-type applicator to give final concentrations of 1000nM-0.244nM, 50nM-0.0122nM positive drug, a 4-fold gradient, 7 total concentrations, and blank wells (without enzyme) and negative control wells (with enzyme, with vehicle DMSO) were set, and 2 multiplex wells were set. After 30min of reaction of the enzyme with the compound or vehicle, 5X 250. Mu. MATP (final concentration of 50. Mu.M) prepared with kinase buffer was mixed with 5X 0.5. Mu.M substrate (final concentration of 0.1. Mu.M, ULIght-poly GT) at 1:1 and added to the wells at 4. Mu.L per well; after sealing the plate, the reaction was carried out at room temperature for 2 hours, and then 5. Mu.L of a 4X 8nM detection reagent (final concentration: 2nM, ab) was added to each well and incubated at room temperature for 1 hour; PE instrument read plate (excitation 620nm, emission 665 nm). Calculate the inhibition rate and calculate IC 50 Values. The results of the measurements are shown in the following Table
/>
/>
Claims (7)
1. An imidazopyrazine BTK inhibitor, characterized by being selected from any one of the following:
or a pharmaceutically acceptable salt thereof, and mixtures thereof.
2. A pharmaceutical composition comprising an imidazopyrazine BTK inhibitor according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, spray or injection.
4. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable carrier is selected from one or more of a filler, a disintegrant, a binder, and a lubricant.
5. Use of an imidazopyrazine BTK inhibitor or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a protein tyrosine kinase inhibitor, which is a Bruton's tyrosine kinase inhibitor.
6. Use of an imidazopyrazine BTK inhibitor according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any of claims 2 to 4 for the manufacture of a medicament for the treatment or prevention of Bruton's tyrosine kinase related diseases.
7. The use according to claim 6, characterized in that: the Bruton's tyrosine kinase related disease is selected from the group consisting of: acute Lymphoblastic Leukemia (ALL), chronic Myelogenous Leukemia (CML), mantle Cell Lymphoma (MCL), carcinoma of large intestine, rheumatoid arthritis, organ transplant rejection, psoriasis, and lupus erythematosus.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110277574.3A CN115073468B (en) | 2021-03-15 | 2021-03-15 | Preparation and application of imidazopyrazines BTK inhibitor |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110277574.3A CN115073468B (en) | 2021-03-15 | 2021-03-15 | Preparation and application of imidazopyrazines BTK inhibitor |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115073468A CN115073468A (en) | 2022-09-20 |
CN115073468B true CN115073468B (en) | 2023-12-22 |
Family
ID=83241787
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110277574.3A Active CN115073468B (en) | 2021-03-15 | 2021-03-15 | Preparation and application of imidazopyrazines BTK inhibitor |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115073468B (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016210165A1 (en) * | 2015-06-24 | 2016-12-29 | Principia Biopharma Inc. | Tyrosine kinase inhibitors |
CN107556317A (en) * | 2016-06-30 | 2018-01-09 | 杭州华东医药集团新药研究院有限公司 | A kind of Imidazopyridine amine phenyl derivatives and application thereof |
CN107759602A (en) * | 2016-08-17 | 2018-03-06 | 中国科学院上海药物研究所 | Compound, its pharmaceutical composition and purposes containing conjugation connection alkene structure |
CN110494433A (en) * | 2017-03-22 | 2019-11-22 | 廖细斌 | Bruton's tyrosine kinase inhibitor |
CN111471048A (en) * | 2020-04-30 | 2020-07-31 | 成都海博为药业有限公司 | Compound with nitrogen-containing bridged ring, spiro ring or fused ring structure and application thereof |
-
2021
- 2021-03-15 CN CN202110277574.3A patent/CN115073468B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016210165A1 (en) * | 2015-06-24 | 2016-12-29 | Principia Biopharma Inc. | Tyrosine kinase inhibitors |
CN107556317A (en) * | 2016-06-30 | 2018-01-09 | 杭州华东医药集团新药研究院有限公司 | A kind of Imidazopyridine amine phenyl derivatives and application thereof |
CN107759602A (en) * | 2016-08-17 | 2018-03-06 | 中国科学院上海药物研究所 | Compound, its pharmaceutical composition and purposes containing conjugation connection alkene structure |
CN110494433A (en) * | 2017-03-22 | 2019-11-22 | 廖细斌 | Bruton's tyrosine kinase inhibitor |
CN111471048A (en) * | 2020-04-30 | 2020-07-31 | 成都海博为药业有限公司 | Compound with nitrogen-containing bridged ring, spiro ring or fused ring structure and application thereof |
Non-Patent Citations (1)
Title |
---|
布鲁顿酪氨酸激酶靶向药物的研究进展;王姝,等;《中国现代应用药学》;第37卷(第4期);3063-3072 * |
Also Published As
Publication number | Publication date |
---|---|
CN115073468A (en) | 2022-09-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109715626B (en) | Heterocyclic compounds as FGFR inhibitors | |
CN113330009B (en) | Azacyclic compounds, preparation method and application thereof | |
CN115073469B (en) | Preparation and application of pyrrolopyrimidine compound as kinase inhibitor | |
TW202237604A (en) | Preparation and use of KRASG12C mutein inhibitor | |
CN115028633B (en) | Preparation and application of pyrrolopyrimidine compound | |
CN114853723B (en) | Preparation and application of indole compound BTK inhibitor | |
CN110229171B (en) | Oxazinoquinazoline and oxazinoquinoline compound and preparation method and application thereof | |
CN115073468B (en) | Preparation and application of imidazopyrazines BTK inhibitor | |
CN115181106B (en) | Quinazoline KRAS G12D Preparation and application of mutant protein inhibitor | |
CN114853752B (en) | Preparation and application of BTK inhibitor pyrido heterocyclic compound | |
CN112939982A (en) | Alkyne heterocyclic BTK inhibitor and preparation method and application thereof | |
CN114957241B (en) | Preparation and Application of Heterocyclic Compounds as Kinase Inhibitors | |
CN115043841B (en) | Preparation and application of heterocyclic compound serving as BTK inhibitor | |
CN110229172B (en) | Acyl-substituted oxazine quinazoline compound, preparation method and application thereof | |
CN114957242B (en) | Preparation and application of pyrido heterocyclic compounds as kinase inhibitors | |
CN112851587A (en) | Alkyne heterocyclic compound for treating cancer and preparation method and application thereof | |
CN115073451A (en) | KRAS G12D Preparation and application of mutant protein inhibitor | |
CN115028634B (en) | Acetylenic pyrazino heterocycle FGFR inhibitor and preparation method and application thereof | |
CN114853740B (en) | Preparation method and application of acetylenic pyrimidine compound as FGFR inhibitor | |
CN114853739B (en) | Acetylenic pyrazine FGFR inhibitor and preparation method and application thereof | |
CN114805359B (en) | Preparation method and application of acetylenic heterocyclic compound FGFR inhibitor | |
CN114057749B (en) | Preparation method and application of irreversible alkyne heterocyclic compound FGFR inhibitor | |
CN115368381B (en) | Preparation and application of heterocyclic inhibitor | |
CN115043832B (en) | FGFR inhibitor acetylenic heterocyclic compound and preparation method and application thereof | |
CN115141176B (en) | Acetylenic indole FGFR inhibitor and preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |