CN102459267B - 用作jak抑制剂的二氢吡咯并萘啶酮化合物 - Google Patents
用作jak抑制剂的二氢吡咯并萘啶酮化合物 Download PDFInfo
- Publication number
- CN102459267B CN102459267B CN201080032853.3A CN201080032853A CN102459267B CN 102459267 B CN102459267 B CN 102459267B CN 201080032853 A CN201080032853 A CN 201080032853A CN 102459267 B CN102459267 B CN 102459267B
- Authority
- CN
- China
- Prior art keywords
- oxo
- naphthyridines
- pyrrolo
- methyl
- pyrrolin
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 247
- 239000003112 inhibitor Substances 0.000 title description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 52
- 201000010099 disease Diseases 0.000 claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 68
- -1 piperidin-1-yl) propionitrile Chemical compound 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 61
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 42
- 150000001412 amines Chemical class 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 37
- 208000024891 symptom Diseases 0.000 claims description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 36
- 238000011282 treatment Methods 0.000 claims description 35
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 28
- PBIUUJCEMUAWJJ-UHFFFAOYSA-N azetidine-3-carbonitrile Chemical compound N#CC1CNC1 PBIUUJCEMUAWJJ-UHFFFAOYSA-N 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 150000001721 carbon Chemical group 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 150000001408 amides Chemical class 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 9
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N 1-Pyrroline Chemical compound C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 5
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 4
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 201000010105 allergic rhinitis Diseases 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 4
- 229960000485 methotrexate Drugs 0.000 claims description 4
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 206010043561 Thrombocytopenic purpura Diseases 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 201000009961 allergic asthma Diseases 0.000 claims description 3
- 230000003356 anti-rheumatic effect Effects 0.000 claims description 3
- 239000003435 antirheumatic agent Substances 0.000 claims description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 3
- 230000001900 immune effect Effects 0.000 claims description 3
- 239000004408 titanium dioxide Substances 0.000 claims description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titanium dioxide Inorganic materials O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
- 229950001902 dimevamide Drugs 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims 2
- PYRYOLOOOPVOHJ-UHFFFAOYSA-N cyclopentane formamide Chemical compound C(=O)N.C1CCCC1 PYRYOLOOOPVOHJ-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 47
- 201000009030 Carcinoma Diseases 0.000 abstract description 8
- 239000000463 material Substances 0.000 abstract description 8
- 208000002250 Hematologic Neoplasms Diseases 0.000 abstract description 7
- 206010061218 Inflammation Diseases 0.000 abstract description 6
- 230000004054 inflammatory process Effects 0.000 abstract description 6
- 229940122245 Janus kinase inhibitor Drugs 0.000 abstract description 4
- 208000035475 disorder Diseases 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 210000000987 immune system Anatomy 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 71
- 239000000243 solution Substances 0.000 description 64
- 239000011541 reaction mixture Substances 0.000 description 56
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- 239000007787 solid Substances 0.000 description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 239000002585 base Substances 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 238000002953 preparative HPLC Methods 0.000 description 32
- 238000003756 stirring Methods 0.000 description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 27
- 239000007821 HATU Substances 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 102000042838 JAK family Human genes 0.000 description 22
- 108091082332 JAK family Proteins 0.000 description 22
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 22
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000004108 freeze drying Methods 0.000 description 18
- 239000003921 oil Substances 0.000 description 17
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 15
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 10
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 9
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 9
- 239000012264 purified product Substances 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 8
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 108091000080 Phosphotransferase Proteins 0.000 description 7
- 239000003513 alkali Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 102000020233 phosphotransferase Human genes 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000002159 abnormal effect Effects 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 230000010261 cell growth Effects 0.000 description 6
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 6
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 6
- 238000013016 damping Methods 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229960004641 rituximab Drugs 0.000 description 6
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 102000000588 Interleukin-2 Human genes 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical group NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical class COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 230000000452 restraining effect Effects 0.000 description 5
- 125000006625 (C3-C8) cycloalkyloxy group Chemical group 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 108010008165 Etanercept Proteins 0.000 description 4
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 4
- 206010025323 Lymphomas Diseases 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 4
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960000403 etanercept Drugs 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- 230000036039 immunity Effects 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229960004622 raloxifene Drugs 0.000 description 4
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 0 C[C@@](*)(C(I)=C1*)N(*)C(*)(*)C=C(*)NC1=NCC(C)=* Chemical compound C[C@@](*)(C(I)=C1*)N(*)C(*)(*)C=C(*)NC1=NCC(C)=* 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 3
- 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 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- 102000004388 Interleukin-4 Human genes 0.000 description 3
- 108090000978 Interleukin-4 Proteins 0.000 description 3
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 description 3
- 206010039361 Sacroiliitis Diseases 0.000 description 3
- 102000013275 Somatomedins Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008512 biological response Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- WVYADZUPLLSGPU-UHFFFAOYSA-N carboxyphenyl salicylate Natural products OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 3
- 229960004630 chlorambucil Drugs 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- 229960003263 cyclopentamine Drugs 0.000 description 3
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 125000005842 heteroatom Chemical class 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 229940028885 interleukin-4 Drugs 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 239000003607 modifier Substances 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 229960000641 zorubicin Drugs 0.000 description 3
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 3
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 2
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 2
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 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 2
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 2
- RPMBPYXLPIWSFJ-UHFFFAOYSA-N 2-aminopentanenitrile Chemical compound CCCC(N)C#N RPMBPYXLPIWSFJ-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 2
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 2
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 2
- 102000003972 Fibroblast growth factor 7 Human genes 0.000 description 2
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 description 2
- 108010029961 Filgrastim Proteins 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 2
- 208000007465 Giant cell arteritis Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 2
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 108010068250 Herpes Simplex Virus Protein Vmw65 Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 2
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 208000016604 Lyme disease Diseases 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000001826 Marfan syndrome Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 102000015336 Nerve Growth Factor Human genes 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 241000009328 Perro Species 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 2
- 102000003923 Protein Kinase C Human genes 0.000 description 2
- 108090000315 Protein Kinase C Proteins 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 208000012322 Raynaud phenomenon Diseases 0.000 description 2
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 206010042971 T-cell lymphoma Diseases 0.000 description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 2
- 229960004176 aclarubicin Drugs 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 229960002964 adalimumab Drugs 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000008361 aminoacetonitriles Chemical class 0.000 description 2
- 229960002550 amrubicin Drugs 0.000 description 2
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 2
- 229960001220 amsacrine Drugs 0.000 description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 2
- 229960001671 azapropazone Drugs 0.000 description 2
- 229960002170 azathioprine Drugs 0.000 description 2
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 2
- 229950011276 belotecan Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 229960000997 bicalutamide Drugs 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229960003261 carmofur Drugs 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 201000010989 colorectal carcinoma Diseases 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 229960003290 cortisone acetate Drugs 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229960002448 dasatinib Drugs 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 229960003603 decitabine Drugs 0.000 description 2
- 201000001981 dermatomyositis Diseases 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 229950004203 droloxifene Drugs 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 102000015694 estrogen receptors Human genes 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 229960001419 fenoprofen Drugs 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 229940125753 fibrate Drugs 0.000 description 2
- 229960004177 filgrastim Drugs 0.000 description 2
- 229960002390 flurbiprofen Drugs 0.000 description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 2
- 229960002074 flutamide Drugs 0.000 description 2
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 229960002258 fulvestrant Drugs 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229940022353 herceptin Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 2
- 229960000240 hydrocodone Drugs 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 229940073062 imuran Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 229960000598 infliximab Drugs 0.000 description 2
- 229940117681 interleukin-12 Drugs 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- GXESHMAMLJKROZ-IAPPQJPRSA-N lasofoxifene Chemical compound C1([C@@H]2[C@@H](C3=CC=C(C=C3CC2)O)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 GXESHMAMLJKROZ-IAPPQJPRSA-N 0.000 description 2
- 229960002367 lasofoxifene Drugs 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229960003881 letrozole Drugs 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229960001786 megestrol Drugs 0.000 description 2
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 150000001457 metallic cations Chemical class 0.000 description 2
- YSNAXVDKFQCDET-UHFFFAOYSA-N methyl 3-formyl-1h-pyrrolo[2,3-b]pyridine-4-carboxylate Chemical class COC(=O)C1=CC=NC2=C1C(C=O)=CN2 YSNAXVDKFQCDET-UHFFFAOYSA-N 0.000 description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 229960004270 nabumetone Drugs 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 2
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 2
- 229960002653 nilutamide Drugs 0.000 description 2
- 150000002829 nitrogen Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-SVYQBANQSA-N oxolane-d8 Chemical compound [2H]C1([2H])OC([2H])([2H])C([2H])([2H])C1([2H])[2H] WYURNTSHIVDZCO-SVYQBANQSA-N 0.000 description 2
- 229960002085 oxycodone Drugs 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 2
- 229960002340 pentostatin Drugs 0.000 description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229960002895 phenylbutazone Drugs 0.000 description 2
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 2
- 229960001221 pirarubicin Drugs 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229960003171 plicamycin Drugs 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 229960004432 raltitrexed Drugs 0.000 description 2
- 229940116176 remicade Drugs 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 229940089617 risedronate Drugs 0.000 description 2
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 2
- 229950009213 rubitecan Drugs 0.000 description 2
- 229960000953 salsalate Drugs 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 201000008261 skin carcinoma Diseases 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229960001674 tegafur Drugs 0.000 description 2
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 2
- 206010043207 temporal arteritis Diseases 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- 229960005026 toremifene Drugs 0.000 description 2
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 2
- 229960005267 tositumomab Drugs 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 229960000653 valrubicin Drugs 0.000 description 2
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 2
- 229960004276 zoledronic acid Drugs 0.000 description 2
- KDIPIULDQHNSED-SNVBAGLBSA-N (2r)-2-[(3-methoxycarbonyl-1h-pyrrolo[2,3-b]pyridin-4-yl)methylamino]butanoic acid Chemical compound CC[C@H](C(O)=O)NCC1=CC=NC2=C1C(C(=O)OC)=CN2 KDIPIULDQHNSED-SNVBAGLBSA-N 0.000 description 1
- HHFUFGKACHWIAV-WHFBIAKZSA-N (2s,4s)-4-fluoropyrrolidine-2-carbonitrile Chemical compound F[C@@H]1CN[C@H](C#N)C1 HHFUFGKACHWIAV-WHFBIAKZSA-N 0.000 description 1
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 1
- NMWKYTGJWUAZPZ-WWHBDHEGSA-N (4S)-4-[[(4R,7S,10S,16S,19S,25S,28S,31R)-31-[[(2S)-2-[[(1R,6R,9S,12S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,53S,56S,59S,62S,65S,68S,71S,76S,79S,85S)-47-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-18-(4-aminobutyl)-27,68-bis(3-amino-3-oxopropyl)-36,71,76-tribenzyl-39-(3-carbamimidamidopropyl)-24-(2-carboxyethyl)-21,56-bis(carboxymethyl)-65,85-bis[(1R)-1-hydroxyethyl]-59-(hydroxymethyl)-62,79-bis(1H-imidazol-4-ylmethyl)-9-methyl-33-(2-methylpropyl)-8,11,17,20,23,26,29,32,35,38,41,48,54,57,60,63,66,69,72,74,77,80,83,86-tetracosaoxo-30-propan-2-yl-3,4,44,45-tetrathia-7,10,16,19,22,25,28,31,34,37,40,49,55,58,61,64,67,70,73,75,78,81,84,87-tetracosazatetracyclo[40.31.14.012,16.049,53]heptaoctacontane-6-carbonyl]amino]-3-methylbutanoyl]amino]-7-(3-carbamimidamidopropyl)-25-(hydroxymethyl)-19-[(4-hydroxyphenyl)methyl]-28-(1H-imidazol-4-ylmethyl)-10-methyl-6,9,12,15,18,21,24,27,30-nonaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29-nonazacyclodotriacontane-4-carbonyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](Cc4ccccc4)NC3=O)[C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3CCC[C@H]3C(=O)N[C@@H](C)C(=O)N2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)C(C)C)C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(=O)N[C@@H](C)C(O)=O NMWKYTGJWUAZPZ-WWHBDHEGSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- HMLGSIZOMSVISS-ONJSNURVSA-N (7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 1
- MPGQQQKGAXDBDN-UHFFFAOYSA-N 1,3-thiazolidin-3-ium;chloride Chemical compound Cl.C1CSCN1 MPGQQQKGAXDBDN-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- LXQMHOKEXZETKB-UHFFFAOYSA-N 1-amino-2-methylpropan-2-ol Chemical compound CC(C)(O)CN LXQMHOKEXZETKB-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- ZZAKLGGGMWORRT-UHFFFAOYSA-N 1-methylsulfonylpiperazine Chemical compound CS(=O)(=O)N1CCNCC1 ZZAKLGGGMWORRT-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 1
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- PVVRRUUMHFWFQV-UHFFFAOYSA-N 2-(methylamino)acetonitrile Chemical compound CNCC#N PVVRRUUMHFWFQV-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- BKMMTJMQCTUHRP-UHFFFAOYSA-N 2-aminopropan-1-ol Chemical class CC(N)CO BKMMTJMQCTUHRP-UHFFFAOYSA-N 0.000 description 1
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 description 1
- AMYYUKGKCJKCBI-UHFFFAOYSA-N 2-methylsulfonylethanamine;hydrochloride Chemical compound Cl.CS(=O)(=O)CCN AMYYUKGKCJKCBI-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- IIXYTWTZMGUQPT-UHFFFAOYSA-N 2-piperidin-4-ylpropan-2-ol Chemical compound CC(C)(O)C1CCNCC1 IIXYTWTZMGUQPT-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- CDBAEFXTCRKJPZ-UHFFFAOYSA-N 3,3-difluoroazetidine;hydron;chloride Chemical compound Cl.FC1(F)CNC1 CDBAEFXTCRKJPZ-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- PYSICVOJSJMFKP-UHFFFAOYSA-N 3,5-dibromo-2-chloropyridine Chemical compound ClC1=NC=C(Br)C=C1Br PYSICVOJSJMFKP-UHFFFAOYSA-N 0.000 description 1
- IMROEAZUSMCUNE-UHFFFAOYSA-N 3-(difluoromethyl)azetidine Chemical compound FC(F)C1CNC1 IMROEAZUSMCUNE-UHFFFAOYSA-N 0.000 description 1
- UNIJBMUBHBAUET-UHFFFAOYSA-N 3-(methylamino)propanenitrile Chemical compound CNCCC#N UNIJBMUBHBAUET-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- KJNZKVPPKUTMLB-UHFFFAOYSA-N 3-[[[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-3-yl]methylamino]methyl]-1h-pyrrolo[2,3-b]pyridine-4-carboxylic acid Chemical compound C1N(C(=O)OC(C)(C)C)CCC1CNCC1=CNC2=NC=CC(C(O)=O)=C12 KJNZKVPPKUTMLB-UHFFFAOYSA-N 0.000 description 1
- NJXPYZHXZZCTNI-UHFFFAOYSA-N 3-aminobenzonitrile Chemical compound NC1=CC=CC(C#N)=C1 NJXPYZHXZZCTNI-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- JEGMWWXJUXDNJN-UHFFFAOYSA-N 3-methylpiperidine Chemical compound CC1CCCNC1 JEGMWWXJUXDNJN-UHFFFAOYSA-N 0.000 description 1
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 description 1
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- MMRCWWRFYLZGAE-ZBZRSYSASA-N 533u947v6q Chemical compound O([C@]12[C@H](OC(C)=O)[C@]3(CC)C=CCN4CC[C@@]5([C@H]34)[C@H]1N(C)C1=C5C=C(C(=C1)OC)[C@]1(C(=O)OC)C3=C(C4=CC=CC=C4N3)CCN3C[C@H](C1)C[C@@](C3)(O)CC)C(=O)N(CCCl)C2=O MMRCWWRFYLZGAE-ZBZRSYSASA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 102100022987 Angiogenin Human genes 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 235000010894 Artemisia argyi Nutrition 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 102000003989 Aurora kinases Human genes 0.000 description 1
- 108090000433 Aurora kinases Proteins 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 241000219193 Brassicaceae Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- NWEQFUUVNJELIA-UHFFFAOYSA-N CC(C)(C)OC(N(CCCF)CCC#N)=O Chemical compound CC(C)(C)OC(N(CCCF)CCC#N)=O NWEQFUUVNJELIA-UHFFFAOYSA-N 0.000 description 1
- DHWUQVQFINIPMG-HXUWFJFHSA-N CC(C)(C)OC([n](cc1C(OC)=O)c2c1c(CN[C@H](C1CC1)C(NC1CCCC1)=O)ccn2)=O Chemical compound CC(C)(C)OC([n](cc1C(OC)=O)c2c1c(CN[C@H](C1CC1)C(NC1CCCC1)=O)ccn2)=O DHWUQVQFINIPMG-HXUWFJFHSA-N 0.000 description 1
- XMVHPTQCRNVUQL-UHFFFAOYSA-N CC(C)(C)OC([n](cc1C=O)c2c1c(C(OC)=O)ccn2)=O Chemical compound CC(C)(C)OC([n](cc1C=O)c2c1c(C(OC)=O)ccn2)=O XMVHPTQCRNVUQL-UHFFFAOYSA-N 0.000 description 1
- NKLWLAVMOZUNDB-MRXNPFEDSA-N CC(C)[C@H](C(NC1CCCC1)=O)NCc1ccnc2c1c(C(O)=O)c[nH]2 Chemical compound CC(C)[C@H](C(NC1CCCC1)=O)NCc1ccnc2c1c(C(O)=O)c[nH]2 NKLWLAVMOZUNDB-MRXNPFEDSA-N 0.000 description 1
- ARDIMIKQEUSKCU-OAHLLOKOSA-N CC(C)[C@H](C(NOCC1CC1)=O)N(Cc(c(c1c[nH]2)c2nc2)c2F)C1=O Chemical compound CC(C)[C@H](C(NOCC1CC1)=O)N(Cc(c(c1c[nH]2)c2nc2)c2F)C1=O ARDIMIKQEUSKCU-OAHLLOKOSA-N 0.000 description 1
- ISFUEODJWLKUJP-HXUWFJFHSA-N CCC(C)=C(CC1)CCN1C([C@@H](C(C)C)N(Cc(c(c1c[nH]2)c2nc2)c2Cl)C1=O)=O Chemical compound CCC(C)=C(CC1)CCN1C([C@@H](C(C)C)N(Cc(c(c1c[nH]2)c2nc2)c2Cl)C1=O)=O ISFUEODJWLKUJP-HXUWFJFHSA-N 0.000 description 1
- XGCYQRFUBXOWRS-JNEOBVTJSA-N CC[C@@H](C)[C@H](C(NC1C=CCC1)=O)NCc1ccnc2c1c(C(OC)=O)c[n]2C(OC(C)(C)C)=O Chemical compound CC[C@@H](C)[C@H](C(NC1C=CCC1)=O)NCc1ccnc2c1c(C(OC)=O)c[n]2C(OC(C)(C)C)=O XGCYQRFUBXOWRS-JNEOBVTJSA-N 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102100037182 Cation-independent mannose-6-phosphate receptor Human genes 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 1
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 1
- 206010008263 Cervical dysplasia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 208000013586 Complex regional pain syndrome type 1 Diseases 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 241000219104 Cucurbitaceae Species 0.000 description 1
- 244000050510 Cunninghamia lanceolata Species 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 229940123014 DNA polymerase inhibitor Drugs 0.000 description 1
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 229940117937 Dihydrofolate reductase inhibitor Drugs 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 208000002197 Ehlers-Danlos syndrome Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 208000007569 Giant Cell Tumors Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 101001028831 Homo sapiens Cation-independent mannose-6-phosphate receptor Proteins 0.000 description 1
- 101500025419 Homo sapiens Epidermal growth factor Proteins 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 208000005045 Interdigitating dendritic cell sarcoma Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 description 1
- 101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 102000003812 Interleukin-15 Human genes 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 102100030703 Interleukin-22 Human genes 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 102000000704 Interleukin-7 Human genes 0.000 description 1
- 108010002335 Interleukin-9 Proteins 0.000 description 1
- 102000000585 Interleukin-9 Human genes 0.000 description 1
- 208000009164 Islet Cell Adenoma Diseases 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- 108010024121 Janus Kinases Proteins 0.000 description 1
- 102000015617 Janus Kinases Human genes 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 208000012528 Juvenile dermatomyositis Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- MQHWFIOJQSCFNM-UHFFFAOYSA-L Magnesium salicylate Chemical compound [Mg+2].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O MQHWFIOJQSCFNM-UHFFFAOYSA-L 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 208000004221 Multiple Trauma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- NRGONRDRXCPMIC-GDKBPFBDSA-N N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CC(C=O)C(O)=O)C(O)=O)C=C1 Chemical compound N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CC(C=O)C(O)=O)C(O)=O)C=C1 NRGONRDRXCPMIC-GDKBPFBDSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 206010031243 Osteogenesis imperfecta Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- VONGZNXBKCOUHB-UHFFFAOYSA-N Phenylmethyl butanoate Chemical compound CCCC(=O)OCC1=CC=CC=C1 VONGZNXBKCOUHB-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000010103 Podophyllin Substances 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 201000001947 Reflex Sympathetic Dystrophy Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 101150001535 SRC gene Proteins 0.000 description 1
- 190014017285 Satraplatin Chemical compound 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Natural products O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 102000005497 Thymidylate Synthase Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102000000887 Transcription factor STAT Human genes 0.000 description 1
- 108050007918 Transcription factor STAT Proteins 0.000 description 1
- 102000006747 Transforming Growth Factor alpha Human genes 0.000 description 1
- 108010009583 Transforming Growth Factors Proteins 0.000 description 1
- 102000009618 Transforming Growth Factors Human genes 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
- 208000008385 Urogenital Neoplasms Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- CLDKAKLHMYILJA-UHFFFAOYSA-N [S].C1=NC=C2NC=NC2=N1 Chemical class [S].C1=NC=C2NC=NC2=N1 CLDKAKLHMYILJA-UHFFFAOYSA-N 0.000 description 1
- 229960003697 abatacept Drugs 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229930188522 aclacinomycin Natural products 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002487 adenosine deaminase inhibitor Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- UAMZETBJZRERCQ-UHFFFAOYSA-N alpha-aminopropionitrile Chemical compound CC(N)C#N UAMZETBJZRERCQ-UHFFFAOYSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 229960004238 anakinra Drugs 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 108010072788 angiogenin Proteins 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 244000030166 artemisia Species 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 description 1
- 229960005207 auranofin Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- AGSPXMVUFBBBMO-UHFFFAOYSA-N beta-aminopropionitrile Chemical compound NCCC#N AGSPXMVUFBBBMO-UHFFFAOYSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- SNHRLVCMMWUAJD-SUYDQAKGSA-N betamethasone valerate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O SNHRLVCMMWUAJD-SUYDQAKGSA-N 0.000 description 1
- 229960004311 betamethasone valerate Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 1
- LOGGAGJVXOASPM-UHFFFAOYSA-L calcium phosphono phosphate hydrate Chemical class O.[Ca+2].OP(O)(=O)OP([O-])([O-])=O LOGGAGJVXOASPM-UHFFFAOYSA-L 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229950005953 camsilate Drugs 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940047495 celebrex Drugs 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 201000010415 childhood type dermatomyositis Diseases 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229960002688 choline salicylate Drugs 0.000 description 1
- 208000002849 chondrocalcinosis Diseases 0.000 description 1
- 208000019069 chronic childhood arthritis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 208000013507 chronic prostatitis Diseases 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920003020 cross-linked polyethylene Polymers 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([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
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- HFXKQSZZZPGLKQ-UHFFFAOYSA-N cyclopentamine Chemical compound CNC(C)CC1CCCC1 HFXKQSZZZPGLKQ-UHFFFAOYSA-N 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
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- OFPUVEGIGZQSSD-UHFFFAOYSA-N diethyl-[2-oxo-2-(3-phenylmethoxyanilino)ethyl]azanium;chloride Chemical compound [Cl-].CC[NH+](CC)CC(=O)NC1=CC=CC(OCC=2C=CC=CC=2)=C1 OFPUVEGIGZQSSD-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 1
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- VXIHRIQNJCRFQX-UHFFFAOYSA-K disodium aurothiomalate Chemical compound [Na+].[Na+].[O-]C(=O)CC(S[Au])C([O-])=O VXIHRIQNJCRFQX-UHFFFAOYSA-K 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003237 epithelioid cell Anatomy 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 229940044170 formate Drugs 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 210000000609 ganglia Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 210000002768 hair cell Anatomy 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940116978 human epidermal growth factor Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- JXYZHMPRERWTPM-UHFFFAOYSA-N hydron;morpholine;chloride Chemical compound Cl.C1COCCN1 JXYZHMPRERWTPM-UHFFFAOYSA-N 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000002473 indoazoles Chemical class 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 108010074108 interleukin-21 Proteins 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 201000002529 islet cell tumor Diseases 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940054136 kineret Drugs 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 229960001320 lapatinib ditosylate Drugs 0.000 description 1
- 229950005692 larotaxel Drugs 0.000 description 1
- SEFGUGYLLVNFIJ-QDRLFVHASA-N larotaxel dihydrate Chemical compound O.O.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@@]23[C@H]1[C@@]1(CO[C@@H]1C[C@@H]2C3)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 SEFGUGYLLVNFIJ-QDRLFVHASA-N 0.000 description 1
- 201000005264 laryngeal carcinoma Diseases 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 201000004962 larynx cancer Diseases 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- YDTFRJLNMPSCFM-YDALLXLXSA-M levothyroxine sodium anhydrous Chemical compound [Na+].IC1=CC(C[C@H](N)C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 YDTFRJLNMPSCFM-YDALLXLXSA-M 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- ZDGGJQMSELMHLK-UHFFFAOYSA-N m-Trifluoromethylhippuric acid Chemical compound OC(=O)CNC(=O)C1=CC=CC(C(F)(F)F)=C1 ZDGGJQMSELMHLK-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940072082 magnesium salicylate Drugs 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- XOGBBTNEIKWLPQ-UHFFFAOYSA-N methyl 1h-pyrrolo[2,3-b]pyridine-4-carboxylate Chemical class COC(=O)C1=CC=NC2=C1C=CN2 XOGBBTNEIKWLPQ-UHFFFAOYSA-N 0.000 description 1
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 1
- 150000005451 methyl sulfates Chemical class 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229950000081 metilsulfate Drugs 0.000 description 1
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 229960005249 misoprostol Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229950007856 mofetil Drugs 0.000 description 1
- 238000009126 molecular therapy Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- AVAWMINJNRAQFS-UHFFFAOYSA-N n,n-dimethylpyrrolidin-3-amine Chemical compound CN(C)C1CCNC1 AVAWMINJNRAQFS-UHFFFAOYSA-N 0.000 description 1
- AZBFJBJXUQUQLF-UHFFFAOYSA-N n-(1,5-dimethylpyrrolidin-3-yl)pyrrolidine-1-carboxamide Chemical compound C1N(C)C(C)CC1NC(=O)N1CCCC1 AZBFJBJXUQUQLF-UHFFFAOYSA-N 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000005486 naphthalic acid group Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-M naproxen(1-) Chemical compound C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-M 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 229950004864 olamine Drugs 0.000 description 1
- 229940035567 orencia Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-M orotate Chemical compound [O-]C(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-M 0.000 description 1
- BWKDAMBGCPRVPI-ZQRPHVBESA-N ortataxel Chemical compound O([C@@H]1[C@]23OC(=O)O[C@H]2[C@@H](C(=C([C@@H](OC(C)=O)C(=O)[C@]2(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]21)OC(C)=O)C3(C)C)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC(C)C)C(=O)C1=CC=CC=C1 BWKDAMBGCPRVPI-ZQRPHVBESA-N 0.000 description 1
- 229950001094 ortataxel Drugs 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 208000022102 pancreatic neuroendocrine neoplasm Diseases 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229960004403 pixantrone Drugs 0.000 description 1
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 description 1
- GDFYVGREOHNWMM-UHFFFAOYSA-N platinum(4+);tetranitrate Chemical class [Pt+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O GDFYVGREOHNWMM-UHFFFAOYSA-N 0.000 description 1
- 229940068582 podophyllin Drugs 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 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
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000008718 systemic inflammatory response Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- AKQXKEBCONUWCL-UHFFFAOYSA-N tert-butyl 3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(N)C1 AKQXKEBCONUWCL-UHFFFAOYSA-N 0.000 description 1
- GJKGQHBSAKUVNM-UHFFFAOYSA-N tert-butyl 4-amino-4-ethylpiperidine-1-carboxylate Chemical compound CCC1(N)CCN(C(=O)OC(C)(C)C)CC1 GJKGQHBSAKUVNM-UHFFFAOYSA-N 0.000 description 1
- DMBKWEHXTOCLTC-UHFFFAOYSA-N tert-butyl 4-amino-4-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C)(N)CC1 DMBKWEHXTOCLTC-UHFFFAOYSA-N 0.000 description 1
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- MODVSQKJJIBWPZ-VLLPJHQWSA-N tesetaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3CC[C@@]2(C)[C@H]2[C@@H](C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C(=CC=CN=4)F)C[C@]1(O)C3(C)C)O[C@H](O2)CN(C)C)C(=O)C1=CC=CC=C1 MODVSQKJJIBWPZ-VLLPJHQWSA-N 0.000 description 1
- 229950009016 tesetaxel Drugs 0.000 description 1
- 150000003527 tetrahydropyrans Chemical class 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
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 190014017283 triplatin tetranitrate Chemical compound 0.000 description 1
- 229950002860 triplatin tetranitrate Drugs 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 208000037964 urogenital cancer Diseases 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000006200 vaporizer Substances 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229950005839 vinzolidine Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
- 229940055725 xarelto Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/16—Peri-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Otolaryngology (AREA)
- Biomedical Technology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开式(I)的JAK抑制剂,其中G1、R1、R2、R3、R4、R5、R6和R7如说明书中定义。本发明还公开了含有所述化合物的药物组合物、试剂盒和制品、制备所述化合物的方法和材料,以及使用所述化合物治疗涉及免疫系统和炎症(包括类风湿性关节炎、血液恶性肿瘤、上皮癌(即恶性上皮肿瘤))的疾病、病症或症状以及其它与JAK相关的疾病、病症或症状的方法。
Description
发明领域
本发明涉及药物化学以及制药科学。本文提供可抑制詹纳斯氏激酶(Janus kinase,JAK)的化合物。
发明背景
纳斯氏激酶(JAK)为细胞质蛋白酪氨酸激酶的一族,包括JAK1、JAK2、JAK3和TYK2。每一种JAK激酶对于某些细胞因子受体是具有选择性的,尽管多种JAK激酶可能受特定细胞因子或信号途径的影响,包括对于IL-2、IL-4、IL-7、IL-9、IL-15以及IL-21的途径。
磷酸化的JAK激酶和许多信号传导子和转录激活子(SignalTransducer and Activator of Transcription,STAT)蛋白质结合。STAT蛋白质为受酪氨酸残基磷酸化作用而活化的DNA结合蛋白,并且起着信号分子和转录因子两者的功能,以及和细胞因子反应基因启动子的特定DNA序列结合。
细胞因子影响细胞分化、增殖以及活化。细胞因子调节炎症反应和免疫反应两者。
在如过敏症、哮喘、自身免疫疾病(如移植排斥、类风湿性关节炎、肌萎缩性侧索硬化症和多发性硬化)以及在实体和血液恶性肿瘤(如白血病和淋巴瘤)的症状中可观察到异常的JAK/STAT信号传送。JAK途径的抑制剂(特别是JAK3)被认为对于治疗此类症状是有治疗作用的。
在WO2007/077949以及WO2008/084861中公开了某些JAK抑制剂。
发明概述
本发明提供式I化合物,
或其药学上可接受的盐类,其中:
G1选自由N和CR8所组成的组;
R1选自由任选取代的C3-8环烷基、任选取代的C3-6杂环烷基、任选取代的C4-14芳基、任选取代的C1-10杂芳基以及任选取代的C1-6烷基组成的组;
R2和R3各自独立地选自由氢和任选取代的C1-4烷基组成的组,或者R2、R3和它们所连接的碳原子形成羰基;
R4选自由氢、任选取代的C1-4烷基、任选取代的C1-4烷氧基、卤基、羟基和氨基所组成的组;
R5选自由氢、任选取代的C1-4烷基、C3-8环烷基和卤基组成的组;
R6和R7各自独立地选自由氢和任选取代的C1-4烷基组成的组,或者R6、R7以及它们所连接的碳原子形成羰基;
R8选自由氢、任选取代的C1-6烷基、任选取代的C1-4烷氧基、C1-9酰胺、C1-5氧代羰基、氰基、任选取代的C3-8环烷基、任选取代的C4-14芳基、任选取代的C1-10杂芳基以及卤基所组成的组;以及
附带条件为不多于一个羰基是由R2、R3、R6和R7形成。
本发明的一方面提供药物组合物,其包括如上定义的式I化合物或药学上可接受的盐,以及药学上可接受的赋形剂。
本发明的另一个方面提供如上定义的式I化合物或药学上可接受的盐类作为药剂的用途。
本发明的另一个方面提供如上定义的式I化合物或药学上可接受的盐用于制备用于治疗与JAK相关的疾病、病症或症状的药剂的用途。
本发明另一个方面提供治疗受试者中与JAK相关的疾病、病症或症状的方法,该方法包括对受试者施用有效量的如上定义的式I化合物或药学上可接受的盐。
本发明的另一个方面提供治疗受试者中的疾病或症状的方法,该方法包括对受试者施用有效量的如上定义的式I化合物或药学上可接受的盐,其中所述疾病或症状选自过敏性鼻炎、过敏性哮喘、特应性皮炎、类风湿性关节炎、多发性硬化、系统性红斑性狼疮、牛皮癣、免疫性血小板减少性紫癜、慢性阻塞性肺疾病以及血栓形成。
本发明的另一个方面提供治疗受试者中的疾病或症状的方法,该方法包含对受试者施用有效量的如上定义的式I化合物或药学上可接受的盐,其中所述疾病或症状选自血液恶性肿瘤以及上皮癌。
本发明的另一个方面提供有效量的如上定义的式I化合物或药学上可接受的盐以及至少一种另外的药理学活性剂的结合物。
本发明还提供制品,其包括至少一种式I化合物和标签。本发明还提供试剂盒,其包括至少一种式I化合物、标签以及用于施用抑制剂的装置。
本发明还提供制备JAK抑制剂及其中间体的方法。
本发明的化合物包括该化合物的所有药学上可接受的复合物、盐类、溶剂化物以及水合物。本发明的化合物还包括该化合物的所有立体异构体、互变异构体以及多晶型物,包括所有晶形和非晶形,无论它们是否为纯的、大体上纯的或混合物。
发明详述
除非另有说明,本公开内容使用如下文提供的定义。
当用在与化学取代基或基元(例如烷基)有关时,术语“取代的(substituted)”是指取代基或基元上的一个或多个氢原子被一个或多个非氢原子或基团所取代,条件是要符合配价要求并且取代成化学上稳定的化合物。
当用在与可测量的数值变量有关时,术语“大约(about)”或“大约(approximately)”是指变量所指的数值以及落于所指数值的实验性误差内(例如在平均值的95%置信区间)或在所指数值的±百分之10之内的变量的所有数值,无论何者较高。
术语“C2-4烯基”是指具有自二至四个碳原子以及一个或多个碳-碳双键的直链或分枝的烯基链,且包括乙烯、丙烯、异丙烯、丁烯、异丁烯、仲丁烯等。
术语“C1-4烷基”是指具有自一至四个碳原子的直链或分枝的烷基链。
术语“任选取代的C1-4烷基”是指任选具有自1至5个取代基的C1-4烷基,该取代基独立地选自由氨基、C1-7酰氨基、C1-8烷基氨基、C2-4烯基、C1-4烷氧基、C1-4硫代烷氧基、C1-9酰胺、C1-5氧代羰基、氰基、C3-8环烷基、C3-8环烷氧基、卤基、羟基、氧代、C1-8磺酰基、任选取代的C1-10杂芳基、任选取代的C3-6杂环烷基、任选取代的C1-10杂芳基以及任选取代的苯基组成的组。
术语“C1-6烷基”是指具有自一至六个碳原子的直链或分枝的烷基链。
术语“任选取代的C1-6烷基”是指任选具有自1至7个取代基的C1-6烷基,该取代基独立地选自由氨基、C1-7酰氨基、C1-8烷基氨基、C2-4烯基、C1-4烷氧基、C1-4硫代烷氧基、C1-14酰胺、C1-5氧代羰基、氰基、C3-8环烷基、C3-8环烷氧基、卤基、羟基、氧代、C1-8磺酰基、任选取代的C1-10杂芳基、任选取代的C3-6杂环烷基、任选取代的C1-10杂芳基以及任选取代的苯基组成的组。
术语“C1-8磺酰基”是指连接至C1-6烷基、C3-8环烷基或任选取代的苯基的磺酰基。
术语“C1-4烷氧基”是指通过氧原子连接的C1-4烷基。
术语“任选取代的C1-4烷氧基”是指任选具有自1至6个取代基的C1-4烷氧基,该取代基独立地选自由C2-4烯基、C1-4烷氧基、C1-9酰胺、C1-5氧代羰基、氰基、C3-8环烷基、卤基、羟基、任选取代的C1-10杂芳基以及任选取代的苯基组成的组。
术语“C1-9酰胺”是指具有两个基团的酰胺,该基团独立地选自由氢和C1-4烷基组成的组,例如,-CONH2、-CONHCH3和-CON(CH3)2。
术语“C1-14酰胺”是指(a)具有两个连接至氮原子的基团的酰胺,该基团独立地选自氢和任选取代的C1-4烷基,例如-CONH2、-CONHCH3和-CON(CH3)2;或(b)在氮原子上具有一个氢和一个非氢取代基的酰胺,其中非氢取代基选自任选取代的C1-4烷基、任选取代的C1-4烷氧基、任选取代的C3-8环烷基、任选取代的C3-6杂环烷基、任选取代的C4-14芳基以及任选取代的C1-10杂芳基,例如,-CONH-(环戊基)、-CONH-(芳基)、-CONH-CH2-(苯基)等。
术语“C1-7酰氨基”是指-NHC(O)R基团,其中R为C1-6烷基。
术语“C1-5氨甲酰基”是指具有末端C1-4烷基的O-或N-连接的氨基甲酸酯。
术语“C1-5脲基”是指具有C1-4烷基的尿素。
术语“C1-8烷基氨基”是指具有一或二个C1-4烷基的氨基。
术语“C4-14芳基”是指具有芳族性以及具有四至十四个碳原子的单环或多环的未饱和、共轭烃,并且包括苯基、联苯、茚基、环戊二烯基、芴基以及萘基。
术语“任选取代的C4-14芳基”是指任选具有1至5个取代基的C4-14芳基,该取代基独立地选自由氨基、C1-8烷基氨基、C1-7酰氨基、C1-5氨甲酰基、C1-6磺酰胺基、C0-6磺酰氨基、C1-5脲基、任选取代的Cl-4烷基、任选取代的C1-4烷氧基、氰基、卤素、羟基、硝基、C1-5氧代羰基以及C1-8磺酰基组成的组。
术语“C1-5氧代羰基”是指氧代羰基(-CO2H)以及其C1-4烷基酯。
术语“C3-8环烷基”是指具有自3至8个碳原子的烷基环,且包括环丙基、2-甲基环丙基、环丁基、环戊基、环己基等。
术语“任选取代的C3-8环烷基”是指任选具有1至6个取代基的C3-8环烷基,该取代基独立地选自由任选取代的C1-4烷基、C2-4烯基、C1-4烷氧基、C1-9酰胺、C1-7酰氨基、C1-8烷基氨基、C1-5氧代羰基、氰基、C3-8环烷基、C3-8环烷氧基、卤代、羟基、硝基、氧代、任选取代的C1-10杂芳基以及任选取代的苯基组成的组。
术语“C3-8环烷氧基”是指通过氧原子连接的C3-8环烷基。
术语“卤素(halogen)”和“卤代(halo)”是指氯代、氟代、溴代或碘代。
术语“C3-6杂环烷基”是指具有一至四个杂原子的4至10元饱和的单环或部分(但非完全)未饱和的环,该杂原子选自由氮、氧和硫组成的组。该氮和硫杂原子可任选被氧化。举例来说,该术语包括氮杂环丁烷、吡咯烷、哌啶、哌嗪、吗啉、四氢吡喃、四氢呋喃、六氢嘧啶、四氢嘧啶、二氢咪唑等。
术语“任选取代的C3-6杂环烷基”是指在环碳原子上任选被1至4个取代基取代的C3-6杂环烷基,该取代基独立地选自由任选取代的C1-4烷基、C2-4烯基、C1-4烷氧基、C1-9酰胺、C1-7酰氨基、C1-8烷基氨基、C1-5氧代羰基、氰基、C3-8环烷基、C3-8环烷氧基、卤代、羟基、硝基、氧代和任选取代的苯基组成的组;以及在任一环上的氮原子任选被取代基取代,该取代基独立地选自由任选取代的C1-4烷基、C2-4烯基、C3-8环烷基、任选取代的C3-6杂环烷基、任选取代的C1-10杂芳基、任选取代的苯基以及C1-8磺酰基组成的组。
术语“C1-10杂芳基”是指五至十二元单环或多环,其具有未饱和的、共轭的环,该环具有芳族性以及具有一至十个碳原子和一个或多个(典型地为1至4个)杂原子,该杂原子选自由氮、氧和硫组成的组。该氮以及硫杂原子可任选被氧化。举例来说,该术语包括氮杂、二氮杂、呋喃、噻吩、咪唑、异噻唑、异噁唑、噁二唑、噁唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶、噻唑、噻二唑、三唑、四唑、苯并氮杂、苯并二氮杂、苯并呋喃、苯并噻吩、苯并咪唑、咪唑并吡啶、吡唑并吡啶、吡咯并吡啶、喹唑啉、噻吩并吡啶、吲哚嗪、咪唑并吡啶、喹啉、异喹啉、吲哚、异吲哚、苯并噁唑、苯并噁二唑、苯并吡唑、苯并噻唑等。
术语“任选取代的C1-10杂芳基”是指在碳上任选具有1至5个取代基的C1-10杂芳基,该取代基独立地选自由氨基、C1-7酰氨基、C1-8烷基氨基、C1-5氨甲酰基、C1-6磺酰胺基、C0-6磺酰氨基、C1-5脲基、任选取代的Cl-4烷基、任选取代的C1-4烷氧基、氰基、卤素、羟基、氧代、硝基、C1-5氧代羰基和C1-8磺酰基组成的组,并且在每一氮上任选具有取代基,该取代基独立地选自由任选取代的Cl-4烷基、C1-8磺酰基、任选取代的C3-6杂环烷基和任选取代的苯基组成的组。
术语“氧代”是指对所连接的碳具有双键以生成酮、醛或酰胺的羰基的氧原子。已了解氧代可连接至具有氧代取代基的基团上任何可行的位置。举例来说,乙酰基自由基(-C(O)CH3)被设想为被氧代取代的烷基,且吡啶酮自由基设想为被氧代取代的C1-10杂芳基。
术语“任选取代的苯基”是指任选具有1至5个取代基的苯基,该取代基独立地选自由氨基、C2-4烯基、Cl-4烷基、C1-4烷氧基、C1-9酰胺、C1-8烷基氨基、C1-5氧代羰基、氰基、卤素、氢、羟基、硝基、C1-8磺酰基和三氟甲基组成的组。
术语“C1-6磺酰胺基”是指-NHS(O)2-R基团,其中R为C1-6烷基。
术语“C0-6磺酰氨基”是指-S(O)2NH-R基团,其中R为选自由氢和C1-6烷基组成的组。
术语“C1-4硫代烷氧基”是指通过硫原子连接的C1-4烷基。
术语“反向对映体(opposite enantiomer)”是指为参考分子的不重叠镜像的分子,其可通过反转参考分子的所有手性中心而获得。举例来说,如果参考分子具有S绝对立体化学构型,那么其反向对映体具有R绝对立体化学构型。同样地,如果参考分子具有S,S绝对立体化学构型,那么其反向对映体具有R,R绝对立体化学构型等。
术语“立体异构体(stereoisomers)”当用在与具有所给的立体化学构型的化合物相关时,是指该化合物的反向对映体,以及是指任何非对映异构体,包括该化合物的几何异构体(Z/E)。举例来说,若化合物具有S,R,Z立体化学构型,其立体异构体将包括其具有R,S,Z构型的反向对映体,以及其具有S,S,Z构型、R,R,Z构型、S,R,E构型、R,S,E构型、S,S,E构型以及R,R,E构型的非对映异构体。若化合物的立体化学构型为未确定的,那么“立体异构体”是指化合物的可能的立体化学构型。
短语“大体上纯的立体异构体”及其变体是指包含至少约95%立体异构体的样本。
短语“纯的立体异构体”及其变体是指包含至少约99.5%立体异构体的样本。
短语“药学上可接受的”是指那些在合理的医学的判断范围内适于用在与患者的组织接触而没有过度的毒性、辐射和过敏反应等,具有合理的效益/风险比率,且可有效地用于预期的目的物质。
术语“赋形剂”是指可能影响药物的生物药效率、但在其他方面不具有药理学活性的任何物质。
术语“药学上可接受的盐类”是指药学上可接受的有机酸和有机碱或无机酸和无机碱的盐类。具使用潜力的酸加成和碱盐描述于S.M.Berge等人,J.Pharm.Sci.(1977)66:1-19以及于Stahl和Wermuth,Handbook of Pharmaceutical Salts:Properties,Selection,and Use(2002)。药学上可接受的盐类的例子包括盐酸盐以及甲磺酸盐。
已了解的是,当本文中所定义的术语提及碳原子的数目时,其所提及的数目是指提及的基团,且不包括可能存在于任何任选的取代基的任何碳。
本领域技术人员将了解本发明的某些化合物以异构体的形式存在。本发明的化合物的立体异构体(以任何比率)和特定的几何异构体、对映体以及非对映体的所有混合物皆在本发明的范围中。
本领域技术人员将了解本发明的某些化合物以互变异构体形式存在。本发明的化合物的所有互变异构体形式皆在本发明的范围中。
短语“本发明的化合物”是指以式I定义的化合物以及在式I范围内的特定化合物,包括在本说明书、实施例和权利要求书中特别指明的化合物。
表1列出本说明书全文使用的缩写。
表1.缩写表
此公开内容和式I化合物有关,包括在说明书和权利要求书中特别指明的化合物,以及其药学可接受的复合物、盐类、溶剂化物和水合物。此公开内容还涉及用于制备式I化合物、包含它们的药物组合物的材料和方法,以及它们用于治疗包括免疫系统和炎症(包括类风湿性关节炎和血液恶性肿瘤、上皮癌(例如恶性上皮肿瘤))的病症、疾病和症状以及其它与JAK相关的疾病、病症或症状的用途。式I化合物包括下列实施方案。
a.一个实施方案与式I化合物有关,其中R4选自由氢、C1-4烷基以及卤代组成的组。
b.另一个实施方案与式I化合物有关,其中R5选自由氢和C1-4烷基组成的组。
c.另一个实施方案与式I化合物有关,其中R4为氢。
d.另一个实施方案与式I化合物有关,其中R5为氢。
e.另一个实施方案与式I化合物有关,其中R4和R5每一个为氢。
f.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8。
g.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8,且R8选自由氢、卤代以及任选取代的C1-6烷基组成的组。
h.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8,且R8选自由氢、卤代以及C1-4烷基组成的组。
i.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8,且R8为卤代。
j.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8,且R8为C1-4烷基。
k.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为CR8,并且R8为甲基。
l.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d和e的任选地任何一个中,式I中的G为N。
m.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为任选取代的C3-8环烷基。
n.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为任选取代的C3-6杂环烷基。
o.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为含氮的C3-6杂环烷基,其在环碳原子上被C1-4烷基取代且在环氮原子上被任选取代的C1-4烷基取代。
p.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为任选取代的C4-14芳基。
q.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为任选取代的C1-10杂芳基。
r.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为任选取代的C1-6烷基。
s.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为具有氧代取代基的C1-6烷基,以及任选取代的C3-6杂环烷基。
t.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为具有氧代取代基的C1-6烷基,以及连接于C1-6烷基相同碳原子上的任选取代的C3-6杂环烷基。
u.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k和l的任选地任何一个中,式I中的R1为被C1-14酰胺取代的C1-6烷基。
v.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k、l、m、n、o、p、q、r、s、t和u的任选地任何一个中,式I中的R2和R3连同它们一起连接的碳原子形成羰基。
w.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k、l、m、n、o、p、q、r、s、t和u的任选地任何一个中,式I中的R2和R3连同它们一起连接的碳原子形成羰基,并且式I中的R6和R7每一个为氢。
x.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k、l、m、n、o、p、q、r、s、t和u的任选地任何一个中,式I中的R6和R7连同它们一起连接的碳原子形成羰基。
y.另一个实施方案与式I化合物有关,且在上述实施方案a、b、c、d、e、f、g、h、i、j、k、l、m、n、o、p、q、r、s、t和u的任选地任何一个中,式I中的R6和R7连同它们一起连接的碳原子形成羰基,并且式I中的R2和R3每一个为氢。
本发明中的化合物可通过许多步骤制备,其中的一些描述如下。除非另有说明,所有取代基为如前定义。每一步骤的产物可通过常规方法回收,包括萃取、蒸发、沉淀、色谱法、过滤、研磨、结晶等。这些步骤可能需要保护某些基团,举例来说,羟基、氨基或羧基,以避免不希望的反应。这些保护基的选择、使用及移除是熟知的且可为常规作法,例如,见T.W.Greene and P.G.M.Wuts,Protective Groupsin Organic Chemistry,John Wiley and Sons(1991)。
方案A描述了式I化合物的形成,其中将R2和R3一起连同它们所连接的碳原子形成羰基(式IA)。
方案A中的步骤1描述了适当的式(a)化合物与适当的式(b)化合物的反应,以提供式(c)化合物。适当的式(a)化合物为其中G1、R4以及R6/R7如同在式IA的最终化合物中所需的化合物,或造成G1、R4以及R6/R7如同在式IA的最终化合物中所需的化合物,且G2为氢或为保护基,并且G3为C1-4烷基(特别地为甲基或乙基)。式(a)的化合物很容易通过多种方法制备,该方法包括烷基-吡咯并吡啶-4-羧酸酯或烷基-吡咯并嘧啶-4-羧酸酯的甲酰化,且如有需要,可通过随后的精制,包括加入有机金属试剂、氧化、转变为卤素以及本领域所熟知的其他反应。适当的式(b)化合物为其中R1如同在式IA的最终化合物中所需的化合物,或造成R1如同在式IA的最终化合物中所需的化合物。
特别地,方案A中的步骤1描述了式(a)化合物和适当的式(b)化合物的还原胺化反应,以提供式(c)的化合物。举例来说,还原胺化反应使用还原剂(例如硼氢化钠、三乙酰氧基硼氢化钠、锌/盐酸、硼氢化锌、氰基硼氢化钠等)于多种条件下进行。该反应在溶剂(例如甲醇、THF等)中进行。典型地,该反应可于约0℃至约60℃的温度范围下进行并典型地需要约1至约24小时以完成。当使用氰基硼氢化钠时,该反应于溶剂(例如甲醇、乙醇、异丙醇以及水或其混合物)中进行。如同本领域所熟知的,在此反应期间监测和调节pH是有利的。
替代地,此还原胺化反应可通过透过在催化剂上的氢化作用进行。多种催化剂适合这一目的,包括钯、铂以及镍催化剂。此氢化作用在适当的溶剂(例如乙酸乙酯、乙醇、甲醇、异丙醇等)中进行,且于大气压至约300psi(2068kPa)的压力范围内以及室温至约100℃的温度下进行。
方案A中的步骤2描述了式(c)化合物的转化,以提供式(d)的化合物。可认识到从酯转化为酸是常见的转化,并有数种方法可影响此反应,包括使用多种在含有溶剂的水中的酸类和碱类的水解作用。
方案A中的步骤3描述了将式(d)化合物转化为式IA的化合物形成酰胺键。此酰胺形成反应为本领域所熟知且领会的。举例来说,可使用常规的酰胺形成条件,例如使用偶联剂的那些条件,该偶联剂包括在肽偶联中使用的那些(例如2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基脲六氟磷酸酯(V)(HATU)、1,3-二环己基碳二亚胺(DCC)以及N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺(EDC)盐酸盐)。如有必要或需要,可使用添加剂(例如4-(二甲基氨基)吡啶、1H-苯并[d][1,2,3]三唑-1-醇(HOBt)等)以促进反应。此反应一般使用碱(例如N-甲基吗啉或三乙胺)于各式各样合适的溶剂(例如二氯甲烷、二甲基甲酰胺、THF等)中进行。
方案B描述了式I化合物的形成,其中将R6和R7一起连同它们所连接的碳原子形成羰基(式IB)。该方案B中的方法步骤与方案A中描述的那些相同。然而,起始材料式(a’)化合物在3-位具有-C(O)OG3基团且在4-位具有羰基(-C(O)-R2/R3),其造成式IA在R6和R7的氧取代。
在方案A和B中描述的方法可依照需要而改变。举例来说,可在沿着描述于方案A和B的途径的不同步骤中加入或移除保护基。此外,在步骤3中形成的化合物可通过烷基化、酰化、水解、氧化、还原、酰胺化、磺化、炔基化、烯基化等被进一步精制,以给出如最终产物所需的R1。
此外,在任选的步骤(未示出)中,式I化合物可被转化为药学上可接受的盐。举例来说,可将式I化合物和适当的酸或碱反应,以提供所需要的盐。替代地,可将式I化合物的前体和碱或碱反应以移除对酸或碱不稳定的保护基或打开前体的内酯或内酰胺基团。另外,式I化合物的盐可通过以适当的酸或碱处理或通过和离子交换树脂接触而转化为另一种盐。反应后,如果该盐能从溶液中沉淀,则可通过过滤而分离所述盐,或者通过蒸发而回收所述盐。盐的离子化程度可由完全离子化变化至几乎无离子化。
式I化合物的有用的盐可包括酸加成盐(包括二酸)以及碱加成盐。药学上可接受的酸加成盐可包括衍生自无机酸(例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、氢氟酸和亚磷酸)的无毒盐类,以及衍生自有机酸(例如脂肪族单羧酸以及脂肪族二羧酸、被苯基取代的链烷酸、羟基烷羧酸、链烷二羧酸、芳香酸、脂族磺酸和芳族磺酸等)的无毒盐类。此盐类包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐、碳酸盐、硫酸氢盐、硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环已氨基磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、葡糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、羟苯酰苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲硫酸盐、萘二甲酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、焦谷氨酸盐、蔗糖盐、硬脂酸盐、琥珀酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐和羟萘甲酸盐。
有用的碱加成盐类可包括衍生自碱类的无毒盐类,包括金属阳离子(例如碱金属阳离子或碱土族金属阳离子,以及胺类)。合适的金属阳离子的例子可包括钠(Na+)、钾(K+)、镁(Mg2+)、钙(Ca2+)、锌(Zn2+)以及铝(Al3+)。合适的胺类的例子可包括精氨酸、N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙胺、二乙醇胺、二环己胺、乙二胺、甘氨酸、赖氨酸,N-甲基葡萄糖胺、醇胺(olamine)、2-氨基-2-羟甲基-丙烷-1,3-二醇以及普鲁卡因。
本发明所述的化合物可单独施用或以药物组合物的形式施用。实际上,本发明所述的化合物通常以药物组合物的形式投药,即,以与至少一种药学上可接受的赋形剂形成的混合物的形式,其比例和性质可通过本发明所选化合物性质、所选给药途径以及常规药学实践来决定。
在另一个实施方案中,本发明提供药物组合物,其包含:本发明的化合物以及药学上可接受的赋形剂。本领域的技术人员可根据所选化合物的特定特征、所治疗的病症或症状、该病症或症状的阶段以及其他相关的情况,容易地选择施用的量、形式和途径。
本发明的药物组合物以药学领域所熟知的方式制备,且包括为活性成分的至少一种本发明的化合物。本发明的化合物的量可根据其特定性质而改变,以及可能合宜地介于剂型重量的约1%至约70%。本药物组合物优选以单位剂型配制,每种剂量典型地包含约0.5mg至约200mg的本发明的化合物。术语“单位剂型”是指物理学上的离散单位,每种单位包含预定量的活性成分(其与合适的药物赋形剂结合),通过在整个给药方案中使用一种或多种单位剂型以产生所需的治疗效果。
在对患者的有效治疗上,本发明的化合物可以任何形式和途径施用,其使得该化合物为生物可利用的。本发明的化合物可通过多种途径施用,包括口服和肠胃外途径,更特别地,通过吸入、皮下注射、肌肉注射、静脉注射、经皮给药、鼻内给药、直肠给药、阴道给药、眼部给药、局部给药、舌下给药及口腔给药、腹腔内给药、静脉注射、动脉内给药、经皮给药、舌下给药、肌肉注射、直肠给药、经口含化、鼻内给药、脂肪内给药以及鞘内给药。举例来说,本发明的药物组合物可以片剂、胶囊剂、扁囊剂、纸剂、锭剂、糯米纸、酏剂、软膏剂、透皮贴剂、气雾剂、吸入剂、栓剂、溶液剂以及混悬剂的形式施用给患者。
术语“药学上可接受的赋形剂”是指典型地用于制备药物组合物以及应为药学上纯的且以其所使用的量为无毒性的那些赋形剂。它们一般来说为固体、半固体或液体材料,其可用作活性成分的媒介物或介质或有助于储存、施用或制造所述组合物。药学上可接受的赋形剂的一些例子可参见Remington’s Pharmaceutical Sciences and theHandbook of Pharmaceutical Excipients,且包括稀释剂、媒介物、载体、软膏基质、粘结剂、崩解剂、润滑剂、助流剂、甜味剂、调味剂、凝胶基质、持续释放基质、稳定剂、防腐剂、溶剂、悬浮剂、缓冲剂、乳化剂、染剂、推进剂、涂层剂以及其他。
在一个特定的变体中,药物组合物适于口服施用,例如片剂或胶囊剂或液体制剂(例如,溶液剂或混悬剂)。在另一个特定的变体中,药物组合物为适用于肠胃外施用的液体制剂。
在另一个实施方案中,本发明提供了治疗与JAK相关的疾病、病症或症状的方法。该方法包括对需要其治疗的患者施用有效量的本发明的化合物。在另一个实施方案中,本发明提供了抑制JAK的方法,其包括将本发明的化合物施用给患者,以抑制体内的JAK途径。在另一个实施方案中,本发明提供抑制JAK的方法,其包括将在体内转化为本发明化合物的第一化合物施用给受试者。
在另一个实施方案中,提供本发明的化合物作为药剂使用。本发明还提供本发明的化合物用于制备药剂的用途,以治疗如本文所述的与JAK相关的疾病、病症或症状。
如本文所用,术语“症状”、“病症”和“疾病”和任一种不健康或不正常的状况有关。短语“与JAK相关的疾病、病症或症状”包括其中JAK抑制作用提供良好的治疗效果的任何疾病、病症或症状,例如那些以异常JAK/STAT信号为特征的,包括增生性病症、心脏病症、神经退化性病症、自身免疫病症、器官移植、炎性病症、免疫病症以及过敏性症状、食物过敏、特应性皮炎和鼻炎。其中本文使用一般术语,以描述与JAK相关的症状,可理解的是,在各种诊断手册和其他材料中提及的更具体描述的症状包括在本发明的范围中。举例来说,可理解增生性病症包括癌症。此外,举例来说,可理解关节炎目前分为数种更具体的病症(例如骨关节炎和类风湿性关节炎和其他),且其全部被本发明所考虑。另一个实施例为系统性炎症反应综合征,其描述和败血症、胰腺炎、多发性创伤、撕裂伤、脑损伤或外科手术、出血性休克、免疫器官损伤以及其它相关的炎症事件,其全部被本发明所考虑。
术语“治疗(treat)”、“治疗(treatment)”和“治疗(treating)”包括改善本文所述的疾病、病症或症状。同时,也可领略本领域的技术人员可通过治疗目前受该疾病、病症或症状所苦的患者、或通过预防性治疗被认为对此症状敏感的患者,而以本发明化合物的有效量影响该状况。因此,术语“治疗(treat)”、“治疗(treatment)”和“治疗(treating)”包括提供减缓、阻断、延迟、控制或停止本文所述的疾病、病症或症状的进程的所有方法,但并不一定表明完全消除所有的症状或治愈该病情。此外,此术语的用途旨在包括对任何一种特定的疾病、病症或症状的预防性和治疗性的处理。
术语“受试者”和“患者”可交替使用,且包括人类和非人类的动物(例如,哺乳动物(如小鼠、大鼠、天竺鼠、狗、猫、兔、牛、马、绵羊、山羊以及猪))。该术语还包括鸟、鱼、爬行动物、两栖动物等。应理解更特别的受试者或患者为人类。同时,更特别的受试者或患者可为非人类的哺乳动物(例如小鼠、大鼠以及狗)。
如本文所用,术语“有效量”是指本发明的化合物在治疗(以单剂量或多剂量施用)患有与JAK相关的疾病、病症或症状的患者的量。有效量可以被为本领域技术人员的主治的诊断医生,通过使用已知技术且通过在类似情况下获得的观察结果而容易地测定。在测定有效量(剂量)时,主治的诊断医生考虑的许多因素包括但不限于:患者的种族、其大小、年龄和综合健康;相关的特定症状、病症或疾病;特定症状、病症或疾病的程度、相关性或严重性;个别患者的反应;所施用的特定化合物;给药途径;施用制剂的生物可利用性的特征;所选的给药方案;合并用药的使用;以及其他有关的情况。本文用途发明的有效量,包括本发明的化合物预期由约每天每公斤体重0.1毫克(mg/kg/天)至约20mg/kg/天变化。具体的量可由熟知的技术人员确定。
如上述所提及的,式I化合物可用来治疗与JAK相关的疾病、病症或症状,且该疾病、病症或症状通常与受试者中的不健康或异常状况有关,JAK的抑制对此提供了良好的治疗效果。更特别地,此病症、疾病和症状可包括免疫系统和炎症反应,包括I型过敏性(变态性)反应(过敏性鼻炎、过敏性哮喘以及特应性皮炎);自身免疫疾病(类风湿性关节炎、多发性硬化、系统性红斑性狼疮、牛皮癣、免疫性血小板减少性紫癜、肌萎缩性侧索硬化症以及器官移植排斥);肺的炎症(慢性阻塞性肺疾病)以及血栓形成。式I化合物还可用于治疗与异常细胞生长相关的病症、疾病和症状,抱括血液恶性肿瘤,例如急性骨髓性白血病、B细胞慢性淋巴性白血病、B细胞淋巴瘤(例如,套细胞淋巴瘤)和T细胞淋巴瘤(例如,外周T细胞淋巴瘤),以及上皮癌(即恶性上皮肿瘤),例如肺癌(小细胞肺癌及非小细胞肺癌)、胰脏癌和结肠癌。
除了上述提及的血液恶性肿瘤和上皮癌,式I化合物还可用于治疗其他种类的癌症,包括白血病(慢性骨髓性白血病及慢性淋巴性白血病);乳腺癌、泌尿生殖癌、皮肤癌、骨癌、前列腺癌以及肝癌;脑癌;喉、胆囊、直肠、副甲状腺、甲状腺、肾上腺、神经组织、膀胱、头、颈、胃、支气管以及肾脏的癌症;基底细胞癌、鳞状细胞癌、转移性皮肤癌、骨肉瘤、尤文肉瘤、网状细胞肉瘤以及卡波西肉瘤;骨髓瘤、巨细胞瘤、胰岛细胞瘤、急性及慢性淋巴性和粒细胞瘤、毛细胞瘤、腺瘤、髓样癌、嗜铬细胞瘤、粘膜神经瘤、肠神经节细胞瘤、增生性角膜神经瘤、类马伐氏综合征瘤、威尔姆氏肿瘤、精原细胞瘤、卵巢瘤、平滑肌瘤、子宫颈发育不良、神经母细胞瘤、视网膜母细胞瘤、骨髓增生异常综合征、横纹肌肉瘤、星状细胞瘤、非霍奇金淋巴瘤、恶性高钙血症、真性红血胞增多症、腺癌、多形性胶质母细胞瘤、神经胶质瘤、淋巴瘤及恶性黑色素瘤等等。
除了癌症以外,式I化合物还可用于治疗其他与异常细胞生长相关的疾病,包括非恶性增生性疾病,例如良性前列腺肥大、再狭窄、增生、滑膜增生病症、视网膜病变或其他的眼部新生血管性病症等等。
式I化合物还可用于治疗除了上述列举的那些以外的自身免疫疾病。此病症、疾病和症状包括克隆氏病、皮肌炎、I型糖尿病、古德巴斯德综合征(Goodpasture's syndrome)、格雷夫斯氏病(Graves'disease)、格巴二氏综合征(Guillain-Barre syndrome)、桥本氏病(Guillain-Barre syndrome)、混合性结缔组织损伤、重症肌无力、嗜睡、寻常性天疱疮、恶性贫血、多发性肌炎,原发性胆汁性肝硬化、舍格伦综合征(syndrome)、颞动脉炎、溃疡性结肠炎、血管炎及韦格纳肉芽肿(Wegener's granulomatosis)等等。
此外,式I化合物可用于治疗炎性疾病,其包括哮喘、慢性炎症、慢性前列腺炎、肾小球性肾炎、过敏、炎性肠病(除了克隆氏病外的溃疡性结肠炎)、骨盆发炎症、再灌流损伤、移植排斥、血管炎及全身性炎症反应综合征。
式I化合物还可用于治疗特定疾病,其可能属于一种或多种上述一般疾病,包括关节炎。除了类风湿关节炎、舍格伦综合征、系统性红斑性狼疮、儿童和青少年的SLE以外,式I化合物还可用于治疗其他关节炎疾病,包括关节强硬性脊椎炎、缺血性坏死、贝塞特氏病(Bechet's disease)、滑囊炎、双氢氧化焦磷酸钙沈积疾病(假性痛风)、腕隧道综合征、艾登二氏综合征(Ehlers-Danlos syndrome)、纤维肌痛、第五疾病、巨大细胞动脉炎、痛风、幼年型皮肌炎、幼年型类风湿性关节炎、幼年型脊椎关节病变、莱姆病(Lyme disease)、马凡氏综合征(Marfan syndrome)、肌炎、骨关节炎、成骨不全症、骨质疏松症、柏哲德氏症(Paget's disease)、牛皮癣关节炎、雷诺氏现象(Raynaud's phenomenon)、反应性关节炎、反射性交感神经营养不良综合征、硬皮症、脊髓狭窄、史提耳氏病(Still's disease)及腱炎等等。
可将所要求以及所公开的化合物和一种或多种其他具药理活性的化合物或疗法结合,用于治疗一种或多种与JAK相关的疾病、病症或症状,其包括涉及免疫系统、炎症以及异常细胞生长的疾病、病症或症状。举例来说,可将式I化合物(包括本说明书和权利要求书特别指明的化合物)以及它们药学上可接受的复合物、盐类、溶剂化物以及水合物,和一种或多种化合物或疗法结合且同时、连续或分开施用,其用于治疗关节炎(包括类风湿性关节炎和骨性关节炎),或用于治疗癌症(包括血液恶性肿瘤(例如急性骨髓白血病、B细胞慢性淋巴白血病、B细胞淋巴瘤和T细胞淋巴瘤)以及恶性肿瘤(例如肺癌、胰脏癌以及结肠癌))。此结合可提供显著的治疗效益,包括较少的副作用、对于服务不足的患者人群改善治疗的能力或协同活性。
举例来说,当用来治疗关节炎时,可将式I化合物和一种或多种非类固醇抗炎药(NSAIDs)、镇痛剂、皮质类固醇、生物反应调节剂以及蛋白质-A免疫吸附疗法结合。替代地或另外地,当治疗类风湿性关节炎时,可将式I化合物和一种或多种缓解病情抗风湿药物(DMARDs)结合,以及当治疗骨性关节炎时,可将式I化合物和一种或多种骨质疏松剂结合。
代表性的NSAIDs包括阿扎丙宗(apazone)、阿斯匹灵、希乐葆(celecoxib)、待克菲那(diclofenac)(带有以及不带有米索前列醇)、待福索(diflunisal)、免痛炎(etodolac)、非诺洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、引朵美洒辛(indomethacin)、可多普洛菲(ketoprofen)、甲氯胺苯酸钠(meclofenamate sodium)、甲芬那酸、美洛西卡(meloxicam)、萘丁美酮(nabumetone)、那普洛仙(naproxen)、奥沙普秦(oxaprozin)、苯基丁氮酮(phenylbutazone)、匹洛西卡(piroxicam)、胆碱和水杨酸镁、双水杨酸盐(salsalate)和苏林达克(sulindac)。代表性的镇痛剂包括对乙酰氨基酚和硫酸吗啡以及可待因、二氢可待因酮(hydrocodone)、氧可酮(oxycodone)、普帕西芬(propoxyphene)以及妥美度(tramadol),其全部带有或不带对乙酰氨基酚。代表性的皮质类固醇包括倍他米松(betamethasone)、醋酸可的松(cortisoneacetate)、地塞米松(dexamethasone)、氢化可的松(hydrocortisone)、甲基强的松龙(methylprednisolone)、强的松龙(prednisolone)以及强的松(prednisone)。代表性的生物反应调节剂包括TNF-α抑制剂,例如阿达木(adalimumab)、依那西普(etanercept)以及因福利美(infliximab);选择性的B-细胞抑制剂,例如利妥昔单抗(rituximab);IL-1抑制剂,例如阿那白滞素(anakinra)以及选择性的共同刺激调节剂,例如阿巴西普(abatacept)。
代表性的DMARDs包括金诺芬(口服金)、咪唑硫嘌呤(azathioprine)、苯丁酸氮芥(chlorambucil)、环磷酰胺、环孢霉素、硫代苹果酸金钠(注射用金)、羟化氯喹、艾炎宁(leflunomide)、甲氨蝶呤、米诺环素(minocycline)、山喜多(myophenolate mofetil)、青霉胺以及柳氮磺胺吡啶。代表性的骨质疏松剂包括双膦酸盐类,例如阿仑膦酸钠(alendronate)、伊班膦酸钠(ibandronate)、利塞膦酸盐(risedronate)和唑来膦酸(zoledronic acid);选择的雌激素受体调节子,例如屈洛昔芬(droloxifene)、拉索昔芬(lasofoxifene)以及雷洛昔芬(raloxifene);荷尔蒙,例如降钙素、雌激素和副甲状腺素;以及免疫抑制剂例如咪唑硫嘌呤(azathioprine)、环孢霉素以及雷帕霉素。
对于治疗类风湿性关节炎特别有用的组合包括式I化合物和甲氨蝶呤,其可单独或和一种或多种生物反应调节剂例如艾炎宁(lefluonomide)、依那西普(etanercept)、阿达木(adalimumab)以及因福利美(infliximab)结合。
对于治疗血栓和再狭窄,可将式I化合物和一种或多种心血管药剂例如钙通道阻滞剂、他汀类(statins)、纤维酸类(fibrates)、β受体阻滞剂、ACE抑制剂以及血小板聚集抑制剂结合。
还可将式I化合物和一种或多种治疗癌症的化合物或疗法结合。这些包括化疗药(即细胞毒性或抗癌药)例如烷基化剂、抗生素、抗代谢剂、植物源性药物以及拓朴异构酶抑制剂,以及通过使用涉及肿瘤生长和进展的特定分子干扰而阻止癌症生长和扩散的分子靶向药物。分子靶向药物包括小分子和生物制剂两者。
代表性的烷基化剂包括双氯乙基胺(氮芥类(例如,苯丁酸氯芥、环磷酰胺、异环磷酰胺、氮芥、美法仑(melphalan)、尿嘧啶氮芥);氮丙啶(例如噻替派(thiotepa));烷基酮磺酸盐(例如马利兰);亚硝基脲(例如卡莫司汀、洛莫司汀和链脲佐菌素);非典型烷基化剂(例如六甲蜜胺、达卡巴嗪和丙卡巴肼);以及铂化合物(例如卡铂、顺铂、奈达铂、奥沙利铂、沙铂以及三铂四硝酸盐(triplatin tetranitrate))。
代表性的抗生素包括蒽环类(例如阿克拉霉素(aclarubicin)、氨柔比星(amrubicin)、柔红霉素(daunorubicin)、阿霉素(doxorubicin)、表柔比星(epirubicin)、伊达比星(idarubicin)、吡柔比星(pirarubicin)、戊柔比星(valrubicin)以及佐柔比星(zorubicin));蒽醌类(例如米托蒽醌(mitoxantrone)和匹杉琼(pixantrone));以及链霉菌属(例如放线菌素、博来霉素(bleomycin)、更生霉素(dactinomycin)、丝裂霉素C(mitomycin C)以及普卡霉素(plicamycin))。
代表性的抗代谢剂包括二氢叶酸还原酶抑制剂(例如氨蝶呤、甲氨蝶呤和爱宁达(pemetrexed));胸苷合成酶抑制剂(例如雷替曲塞(raltitrexed)和爱宁达(pemetrexed));亚叶酸(例如甲酰四氢叶酸);腺苷脱氨酶抑制剂(例如喷司他丁(pentostatin));卤代/核糖核苷酸还原酶抑制剂(例如克拉屈滨、克罗拉滨和氟达拉滨);硫嘌呤类(例如硫鸟嘌呤和巯嘌呤);胸苷酸合成酶抑制剂(例如氟尿嘧啶、卡培他滨、替加氟(tegafur)、卡莫氟(carmofur)和氟尿苷);DNA聚合酶抑制剂(例如阿糖胞苷(cytarabine));核糖核苷酸还原酶抑制剂(例如吉西他滨(gemcitabine));去甲基化剂(例如阿扎胞苷(azacitidine)和地西他滨(decitabine);以及核糖核苷酸还原酶抑制剂(例如羟基脲);以及降天冬酰胺药(例如天冬酰胺酶)。
代表性的植物源性药物包括长春花生物碱类(例如:长春新碱、长春碱、长春地辛、长春利定和长春瑞滨)、鬼臼毒素类(例如:依托泊苷和替尼泊苷)以及紫杉烷类(例如:多西他赛(docetaxel)、莱龙太素(larotaxel)、奥他赛(ortataxel)、紫杉醇(paclitaxel)和替司他赛(tesetaxel))。
代表性的I型拓朴异构酶抑制剂包括喜树碱(例如贝洛替康(belotecan)、伊立替康(irinotecan)、鲁比替康(rubitecan)以及拓扑替康(topotecan))。代表性的II型拓朴异构酶抑制剂包括安吖啶(amsacrine)、依托泊甘(etoposide)、磷酸依托泊甘以及替尼泊苷,其为鬼臼素(epipodophyllotoxins)的衍生物。
分子靶向疗法包括生物制剂例如细胞激素以及其他免疫调节剂。有效用的细胞激素包括白细胞介素-2(IL-2,阿地白介素)、白细胞介素4(IL-4)、白细胞介素12(IL-12)以及干扰素,其包括多于23种相关的亚型。其他细胞激素包括粒细胞集落刺激因子(非格司亭(filgrastim))以及粒细胞-巨噬细胞集落刺激因子CSF(沙格莫丁(sargramostim))。其他免疫调节剂包括卡介苗、左美索(levamisole)以及奥曲肽(octreotide);抗肿瘤抗原的单株抗体,例如曲妥珠单抗(trastuzumab)和利妥昔单抗(rituximab);以及癌症疫苗,其诱发对肿瘤的免疫反应。
此外,用涉及肿瘤生长和进展的特定分子干扰的分子靶向药物包括表皮生长因子(EGF)、转化生长因子-α(TGFα)、TGFβ、调蛋白、类胰岛素生长因子(IGF)、纤维母细胞生长因子(FGF)、角质细胞生长因子(KGF)、细胞集落刺激因子(CSF)、红血球生成素(EPO)、白细胞介素-2(IL-2)、神经生长因子(NGF)、血小板源生长因子(PDGF)、肝细胞生长因子(HGF)、血管表皮细胞生长因子(VEGF)、血管生成素、表皮生长因子受体(EGFR)、人类表皮细胞生长因子受体2(HER2)、HER4、类胰岛素生长因子1受体(IGF1R)、IGF2R、纤维母细胞生长因子1受体(FGF1R)、FGF2R、FGF3R、FGF4R、血管表皮细胞生长因子受体(VEGFR)、带有类免疫球蛋白和类上皮细胞生长因子区域2(Tie-2)的酪氨酸激酶、血小板源生长因子受体(PDGFR)、Abl、Bcr-Abl、Raf、类FMS酪氨酸激酶3(FLT3)、c-Kit、Src、蛋白激酶c(PKC)、原肌凝蛋白受体激酶(Trk)、Ret、雷帕霉素的哺乳动物靶(mTOR)、极光激酶、保罗样激酶(PLK)、丝裂原活化蛋白激酶(MEK)、间质-上皮转变因子(c-MET)、细胞周期蛋白依赖性激酶(CDK)、Akt、细胞外信号调节激酶(ERK)、聚(腺苷二磷酸核糖)聚合酶(PARP)等的抑制剂。
特定的分子靶向药物包括选择性雌激素受体调节子,例如它莫西芬(tamoxifen)、托瑞米芬(toremifene)、氟维司群(fulvestrant)和雷洛昔芬(raloxifene);抗雄激素,例如比卡鲁胺(bicalutamide)、尼鲁米特(nilutamide)、甲地孕酮(megestrol)和氟他胺(flutamide);以及芳香酶抑制剂,例如依西美坦(exemestane)、阿那曲唑(anastrozole)和来曲唑(letrozole)。其他具体的分子靶向药物包括抑制信号转导的药剂,例如伊马替尼(imatinib)、达沙替尼(dasatinib)、尼洛替尼(nilotinib)、曲妥珠单抗(trastuzumab)、吉非替尼(gefitinib)、埃罗替尼(erlotinib),西妥昔单抗(cetuximab)、拉帕替尼(lapatinib)、帕尼单抗(panitumumab)和特癌适(temsirolimus);诱发细胞凋亡的药剂,例如波替单抗(bortezomib);阻止血管生成的药剂,例如贝伐单抗(bevacizumab)、索拉非尼(sorafenib)和舒尼替尼(sunitinib);帮助免疫系统摧毁癌细胞的药剂,例如利妥昔单抗(rituximab)和阿来组单抗(alemtuzumab);以及输送毒性分子至癌细胞的单株抗体,例如吉妥单抗(gemtuzumab ozogamicin)、托西莫单抗(tositumomab)、131碘-托西莫单抗和替伊莫单抗(ibritumomab tiuxetan)。
本发明还提供制成品,其包括至少一种本发明的化合物以及标签。该标签可包括关于制造商、剂量、欲治疗症状以及该化合物或药物组合物的用途的信息。
在另一个实施方案中,本发明提供试剂盒:其包括至少一种本发明的化合物、标签以及投药装置。该装置可能包括混合瓶、用于形成溶液或悬浮液的液体、管子、注射器等。
生物活性:JAK抑制作用
可使用各种方法评估化合物抑制JAK活性的能力,包括体外和体内的试验。下列体外的试验测量测试化合物抑制JAK2和JAK3介导的FAM标记的JAK专一性底物磷酸化作用的能力。
纯化的JAK2和JAK3蛋白质购买自Invitrogen。、使用在包含50mM HEPES、10mM NaCl、10mM MgCl2、0.2mM EDTA、0.01%EDA(35)、1mM DTT、0.1mg/mL BSA的缓冲液中的黑色384细胞微孔培养板在pH7.3下测定JAK2和JAK3抑制作用。每一种测试化合物在DMSO中使用2倍系列稀释为11个数据点,并且被加入缓冲液中,使得每一种稀释包含3%DMSO。
JAK2抑制作用试验
往每一个孔中加入2μL的3μM5FAM-KKKKEEIYFFFG-NH2和45μM ATP(在缓冲液中)、2μL被稀释的测试化合物(在培养基中有3%DMSO)以及2μL的在缓冲液中的0.6nM JAK2。将反应混合物于室温下培养60分钟并通过加入50mM HEPeX、30mM EDTA以及0.1%Tx-100(pH7.3)进行淬灭。在反应后为定量荧光标记的底物和产物,将测试板装于通过基于微流体的分离而测量转换百分率的Caliper LC-3000上。
JAK3抑制作用试验
于每一个孔中加入2μL的3μM5FAM-KKKKEEIYFFFG-NH2和15μM ATP(在缓冲液中)、2μL被稀释的测试化合物(在培养基中有3%DMSO)以及2μL的在缓冲液中的1.2nM JAK3。将反应混合物于室温下培养60分钟并通过加入50mM HEPES、30mM EDTA以及0.1%Tx-100(pH7.3)进行淬灭。在反应后为定量荧光标记的底物和产物,将测试板装于通过基于微流体的分离而测量转换百分率的Caliper LC-3000上。
通过该化合物浓度和抑制百分率对标准IC50方程的的非线性曲线拟合计算相应的IC50数值。
实施例
本发明进一步以下列实施例和制备说明。这些实施例和制备不以任何方式限制本发明的范围。在下述实施例中的许多化合物获得了1H核磁共振(NMR)光谱。从四甲基硅烷的百万分之几的低场给出化学位移特征(δ),对于主要波峰的指定使用常见的缩写,包括s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)以及br(宽峰)。对于常见的溶剂使用下列缩写:CDCl3(氘代氯仿)、DMSO-d6(氘代二甲基亚砜)、CD3OD(氘代甲醇)以及THF-d8(氘代四氢呋喃)。使用电喷雾电离(ESI)或大气压化学电离(APCI)记录质谱([M+H])。
其中指出,某些制备和实施例的产物通过批量操作触发器HPLC(泵:WatersTM2525;MS:ZQTM;软体:MassLynxTM)、快速色谱法或制备薄层色谱法(TLC)纯化。使用酸性或碱性条件进行制备HPLC。酸性条件典型地为在带有0.05%TFA的溶剂A:水中的梯度液以及在带有0.035%TFA的溶剂B:乙腈中的梯度液;碱性条件为在溶剂A:10nM NH4HCO3(在水中)中的梯度液以及在溶剂B:10nMNH4HCO3(在20/80(v/v)水/乙腈)中的梯度液。除非指出为碱性条件,否则所提的制备HPLC条件使用酸性条件。制备基TLC典型地在硅胶60F254板上进行。在通过色谱法分离后,溶剂被移除且通过在离心蒸发器(例如GeneVacTM)、旋转型蒸发器、真空瓶等干燥而获得产物。在惰性气氛(例如氮气)或反应气氛(例如H2)下的反应典型地在约1个大气压(14.7psi)下而进行。
许多用于实施例中的缩写列于上述的表1中。除非在说明书中另有说明,未列于表1的缩写具有其通常含义。
制备A:3-甲酰-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯
将1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(500mg,2.84mmol)以及六亚甲基四胺(796mg,5.68mmol)于水(8mL)和冰乙酸(16mL)中合并,并且于100℃加热过夜,然后冷却至室温。将反应混合物用乙酸乙酯萃取并将有机物经由MgSO4干燥,并在真空中浓缩,以提供残余物。通过硅胶色谱法(50%EtOAc/己烷)纯化残余物,以提供为白色固体的标题化合物。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.57(s,1H),8.48(d,1H,J=4.8Hz),7.48(d,1H,J=4.8Hz),5.74(d,1H,J=6.8Hz),3.91(s,3H),2.78(s,3H)。[M+H]测量值为205。
制备B:4-甲基-3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁酯
将3-甲酰-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(150mg,0.735mmol)溶解于DMF(5mL)中,并且将三乙胺(0.31mL,2.20mmol)加至溶液中。然后加入二碳酸二叔丁酯(240mg,1.10mmol),并使混合物于室温下搅拌3小时。将溶液在真空中浓缩。通过硅胶色谱法(30%EtOAc/己烷)纯化,以提供165mg为白色固体的标题化合物。1H NMR(400MHz,CD3OD)δ10.16(s,1H),8.64(s,1H),8.57(d,1H,J=5.0Hz),7.63(d,1H,J=5.1Hz),4.00(s,3H),1.72(s,9H)。[M+H]测量值为305。
实施例1:4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯
将3-甲酰-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(160mg,0.784mmol)以及4-氨基哌啶-1-羧酸叔丁酯(188mg,0.940mmol)于MeOH(3mL)和THF(3mL)中在50℃下合并3小时。然后于室温下加入硼氢化钠(59mg,1.567mmol)并使其搅拌10分钟。将混合物用水淬灭并用乙酸乙酯萃取。将有机物经由MgSO4干燥,并在真空中浓缩,以提供3-((1-(叔丁氧基羰基)哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(60mg),将其用于下一步骤。1H NMR(400MHz,CD3OD)δ8.32(d,1H,J=5.1Hz),7.61-7.62(m,2H),4.07-4.13(m,4H),4.01(s,3H),2.81-2.84(m,3H),1.96-1.98(m,2H),1.45-1.47(m,2H),1.45(s,9H)。[M+H]测量值为389。
将3-((1-(叔丁氧基羰基)哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(60mg,0.154mmol)于MeOH(2mL)、1N NaOH(3mL)和THF(2mL)中搅拌16小时。然后将1N HCl逐滴加入直到pH=5并将该混合物用水稀释且用乙酸乙酯萃取。分离有机物,经由MgSO4干燥,并在真空中浓缩。经由基础制备HPLC纯化,用在A中的10%至35%B洗脱,以提供50mg的3-((1-(叔丁氧基羰基)哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸。1H NMR(400MHz,CD3OD)δ11.84(s,1H),8.21(d,1H,J=4.8Hz),7.67(s,1H),7.34(d,1H,J=4.8Hz),4.14(m,2H),3.96(m,2H),3.04-3.09(m,1H),2.77(m,2H),2.02-2.03(m,2H),1.42-1.43(m,2H),1.40(s,9H)。[M+H]测量值为375。
将3-((1-(叔丁氧基羰基)哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸(35mg,0.093mmol)、HATU(71mg,0.187mmol)和吡啶(0.023mL,0.280mmol)在DMF(3mL)中于室温下搅拌2小时。将溶液在真空中浓缩,并经由基础制备HPLC纯化,用在A中的10%至35%B洗脱,以提供18mg为黄色固体的标题化合物。1H NMR(400MHz,CD3OD)δ7.59(m,1H),7.39-7.49(m,1H),4.98(d,2H,J=1.5Hz),4.77-4.79(m,1H),4.25-4.28(m,2H),2.87-2.92(m,2H),1.91-1.94(m,2H),1.78-1.90(m,2H),1.48(s,9H)。[M+H]测量值为357。
实施例2:4-(哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯(18mg,0.051mmol)溶解于TFA(1mL)和DCM(2mL)中,并使其在室温下搅拌15分钟。将混合物在真空中浓缩,并经由制备HPLC用在A中的10%至40%B纯化,并提供12mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ8.71-8.72(s,1H),8.42(d,1H,J=8.4Hz),7.62(s,1H),7.48-7.49(m,2H),5.02(s,1H),4.69-4.75(m,2H),3.58-3.61(m,2H),3.19-3.26(m,2H),2.33-2.39(m,2H),2.10-2.15(m,2H)。[M+H]测量值为257。
实施例3:3-氧代-3-(4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)丙腈
将4-(哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮(34mg,0.133mmol)和三乙胺(0.055mL,0.398mmol)溶解于EtOH(4mL)中,并冷却至0℃且使其搅拌10分钟。接着将溶解于EtOH(1mL)的2-氰乙酸2,5-二氧代吡咯烷-1-基酯(29mg,0.159mmol)逐滴加入并使混合物于0℃下搅拌30分钟。将溶液在真空中浓缩,并经由制备HPLC纯化,用在A中的10%至40%B洗脱,并提供10mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ7.60(m,1H),7.43(m,1H),4.98(s,2H),4.84-4.88(m,1H),4.68-4.72(m,1H),3.89-3.95(m,3H),3.33(m,1H),2.80-2.88(m,1H),1.86-2.05(m,4H)。[M+H]测量值为324。
实施例4:4-甲基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯
将3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(71mg,0.233mmol)溶解于DCM(5mL)并将4-氨基-4-甲基哌啶-1-羧酸叔丁酯(50mg,0.233mmol)加至溶液中,并使其于室温下搅拌2小时。然后加入三乙酰氧基硼氢化钠(148mg,0.700mmol)并将混合物于室温下搅拌2小时。将溶液用水淬灭并用DCM萃取。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(70%EtOAc/己烷)纯化,以提供90mg的3-((1-(叔丁氧基羰基)-4-甲基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基-4-甲酯。[M+H]测量值为403。
将3-((1-(叔丁氧基羰基)-4-甲基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基-4-甲酯(90mg,0.179mmol)于MeOH(2mL)、1N NaOH(3mL)以及THF(2mL)中搅拌16小时。将混合物在真空中浓缩。经由基础制备HPLC用在A中的15%至35%B进行纯化,以提供34mg的3-((1-(叔丁氧基羰基)-4-甲基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸。[M+H]测量值为389。
将3-((1-(叔丁氧基羰基)-4-甲基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸(34mg,0.088mmol)、HATU(67mg,0.175mmol)以及吡啶(0.021mL,0.263mmol)在DMF(3mL)中于室温下搅拌2小时。将溶液在真空中浓缩,以提供标题化合物,无需进一步纯化即可使用。
实施例5:4-(4-甲基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将于实施例4中获得的粗3-((1-(叔丁氧基羰基)-4-甲基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸溶解于DCM(3mL)和TFA(1mL)中,并使其于室温下搅拌1小时。将溶液在真空中浓缩,并经由制备HPLC用在A中的5%至20%B进行纯化,以提供21mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ8.74(s,1H),8.42(m,1H),7.59(m,1H),7.43(m,1H),5.05(s,2H),3.29-3.33(m,2H),3.22-3.23(m,2H),2.93-2.97(m,2H),2.20-2.26(m,2H),3.17(s,3H)。[M+H]测量值为271。
实施例6:3-(4-甲基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)-3-氧代丙腈
将4-(4-甲基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮(21mg,0.078mmol)以及三乙胺(0.032mL,0.233mmol)溶解于EtOH(4mL)并冷却至0℃,并使其搅拌10分钟。然后将溶解于EtOH(1mL)中的2-氰乙酸2,5-二氧代吡咯烷-1-基酯(17mg,0.093mmol)逐滴加入,并使混合物于0℃下搅拌30分钟。将溶液在真空中浓缩,并经由制备HPLC用在A中的10%至40%B进行纯化,以提供13mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ7.61(m,1H),7.43(m,1H),5.08(s,2H),3.90(m,2H),3.72(m,1H),3.61-3.62(m,1H),3.51-3.52(m,2H),2.65-2.69(m,1H),2.51-2.57(m,1H),2.22-2.26(m,1H),2.10-2.12(m,1H),1.66(s,3H)。[M+H]测量值为338。
实施例7:4-乙基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯
将3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(211mg,0.692mmol)溶解于MeOH(10mL)并加入4-氨基-4-乙基哌啶-1-羧酸叔丁酯(158mg,0.692mmol),接着加入2滴乙酸。让溶液于室温下搅拌2小时。然后在6小时期间内于室温下加入氰基硼氢化钠(44mg,0.692mmol)。将溶液用水淬灭并用乙酸乙酯萃取。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(70%EtOAc/己烷)纯化,以提供127mg的3-((1-(叔丁氧基羰基)-4-乙基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯。[M+H]测量值为417。
将3-((1-(叔丁氧基羰基)-4-乙基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(123mg,0.238mmol)于MeOH(3mL)、1N NaOH(3mL)以及THF(2mL)中搅拌16小时。将混合物在真空中浓缩。经由基础制备HPLC用在A中的20%至50%B进行纯化,以提供60mg的3-((1-(叔丁氧基羰基)-4-乙基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸。1H NMR(400MHz,CD3OD)δ8.29(d,1H,J=4.8Hz),7.68(s,1H),7.52(d,1H,J=5.1Hz),4.31(s,2H),3.95-4.01(m,1H),2.03(q,2H,J=7.6Hz),1.92-1.94(m,4H),1.47(s,9H),1.46(m,2H),1.07(t,1H,J=7.3Hz)。[M+H]测量值为403。
将3-((1-(叔丁氧基羰基)-4-乙基哌啶-4-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸(50mg,0.124mmol)、HATU(94mg,0.248mmol)以及4-二甲基氨基吡啶(46mg,0.373mmol)在DMF(3mL)中于室温下搅拌1小时。将溶液在真空中浓缩,以提供标题化合物,无需进一步纯化即可使用。
实施例8:4-(4-乙基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将4-乙基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯(50mg,0.124mmol)、HATU(94mg,0.248mmol)以及4-二甲基氨基吡啶(46mg,0.373mmol)在DMF(3mL)中于室温下搅拌1小时。将溶液在真空中浓缩并溶解于DCM(3mL)和TFA(1mL)中,并使其于室温下搅拌1小时。将溶液在真空中浓缩,并经由制备HPLC用在A中的10%至30%B进行纯化,以提供28mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ7.36(m,1H),7.27(m,1H),5.04(s,2H),3.22-3.34(m,2H),3.19-3.21(m,2H),2.95-2.98(m,2H),2.13-2.23(m,4H),0.97(t,3H,J=7.6Hz)。[M+H]测量值为285。
实施例9:3-(4-乙基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)-3-氧代丙腈
将4-(4-乙基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮(25mg,0.088mmol)和三乙胺(0.037mL,0.264mmol)溶解于EtOH(3mL)并冷却至0℃,并使其搅拌10分钟。然后将溶解于EtOH(1mL)的2-氰乙酸2,5-二氧代吡咯烷-1-基酯(19mg,0.106mmol)逐滴加入,并使混合物于0℃下搅拌30分钟。将溶液在真空中浓缩,并经由制备HPLC用在A中的10%至50%B进行纯化,以提供16mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ7.03(m,1H),6.86(m,1H),4.53(d,2H,J=2.0Hz),3.08-3.11(m,2H),2.93-2.94(m,2H),2.72-2.73(m,2H),2.04-2.09(m,1H),1.91-1.94(m,1H),1.36-1.72(m,4H),0.35(t,3H,J=7.6Hz)。[M+H]测量值为352。
实施例10:4-(戊烷-3-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将戊-3-胺(18mg,0.21mmol)加至在带有AcOH(2滴)的MeOH(3mL)中的3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(40mg,0.13mmol)的溶液。在室温下搅拌90分钟后,加入氰基硼氢化钠(33mg,0.53mmol),并将反应物搅拌另外的3小时。将混合物用NaHCO3饱和溶液淬灭,并用乙酸乙酯萃取。将有机物经由MgSO4干燥,并在真空中浓缩,以提供为澄清油状物的42mg粗3-((戊烷-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯,无需进一步纯化即可使用。[M+H]测量值为376。
将于带有1N NaOH(1mL)的MeOH(3mL)中的3-((戊烷-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(42mg,0.11mmol)在50℃下搅拌3小时。将反应物冷却至室温,用1N HCl中和,并在真空中浓缩。将残余物溶解于DMF(3mL)中。加入HATU(71mg,0.187mmol),并将反应物于室温下搅拌2小时。将溶液在真空中浓缩,并经由制备HPLC用在溶剂A中的15%至70%溶剂B梯度液洗脱纯化,以提供为灰白色固体的16mg标题化合物。1H NMR(400MHz,CD3OD)δ8.33(d,1H,J=4.8Hz),7.38(d,1H,J=4.8Hz),7.18(s,1H),4.76(s,2H),4.68-4.80(m,1H),1.60-1.71(m,4H),0.87(s,6H)。[M+H]测量值为244。
实施例11:4-(1-环丙基-3-羟丙基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将3-氨基-3-环丙基丙-1-醇(30mg,0.26mmol)加至在带有AcOH(2滴)的MeOH(3mL)中的3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(39.6mg,0.13mmol)的溶液中。于室温下搅拌90分钟后,加入氰基硼氢化钠(33mg,0.53mmol)并将反应物搅拌另外的3小时。将混合物用NaHCO3饱和溶液淬灭,并用乙酸乙酯萃取。将有机物经由MgSO4干燥,并在真空中浓缩,以提供为黄色油状物的50mg粗3-((1-环丙基-3-羟丙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯,无需进一步纯化即可使用。[M+H]测量值为404。
将3-((1-环丙基-3-羟丙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(50mg,0.12mmol)在带有1N NaOH(1mL)的MeOH(3mL)中于室温下搅拌16小时。将反应物用1N HCl中和,并在真空中浓缩。将残余物溶解于DMF(3mL)。加入HATU(47mg,0.12mmol),并将反应物于室温下搅拌2小时。将溶液在真空中浓缩,并经由制备HPLC用在溶剂A中的15%至70%溶剂B梯度液洗脱纯化,以提供为灰白色固体的16mg标题化合物。1H NMR(400MHz,CD3OD)δ8.34(d,1H,J=4.8Hz),7.35(d,1H,J=4.8Hz),7.28(s,1H),5.10(AB q,2H,J=76.4,16.8Hz),4.08-4.20(m,1H),3.59(t,2H,J=6.4Hz),2.02-2.14(m,2H),1.17-1.30(m,1H),0.73-0.79(m,1H),0.42-0.54(m,2H),0.24-0.33(m,1H)。[M+H]测量值为272。
实施例12:3-((5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)甲基)吡咯烷-1-羧酸叔丁酯
将AcOH(5滴)和3-(氨基甲基)吡咯烷-1-羧酸叔丁酯(90mg,0.45mmol)加入3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(91mg,0.3mmol)于MeOH(2mL)的溶液中。在室温下搅拌60分钟后,将反应混合物冷却至0℃。加入氰基硼氢化钠(57mg,0.9mmol),并将反应混合物于室温下搅拌另外的3小时。将混合物用水淬灭并用乙酸乙酯萃取。将合并的有机层用NaHCO3饱和溶液和盐水洗涤,经由Na2SO4干燥,并在真空中浓缩,以提供为无色油状物的125mg粗3-(((1-(叔丁氧基羰基)吡咯烷-3-基)甲基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯,无需进一步纯化即可使用。[M+H]测量值为489.40。
将1N LiOH(0.358mL,0.358mmol)于0℃加至3-(((1-(叔丁氧基羰基)吡咯烷-3-基)甲基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(70mg,0.143mmol)于二噁烷(2mL)的溶液中,并于室温下搅拌4小时。将反应混合物用醚萃取并用1N HCl中和水层,并在真空中浓缩,以提供为灰白色固体的3-(((1-(叔丁氧基羰基)吡咯烷-3-基)甲基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸。[M+H]测量值为375。
将3-(((1-(叔丁氧基羰基)吡咯烷-3-基)甲基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸溶解于DMF(3mL)中。加入HATU(158mg,0.417mmol)和DMAP(40mg,0.278mmol)。并将反应物于室温下搅拌2小时。在真空中浓缩,并经由制备HPLC用在溶剂A中的30%至50%溶剂B梯度液洗脱纯化,以提供为浅棕色油状物的14.5mg标题化合物。1H NMR(400MHz,CD3OD)δ1.46(br.s.,9H)1.70-1.81(m,1H)1.99-2.11(m,1H)2.78(dt,J=14.34,7.11Hz,1H)3.11-3.22(m,1H)3.32-3.36(m,1H)3.47-3.57(m,2H)3.72(d,J=7.33Hz,1H)3.76-3.89(m,1H)5.09(s,2H)7.38(s,1H)7.51(d,J=5.31Hz,1H)8.42(d,J=5.56Hz,1H)。[M+H]测量值为357。
实施例13:4-(吡咯烷-3-基甲基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将在二噁烷(0.019mL,0.075mmol)中的4N HCl于0℃加至3-((5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)甲基)吡咯烷-1-羧酸叔丁酯(10mg,0.03mmol)于二噁烷的溶液中,并将反应混合物搅拌1小时,以提供固体物。将固体物过滤并干燥,以提供为其HCl盐的标题化合物(8.0mg)。1H NMR(400MHz,CD3OD)δ1.90(br.s.,1H)2.24(br.s.,1H)2.96(br.s.,1H)3.17(br.s.,2H)3.59(d,J=5.05Hz,1H)3.71-3.83(m,2H)3.87(br.s.,1H)5.18(br.s.,2H)7.64(br.s.,1H)7.80(br.s.,1H)8.55(br.s.,1H)。[M+H]测量值为257。
实施例14:3-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯
将3-氨基哌啶-1-羧酸叔丁酯(300mg,1.50mmol)于0℃加至3-甲酰-1H-吡咯并[2,3-b]吡啶-1,4-二甲酸1-叔丁基4-甲酯(304mg,1.00mmol)于9:1MeOH-乙酸(2mL)的溶液中,并将反应混合物于室温下搅拌1小时。将氰基三氢硼化钠(314mg,5.00mmol)分批缓慢加入,并将反应混合物于室温下搅拌过夜,用水淬灭,并用乙酸乙酯萃取。将合并的有机层用饱和NaHCO3和盐水洗涤,经由Na2SO4干燥,并在真空中浓缩。将残余物经由硅胶色谱法(30%至70%己烷-EtOAc)纯化,以提供为无色油状物的307mg3-((1-(叔丁氧基羰基)哌啶-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯。[M+H]测量值为389。
将1N LiOH(2.03mL,2.03mmol)于0℃加至3-((1-(叔丁氧基羰基)哌啶-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(315mg,0.811mmol)于二噁烷(5mL)的溶液中并于室温下搅拌4小时。将反应混合物在醚和水之间分配,将分离的水层用1N HCl中和,并在真空中浓缩,以提供为灰白色固体的3-((1-(叔丁氧基羰基)哌啶-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸。[M+H]测量值为375。
将3-((1-(叔丁氧基羰基)哌啶-3-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-4-甲酸溶解于DMF(5mL)。加入HATU(914mg,2.4mmol)和DMAP(196mg,1.6mmol),并将反应物于室温下搅拌2小时。将溶液在真空中浓缩,并经由制备HPLC用在溶剂A中的30%至50%溶剂B梯度液洗脱纯化,以提供为浅黄色固体的123mg标题化合物。1H NMR(400MHz,CD3OD)δ1.48(s,9H)1.59-1.70(m,1H)1.88(d,J=13.39Hz,1H)1.95-2.02(m,1H)2.06(dd,J=12.25,3.92Hz,1H)2.75(br.s.,1H)3.15(t,J=11.62Hz,1H)4.04-4.20(m,2H)4.51(br.s.,1H)4.93-5.14(m,2H)7.44(s,1H)7.58(d,J=5.31Hz,1H)8.43(d,J=5.56Hz,1H)。[M+H]测量值为357。
实施例15:4-(哌啶-3-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将在二噁烷(0.018mL,0.07mmol)中的4N HCl于0℃加至3-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯(10mg,0.028mmol)于二噁烷的溶液中,并将反应混合物搅拌1小时。以提供固体物。将固体物过滤并干燥,以提供为其HCl盐的标题化合物(5.6mg)。1H NMR(400MHz,CD3OD)δ1.82-2.13(m,2H)2.13-2.31(m,2H)3.02(td,J=13.07,2.91Hz,1H)3.41(d,J=1.77Hz,1H)3.44-3.51(m,2H)4.68-4.84(m,1H)5.00-5.19(m,2H)7.59(s,1H)7.73(d,J=6.06Hz,1H)8.52(d,J=6.06Hz,1H))。[M+H]测量值为257。
实施例16:4-(4-乙基-1-丙酰基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将4-(4-乙基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮(12mg,0.042mmol)、丙酸(4mg,0.055mmol)、4-二甲基氨基吡啶(10mg,0.084mmol)和HATU(32mg,0.084mmol)于室温溶解于DMF(3mL)中,并使其搅拌3小时。将溶液在真空中浓缩,并经由制备HPLC用在A中的10%至40%B进行纯化,以提供4.6mg为其TFA盐的标题化合物。1H NMR(400MHz,CD3OD)δ7.58(m,1H),7.41(m,1H),5.12(s,2H),3.70-3.74(m,1H),3.59-3.63(m,3H),2.58-2.61(m,1H),2.41-2.43(m,3H),2.21-2.30(m,4H),1.11(t,3H,J=7.6Hz),0.94(t,3H,J=7.6Hz)。[M+H]测量值为341。
实施例17:4-(4-乙基-1-(嘧啶-4-基)哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮
将4-(4-乙基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮(10mg,0.035mmol)、三乙胺(0.049mL,0.352mmol)以及4-氯嘧啶(8mg,0.070mmol)溶解于DMF(1.5mL),并于140℃微波辐射加热30分钟。将溶液在真空中浓缩,并经由制备HPLC用在A中的10%至40%B进行纯化,以提供6.5mg为其TFA盐的标题化合物。1HNMR(400MHz,CD3OD)δ8.66(s,1H),8.14(dd,1H,J=7.6,1.3Hz),7.51(s,1H),7.37(s,1H),7.11(d,1H,J=7.5Hz),5.14(s,2H),4.27(m,1H),4.11(m,1H),3.86-3.87(m,1H),3.80-3.82(m,1H),2.86(m,1H),2.73(m,1H),2.38(m,1H),2.24-2.31(m,4H),0.99(t,3H,J=7.6Hz)。MS(ES)[M+H]测量值为363。
制备C:(S)-2-氨基-1-(吡咯烷-1-基)丁-1-酮
步骤A:(S)-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯
将Et3N(1.920mL,13.78mmol)加至(S)-2-(叔丁氧基羰基氨基)丁酸(1.4g,6.89mmol)、HATU(3.14g,8.27mmol)以及吡咯烷(1.216mL,13.78mmol)于DCM(50mL)的混合物中。将反应混合物于室温下搅拌5小时,然后用NaHCO3饱和水溶液和盐水洗涤。将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供为浅黄色油状物的标题化合物(1.75g,99%)。1H NMR(500MHz,CDCl3)δ0.94(t,J=7.57Hz,3H)1.34-1.48(m,9H),1.49-1.68(m,1H)1.68-1.81(m,1H)1.81-1.92(m,2H)1.92-2.03(m,2H)3.34-3.47(m,2H)3.52(dt,J=12.08,7.14Hz,1H)3.65(dt,J=10.13,6.65Hz,1H)4.30-4.42(m,1H)5.35(d,J=8.30Hz,1H)。
步骤B:(S)-2-氨基-1-(吡咯烷-1-基)丁-1-酮
将(S)-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯(1.75g,6.83mmol)于50%TFA/DCM(10mL)中搅拌1小时。将反应混合物浓缩并分离为澄清油状物的TFA盐。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.85g,5.44mmol,79%)。1H NMR(500MHz,CDCl3)δ1.02(t,J=7.45Hz,3H)1.78-2.01(m,6H)3.30-3.46(m,2H)3.51(dt,J=12.20,7.32Hz,1H)3.59(dt,J=10.25,6.59Hz,1H)4.14(t,J=6.10Hz,1H)8.38(br.s.,3H)。
实施例18:(S)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
步骤A:(S)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将三乙酰氧基硼氢化钠(279mg,1.315mmol)和(S)-2-氨基-1-(吡咯烷-1-基)丁-1-酮(123mg,0.789mmol)于DCE(2mL)中的混合物于室温下搅拌30分钟。将反应混合物冷却至0℃。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(200mg,0.657mmol)于DCE(2mL)中的溶液,接着加入乙酸(1滴)。将反应物于0℃搅拌30分钟,然后于室温下搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(83mg,28.4%)。对于C23H32N4O5,[M+H]计算值为445;测量值为445.5。
步骤B:(S)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将(S)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(88mg,0.198mmol)、MeOH(1mL)和THF(1mL)加至带有搅拌子的20mL圆底烧瓶中。加入NaOH(12N,1mL)水溶液,并将反应混合物于53℃下搅拌16小时。将溶剂移除并将生成的残余物进一步经由制备批量操作触发器LC-MS(AcCN/H2O,1-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(6mg,9.17%)。对于C17H22N4O3,[M+H]计算值为331;测量值为331.6。
步骤C:(S)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(S)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸(6mg,0.018mmol)加至为搅拌配备的8mL闪烁管中。加入N,N-二甲基甲酰胺(2mL)、HATU(8.29mg,0.022mmol)以及4-甲基吗啉(2.2mg,0.022mmol)并使溶液于室温下搅拌1小时。将溶剂移除并将生成的残余物进一步经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色固体的标题化合物(2.8mg,49.4%)。1H NMR(500MHz,CD3OD)δ0.97(t,J=7.32Hz,3H)1.74-1.98(m,5H)1.98-2.14(m,1H)3.08-3.22(m,1H)3.37-3.47(m,1H)3.65-3.77(m,1H)4.07(s,1H)5.05(s,2H)5.62(dd,J=8.54,7.08Hz,1H)7.11(d,J=4.88Hz,1H)7.80(s,1H)8.29(br.s.,1H)。对于C17H20N4O2,[M+H]计算值为313;测量值为313.6。
制备D:(R)-2-氨基-1-(吡咯烷-1-基)丁-1-酮
步骤A:(R)-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)丁酸(1.5g,7.38mmol)、HATU(3.37g,8.86mmol)和吡咯烷(1.303mL,14.76mmol)于DCM(50mL)中的混合物中加入Et3N(2.057mL,14.76mmol)。将反应混合物于室温下搅拌5小时,然后用NaHCO3饱和水溶液和盐水洗涤。将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供为浅黄色油状物的标题化合物(1.6g,85%)。1H NMR(500MHz,CDCl3)δ0.88-1.04(m,3H)1.38-1.48(m,9H)1.52-1.64(m,1H)1.69-1.79(m,1H)1.82-1.92(m,2H)1.92-2.02(m,2H)3.36-3.47(m,2H)3.53(dt,J=12.08,7.14Hz,1H)3.65(dt,J=10.01,6.47Hz,1H)4.30-4.43(m,1H)5.37(d,J=8.30Hz,1H)。
步骤B:(R)-2-氨基-1-(吡咯烷-1-基)丁-1-酮
将在50%TFA/DCM(10mL)中的(R)-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯(1.6g,6.24mmol)搅拌1小时。将反应混合物浓缩并分离为澄清油状物的TFA盐。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.91g,5.82mmol,79%)。1H NMR(400MHz,CDCl3)δ1.03(t,J=7.45Hz,3H)1.78-2.03(m,6H)3.29-3.46(m,2H)3.46-3.54(m,1H)3.54-3.66(m,1H)4.14(t,J=6.19Hz,1H)。
实施例19:(R)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
步骤A:(R)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将三乙酰氧基硼氢化钠(237mg,1.116mmol)和(R)-2-氨基-1-(吡咯烷-1-基)丁-1-酮(131mg,0.837mmol)于DCE(2mL)的混合物中在室温下搅拌30分钟。将反应混合物冷却至0℃。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(200mg,0.657mmol)于DCE(2mL)中的溶液,接着加入乙酸(1滴)。将反应物于0℃下搅拌30分钟,然后在室温下搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(260mg,93%)。对于C23H32N4O5,[M+H]计算值为445;测量值为445.5。
步骤B:(R)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将(R)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(150mg,0.337mmol)、MeOH(1mL)和THF(1mL)加至带有搅拌子的20mL圆底烧瓶。加入NaOH(12N,1mL)水溶液,并将反应混合物于53℃下搅拌16小时。将溶剂移除,并将生成的残余物进一步经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(8.7mg,0.026mmol,7.80%)。对于C17H22N4O3,[M+H]计算值为331;测量值为331.6。
步骤C:(R)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(S)-4-((1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸(8.7mg,0.026mmol)加至为搅拌配备的8mL闪烁管中。加入N,N-二甲基甲酰胺(2mL)、HATU(12.02mg,0.032mmol)和4-甲基吗啉(3.20mg,0.022mmol),并使溶液于室温下搅拌1小时。将溶剂移除,并将生成的残余物进一步经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色固体的标题化合物(1.6mg,19.5%)。1H NMR(500MHz,CD3OD)δ0.88-1.04(m,3H)1.75-1.98(m,4H)1.98-2.05(m,2H)3.43-3.50(m,3H)3.50-3.57(m,1H)5.07(s,2H)5.62(dd,J=8.79,6.83Hz,1H)7.13(d,J=4.88Hz,1H)7.81(s,1H)8.28(d,J=5.37Hz,1H)。对于C17H20N4O2,[M+H]计算值为313;测量值为313.6。
制备E:(R)-2-氨基-3-甲基-1-(吡咯烷-1-基)丁-1-酮
步骤A:(R)-3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)-3-甲基丁酸(1.0g,4.60mmol)、HATU(2.1g,5.52mmol)和吡咯烷(0.812mL,9.21mmol)于DCM(30mL)的混合物中加入Et3N(1.28mL,9.21mmol)。将反应混合物于室温下搅拌5小时,然后用饱和NaHCO3水溶液和盐水洗涤。将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供为浅黄色油状物的标题化合物(1.18g,95%)。1H NMR(400MHz,CDCl3)δ0.95(d,J=18.95Hz,3H)0.95(d,J=5.31Hz,3H)1.30-1.53(m,9H)1.77-2.07(m,5H)3.33-3.59(m,3H)3.59-3.80(m,1H)4.25(dd,J=9.35,6.57Hz,1H)5.30(d,J=9.09Hz,1H)。
步骤B:(R)-2-氨基-3-甲基-1-(吡咯烷-1-基)丁-1-酮
将在50%TFA/DCM(10mL)中的(R)-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基羧酸叔丁酯(1.18g,4.37mmol)搅拌1小时。将反应混合物浓缩并分离为澄清油状物的TFA盐。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.69g,92%)。1H NMR(400MHz,CDCl3)δ1.08(d,J=7.07Hz,3H)1.06(d,J=7.07Hz,3H)1.77-2.04(m,4H)2.12-2.26(m,1H)3.26-3.45(m,2H)3.45-3.58(m,1H)3.63(dt,J=9.98,6.51Hz,1H)4.01(d,J=5.56Hz,1H)。
实施例20:(R)-4-(3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
步骤A:(R)-3-甲基4-((3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯
将在DCE(2mL)中的三乙酰氧基硼氢化钠(139mg,0.657mmol)和(R)-2-氨基-3-甲基-1-(吡咯烷-1-基)丁-1-酮(84mg,0.493mmol)的混合物于室温下搅拌30分钟。将反应混合物冷却至0℃。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(100mg,0.329mmol)于DCE(2mL)中的溶液,接着加入乙酸(1滴)。将反应物于0℃下搅拌30分钟,并接着于室温下搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(128mg,85%)。对于C24H34N4O5,[M+H]计算值为459;测量值为459.6。
步骤B:(R)-4-((3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将(R)-4-((3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(134mg,0.292mmol)加至为搅拌配备的8mL闪烁管中。加入NaOH水溶液(12N,2mL)和MeOH(1mL),并将溶液于53℃下搅拌48小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物。
步骤C:(R)-4-(3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(133mg,0.351mmol)和4-甲基吗啉(35.5mg,0.351mmol)的混合物中将(R)-4-((3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,1-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(28mg,29.4%来自步骤B的起始材料)。1H NMR(400MHz,CD3OD)δ0.92(d,J=6.57Hz,3H)1.04(d,J=6.32Hz,3H)1.78-1.94(m,3H)1.94-2.02(m,1H)2.02(s,1H)2.45-2.65(m,1H)3.38-3.56(m,2H)3.61-3.79(m,2H)5.04-5.15(m,1H)5.45(d,J=11.12Hz,1H)7.30(d,J=5.56Hz,1H)7.91(s,1H)8.35(d,J=5.56Hz,1H)。对于C18H22N4O2,[M+H]计算值为327;测量值为327.6。
制备F:(R)-2-氨基-4-甲基-1-(吡咯烷-1-基)戊-1-酮
步骤A:(R)-4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)-4-甲基戊酸(1.0g,4.32mmol)、HATU(1.97g,5.19mmol)和吡咯烷(0.76mL,8.65mmol)于DCM(30mL)的混合物中加入Et3N(1.2mL,8.65mmol)。将反应混合物于室温下搅拌5小时,并接着以饱和NaHCO3水溶液和盐水洗涤。将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供为浅黄色油状物的标题化合物(1.17g,95%)。
步骤B:(R)-2-氨基-4-甲基-1-(吡咯烷-1-基)戊-1-酮
将在50%TFA/DCM(10mL)中的(R)-4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基羧酸叔丁酯搅拌1小时。将反应混合物浓缩并分离为澄清油状物的TFA盐。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.71g,93%)。1H NMR(400MHz,CDCl3)δ0.96(t,J=6.57Hz,6H)1.42-1.60(m,1H)1.75-2.04(m,6H)3.26-3.44(m,2H)3.45-3.56(m,1H)3.61(dt,J=9.85,6.57Hz,1H)4.15(dd,J=8.84,4.29Hz,1H)。
实施例21:(R)-4-(4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
步骤A:(R)-4-((4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将三乙酰氧基硼氢化钠(139mg,0.657mmol)和(R)-2-氨基-4-甲基-1-(吡咯烷-1-基)戊-1-酮(91mg,0.493mmol)于DCE(2mL)中的混合物于室温下搅拌30分钟。将反应混合物冷却至0℃。加入3-甲基4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯(100mg,0.329mmol)于DCE(2mL)中的溶液,接着加入乙酸(1滴)。将反应物于0℃下搅拌30分钟,并接着于室温下搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(160mg,93%)。对于C25H36N4O5,[M+H]计算值为473;测量值为473.7。
步骤B:(R)-4-((4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将(R)-3-甲基4-((4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯(160mg,0.339mmol)于氮气下加至为搅拌配备的8mL闪烁管中。加入NaOH水溶液(12N,2mL)和MeOH(1mL),并将溶液于53℃下搅拌48小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物。
步骤C:(R)-4-(4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(133mg,0.351mmol)和4-甲基吗啉(35.5mg,0.351mmol)的混合物中将(R)-4-((4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,1-50%)纯化。将馏分收集、浓缩并在真空中干燥,以提供为黄色油状物的标题化合物(53mg,46%来自步骤B的起始材料)。1H NMR(400MHz,CDCl3)δ0.96(t,J=6.57Hz,6H)1.42-1.60(m,1H)1.75-2.04(m,6H)3.26-3.44(m,2H)3.45-3.56(m,1H)3.61(dt,J=9.85,6.57Hz,1H)4.15(dd,J=8.84,4.29Hz,1H)。对于C19H24N4O2,[M+H]计算值为341;测量值为341.6。
制备G:(R)-2-氨基-N-环戊基-3-甲基丁酰胺
步骤A:(R)-1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)-3-甲基丁酸(0.5g,2.301mmol)、HATU(1.05g,2.76mmol)和环戊胺(0.455mL,4.60mmol)于DCM(20mL)的混合物中加入Et3N(0.642mL,4.60mmol)。将反应混合物于室温下搅拌5小时,用NaHCO3饱和水溶液和盐水洗涤,经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供标题化合物(0.61g,94%)。
步骤B:(R)-2-氨基-N-环戊基-3-甲基丁酰胺
将在50%TFA/DCM(10mL)中的(R)-1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基羧酸叔丁酯搅拌1小时。将反应混合物浓缩,并分离为澄清油状物的TFA盐。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.37g,92%)。1H NMR(400MHz,CDCl3)δ0.96-1.08(m,6H)1.35-1.51(m,1H)1.51-1.74(m,4H)1.90(td,J=12.82,6.19Hz,3H)2.08-2.23(m,1H)3.82(d,J=6.82Hz,1H)4.02-4.21(m,1H)7.32-7.53(m,0H)7.40(d,J=7.07Hz,1H)。
实施例22:(R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
步骤A:(R)-3-甲基4-((1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯
将三乙酰氧基硼氢化钠(104mg,0.493mmol)和(R)-2-氨基-N-环戊基-3-甲基丁酰胺(68.1mg,0.370mmol)于DCE(2mL)的混合物于室温下搅拌30分钟。将反应混合物冷却至0℃。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(75mg,0.246mmol)于DCE(2mL)中的溶液,再加入乙酸(1滴)。将反应混合物于0℃下搅拌30分钟,并接着于室温下搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(105mg,90%)。对于C25H36N4O5,[M+H]计算值为473;测量值为473.7。
步骤B:(R)-4-((1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将(R)-4-((1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(105mg,0.222mmol)于氮气下加至为搅拌配备的8mL闪烁管中。加入NaOH水溶液(12N,2mL)和MeOH(1mL),并将溶液于53℃下搅拌48小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物。
步骤C:(R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(101mg,0.267mmol)和4-甲基吗啉(27.0mg,0.267mmol)的混合物中将(R)-4-((1-(环戊基氨基)-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,1-50%)纯化。将馏分收集、浓缩并在真空中干燥,以提供为黄色油状物的标题化合物(23mg,30%来自步骤B的起始材料)。1H NMR(400MHz,CD3OD)δ0.99-1.04(m,3H)1.04-1.08(m,3H)1.28-1.38(m,1H)1.42-1.67(m,4H)1.72(br.s.,2H)1.77-2.00(m,2H)2.79-2.90(m,1H)4.02-4.21(m,2H)5.12(d,J=9.35Hz,1H)7.78(d,J=5.31Hz,1H)7.93-8.08(m,1H)8.63(d,J=5.30Hz,1H)。对于C19H24N4O2,[M+H]计算值为341;测量值为341.4。
制备H:(2R,3R)-2-氨基-N-环戊基-3-甲基戊酰胺
步骤A:(2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基羧酸叔丁酯
往(2R,3R)-2-(叔丁氧基羰基氨基)-3-甲基戊酸(0.5g,2.162mmol)、HATU(0.986g,2.59mmol)和环戊胺(0.427mL,4.32mmol)于DCM(10mL)的混合物中加入Et3N(0.603mL,4.32mmol)。将反应混合物于室温下搅拌5小时,然后用NaHCO3饱和水溶液和盐水洗涤,将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供标题化合物(0.56g,87%)。1H NMR(400MHz,CDCl3)δ0.82-0.89(m,3H)0.92(t,J=7.45Hz,3H)1.32-1.41(m,6H)1.44(s,9H)1.55-1.77(m,3H)1.84-2.04(m,2H)2.99(d,J=4.29Hz,1H)3.96(dd,J=8.72,5.43Hz,1H)4.21(dt,J=13.89,6.95Hz,1H)5.02(br.s.,1H)5.93(br.s.,1H)。
步骤B:(2R,3R)-2-氨基-N-环戊基-3-甲基戊酰胺
将(2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基羧酸叔丁酯和50%TFA/DCM(10mL)的混合物搅拌1小时。将反应混合物浓缩,并分离为澄清油状物的TFA盐类。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.34g,90%)。经由TLC(经由茚三酮染色而显现)得到纯化产物。
实施例23:(2R,3R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺
步骤A:3-甲基4-(((2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯
将三乙酰氧基硼氢化钠(104mg,0.493mmol)和(2R,3R)-2-氨基-N-环戊基-3-甲基戊酰胺(48.9mg,0.246mmol)于DCE(2mL)中的混合物于室温下搅拌30分钟。将4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(75mg,0.246mmol)加至混合物中。将反应混合物于室温下搅拌1小时并随后浓缩,以提供为粗中间体的标题化合物。对于C26H38N4O5,[M+H]计算值为487;测量值为487.7。
步骤B:4-(((2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗4-(((2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯加入MeOH(1mL)和NaOH水溶液(12N,2mL)。将反应混合物于53℃下搅拌16小时,然后经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C20H28N4O3,[M+H]计算值为373;测量值为373.7。
步骤C:(2R,3R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(112mg,0.296mmol)和4-甲基吗啉(37.4mg,0.370mmol)的混合物中将4-(((2R,3R)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(32mg,37%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ0.61-0.72(m,2H)0.90-1.06(m,5H)1.37-1.66(m,7H)1.66-1.77(m,2H)1.77-1.99(m,4H)3.98-4.22(m,1H)4.85-4.97(m,2H)5.21(d,J=9.35Hz,1H)。对于C20H26N4O2,[M+H]计算值为355;测量值为355.5。
实施例24:(2R,3S)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺
步骤A:(2R,3S)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-3-甲基戊酸
将三乙酰氧基硼氢化钠(104mg,0.493mmol)、(2R,3S)-2-氨基-3-甲基戊酸(43.1mg,0.329mmol)和DCM(2mL)加至10mL圆底烧瓶中。将混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,再用MeOH淬灭(3滴)。将混合物浓缩,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C21H29N3O6,[M+H]计算值为420;测量值为420.6。
步骤B:4-(((2R,3S)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
往(2R,3S)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-3-甲基戊酸中加入THF(2mL),接着加入HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)。将悬浮液于43℃搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C26H38N4O5,[M+H]计算值为487;测量值为487.7。
步骤C:4-(((2R,3S)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗4-(((2R,3S)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯进行浓缩并重新溶解于MeOH(1mL)。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C20H28N4O3,[M+H]计算值为373;测量值为373.7。
步骤D:(2R,3S)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将4-(((2R,3S)-1-(环戊基氨基)-3-甲基-1-氧代戊烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(6mg,10%来自步骤A的起始材料)。1H NMR(500MHz,CD3OD)δ0.89(d,J=6.35Hz,3H)0.95-1.06(m,3H)1.15-1.26(m,1H)1.35-1.45(m,1H)1.45-1.63(m,4H)1.70(br.s.,1H)1.81-2.02(m,2H)2.10-2.19(m,1H)2.28(br.s.,1H)3.34(s,1H)4.02-4.16(m,1H)5.04-5.18(m,1H)5.40-5.56(m,1H)7.29(d,J=5.37Hz,1H)7.90(s,1H)8.34(d,J=5.37Hz,1H)。对于C20H26N4O2,[M+H]计算值为355;测量值为355.5。
实施例25:(R)-N-环戊基-2-环丙基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H3H5H)-基)乙酰胺
步骤A:(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-2-环丙基乙酸
将三乙酰氧基硼氢化钠(104mg,0.493mmol)、(R)-2-氨基-2-环丙基乙酸(37.8mg,0.329mmol)和DCM(2mL)加至10mL圆底烧瓶中。将反应混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,然后用MeOH淬灭(3滴)。将混合物浓缩,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C20H25N3O6,[M+H]计算值为404;测量值为404.3。
步骤B:(R)-4-((2-(环戊基氨基)-1-环丙基-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
往(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-2-环丙基乙酸中加入THF(2mL),接着加入HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)。将悬浮液于43℃搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C25H34N4O5,[M+H]计算值为471;测量值为471.5。
步骤C:(R)-4-((2-(环戊基氨基)-1-环丙基-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗(R)-4-((2-(环戊基氨基)-1-环丙基-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯进行浓缩并重新溶解于MeOH(1mL)中。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C19H24N4O3,[M+H]计算值为357;测量值为357.5。
步骤D:(R)-N-环戊基-2-环丙基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将(R)-4-((2-(环戊基氨基)-1-环丙基-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(4.4mg,8%来自步骤A的起始材料)。1H NMR(500MHz,CD3OD)δ0.38(d,J=5.37Hz,1H)0.73(t,J=4.90Hz,1H)0.82(br.s.,1H)1.45-1.57(m,2H)1.60(s,2H)1.73(br.s.,2H)1.83-1.98(m,2H)3.09-3.22(m,1H)3.68-3.77(m,1H)4.13(d,J=5.86Hz,1H)5.48-5.58(m,2H)7.29(d,J=5.37Hz,1H)7.84(s,1H)8.35(br.s.,1H)。对于C19H22N4O2,[M+H]计算值为339;测量值为339.5。
实施例26:(R)-N-环戊基-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
步骤A:(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-3,3-二甲基丁酸
将三乙酰氧基硼氢化钠(104mg,0.493mmol)、(R)-2-氨基-3,3-二甲基丁酸(43.1mg,0.329mmol)和DCM(2mL)加至10mL圆底烧瓶中。将混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,然后用MeOH淬灭(3滴)。将混合物浓缩,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C21H29N3O6,[M+H]计算值为420;测量值为420.3。
步骤B:(R)-3-甲基4-((1-(环戊基氨基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯
将THF(2mL)、HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)加至(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-3,3-二甲基丁酸中,将悬浮液于43℃搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C26H38N4O5,[M+H]计算值为487;测量值为487.6。
步骤C:(R)-4-((1-(环戊基氨基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗(R)-4-((1-(环戊基氨基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯浓缩并重新溶解于MeOH(1mL)中。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C20H28N4O3,[M+H]计算值为373;测量值为373.6。
步骤D:(R)-N-环戊基-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将(R)-4-((1-(环戊基氨基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(9.2mg,15.8%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ1.16(s,9H)1.36-1.65(m,4H)1.65-1.77(m,2H)1.78-2.05(m,2H)4.11(t,J=6.82Hz,1H)5.30-5.51(m,2H)5.51-5.69(m,1H)7.13-7.31(m,1H)7.25(d,J=5.56Hz,1H)7.87(s,1H)8.32(d,J=5.31Hz,1H)。对于C20H26N4O2,[M+H]计算值为355;测量值为355.6。
实施例27:(R)-N,2-二环戊基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺
步骤A:(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-2-环戊基乙酸
将三乙酰氧基硼氢化钠(104mg,0.493mmol)、(R)-2-氨基-2-环戊基乙酸(47.1mg,0.329mmol)和DCM(2mL)加至10mL圆底烧瓶中。将混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,然后用MeOH淬灭(3滴)。浓缩混合物,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C22H29N3O6,[M+H]计算值为432;测量值为432.4。
步骤B:(R)-4-((1-环戊基-2-(环戊基氨基)-2-氧基乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将THF(2mL)、HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)加至(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-2-环戊基乙酸中。将悬浮液于43℃搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C27H38N4O5,[M+H]计算值为499;测量值为499.6。
步骤C:(R)-4-((1-环戊基-2-(环戊基氨基)-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗(R)-4-((1-环戊基-2-(环戊基氨基)-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯浓缩并重新溶解于MeOH(1mL)中。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C21H28N4O3,[M+H]计算值为384;测量值为384.6。
步骤D:(R)-N,2-二环戊基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将(R)-4-((1-环戊基-2-(环戊基氨基)-2-氧代乙基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(11mg,18.7%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ1.22-1.34(m,1H)1.34-1.45(m,2H)1.54-1.78(m,10H)1.78-2.00(m,3H)2.65-2.84(m,1H)4.00-4.15(m,1H)5.08(d,J=11.37Hz,1H)5.21(s,1H)5.47(s,1H)7.12-7.36(m,1H)7.24(d,J=5.31Hz,1H)7.86(s,1H)8.32(d,J=5.31Hz,1H)。对于C21H26N4O2,[M+H]计算值为367;测量值为367.6。
实施例28:(R)-N-环戊基-4,4,4-三氟-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
步骤A:(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-4,4,4-三氟丁酸
将三乙酰氧基硼氢化钠(104mg,0.493mmol)、2-氨基-4,4,4-三氟丁酸(51.6mg,0.329mmol)和DCM(2mL)加至10mL圆底烧瓶中。将混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,然后用MeOH淬灭(3滴)。将混合物浓缩,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C19H22F3N3O6,[M+H]计算值为446;测量值为446.5。
步骤B:(R)-4-((1-(环戊基氨基)-4,4,4-三氟-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将THF(2mL)、HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)加至(R)-2-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-4,4,4-三氟丁酸中。将生成的悬浮液于43℃下搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C24H31F3N4O5,[M+H]计算值为513;测量值为513.6。
步骤C:(R)-4-((1-(环戊基氨基)-4,4,4-三氟-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗(R)-4-((1-(环戊基氨基)-4,4,4-三氟-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯进行浓缩并重新溶解于MeOH(1mL)中。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C18H21F3N4O3,[M+H]计算值为399;测量值为399.6。
步骤D:(R)-N-环戊基-4,4,4-三氟-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将(R)-4-((1-(环戊基氨基)-4,4,4-三氟-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(4.5mg,7.2%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ1.32-1.62(m,4H)1.62-1.78(m,2H)1.82-2.05(m,2H)2.87-3.07(m,1H)3.07-3.21(m,1H)4.10-4.24(m,1H)5.13(d,J=19.20Hz,1H)5.26(d,J=18.95Hz,1H)5.41(dd,J=8.08,5.31Hz,1H)7.24(d,J=5.31Hz,1H)7.90(s,1H)8.36(d,J=5.05Hz,1H)。对于C18H19F3N4O2,[M+H]计算值为381;测量值为381.5。
制备I:(R)-2-氨基-N-环戊基-3-羟基-3-甲基丁酰胺
步骤A:(R)-1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)-3-羟基-3-甲基丁酸(0.5g,2.144mmol)、HATU(0.978g,2.57mmol)和环戊胺(0.423mL,4.29mmol)于DCM(10mL)的混合物中加入Et3N(0.598mL,4.29mmol)。将反应混合物于室温下搅拌5小时,然后用NaHCO3饱和水溶液和盐水洗涤,将有机物经由MgSO4干燥、浓缩,并经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供标题化合物(0.6g,93%)。
步骤B:(R)-2-氨基-N-环戊基-3-羟基-3-甲基丁酰胺
将(R)-1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基羧酸叔丁酯和50%TFA/DCM(10mL)的混合物搅拌1小时。将生成的产物浓缩并分离为澄清油状物的TFA盐。经由快速柱色谱法(MeOH/DCM,0-10%)纯化,以提供为白色固体的标题化合物(游离碱,0.37g,93%)。1H NMR(400MHz,DMSO-d6)δ1.13(s,3H)1.23(s,3H)1.40(s,2H)1.44-1.69(m,4H)1.73-2.01(m,2H)3.48(s,1H)3.89-4.16(m,1H)5.33(s,1H)7.87-7.89(m,2H)8.33(d,J=7.33Hz,1H)。
实施例29:(R)-N-环戊基-3-羟基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
步骤A:(R)-4-((1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将三乙酰氧基硼氢化钠(104mg,0.493mmol)和(R)-2-氨基-N-环戊基-3-羟基-3-甲基丁酰胺(49.4mg,0.246mmol)于DCE(2mL)的混合物于室温下搅拌30分钟。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(75mg,0.246mmol),并将反应混合物于室温下搅拌1小时。反应后,将混合物浓缩,以提供标题化合物。对于C25H36N4O6,[M+H]计算值为489;测量值为489.3。
步骤B:(R)-4-((1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
往(R)-4-((1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯中加入MeOH(1mL)和NaOH水溶液(12N,2mL)。将反应混合物于53℃下搅拌16小时,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C19H26N4O4计算[M+H],375;测量值为374.5。
步骤C:(R)-N-环戊基-3-羟基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(112mg,0.296mmol)和4-甲基吗啉(37.4mg,0.370mmol)的混合物中将(R)-4-((1-(环戊基氨基)-3-羟基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将生成的产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(6.5mg,7.4%来自步骤A的起始材料)。1H NMR(500MHz,CD3OD)δ1.20(s,3H)1.37-1.41(m,3H)1.41-1.79(m,5H)1.85-2.00(m,3H)4.19(s,1H)5.14-5.26(m,1H)5.35(s,1H)5.64-5.77(m,1H)7.22(d,J=5.37Hz,1H)7.89(s,1H)8.31(d,J=5.37Hz,1H)。对于C19H24N4O3计算[M+H],357;测量值为357.5。
制备J:(R)-2-氨基-3-氰基-N-环戊基丙酰胺
步骤A:(R)-3-氰基-1-(环戊基氨基)-1-氧代丙烷-2-基氨基羧酸叔丁酯
往(R)-2-(叔丁氧基羰基氨基)-3-氰丙酸(0.5g,2.334mmol)、HATU(0.986g,2.59mmol)和环戊胺(0.461mL,4.67mmol)于DCM(10mL)的混合物中加入Et3N(0.651mL,4.67mmol)。将反应混合物于室温下搅拌5小时,然后用NaHCO3饱和水溶液和盐水洗涤,将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-10%)纯化,以提供标题化合物(0.61g,93%)。1H NMR(400MHz,CD3OD)δ1.50(s,9H)1.57-1.73(m,4H)1.79-1.87(m,3H)1.89-2.02(m,1H)2.05-2.19(m,3H)2.76-2.95(m,1H)3.87(t,J=7.07Hz,1H)。
步骤B:(R)-2-氨基-3-氰基-N-环戊基丙酰胺
将(R)-3-氰基-1-(环戊基氨基)-1-氧代丙烷-2-基氨基羧酸叔丁酯和50%TFA/DCM(10mL)的混合物搅拌1小时。反应后,将混合物浓缩,以提供为澄清油状物的标题化合物(TFA盐,0.265g,41%)。经由TLC(经由茚三酮染色而显现)使产物纯化。
制备K:5-氯-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
步骤A:5-氯-3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛
往5-氯-1H-吡咯并[2,3-b]吡啶-4-甲醛(5.0g,27.7mmol)于EtOH(100mL)的溶液中加入碘(8.43g,33.2mmol)、碘化钠(4.98g,33.2mmol)和NaOH水溶液(1N,35mL,35mmol)。在室温下搅拌4小时后,将反应混合物用水(200mL)稀释。经由过滤收集橙色沉淀物,并在真空下干燥。将固体溶解于DMF(60mL)中并缓慢加入氢化钠(60%,1.33g,33.2mmol)。将深红色溶液于室温下搅拌30分钟。加入甲苯磺酰氯(5.81g,30.5mmol),并将混合物于室温下搅拌2小时。将混合物用EtOAc稀释,并将反应物用水淬灭。将有机物分离,用NaHSO3(0.1N)水溶液和盐水洗涤,经由MgSO4干燥并浓缩。经由硅胶色谱法(3:1:1己烷/DCM/EtOAc)纯化,以提供为黄色固体的标题化合物(8.96g,70%)。1H NMR(500MHz,DMSO-d6)δ3.15(s,3H),8.24(d,J=8.5Hz,2H),8.81(d,J=8.5Hz,2H),9.17(s,1H),9.38(s,1H),11.81(s,1H)。对于C15H10ClIN2O3S,[M+H]计算值为461,463;测量值为461,463。
步骤B:5-氯-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将氯化锂(1.05g,24.7mmol)和一水合甲酸锂(1.73g,24.7mmol)于氮气下在干燥可密封的管中合并。加入DMF(20mL)、5-氯-3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛(3.8g,8.25mmol)、乙酸酐(1.56mL,16.5mmol)和乙酸钯(185mg,0.83mmol)。将DIPEA(2.87mL)加入,并将反应管密封并于52℃加热3小时。用MeOH/DCM(20%)吸收反应混合物并过滤,以移除不溶的黑色的碳材料。将黄色溶液在真空中浓缩,溶解于MeOH/DCM(10%)中并用HCl水溶液(0.1N)清洗。将水层用MeOH/DCM(10%,2x)萃取。将有机物合并,经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(10-15%MeOH/DCM)纯化,以提供为浅棕黄色固体的标题化合物(2.34g,75%)。1H NMR(500MHz,CD3OD)δ3.15(s,3H),8.24(d,J=8.5Hz,2H),8.81(d,J=8.5Hz,2H),9.17(s,1H),9.38(s,1H),11.81(s,1H)。对于C16H11ClN2O5S,[M+H]计算值为379、381;测量值为379、381。
实施例30:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-氰基-N-环戊基丙酰胺
步骤A:(R)-5-氯-4-((3-氰基-1-(环戊基氨基)-1-氧代丙烷-2-基氨基)甲基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将三乙酰氧基硼氢化钠(26.5mg,0.125mmol)和(R)-2-氨基-3-氰基-N-环戊基丙酰胺(22.70mg,0.125mmol)于DCM(1mL)的混合物在室温下搅拌10分钟。将反应混合物冷却至0℃。加入在DCM(1mL)中的5-氯-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸(30mg,0.063mmol)的溶液。将反应混合物于0℃下搅拌20分钟,然后浓缩,以提供标题化合物。对于C26H28ClN5O5S,[M+H]计算值为544;测量值为544.2。
步骤B:(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-氰基-N-环戊基丙酰胺
将(R)-5-氯-4-((3-氰基-1-(环戊基氨基)-1-氧代丙烷-2-基氨基)甲基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸、THF(5mL)、HATU(28.6mg,0.075mmol)和4-甲基吗啉(19.01mg,0.188mmol)的混合物于室温下搅拌2小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-90%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C25H24ClN5O4S,[M+H]计算值为526;测量值为526.2。
步骤C:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-氰基-N-环戊基丙酰胺
将(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-氰基-N-环戊基丙酰胺于MeOH(2mL)的溶液中加入NaOH水溶液(1N,0.5mL)。将反应混合物搅拌20分钟,并将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(0.5mg,2.1%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ1.37-1.72(m,4H)1.83-1.95(m,4H)3.22-3.26(m,2H)3.69-3.76(m,1H)5.11(s,1H)5.14-5.17(m,1H)5.18(s,1H)7.88(s,1H)8.27(s,1H)。对于C18H18ClN5O2,[M+H]计算值为372;测量值为372.4。
实施例31:N-环戊基-1-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)环戊烷甲酰胺
步骤A:1-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)环戊烷甲酸
将在DCM(2mL)中的三乙酰氧基硼氢化钠(104mg,0.493mmol)和1-氨基环戊烷甲酸(42.4mg,0.329mmol)加至10mL圆底烧瓶中。将反应混合物于室温下搅拌30分钟,之后加入在DCM(2mL)中的4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(50mg,0.164mmol)。将反应物于室温下搅拌2小时,然后用MeOH淬灭(3滴)。将混合物浓缩,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C21H27N3O6,[M+H]计算值为418;测量值为418.3。
步骤B:4-((1-(环戊基氨甲酰基)环戊基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将THF(2mL)、HATU(94mg,0.246mmol)、环戊胺(70.0mg,0.822mmol)和4-甲基吗啉(83mg,0.822mmol)加至1-((1-(叔丁氧基羰基)-3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)环戊烷甲酸中。将悬浮液于43℃下搅拌36小时,以提供标题化合物,使其无需进一步纯化即可用于下一步骤。对于C26H36N4O5,[M+H]计算值为485;测量值为485.4。
步骤C:4-((1-(环戊基氨甲酰基)环戊基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸
将粗3-甲基4-((1-(环戊基氨甲酰基)环戊基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁酯浓缩并重新溶解于MeOH(1mL)中。加入NaOH(12N,2mL)水溶液,并将反应混合物于53℃搅拌16小时。将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。对于C20H26N4O3,[M+H]计算值为371;测量值为371.6。
步骤D:N-环戊基-1-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)环戊烷甲酰胺
以类似于实施例19的步骤C的方式,在THF(2mL)、HATU(94mg,0.246mmol)和4-甲基吗啉(83mg,0.822mmol)的混合物中将4-((1-(环戊基氨甲酰基)环戊基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲酸环化,并将产物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(2.7mg,4.8%来自步骤A的起始材料)。1H NMR(500MHz,CD3OD)δ1.45(d,J=7.32Hz,1H)1.52(d,J=4.88Hz,1H)1.61(br.s.,1H)1.79(br.s.,2H)1.82-1.91(m,1H)1.96-2.02(m,1H)2.06-2.23(m,4H)2.50(d,J=13.18Hz,1H)2.98(br.s.,1H)3.21-3.29(m,2H)3.38-3.42(m,1H)4.03-4.17(m,1H)5.29(s,1H)7.20(br.s.,1H)7.75(s,1H)8.31(br.s.,1H)。对于C20H24N4O2,[M+H]计算值为353;测量值为353.5。
制备L:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸
步骤A:(R)-2-((5-氯-3-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)甲氨基)-3-甲基丁酸叔丁酯
将三乙酰氧基硼氢化钠(517mg,2.44mmol)和D-缬氨酸叔丁酯、HCl盐(512mg,2.44mmol)于DCM(15mL)中合并。将反应混合物于室温下搅拌20分钟并冷却至0℃。加入5-氯-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸(660mg,1.74mmol),并将反应物于0℃下搅拌1小时。将溶液在真空中浓缩,以提供为黄色泡沫物的标题化合物,使其无需进一步纯化即可用于下一步骤。
步骤B:(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯
将(R)-2-((5-氯-3-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)-3-甲基丁酸叔丁酯重新溶解于THF(40mL)。加入HATU(994mg,2.61mmol)和N-甲基吗啉(291μL,2.61mmol)并将反应混合物于50℃下搅拌2小时。加入另外的HATU(497mg,1.30mmol)和N-甲基吗啉(85μL,1.30mmol),并将反应混合物于50℃下搅拌另外的2小时。然后将反应混合物冷却,用EtOAc稀释,并用盐水洗涤。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(1:2:2EtOAc/己烷/DCM)纯化,以提供为黄色固体的标题化合物(660mg,73%来自步骤A的起始材料)。1H NMR(500MHz,CDCl3)δ0.80(d,J=7.0Hz,3H),1.01(d,J=7.0Hz,3H),1.36(s,9H),2.29-2.36(m,1H),2.34(s,3H),4.77-5.04(m,3H),7.44(d,J=8.5Hz,2H),8.06(d,J=8.5Hz,2H),8.28(s,1H),8.47(s,1H)。对于C25H28ClN3O5S,[M+H]计算值为518,520;测量值为518,520。
步骤C:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸
将(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯(650mg,1.25mmol)、EtOH(4mL)和NaOH水溶液(1N,2mL)的混合物于室温下搅拌40分钟。然后将混合物用DCM稀释,并用盐水洗涤。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(5%MeOH/DCM)纯化,以提供黄色油状物(425mg),将其溶解于50%TFA/DCM中。将溶液于室温下搅拌1小时,浓缩并在真空下干燥,以提供为黄色固体的标题化合物(360mg,93%)。1H NMR(500MHz,CD3OD)δ0.91(d,J=7.0Hz,3H),1.11(d,J=7.0Hz,3H),2.36-2.47(m,1H),4.80-5.08(m,3H),7.76(s,1H),8.19(s,1H)。对于C14H14ClN3O3,[M+H]计算值为308,310;测量值为308,310。
实施例32:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(氰甲基)-3-甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、2-氨基乙腈(3.64mg,0.065mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(3.8mg,33.8%)。1H NMR(400MHz,CD3OD)δ0.85-0.97(m,3H)1.02(d,J=6.57Hz,1H)1.07(d,J=6.32Hz,2H)2.53(dt,J=11.18,6.54Hz,1H)3.52-3.86(m,2H)4.89-5.04(m,1H)5.07(d,J=11.37Hz,1H)5.51(d,J=10.86Hz,1H)7.80-7.89(m,1H)8.13-8.34(m,1H)。对于C16H16ClN5O2,[M+H]计算值为346;测量值为346.4。
实施例33:1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-3-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、吡咯烷-3-甲腈(3.12mg,0.032mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(1.3mg,10.4%)。1H NMR(400MHz,CD3OD)δ0.92(s,3H)1.00-1.12(m,3H)2.27-2.35(m,1H)2.56(d,J=6.57Hz,1H)3.40(d,J=6.82Hz,1H)3.51-3.68(m,1H)3.74(d,J=6.57Hz,1H)3.79-3.94(m,1H)3.96-4.03(m,1H)4.88-5.00(m,2H)5.03-5.23(m,1H)5.39-5.48(m,1H)7.87(d,J=12.63Hz,1H)8.21-8.30(m,1H)。对于C19H20ClN5O2,[M+H]计算值为386;测量值为386.4。
实施例34:(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)哌啶-4-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、哌啶-4-甲腈(3.58mg,0.032mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(3.3mg,25.4%)。1H NMR(400MHz,CD3OD)δ0.84-0.93(m,3H)0.96-1.08(m,3H)1.42-1.60(m,1H)1.72-1.82(m,2H)1.82-2.00(m,1H)2.49-2.66(m,1H)2.92-3.07(m,1H)3.49-3.73(m,2H)3.78-4.00(m,1H)4.00-4.11(m,1H)4.90(d,J=7.58Hz,1H)4.92-5.01(m,1H)5.53(dd,J=10.86,3.54Hz,1H)7.82-7.92(m,1H)8.15-8.30(m,1H)。对于C20H22ClN5O2,[M+H]计算值为400;测量值为400.4。
实施例35:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(4-氰苯基)-3-甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、4-氨基苄腈(7.68mg,0.065mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(2mg,15.1%)。1H NMR(400MHz,CD3OD)δ0.90-1.03(m,3H)1.07-1.15(m,3H)2.59(dt,J=11.24,6.63Hz,1H)5.01(d,J=19.45Hz,1H)5.21(d,J=11.12Hz,1H)5.42(d,J=19.45Hz,1H)7.64-7.66(m,1H)7.66-7.68(m,1H)7.80-7.82(m,1H)7.82-7.84(m,1H)7.86(s,1H)8.25(s,1H)。对于C21H18ClN5O2,[M+H]计算值为408;测量值为408.4。
实施例36:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(3-氰苯基)-3-甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、3-氨基苄腈(7.68mg,0.065mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(1.8mg,13.58%)。1H NMR(400MHz,CD3OD)δ1.00(d,J=6.60Hz,3H)1.12(d,J=6.57Hz,3H)2.60(s,1H)5.02(d,J=19.71Hz,1H)5.20(d,J=11.12Hz,1H)5.43(d,J=19.71Hz,1H)7.43(dt,J=7.77,1.42Hz,1H)7.48(t,J=7.96Hz,1H)7.81-7.85(m,1H)7.86(s,1H)8.08(t,J=1.64Hz,1H)8.25(s,1H)。对于C21H18ClN5O2,[M+H]计算值为408;测量值为408.4。
实施例37:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((S)-1-氰基丁烷-2-基)-3-甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、(S)-3-氨基戊腈(3.19mg,0.032mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(3.1mg,24.6%)。1H NMR(400MHz,CD3OD)δ0.93(d,J=6.57Hz,3H)0.97(t,J=7.33Hz,3H)1.07(d,J=6.57Hz,3H)1.51-1.69(m,2H)2.44-2.58(m,2H)2.58-2.72(m,1H)4.07(br.s.,1H)4.86-4.97(m,1H)5.08(d,J=11.12Hz,1H)5.31(d,J=19.71Hz,1H)7.84(s,1H)8.23(s,1H)。对于C19H22ClN5O2,[M+H]计算值为388;测量值为388.4。
实施例38:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((R)-1-氰基丁烷-2-基)-3-甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、(R)-3-氨基戊腈(3.19mg,0.032mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(2.9mg,23.01%)。1H NMR(400MHz,CD3OD)δ0.82(t,J=7.45Hz,3H)0.89-0.99(m,3H)1.11(d,J=6.57Hz,3H)1.44-1.68(m,2H)2.41-2.56(m,1H)2.63(dd,J=16.93,7.33Hz,1H)2.76(dd,J=16.93,5.05Hz,1H)3.99(d,J=10.61Hz,1H)4.95(d,J=19.96Hz,1H)5.05(d,J=11.37Hz,1H)5.35(d,J=19.71Hz,1H)7.85(s,1H)8.20-8.27(m,1H)。对于C19H22ClN5O2,[M+H]计算值为388;测量值为388.4。
实施例39:(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)氮杂环丁烷-3-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、氮杂环丁烷-3-甲腈(2.7mg,0.032mmol)、4-甲基吗啉(4.93mg,0.049mmol)和HATU(14.83mg,0.039mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,5-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为半固体的标题化合物(3.7mg,30.6%)。1H NMR(400MHz,CD3OD)δ0.94(t,J=6.32Hz,3H)1.07(dd,J=18.19,6.32Hz,3H)2.44-2.59(m,1H)3.47-3.79(m,1H)4.15-4.40(m,2H)4.57(dt,J=9.73,4.99Hz,1H)4.63-4.78(m,1H)4.84(d,J=19.71Hz,1H)5.06-5.30(m,2H)7.82(d,J=11.37Hz,1H)8.25(d,J=5.56Hz,1H)。对于C18H18ClN5O2,[M+H]计算值为372;测量值为372.4。
制备M:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸
步骤A:(R)-4-((1-(苄氧基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-5-氯-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将三乙酰氧基硼氢化钠(86mg,0.407mmol)、(R)-2-氨基-3,3-二甲基丁酸苄酯(130mg,0.407mmol)和DCM(2mL)加至10mL圆底烧瓶中。将混合物于室温下搅拌10分钟,再冷却至0℃。将5-氯-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸(130mg,0.271mmol)加入,并将反应混合物于0℃下搅拌20分钟,以提供标题化合物。对于C29H30ClN3O6S,[M+H]计算值为584;测量值为584.0。
步骤B:(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸苄酯
将粗(R)-4-((1-(苄氧基)-3,3-二甲基-1-氧代丁烷-2-基氨基)甲基)-5-氯-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸于HATU(124mg,0.326mmol)和4-甲基吗啉(82mg,0.814mmol)中回流加热3小时。随后将反应混合物浓缩并且在真空中干燥,以提供标题化合物。对于C29H28ClN3O5S,[M+H]计算值为566;测量值为566.0。
步骤C:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸
将粗(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸苄酯溶解于MeOH/THF(50%,5mL)中。加入NaOH水溶液(1N,2mL)。将反应混合物于50℃下搅拌16小时并经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(34mg,38.9%来自步骤A的起始材料)。1H NMR(400MHz,CD3OD)δ1.22-1.32(m,9H)4.92(br.s.,1H)5.18(d,J=18.95Hz,1H)5.33(d,J=18.95Hz,1H)7.88(s,1H)8.29(s,1H)。对于C15H16ClN3O3,[M+H]计算值为322;测量值为322.5。
实施例40:(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(2-氰乙基)-3,3-二甲基丁酰胺
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸(5mg,0.016mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3-氨基丙腈(1.089mg,0.016mmol)、HOBt(3.57mg,0.023mmol)、EDC(4.47mg,0.023mmol)和N,N-二甲基吡啶-4-胺(1.898mg,0.016mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色油状物的标题化合物(3.2mg,55.1%)。1H NMR(500MHz,CD3OD)δ1.19(s,9H)2.63-2.72(m,2H)3.38-3.53(m,2H)4.89(br.s.,1H)5.29(d,J=19.04Hz,1H)5.41(d,J=19.00Hz,2H)7.85(s,1H)8.24(s,1H)8.55(d,J=4.88Hz,1H)。对于C18H20ClN5O2,[M+H]计算值为374;测量值为374.5。
实施例41:(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-di甲基丁酰基)氮杂环丁烷-3-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸(25mg,0.078mmol)于氮气下加至为搅拌配备的8mL闪烁管中。将THF(0.5mL)、氮杂环丁烷-3-甲腈盐酸盐(18.45mg,0.155mmol)、HATU和4-甲基吗啉(11.79mg,0.117mmol)加入并将溶液于25℃下搅拌1小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,15-40%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为黄色半固体的标题化合物(4.1mg,13.7%)。1H NMR(400MHz,CD3OD)δ1.17(s,9H)3.50-3.78(m,1H)4.17(br.s.,1H)4.25-4.37(m,1H)4.41-4.69(m,2H)5.17-5.30(m,2H)5.44(s,1H)7.87(br.s.,1H)8.25(s,1H)。对于C19H20ClN5O2,[M+H]计算值为386;测量值为386.4。
制备N:5-氟-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
步骤A:(5-氟-1H-吡咯并[2,3-b]吡啶-4-基)甲醇
将5-氟-1H-吡咯并[2,3-b]吡啶-4-甲酸甲酯(2.4g,12.36mmol)于氮气下加至烘干的为搅拌配备的200mL圆底烧瓶。加入THF(100mL)并将无色溶液冷却至0℃。加入氢化铝锂(27.2mL,27.2mmol)并将溶液于0℃下搅拌3小时。将反应物用EtOAc(100mL)淬灭;加入盐水(100mL),并用EtOAc萃取水相三次。将有机物经由Na2SO4干燥并浓缩,以提供为黄色细粉的标题化合物(2.01g,98%)。1H NMR(400MHz,CD3OD)δ4.96(d,J=1.26Hz,2H)6.72(d,J=3.54Hz,1H)7.44(d,J=3.54Hz,1H)8.06(d,J=2.78Hz,1H)。对于C8H7FN2O,[M+H]计算值为167;测量值为167.5。
步骤B:5-氟-1H-吡咯并[2,3-b]吡啶-4-甲醛
将在THF(100mL)中的(5-氟-1H-吡咯并[2,3-b]吡啶-4-基)甲醇(2.01g,12.10mmol)于氮气下加至装有搅拌棒的250mL圆底烧瓶中。加入二氧化锰(10.52g,121mmol)并将反应混合物于60℃下搅拌2小时。将有机物经由硅藻土垫过滤,用EtOAc(100mL)冲洗并浓缩。将生成的固体用EtOAc(50mL)湿磨并过滤,以提供为浅黄色固体的标题化合物(1.3g,65.5%)。1H NMR(400MHz,CD3OD)δ4.59(s,1H)5.34(d,J=3.54Hz,1H)5.86-6.08(m,1H)6.58(d,J=3.28Hz,1H)。对于C8H5FN2O,[M+H]计算值为165;测量值为165.5。
步骤C:5-氟-3-碘代-1H-吡咯并[2,3-b]吡啶-4-甲醛
往5-氯-1H-吡咯并[2,3-b]吡啶-4-甲醛(2.45g,14.93mmol)于EtOH(20mL)的溶液中加入碘(4.55g,17.91mmol)、碘化钠(2.68g,17.91mmol)和NaOH水溶液(1N,15mL)。将反应混合物在25℃下搅拌4小时,并用NaHSO3(0.1N)水溶液稀释。经由过滤收集橙色沉淀物,并在真空下干燥,以提供为黄色固体的标题化合物(6.54g,82%)。对于C8H4FIN2O,[M+H]计算值为291;测量值为291.5。
步骤D:5-氟-3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛
往5-氟-3-碘代-1H-吡咯并[2,3-b]吡啶-4-甲醛于DMF(12mL)的溶液中加入NaOH(0.716g,17.91mmol)。将深红色溶液搅拌30分钟,之后加入4-甲苯-1-磺酰氯(3.13g,16.42mmol)。将反应混合物搅拌2小时,随后用EtOAc稀释,并且用水和盐水洗涤。将萃取物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(DCM,100%)纯化,以提供为浅黄色固体的标题化合物(3.65g,55%)。1H NMR(400MHz,DMSO-d6)δ2.36(s,3H)7.45(m,J=8.08Hz,2H)8.02(m,J=8.34Hz,2H)8.42(s,1H)8.59(d,J=2.53Hz,1H)11.13(s,1H)。对于C15H10FIN2O3S,[M+H]计算值为445;测量值为445.1。
步骤E:5-氟-4-甲酰基-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将氯化锂(0.472g,11.14mmol)和甲酸锂(0.579g,11.14mmol)在可密封的干燥管中合并。加入DMF(10mL)、5-氟-3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛(1.650g,3.71mmol)、乙酸酐(0.702mL,7.43mmol)和二乙酰氧基钯(0.083g,0.371mmol)。将N-乙基-N-异丙基丙-2-胺(1.294mL,7.43mmol)加入,并将混合物密封并于56℃加热3小时。用MeOH/DCM(20%)吸收反应混合物并过滤。将黄色溶液浓缩,并将残余物溶解于MeOH/DCM(10%)并用HCl水溶液(0.1N)洗涤。将水层再萃取两次。将有机物合并,经由MgSO4干燥,并浓缩为橙色油状物,将其于醚(300mL)中湿磨。过滤沉淀物,并且在真空中干燥,以提供为浅黄色固体的标题化合物(1.15g,77%)。1H NMR(400MHz,DMSO-d6)δ2.37(s,3H)7.47(d,J=8.08Hz,2H)8.10(d,J=8.10Hz,2H)8.54-8.65(m,2H)10.60(s,1H)13.45(br.s.,1H)。对于C15H10FIN2O3S,[M+H]计算值为363;测量值为363.4。
制备O:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸
步骤A:(R)-4-((1-叔丁氧基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将三乙酰氧基硼氢化钠(1.143g,5.39mmol)、(R)-2-氨基-3-甲基丁酸叔丁酯盐酸盐(1.131g,5.39mmol)和DCM(20mL)的混合物于室温下搅拌10分钟。将反应混合物冷却至0℃。加入5-氟-4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸酯(1.299g,3.60mmol)并将反应物于0℃下搅拌20分钟,以提供标题化合物。对于C25H30FN3O6S,[M+H]计算值为520;测量值为520.2。
步骤B:(R)-2-(6-氟-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯
将粗(R)-4-((1-叔丁氧基-3-甲基-1-氧代丁烷-2-基氨基)甲基)-5-氟-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸于HATU(2.60g,7.19mmol)和4-甲基吗啉(1.091g,10.79mmol)中回流加热3小时。经由LC-MS使反应并不完全。加入HATU(1.37g,mmol,3.79mmol)和4-甲基吗啉(1.091g,10.79mmol)并将反应混合物回流搅拌16小时。反应后,将混合物用NaHCO3(饱和)水溶液洗涤并用DCM萃取。将有机物用盐水洗涤,经由Na2SO4干燥,并浓缩成棕色油状物。经由二氧化硅柱色谱法(EtOAc/DCM,0-20%)纯化,以提供为白色泡沫物的标题化合物(0.933g,51.7%)。1H NMR(400MHz,DMSO-d6)δ0.80(d,J=6.57Hz,3H)1.02(d,J=6.57Hz,3H)1.39(s,9H)2.31-2.39(m,4H)4.77(d,J=10.61Hz,1H)5.02(d,J=7.58Hz,2H)7.46(d,J=7.83Hz,2H)8.08(d,J=8.34Hz,2H)8.29(s,1H)8.44(d,J=2.78Hz,1H)。对于C25H28FN3O5S,[M+H]计算值为502;测量值为502.3。
步骤C:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯
往(R)-2-(6-氟-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯(933mg,1.860mmol)于MeOH(4mL)的搅拌溶液中加入NaOH水溶液(1N,2mL)。将反应混合物于25℃下搅拌40分钟。将反应物在DCM和盐水之间分配。将有机物经由MgSO4干燥并浓缩。经由二氧化硅柱色谱法(MeOH/DCM,0-5%)纯化,以提供为黄色油状物的标题化合物(0.39g,60.4%)。对于C18H22FN3O3,[M+H]计算值为348;测量值为348.5。
步骤D:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸
将在DCM/TFA(50%,10mL)中的(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸叔丁酯搅拌1小时,浓缩并且在真空中干燥,以提供为淡棕色固体的标题化合物(0.32g,59.1%)。1H NMR(400MHz,DMSO-d6)δ0.84(d,J=6.30Hz,3H)1.04(d,J=6.32Hz,3H)2.39(dt,J=10.61,6.57Hz,1H)4.83(d,J=10.61Hz,1H)5.04(d,J=9.60Hz,2H)7.98(s,1H)8.26(s,1H)12.39(br.s.,1H)。对于C14H14FN3O3,[M+H]计算值为292;测量值为292.5。
实施例42:(R)-1-(2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)氮杂环丁烷-3-甲腈
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(60mg,0.206mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、氮杂环丁烷-3-甲腈盐酸盐(0.309,36.6mg)、HOBt(47.3mg,0.309mmol)、EDC(59.2mg,0.309mmol)和N,N-二甲基吡啶-4-胺(37.7mg,0.309mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集、浓缩,并且在真空中干燥,以提供为TFA盐的标题化合物。使用二氧化硅柱色谱法(MeOH/DCM,0-10%)将残余物进一步纯化,提供为白色固体的标题化合物(游离碱,25.2mg,34.4%)。1H NMR(400MHz,DMSO-d6)δ0.78(dd,J=6.57,3.79Hz,3H)0.95(dd,J=13.01,6.44Hz,3H)1.09(t,J=6.95Hz,1H)3.53-3.86(m,1H)3.94-4.10(m,1H)4.10-4.29(m,2H)4.29-4.48(m,1H)4.87(dd,J=18.82,8.21Hz,1H)4.96-5.14(m,2H)7.99(dd,J=5.43,2.40Hz,1H)8.25(t,J=2.78Hz,1H)12.39(br.s.,1H)。对于C18H18FN5O2,[M+H]计算值为356;测量值为356.5。
实施例43:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3-(甲基氨基)丙腈(0.077,6.5mg)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为黄色油状物的标题化合物(6.1mg,33.1%)。1H NMR(400MHz,CD3OD)δ0.79-0.93(m,3H)0.97-1.06(m,3H)2.49-2.67(m,1H)2.71-2.80(m,2H)3.00(s,1H)3.24(s,2H)3.57-4.02(m,2H)4.99(s,1H)5.08-5.22(m,1H)5.52-5.63(m,1H)7.80-7.96(m,1H)8.16(d,J=3.03Hz,1H)。对于C18H20FN5O2,
[M+H]计算值为358;测量值为358.4。
实施例44:(2R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(四氢呋喃-3-基)丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、四氢呋喃-3-胺(0.077,6.7mg)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为白色固体的标题化合物(7.3mg,39.3%)。1H NMR(400MHz,CD3OD)δ0.93(d,J=6.57Hz,3H)1.04(dd,J=6.57,2.78Hz,3H)1.74-1.95(m,1H)2.21(d,J=7.83Hz,1H)2.42-2.54(m,1H)3.50-3.67(m,1H)3.69-3.97(m,3H)4.37(td,J=3.85,1.89Hz,1H)4.96-5.12(m,2H)5.36-5.52(m,1H)7.86(s,1H)8.17(d,J=3.28Hz,1H)。对于C18H21FN4O3,[M+H]计算值为361;测量值为361.4。
实施例45:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(1,1-二氧代四氢噻吩-3-基)丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、1,1-二氧代四氢噻吩-3-基胺(10.4mg,0.077)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为白色固体的标题化合物(5.1mg,24.3%)。1H NMR(400MHz,CD3OD)δ0.93(dd,J=6.57,1.26Hz,3H)1.05(dd,J=6.32,3.79Hz,3H)2.06-2.28(m,1H)2.40-2.59(m,2H)2.98(td,J=12.57,7.45Hz,1H)3.04-3.18(m,1H)3.21-3.29(m,1H)3.35-3.53(m,1H)4.51-4.66(m,1H)4.95-5.12(m,2H)5.40(dd,J=19.20,13.39Hz,1H)7.83-7.89(m,1H)8.17(dd,J=3.28,1.52Hz,1H)。对于C18H21FN4O4S,[M+H]计算值为409;测量值为409.3。
实施例46:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(2-(甲磺酰基)乙基)丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)于氮气下加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、2-(甲磺酰基)乙胺盐酸盐(8.2mg,0.051mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为白色固体的标题化合物(8mg,39.2%)。1H NMR(400MHz,CD3OD)δ0.91(d,J=6.82Hz,3H)1.05(d,J=6.32Hz,3H)2.50(dq,J=17.94,6.57Hz,1H)2.92(s,3H)3.22-3.28(m,1H)3.33-3.38(m,1H)3.61(dt,J=14.40,6.57Hz,1H)3.73(dt,J=14.40,6.57Hz,1H)4.94-5.13(m,2H)5.19-5.40(m,1H)7.85(s,1H)8.17(d,J=3.28Hz,1H)。对于C17H21FN4O4S,[M+H]计算值为398;测量值为398.3。
制备P:(1,1-二氧代-六氢-6-噻喃-4-基)-胺盐酸盐
将苄基-(1,1-二氧代-六氢-6-噻喃-4-基)胺(500mg,2.089mmol)和钯/碳(111mg,1.045mmol)于氮气下加至为搅拌配备的100mL圆底烧瓶中。将甲醇(15mL)和HCl水溶液(4N,0.172mL,2.089mmol)加入,并将溶液于60℃下搅拌48小时。将反应混合物经由硅藻土过滤并浓缩,以提供为橙色固体的标题化合物(241mg,62.1%)。1H NMR(400MHz,DMSO-d6)δ1.88-2.12(m,2H)2.26(d,J=11.87Hz,2H)3.08-3.22(m,2H)3.23-3.29(m,2H)3.39(br.s.,1H)8.34(br.s.,2H)。
实施例47:(R)-N-(1,1-二氧代四氢-2H-噻喃-4-基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)于氮气下加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、(1,1-二氧代-六氢-6-噻喃-4-基)胺盐酸盐(10mg,0.051mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为黄色油状物的标题化合物(6.4mg,29.4%)。1H NMR(500MHz,CD3OD)δ0.93(d,J=6.83Hz,3H)1.04(dd,J=6.35,2.93Hz,3H)1.61-1.80(m,1H)1.89-2.01(m,1H)2.06-2.30(m,4H)2.36-2.54(m,2H)3.32-3.38(m,1H)4.19-4.38(m,1H)4.93-5.11(m,2H)5.45(dd,J=18.79,5.13Hz,1H)7.86(s,1H)8.17(d,J=2.93Hz,1H)。对于C19H23FN4O4S,[M+H]计算值为423;测量值为423.3。
实施例48:4-{(1R)-1-[(1,1-二氧代硫代吗啉-4-基)羰基]-2-甲基丙基}-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、1,1-二氧化硫代吗啉盐酸盐(8.84mg,0.51mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为白色固体的标题化合物(9.8mg,46.6%)。1H NMR(400MHz,CD3OD)δ0.92(d,J=6.82Hz,3H)1.02(d,J=6.32Hz,3H)2.60(dt,J=10.61,6.57Hz,1H)2.90-3.03(m,1H)3.03-3.25(m,3H)3.86-4.01(m,1H)4.13(ddd,J=14.78,8.59,2.40Hz,1H)4.21-4.41(m,2H)4.92-5.06(m,1H)5.06-5.18(m,1H)5.57(d,J=10.61Hz,1H)7.89(s,1H)8.18(d,J=3.28Hz,1H)。对于C18H21FN4O4S,[M+H]计算值为409;测量值为409.3。
实施例49:(R)-N-(环丙基甲氧基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、O-(环丙基甲基)羟基胺盐酸盐(6.4mg,0.051mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。将反应混合物经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化。将馏分收集并冻干,以提供为白色固体的标题化合物(5mg,23%)。1H NMR(400MHz,CD3OD)δ0.16-0.24(m,2H)0.39-0.55(m,2H)0.93(d,J=6.57Hz,3H)1.05(d,J=6.32Hz,3H)1.06-1.15(m,1H)2.53(dt,J=11.24,6.51Hz,1H)3.55-3.73(m,2H)4.94(d,J=11.37Hz,1H)5.07(d,J=19.20Hz,1H)5.46(d,J=18.44Hz,1H)7.86(s,1H)8.17(d,J=3.28Hz,1H)。对于C18H21FN4O3,[M+H]计算值为361;测量值为361.4。
制备Q:3,3-二氟环戊胺
步骤A:3,3-二氟环戊基氨基羧酸叔丁酯
往3-氧代环戊基氨基羧酸叔丁酯(0.5g,2.509mmol)于DCM(12mL)的溶液中于0℃逐滴加入DeoxofluorTM(0.658mL,5.02mmol)。在加入完成后,使反应混合物温热至室温,并搅拌18小时。将反应混合物缓慢倒入冰冷的NaHCO3(饱和)水溶液中。将水层用DCM萃取3次。将合并的有机层经由MgSO4干燥、浓缩并且在真空中干燥。经由二氧化硅柱色谱法(MeOH/DCM,0-5%)纯化,以提供为黄色油状物的标题化合物(0.52g,94%)。
步骤B:3,3-二氟环戊胺
将3,3-二氟环戊基氨基羧酸叔丁酯和DCM/TFA(50%,7mL)的混合物于25℃下搅拌30分钟。将反应混合物浓缩下来并在真空中干燥,以提供为橙色半固体、TFA盐的标题化合物(0.51g,99%)。1H NMR(400MHz,DMSO-d6)δ1.69-1.88(m,1H)2.00-2.22(m,3H)2.22-2.38(m,1H)2.56(d,J=6.32Hz,1H)3.71(d,J=5.31Hz,1H)8.20(br.s.,3H)。
实施例50:(2R)-N-(3,3-二氟环戊基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)于氮气下加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3,3-二氟环戊胺(11.2mg,0.051mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化反应混合物。将馏分收集并冻干,以提供为棕色油状物的标题化合物(8mg,39.4%)。1H NMR(500MHz,CD3OD)δ0.93(d,J=6.83Hz,3H)1.04(dd,J=6.35,2.93Hz,3H)1.62-1.80(m,1H)1.87-2.02(m,1H)2.14-2.28(m,2H)2.35-2.58(m,2H)3.35(s,1H)4.22-4.35(m,1H)4.94-5.10(m,2H)5.45(dd,J=18.79,5.13Hz,1H)7.86(s,1H)8.17(d,J=2.93Hz,1H)。对于C19H21F3N4O2,[M+H]计算值为395;测量值为395.4。
制备R:3-(氟甲基)氮杂环丁烷-3-甲腈、TFA盐
步骤A:3-氰基-3-(氟甲基)氮杂环丁烷-1-羧酸叔丁酯
将二异丙基胺(0.659mL,4.66mmol)于氮气下加至为搅拌配备的烘干的25mL圆底烧瓶中。将THF(5mL)加入,并将无色溶液冷却至0℃。将n-BuLi(2.92mL,4.66mmol)加至此溶液,并将溶液于0℃下搅拌30分钟。将溶液冷却至-78℃,并加入3-氰基氮杂环丁烷-1-羧酸叔丁酯(0.5g,2.74mmol)于THF(3mL)的溶液,并将溶液于-78℃下搅拌30分钟。将氟溴甲烷(0.403g,3.57mmol)于-78℃逐滴加入。将反应混合物搅拌30分钟,然后使其温热至25℃并搅拌16小时。用NH4Cl水溶液(5mL)于0℃淬灭反应混合物并用DCM(3x)萃取。将萃取物经由Na2SO4干燥。经由二氧化硅柱色谱法(MeOH/DCM,0-5%)纯化,以提供为黄色油状物的标题化合物(0.52g,94%)。
步骤B:3-(氟甲基)氮杂环丁烷-3-甲腈,TFA盐
将3-氰基-3-(氟甲基)氮杂环丁烷-1-羧酸叔丁酯和DCM/TFA(50%,5mL)于25℃下搅拌30分钟。将反应混合物浓缩并于高度真空下干燥,以提供为橙色半固体的标题化合物(145mg,0.687mmol,25%)。1H NMR(400MHz,CDCl3)δ1.47(dd,J=5.05,2.02Hz,9H)4.03(br.s.,2H)4.29(br.s.,2H)4.62(br.s.,1H)4.73(br.s.,1H)。
实施例51:(R)-3-(氟甲基)-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(80mg,0.293mmol)于氮气下加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3-(氟甲基)氮杂环丁烷-3-甲腈(93mg,0.439mmol)、HOBt(67.2mg,0.439mmol)、EDC(84mg,0.439mmol)和N,N-二甲基吡啶-4-胺(53.6mg,0.439mmol)加入,将溶液于25℃下搅拌4小时。经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化反应混合物。将馏分收集并冻干,以提供为白色固体的标题化合物(34.5mg,25.3%)。1H NMR(400MHz,DMSO-d6)δ0.78(dd,J=6.57,3.79Hz,3H)0.97(dd,J=12.88,6.32Hz,3H)2.30-2.41(m,1H)3.99(dd,J=9.98,4.42Hz,1H)4.22(d,J=9.35Hz,2H)4.36(s,1H)4.62-4.71(m,1H)4.76-4.88(m,2H)4.87-5.03(m,1H)5.02-5.09(m,1H)7.09(t,J=4.80Hz,1H)7.88(dd,J=5.56,2.27Hz,1H)8.27(t,J=5.31Hz,1H)12.25(d,J=8.84Hz,1H)。对于C19H20FN5O2,[M+H]计算值为370;测量值为370.5。
制备S:3-氰基-3-甲基氮杂环丁烷,TFA盐
步骤A:3-氰基-3-甲基氮杂环丁烷-1-羧酸叔丁酯
将二异丙基胺(1.318mL,9.33mmol)于氮气下加至为搅拌配备的、烘干的25mL圆底烧瓶中。将THF(10mL)加入,并将无色溶液冷却至0℃。将在己烷中的n-BuLi(1.6N,5.83mL,9.33mmol)逐滴加入,并将溶液于0℃下搅拌30分钟。将溶液冷却至-78℃,并加入3-氰基氮杂环丁烷-1-羧酸叔丁酯(1g,5.49mmol)于THF(3mL)的溶液,并将溶液于-78℃下搅拌30分钟。将碘甲烷(0.445mL,7.13mmol)于-78℃逐滴加入。将反应混合物搅拌30分钟;然后使其缓慢温热至25℃并搅拌16小时。用NH4Cl水溶液(5mL)于0℃淬灭反应混合物并用DCM(3次)萃取。将萃取物经由Na2SO4干燥。经由二氧化硅柱色谱法(MeOH/DCM,0-5%)纯化,以提供为黄色油状物的标题化合物(0.35g,32%)。1H NMR(500MHz,CDCl3)δ1.45(s,9H)1.67(s,3H)3.80(d,J=8.30Hz,2H)4.29(d,J=8.79Hz,2H)。
步骤B:3-氰基-3-甲基氮杂环丁烷、TFA盐
将3-氰基-3-甲基氮杂环丁烷-1-羧酸叔丁酯(0.345g,1.758mmol)和DCM/TFA(50%,7mL)的混合物于25℃下搅拌30分钟。将反应混合物浓缩,并且在真空中干燥,以提供为橙色半固体的标题化合物(0.22g,1.139mmol,64.8%)。1H NMR(400MHz,DMSO-d6)δ1.65(s,3H)3.92(d,J=11.12Hz,2H)4.34(d,J=11.12Hz,2H)9.23(br.s.,2H)。
实施例52:(R)-1-(2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)-3-甲基氮杂环丁烷-3-甲腈
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3-氰基-3-甲基氮杂环丁烷(15mg,0.077mmol)、HOBt(11.83mg,0.077mmol)、EDC(14.81mg,0.077mmol)和N,N-二甲基吡啶-4-胺(9.44mg,0.077mmol)加入并将溶液于25℃下搅拌4小时。经由制备批量操作触发器LC-MS(AcCN/H2O,20-50%)纯化反应混合物。将馏分收集并冻干,以提供为白色固体的标题化合物(9mg,47.3%)。1H NMR(400MHz,DMSO-d6)δ0.79(dd,J=6.69,2.91Hz,3H)0.96(dd,J=9.09,6.57Hz,3H)1.41-1.73(m,3H)2.26-2.44(m,1H)3.85(dd,J=15.66,9.85Hz,1H)4.06(d,J=9.35Hz,2H)4.61(s,1H)4.88(dd,J=19.20,6.82Hz,1H)5.03(d,J=11.12Hz,1H)5.07-5.18(m,1H)7.99(t,J=3.16Hz,1H)8.25(t,J=2.65Hz,1H)12.40(br.s.,1H)。对于C19H20FN5O2,[M+H]计算值为370;测量值为370.5。
实施例53:(R)-3-甲基-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(80mg,0.293mmol)加至为搅拌配备的8mL闪烁管中。将DMF(0.5mL)、3-氰基-3-甲基氮杂环丁烷(85mg,0.439mmol)、HOBt(67.2mg,0.439mmol)、EDC(84mg,0.439mmol)和N,N-二甲基吡啶-4-胺(53.6mg,0.439mmol)加入并将溶液于25℃下搅拌4小时。将馏分收集并冻干,以提供为白色固体的标题化合物(31.5mg,30.6%)。1HNMR(400MHz,DMSO-d6)δ0.78(dd,J=6.82,3.28Hz,3H)0.96(dd,J=8.59,6.32Hz,3H)1.44-1.68(m,3H)2.26-2.44(m,1H)3.84(dd,J=9.47,5.18Hz,1H)3.99-4.14(m,1H)4.21(dd,J=9.47,5.68Hz,1H)4.34-4.65(m,1H)4.85(dd,J=19.45,5.56Hz,1H)4.96-5.11(m,2H)7.08(d,J=5.05Hz,1H)7.86(d,J=4.04Hz,1H)8.26(dd,J=4.80,3.28Hz,1H)12.22(br.s.,1H)。对于C19H21N5O2,[M+H]计算值为352;测量值为352.5。
制备T:带有2,2,2-三氟乙酸(1:1)的(R)-2-((3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)丁酸化合物
步骤A:(R)-4-((1-叔丁氧基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯
将三乙酰氧基硼氢化钠(9.86mmol)和(R)-2-氨基丁酸叔丁酯盐酸盐(5.59mmol)加至100mL的圆底烧瓶中,然后加入DCE(20mL)。将反应混合物于室温下搅拌30分钟并冷却至0℃。加入4-甲酰-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(3.29mmol)于DCE(20mL)的溶液。将反应混合物于0℃下搅拌30分钟,并于室温搅拌3小时。经由二氧化硅柱色谱法(EtOAc/DCM,0-10%)纯化,以提供为黄色油状物的标题化合物(1.4g,95%)。对于C23H33N3O6,[M+H]计算值为448;测量值为448.6。
步骤B:带有2,2,2-三氟乙酸(1:1)的(R)-2-((3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)丁酸化合物
将(R)-4-((1-叔丁氧基-1-氧代丁烷-2-基氨基)甲基)-1H-吡咯并[2,3-b]吡啶-1,3-二甲酸1-叔丁基3-甲酯(1.45g,3.24mmol)和DCM(10mL)加至为搅拌配备的100mL圆底烧瓶中。加入TFA(10mL)并将反应混合物于室温下搅拌30分钟。将反应混合物浓缩并且在真空中干燥,以提供为黄色油状物的标题化合物(1.3g,99%)(TFA盐)。对于C14H17N3O4,[M+H]计算值为292;测量值为292.6。
实施例54至74
根据下列的一般程序A制造实施例54至74的化合物。
将(R)-2-((3-(甲氧基羰基)-1H-吡咯并[2,3-b]吡啶-4-基)甲基氨基)丁酸(43.4mg,0.149mmol)和HATU(68.0mg,0.179mmol)加至为搅拌配备的8mL闪烁管中。加入THF(2mL)、4-甲基吗啉(0.049mL,0.447mmol)和合适的胺NHR1R2(0.447mmol)。将悬浮液于室温下搅拌4小时且然后浓缩,以提供粗中间体A,随后将其再溶解于MeOH(1mL)中。加入NaOH水溶液(12N,2mL)并且将反应混合物于53℃下搅拌16小时。经由制备批量操作触发器LC-ms(AcCN/H2O,1-50%)纯化残余物。将馏分收集、浓缩、并且在真空中干燥,以提供中间体B,在THF(2mL)、HATU(68.0mg,0.179mmol)和4-甲基吗啉(0.049mL,0.447mmol)的混合物中于室温下将中间体B环化4至16小时。经由制备批量操作触发器LC-MS(AcCN/H2O,1-50%)纯化产物。将馏分收集、浓缩,并且在真空中干燥,以提供标题化合物。
实施例54:(R)-4-(1-吗啉代-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用吗啉作为胺NHR1R2(2.1mg,4.2%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.96(t,J=7.45Hz,3H)1.99-2.13(m,2H)3.43-3.51(m,1H)3.53-3.62(m,2H)3.62-3.73(m,4H)5.06(d,J=10.86Hz,2H)5.66-5.78(m,1H)7.21(d,J=5.31Hz,1H)7.86(s,1H)8.32(d,J=5.31Hz,1H)。对于C17H20N4O3,[M+H]计算值为329;测量值为329.6。
实施例55:(R)-4-(1-(4-甲基哌嗪-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用1-甲基哌嗪作为胺NHR1R2(3.2mg,6.3%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ-0.52(t,J=7.33Hz,3H)0.42-0.60(m,2H)1.33(s,3H)1.43(d,J=12.88Hz,3H)1.58-1.74(m,1H)1.84-1.93(m,3H)1.93-2.05(m,2H)4.28(s,1H)5.64(d,J=5.31Hz,1H)6.34(s,1H)6.81(d,J=5.05Hz,1H)。对于C18H23N5O2,[M+H]计算值为342;测量值为342.6。
实施例56:4-((2R)-1-(3-羟基吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用1-吡咯烷-3-醇作为胺NHR1R2(16mg,32.7%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.90-1.08(m,3H)1.82-2.12(m,4H)2.91(s,1H)3.41-3.67(m,2H)3.74(t,J=11.60Hz,2H)4.28-4.50(m,1H)4.85-4.98(m,2H)7.13(d,J=5.31Hz,1H)7.81(t,J=3.41Hz,1H)8.28(d,J=5.81Hz,1H)。对于C17H20N4O3,[M+H]计算值为329;测量值为329.6。
实施例57:(R)-N-环戊基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用环戊胺作为NHR1R2(6.3mg,13%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.98(q,J=7.50Hz,3H)1.38-1.52(m,2H)1.52-1.63(m,2H)1.63-1.79(m,2H)1.80-2.01(m,2H)2.12-2.17(m,2H)3.99-4.19(m,1H)5.23(dd,J=9.35,6.82Hz,1H)5.27-5.37(m,1H)5.48(s,2H)7.23(d,J=5.56Hz,1H)7.85(s,1H)8.32(d,J=5.56Hz,1H)。对于C18H22N4O2,[M+H]计算值为327;测量值为327.6。
实施例58:4-((2R)-1-(3-(4-氟苯基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用3-(4-氟苯基)吡咯烷作为胺NHR1R2(14mg,23.1%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.89-1.06(m,3H)1.80(s,2H)2.19-2.39(m,2H)3.33-3.55(m,2H)3.56-3.65(m,1H)3.68-3.83(m,1H)3.84-3.96(m,1H)3.98-4.24(m,1H)5.03-5.35(m,2H)6.68-6.83(m,1H)6.86-6.99(m,1H)6.99-7.09(m,2H)7.10-7.37(m,1H)7.78-7.95(m,1H)8.34(d,J=5.31Hz,1H)。对于C23H23FN4O2,[M+H]计算值为407;测量值为407.6。
实施例59:4-((2R)-1-(3-(二甲基氨基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用N,N-二甲基吡咯烷-3-胺作为NHR1R2(20mg,37.8%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.87-1.05(m,3H)1.88-2.12(m,2H)2.12-2.26(m,1H)2.43(d,J=8.84Hz,1H)2.64-2.85(m,3H)2.85-3.02(m,4H)3.43-3.68(m,1H)3.68-3.90(m,1H)3.90-4.03(m,1H)4.03-4.26(m,0H)4.99-5.19(m,2H)5.51-5.71(m,1H)7.08-7.25(m,1H)7.79-7.92(m,1H)8.32(d,J=5.31Hz,1H)。对于C19H25N5O2,[M+H]计算值为356;测量值为356.6。
实施例60:4-((2R)-1-(3-(甲氧基甲基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用3-(甲氧基甲基)吡咯烷作为胺NHR1R2(12mg,22.6%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.98(td,J=7.39,1.89Hz,3H)1.62-1.80(m,1H)1.85-2.12(m,5H)2.35-2.60(m,1H)3.32-3.35(m,3H)3.37-3.51(m,2H)3.52-3.70(m,1H)3.70-3.85(m,1H)5.06-5.29(m,2H)5.53-5.69(m,1H)7.19-7.35(m,1H)7.89(s,1H)8.34(d,J=5.31Hz,1H)。对于C19H24N4O3,[M+H]计算值为357;测量值为357.6。
实施例61:4-((2R)-1-(3-甲基哌啶-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用3-甲基哌啶作为胺NHR1R2(10.8mg,21.3%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.71(d,J=6.32Hz,1H)0.83-1.04(m,7H)1.14(br.s.,1H)1.68(d,J=10.36Hz,2H)1.81-2.07(m,2H)2.54-2.77(m,1H)2.95-3.10(m,1H)4.01(d,J=14.65Hz,1H)4.20-4.51(m,1H)4.89-5.04(m,1H)5.04-5.18(m,1H)5.71-5.87(m,1H)7.19-7.26(m,1H)7.89(d,J=4.80Hz,1H)8.33(d,J=5.31Hz,1H)。对于C19H24N4O2,[M+H]计算值为341;测量值为341.6。
实施例62:(R)-4-(1-(4-(2-羟基丙烷-2-基)哌啶-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用2-(哌啶-4-基)丙-2-醇作为胺NHR1R2(10mg,17.5%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.80(s,3H)0.85(s,3H)0.92-1.00(m,3H)1.43-1.56(m,1H)1.60(d,J=13.89Hz,1H)1.77(d,J=12.88Hz,1H)1.83-1.95(m,2H)1.95-2.06(m,2H)2.48-2.66(m,1H)2.86-3.07(m,1H)4.16(d,J=15.66Hz,1H)4.64(d,J=14.15Hz,1H)4.87-5.03(m,1H)5.03-5.19(m,1H)5.75(t,J=7.58Hz,1H)7.23(d,J=5.31Hz,1H)7.81-7.94(m,1H)8.23-8.37(m,1H)。对于C21H28N4O3,[M+H]计算值为385;测量值为385.6。
实施例63:(R)-4-(1-(4-(甲基磺酰基)哌嗪-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用1-(甲基磺酰基)哌嗪作为胺NHR1R2(7.3mg,12.1%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.97(t,J=7.45Hz,3H)1.85-2.06(m,2H)2.75(s,3H)3.06(br.s.,1H)3.09-3.19(m,1H)3.26(dd,J=3.16,1.64Hz,2H)3.68(br.s.,1H)3.74(br.s.,1H)3.79(br.s.,2H)4.96-5.14(m,2H)5.76(dd,J=8.34,6.82Hz,1H)7.23(d,J=5.31Hz,1H)7.89(s,1H)8.32(d,J=5.56Hz,1H)。对于C18H23N5O4S,[M+H]计算值为406;测量值为406.6。
实施例64:(R)-4-(1-氧代-1-(4-(吡啶-2-基)哌嗪-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
使用1-(吡啶-2-基)哌嗪作为胺NHR1R2(3步骤,5.2%),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.88-1.04(m,3H)1.93-2.09(m,2H)3.54-3.63(m,1H)3.69(d,J=11.12Hz,1H)3.72-3.87(m,3H)3.87-3.95(m,2H)3.98(br.s.,1H)5.05(q,J=19.28Hz,2H)5.80(dd,J=8.34,6.82Hz,1H)6.99(t,J=6.69Hz,1H)7.14(d,J=5.05Hz,1H)7.33(d,J=9.35Hz,1H)7.84(s,1H)7.92(dd,J=6.32,1.26Hz,1H)8.01(ddd,J=9.22,7.20,1.77Hz,1H)8.29(d,J=5.30Hz,1H)。对于C22H24N6O2,[M+H]计算值为405;测量值为405.6。
实施例65:(R)-N-环丙基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用环丙胺作为胺NHR1R2(1.7mg,2.2%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.44-0.53(m,2H)0.96(t,J=7.33Hz,3H)2.66-2.73(m,4H)3.71-3.81(m,1H)5.05-5.29(m,1H)5.44-5.52(m,2H)7.52(dd,J=8.46,4.42Hz,1H)8.43(dd,J=8.34,1.26Hz,1H)8.73(d,J=3.54Hz,1H)。对于C16H18N4O2,[M+H]计算值为299;测量值为299.6。
实施例66:(R)-N-(环丙基甲基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用环丙基甲胺作为NHR1R2(9mg,11.2%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.13-0.22(m,2H)0.40-0.48(m,2H)0.90-1.06(m,4H)1.86-2.01(m,1H)2.05-2.16(m,1H)3.06(d,J=6.82Hz,2H)5.04-5.13(m,1H)5.13-5.22(m,1H)5.28(dd,J=9.47,6.69Hz,1H)7.14(d,J=5.05Hz,1H)7.81(s,1H)8.29(d,J=4.80Hz,1H)。对于C17H20N4O2,[M+H]计算值为313;测量值为313.6。
实施例67:(R)-N-异丁基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用2-甲基丙-1-胺作为NHR1R2(5.2mg,6.4%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.87(d,J=6.32Hz,6H)0.99(t,J=7.45Hz,3H)1.78(dt,J=13.58,6.73Hz,1H)1.95(ddd,J=14.15,9.35,7.33Hz,1H)2.11(dt,J=14.65,7.33Hz,1H)3.01(dd,J=6.95,1.64Hz,2H)5.04-5.19(m,1H)5.19-5.32(m,2H)7.24(d,J=5.31Hz,1H)7.87(s,1H)8.33(d,J=5.56Hz,1H)。对于C17H22N4O2,[M+H]计算值为315;测量值为315.6。
实施例68:(R)-N-异丁基-N-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用N,2-二甲基丙-1-胺作为NHR1R2(10.5mg,12.4%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.85(td,J=6.95,6.06Hz,5H)0.90-1.09(m,4H)1.84-2.09(m,4H)2.94(s,1H)3.05-3.16(m,2H)3.24(dd,J=7.45,3.92Hz,1H)3.46(dd,J=14.27,8.21Hz,1H)5.11(s,1H)5.68-5.90(m,1H)7.15-7.33(m,1H)7.88(d,J=3.28Hz,1H)8.32(dd,J=5.31,3.03Hz,1H)。对于C18H24N4O2,[M+H]计算值为329;测量值为329.6。
实施例69:(2R)-N-(1-羟基丙烷-2-基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用2-氨基丙-1-醇作为胺NHR1R2(27mg,33.1%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.88-1.03(m,2H)1.04-1.19(m,2H)1.85-2.00(m,1H)2.04-2.17(m,1H)2.75-2.87(m,1H)2.87-3.05(m,1H)3.05-3.21(m,1H)3.38-3.56(m,2H)3.93-4.05(m,1H)4.97-5.13(m,1H)5.13-5.32(m,1H)7.05-7.19(m,1H)7.80(s,1H)8.27(d,J=5.05Hz,1H)。对于C16H20N4O3,[M+H]计算值为317;测量值为317.6。
实施例70:(R)-N-(2-羟基-2-甲基丙基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用1-氨基-2-甲基丙-2-醇作为胺NHR1R2(12mg,14.1%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ1.00(t,J=7.33Hz,3H)1.13(d,J=2.27Hz,6H)1.90-2.02(m,1H)2.08-2.22(m,1H)3.15-3.26(m,2H)5.07-5.21(m,1H)5.21-5.37(m,2H)7.28(d,J=5.56Hz,1H)7.89(s,1H)8.34(d,J=5.56Hz,1H)。对于C17H22N4O3,[M+H]计算值为331;测量值为331.6。
实施例71:(R)-N-((S)-2,3-二羟丙基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用(S)-3-氨基丙烷-1,2-二醇作为胺NHR1R2(1.9mg,2.2%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.98(t,J=7.33Hz,2H)1.29(s,1H)1.86-2.02(m,1H)2.06-2.19(m,1H)2.70(s,1H)3.08-3.29(m,1H)3.40-3.51(m,2H)3.61-3.77(m,1H)5.02-5.32(m,3H)7.16(d,J=4.80Hz,1H)7.82(s,1H)8.31(br.s.,1H)。对于C16H20N4O4,[M+H]计算值为333;测量值为333.6。
实施例72:(R)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-苯基丁酰胺
使用苯胺作为胺NHR1R2(5mg,5.8%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ1.05(t,J=7.33Hz,3H)2.04-2.13(m,1H)2.13-2.28(m,1H)5.11-5.27(m,1H)5.31-5.47(m,2H)7.00-7.14(m,1H)7.21(d,J=5.31Hz,1H)7.23-7.36(m,2H)7.54(dd,J=8.59,1.01Hz,2H)7.85(s,1H)8.32(br.s.,1H)。对于C19H18N4O2,[M+H]计算值为335;测量值为335.6。
实施例73:(R)-N-(1-(甲基磺酰基)哌啶-4-基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
使用1-(甲基磺酰基)哌啶-4-胺作为NHR1R2(20mg,18.5%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.99(t,J=7.33Hz,2H)1.26-1.42(m,2H)1.46-1.67(m,2H)1.84-2.00(m,2H)2.06-2.25(m,1H)2.76-2.94(m,4H)3.22(quin,J=6.95Hz,1H)3.33-3.39(m,2H)3.59-3.88(m,3H)5.11-5.27(m,1H)7.29(d,J=5.31Hz,1H)7.89(s,1H)8.35(d,J=5.31Hz,1H)。对于C19H25N5O4S,[M+H]计算值为420;测量值为420.6。
实施例74:(2R)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((四氢呋喃-2-基)甲基)丁酰胺
使用(四氢呋喃-2-基)甲胺作为NHR1R2(3.1mg,3.5%,3步骤),根据一般程序A制备所述标题化合物。1H NMR(400MHz,CD3OD)δ0.98(td,J=7.39,1.64Hz,3H)1.55(s,1H)1.75-2.02(m,4H)2.12(dt,J=14.46,7.29Hz,1H)3.18-3.30(m,2H)3.57-3.73(m,1H)3.73-3.87(m,1H)3.96(dd,J=11.12,6.32Hz,1H)5.01-5.22(m,2H)5.29(dt,J=9.35,6.82Hz,1H)7.16(d,J=5.05Hz,1H)7.83(s,1H)8.30(d,J=5.05Hz,1H)。对于C18H22N4O3,[M+H]计算值为343;测量值为343.6。
实施例75:(2R)-N-(1-氰乙基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将2-氨基丙腈盐酸盐(8.23mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。反应后,经由制备HPLC(带有0.035%TFA的10-55%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为白色固体的标题化合物(11mg,62%)。1H NMR(500MHz,DMSO-d6)δ1.20-1.26(m,3H),1.32-1.39(m,3H),1.77-1.82(m,3H),2.76-2.84(m,1H),5.06-5.22(m,1H),5.36-5.44(m,2H),5.77(dd,J=19.0,2.0Hz,1H),8.38(dd,J=10.5,2.0Hz,1H),8.65(t,J=3.0Hz,1H),9.47(d,J=2.0Hz,1H),12.78(br d,J=7.5Hz,1H)。对于C17H18FN5O2,[M+H]计算值为344;测量值为344。
实施例76:(R)-4-(1-(3,3-二氟氮杂环丁烷-1-基)-3-甲基-1-氧代丁烷-2-基)-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将3,3-二氟氮杂环丁烷盐酸盐(10.0mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。反应后,经由制备HPLC(带有0.035%TFA的10-60%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为白色固体的标题化合物(10mg,53%)。1H NMR(500MHz,DMSO-d6)δ0.80(d,J=6.0Hz,3H),0.96(d,J=6.0Hz,3H),2.30-2.41(m,1H),4.26-4.36(m,2H),4.41-4.51(m,1H),4.70-4.79(m,1H),5.00(AB q,J=104.5,22.0Hz,2H),5.07(d,J=23.0Hz,1H),7.99(d,J=2.5Hz,1H),8.24(d,J=2.5Hz,1H),12.40(s,1H)。对于C17H17F3N4O2,[M+H]计算值为367;测量值为367。
实施例77:(R)-4-(1-(1,1-二氧化噻唑烷-3-基)-3-甲基-1-氧代丁烷-2-基)-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将1,1-二氧化噻唑烷盐酸盐(12.17mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-45%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为白色固体的标题化合物(8.8mg,43%)。1H NMR(500MHz,DMSO-d6)δ0.76-0.81(m,3H),0.95(d,J=6.5Hz,3H),2.41-2.50(m,1H),3.35-3.45(m,2H),3.80-3.89(m,2H),4.49-4.91(m,4H),5.18-5.42(m,1H),8.01(d,J=2.5Hz,1H),8.24(d,J=2.5Hz,1H),12.43(s,1H)。对于C17H19FN4O4S,[M+H]计算值为395;测量值为395。
实施例78:(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N,3-二甲基-N-(2-(甲基磺酰基)乙基)丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将N-甲基-2-(甲基磺酰基)乙胺(10.60mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-45%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为白色固体的标题化合物(12mg,57%产率)。1H NMR(500MHz,CD3OD)δ0.77(d,J=6.5Hz,3H),0.95(d,J=6.5Hz,3H),2.41-2.49(m,1H),2.97(s,3H),3.05(s,3H),3.36(t,J=6.5Hz,2H),3.78(t,J=6.5Hz,2H),4.81-4.96(m,2H),5.36(d,J=11.0Hz,1H),7.97(d,J=2.5Hz,1H),8.23(d,J=2.5Hz,1H),12.39(s,1H)。对于C18H23FN4O4S,[M+H]计算值为411;测量值为411。
实施例79:(R)-N-(氰甲基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N,3-二甲基丁酰胺
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将2-(甲基氨基)乙腈(5.41mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-55%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为浅黄色固体的标题化合物(7.8mg,44%)。1HNMR(500MHz,DMSO-d6)δ0.78(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H),2.44-2.51(m,1H),3.12(s,3H),4.39(AB q,J=84.5,17.5Hz,2H),4.89(d,J=5.5Hz,2H),5.42(d,J=11.0Hz,1H),8.00(d,J=2.5Hz,1H),8.24(d,J=2.5Hz,1H),12.43(s,1H)。对于C17H18FN5O2,[M+H]计算值为344;测量值为344。
实施例80:(R)-4-(1-(3-(二氟甲基)氮杂环丁烷-1-基)-3-甲基-1-氧代丁烷-2-基)-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮
将(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(15mg,0.051mmol)、HOBt水合物(9.46mg,0.062mmol)和EDC盐酸盐(14.81mg,0.077mmol)于DMF(2mL)中合并。将3-(二氟甲基)氮杂环丁烷(8.27mg,0.077mmol)和4-甲基吗啉(0.023mL,0.206mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-60%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为白色固体的标题化合物(9.8mg,50%)。1H NMR(500MHz,DMSO-d6)δ0.78(d,J=6.0Hz,3H),0.94(d,J=6.0Hz,3H),2.31-2.39(m,1H),2.99-3.15(m,1H),3.77-4.35(m,4H),4.82-5.11(m,3H),6.10-6.41(m,1H),7.98(d,J=2.5Hz,1H),8.24(d,J=2.5Hz,1H),12.39(s,1H)。对于C18H19F3N4O2,[M+H]计算值为381;测量值为381。
制备U:4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
步骤A:3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛
往1H-吡咯并[2,3-b]吡啶-4-甲醛(2.0g,13.7mmol)于EtOH(40mL)的溶液中加入碘(4.17g,16.4mmol)、碘化钠(2.46g,16.4mmol)和NaOH水溶液(1N,16mL)。在室温下搅拌4小时后,将反应混合物用水(200mL)稀释,并经由过滤收集橙色沉淀物,并在真空下干燥。将固体溶解于DMF(20mL)中;缓慢加入氢化钠(60%,660mg,16.4mmol),并且将深红色溶液于室温下搅拌30分钟后,加入甲苯磺酰氯(2.87g,15.1mmol)。将反应混合物于室温下搅拌另外的2小时,然后用EtOAc稀释,并用水淬灭。将有机物分离,用NaHSO3水溶液(0.1N)和盐水洗涤,经由MgSO4干燥并在真空中浓缩。经由硅胶色谱法(3:1:1己烷/DCM/EtOAc)纯化,以提供为黄色固体的标题化合物(3.48g,60%)。1H NMR(500MHz,DMSO-d6)δ2.33(s,3H),7.43(d,J=8.5Hz,2H),7.63(d,J=5.0Hz,1H),8.03(d,J=8.5Hz,2H),8.39(s,1H),8.60(d,J=5.0Hz,1H),11.31(s,1H)。对于C15H11IN2O3S,[M+H]计算值为427;测量值为427。
步骤B:4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸
将氯化锂(358mg,8.45mmol)和一水合甲酸锂(591mg,8.45mmol)于氮气下在干燥可密封管中合并。加入DMF(12mL)、3-碘代-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-甲醛(1.2g,2.82mmol)、乙酸酐(532mL,5.63mmol)和乙酸钯(63mg,0.28mmol)。加入DIPEA(981μL),且将反应管密封并于56℃加热4小时。用MeOH/DCM(20%)吸收反应混合物并过滤以移除不溶的黑色的碳材料。将黄色溶液在真空中浓缩,溶解于MeOH/DCM(10%)中并用HCl水溶液(0.1N)洗涤。将水层用MeOH/DCM(10%)萃取两次。将有机物合并,经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(10-15%MeOH/DCM)纯化,以提供为棕黄色固体的标题化合物(866mg,89%)。1H NMR(500MHz,DMSO-d6)δ2.35(s,3H),7.45(d,J=8.5Hz,2H),7.62(d,J=5.0Hz,1H),8.11(d,J=8.5Hz,2H),8.58-8.62(m,2H),11.02(s,1H),13.20(br s,1H)。对于C16H12N2O5S,[M+H]计算值为345;测量值为345。
制备V:(R)-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
步骤A:(R)-3-甲基-2-(3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸叔丁酯
将三乙酰氧基硼氢化钠(603mg,2.85mmol)和D-缬胺酸叔丁酯HCl盐(597mg,2.85mmol)于DCM(15mL)中合并。将反应混合物于室温下搅拌20分钟,然后冷却至0℃。加入4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸(700mg,2.03mmol),并将溶液搅拌1小时。将溶液在真空中浓缩,以提供白色泡沫物,将其再溶解于THF(40mL)中。加入HATU(1.16g,3.05mmol)和N-甲基吗啉(339μL,3.05mmol),并将反应混合物于52℃下搅拌2小时。加入另外的HATU(580mg,1.53mmol)和N-甲基吗啉(170μL,1.53mmol),并将反应混合物于52℃下另外搅拌2小时。随后将溶液冷却,用EtOAc稀释,并用盐水洗涤。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(1:2:2EtOAc/己烷/DCM)纯化,以提供为黄色油状物的标题化合物,将其静置凝固(840mg,85%)。1H NMR(500MHz,CDCl3)δ0.86(d,J=7.0Hz,3H),1.08(d,J=7.0Hz,3H),1.42(s,9H),2.25-2.34(m,1H),2.35(s,3H),4.77-5.14(m,3H),7.05(d,J=5.0Hz,1H),7.28(d,J=7.5Hz,2H),8.05-8.10(m,3H),8.45(d,J=5.0Hz,1H)。对于C25H29N3O5S,[M+H]计算值为484;测量值为484。
步骤B:(R)-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
将(R)-3-甲基-2-(3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸叔丁酯(840mg,1.74mmol)、MeOH(4mL)和NaOH水溶液(1N,2mL)的混合物于室温下搅拌40分钟。将材料用DCM稀释并用盐水洗涤。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(5%MeOH/DCM)纯化,以提供黄色油状物(390mg),将其溶解于TFA/DCM(50%)并于室温下搅拌1小时。将此溶液浓缩并在真空下干燥,以提供为棕黄色固体的标题化合物(320mg,67%)。1H NMR(500MHz,CD3OD)δ0.88(d,J=7.0Hz,3H),1.10(d,J=7.0Hz,3H),2.35-2.44(m,1H),4.95-5.33(m,3H),7.34(d,J=6.0Hz,1H),7.90(s,1H),8.33(d,J=6.0Hz,1H)。对于C14H15N3O3,[M+H]计算值为274;测量值为274。
实施例81:(R)-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸-3-甲酸(80mg,0.29mmol)、HOBt(54mg,0.35mmol)和EDC(84mg,0.44mmol)于DMF(2mL)中合并。将氮杂环丁烷-3-甲腈HCl盐(52mg,0.44mmol)和N-甲基吗啉(130μL,1.17mmol)加入,并将溶液于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-45%AcCN/水)纯化,接着经由硅胶色谱法(8%MeOH/DCM)纯化,以提供为白色固体的标题化合物(28mg,28%)。1H NMR(500MHz,DMSO-d6)δ0.90(dd,J=6.5,2.0Hz,3H),1.06(dd,J=6.5,2.0Hz,3H),2.42-2.51(m,1H),3.61-3.75(m,1H),4.15-4.68(m,4H),4.95-5.21(m,3H),7.09(t,J=5.0Hz,1H),7.81(d,J=12.5Hz,1H),8.27(t,J=5.0Hz,1H)。对于C18H19N5O2,[M+H]计算值为338;测量值为338。
制备W:(R)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
步骤A:(R)-2-氨基-3,3-二甲基丁酸苄酯,TFA盐
将苄基溴(2.26mL,19.0mmol)于0℃加至(R)-2-(叔丁氧基羰基氨基)-3-3-二甲基丁酸(4.0g,17.3mmol)于AcCN(80mL)的搅拌溶液中。将DBU(3.13mL,20.8mmol)缓慢加入,且将溶液搅拌3小时,同时温热至室温。将溶液在真空中浓缩,用EtOAc吸收,并用HCl水溶液(1N)、NaHCO3(饱和)水溶液和盐水洗涤。将有机物经由MgSO4干燥并浓缩。将得到的澄清油状物溶解于TFA/DCM(50%,16mL)中并于室温下搅拌1小时。将此溶液浓缩并经由短二氧化硅柱(10%MeOH/DCM)纯化,以提供为白色粉末的标题化合物(5.02g,87%)。1H NMR(500MHz,DMSO-d6)δ1.05(s,9H),3.72(s,1H),5.17(AB q,J=40.0,12.0Hz,2H),7.25-7.35(m,5H),8.20(br s,2H)。
步骤B:(R)-3,3-二甲基-2-(3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸苄酯
将三乙酰氧基硼氢化钠(665mg,3.14mmol)和(R)-2-氨基-3,3-二甲基丁酸苄酯,TFA盐(1.05g,2.85mmol)于DCM(15mL)中合并。将反应混合物于室温下搅拌20分钟,然后冷却至0℃。将4-甲酰-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-3-甲酸(900mg,2.61mmol)加入,并将反应混合物搅拌1小时。将溶液在真空中浓缩,以提供棕黄色泡沫物,将其再溶解于THF(40mL)中。加入HATU(1.49g,3.92mmol)和N-甲基吗啉(436μL,3.92mmol),并将反应混合物于52℃下搅拌2小时。加入另外的HATU(750mg,1.96mmol)和N-甲基吗啉(218μL,1.96mmol)。将反应混合物另外搅拌2小时、冷却、用EtOAc稀释、并以盐水洗涤。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(1:2:2EtOAc/己烷/DCM)纯化,以提供为淡黄色油状物/泡沫物的标题化合物(970mg,70%)。1H NMR(500MHz,CDCl3)δ1.12(s,9H),2.33(s,3H),5.06(AB q,J=66.5,24.0Hz,2H),5.11(s,2H),5.48(br s,1H),6.98(d,J=5.0Hz,1H),7.14-7.28(m,7H),8.03-8.11(m,3H),8.42(d,J=5.0Hz,1H)。对于C29H29N3O5S,[M+H]计算值为532;测量值为532。
步骤C:(R)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
将(R)-3,3-二甲基-2-(3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸苄酯(950mg,1.79mmol)、MeOH(4mL)和NaOH水溶液(1N,2mL)的混合物于室温下搅拌40分钟。将混合物用DCM稀释并用盐水洗涤。将有机物经由MgSO4干燥,并在真空中浓缩。经由硅胶色谱法(5%MeOH/DCM)纯化,以提供黄色油状物(500mg),将其用MeOH吸收并用10%Pd/C于H2气球在室温下搅拌1小时。将反应混合物经由硅藻土过滤,并在真空中浓缩,以提供为灰白色固体的标题化合物(380mg,74%)。1H NMR(500MHz,DMSO-d6)δ1.13(s,9H),4.12(br s,1H),5.05-5.15(m,2H),7.08(d,J=5.0Hz,1H),7.84(d,J=2.5Hz,1H),8.25(d,J=5.0Hz,1H)。对于C15H17N3O3,[M+H]计算值为288;测量值为288。
实施例82:(R)-1-(3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(80mg,0.278mmol)、HOBt水合物(51.2mg,0.334mmol)和EDC盐酸盐(80mg,0.418mmol)于DMF(2mL)中合并。将氮杂环丁烷-3-甲腈盐酸盐(49.5mg,0.418mmol)和4-甲基吗啉(0.124mL,1.114mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-50%AcCN/H2O)纯化产物,在真空中浓缩,并经由快速柱色谱法(8%MeOH/DCM)纯化,以提供标题化合物(38mg,39%)。1H NMR(500MHz,CD3OD)δ1.17(s,9H),3.58-3.72(m,1H),4.13-4.65(m,4H),5.35-5.45(m,3H),7.28-7.38(m,1H),7.95(d,J=15.5Hz,1H),8.33-8.40(m,1H)。对于C19H21N5O2,[M+H]计算值为352;测量值为352。
实施例83:(R)-N-(氰甲基)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺
将(R)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(40.0mg,0.139mmol)、HOBt水合物(25.6mg,0.167mmol)和EDC盐酸盐(40.0mg,0.209mmol)于DMF(2mL)中合并。将2-氨基乙腈(11.71mg,0.209mmol)和4-甲基吗啉(0.062mL,0.557mmol)加入,并将反应混合物于室温下搅拌2小时。经由制备HPLC(带有0.035%TFA的10-45%AcCN/H2O)纯化产物,在真空中浓缩并且冻干,以提供为浅黄色固体的标题化合物(36mg,59%)。1H NMR(500MHz,DMSO-d6)δ1.09(s,9H),4.01-4.12(m,2H),5.13-5.22(m,2H),5.33(br s,1H),7.10(d,J=4.5Hz,1H),7.87(s,1H),8.26(d,J=4.5Hz,1H),8.86(br s,1H),12.25(br s,1H)。对于C17H19N5O2,[M+H]计算值为326;测量值为326。
实施例84:(S)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-2-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)、HATU(15mg,0.039mmol)、(S)-吡咯烷-2-甲腈盐酸盐(4mg,0.032mmol)和N-甲基吗啉(90μL,0.097mmol)在THF(0.5mL)中合并。,将反应混合物于氮气在40℃下搅拌10分钟,然后于室温下搅拌30分钟。将此溶液浓缩并经由制备HPLC(带有0.035%TFA的10-50%AcCN/H2O)纯化,以提供为黄色薄膜的标题化合物(4mg,29%)。1H NMR(500MHz,CD3OD)δ0.94(d,J=6.9Hz,3H),1.06(d,J=6.3Hz,3H),1.04-1.13(m,1H),2.12-2.17(m,2H),2.25-2.29(m,2H),2.60-2.63(m,1H),3.72-3.75(m,1H),3.83-3.87(m,1H),4.90(d,J=13.7Hz,1H),5.05(d,J=12.7Hz,1H),5.50(d,J=7.3Hz,1H),7.86(s,1H),8.25(s,1H)。对于C19H20ClN5O2,[M+H]计算值为386;测量值为386。
实施例85:(R)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-2-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)、HATU(15mg,0.039mmol)、(R)-吡咯烷-2-甲腈盐酸盐(4mg,0.032mmol)和N-甲基吗啉(90μL,0.097mmol)在THF(0.5mL)中合并。将反应混合物于氮气在40℃下搅拌10分钟,然后于室温下搅拌30分钟。将此溶液浓缩并经由制备HPLC(带有0.035%TFA的10-50%AcCN/H2O)纯化,以提供为白色固体的标题化合物(2mg,18%)。1H NMR(500MHz,CD3OD)δ0.94(d,J=6.9Hz,3H),1.06(d,J=6.3Hz,3H),1.03-1.12(m,1H),2.12-2.17(m,2H),2.25-2.27(m,2H),2.59-2.63(m,1H),3.72-3.74(m,1H),3.83-3.86(m,1H),4.92(d,J=5.9Hz,1H),5.06(d,J=13.2Hz,1H),5.46(d,J=11.8Hz,1H),7.86(s,1H),8.25(s,1H)。对于C19H20ClN5O2,[M+H]计算值为386;测量值为386。
实施例86:(2S,4S)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)-4-氟吡咯烷-2-甲腈
将(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸(10mg,0.032mmol)、HATU(15mg,0.039mmol)、(2S,4S)-4-氟吡咯烷-2-甲腈(4mg,0.032mmol)和N-甲基吗啉(90μL,0.097mmol)于THF(0.5mL)中合并。将反应混合物于氮气下在40℃下搅拌10分钟,且然后于室温下搅拌30分钟。将此溶液浓缩并经由制备HPLC(带有0.035%TFA的10-50%AcCN/H2O)纯化,以提供为白色固体的标题化合物(2mg,12%)。1H NMR(500MHz,CD3OD)δ0.94(d,J=6.3Hz,3H),1.05(d,J=6.3Hz,3H),1.03-1.15(m,1H),2.56-2.65(m,3H),23.89-3.91(m,1H),4.25-4.30(m,1H),4.83-4.87(m,1H),5.09-5.13(m,1H),5.39-5.41(m,1H),5.47-5.66(m,1H),7.87(s,1H),8.27(s,1H)。对于C19H19ClFN5O2,[M+H]计算值为404;测量值为404。
制备X:(R)-3,3-二甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
步骤A:(R)-3,3-二甲基-2-(6-甲基-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
将(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸苄酯(10mg,0.018mmol)、Pd(Ph3P)4(10mg,0.009mmol)和二噁烷(1mL)在2mL微波瓶中合并。将混合物用氮吹扫,并加入三甲基铝(2.0M/甲苯,0.053mL,0.11mmol)。将瓶密封,并将反应混合物在Biotage InitiatorTM微波炉中于120℃加热1小时。将反应重复三次,每次反应中增加(R)-2-(6-氯-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酸苄酯(30mg)的量。将反应混合物合并,将得到的混合物浓缩,并经由制备HPLC(带有0.035%TFA的30-70%AcCN/H2O)纯化,以提供为黄色油状物的标题化合物(36mg,44%)。1H NMR(500MHz,CD3OD)δ1.21(s,9H),2.30(s,3H),2.36(s,3H),4.94(s,1H),5.07(d,J=18.6Hz,1H),5.21(d,J=19.0Hz,1H),7.36(d,J=8.3Hz,2H),8.04(d,J=4.9Hz,2H),8.10(s,1H),8.22(s,1H)。对于C23H25N3O5S,[M+H]计算值为456;测量值为456。
步骤B:(R)-3,3-二甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸
在50mL圆底烧瓶中将(R)-3,3-二甲基-2-(6-甲基-3-氧代-1-甲苯磺酰基吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(36mg,0.079mmol)溶解于THF(3mL)、MeOH(3mL)和NaOH水溶液(1N,3mL)中。将反应混合物在油浴中于50℃加热30分钟,然后冷却至室温。将此溶液浓缩并经由制备HPLC(带有0.035%TFA的10-35%AcCN/H2O)纯化,以提供标题化合物(10mg,42%)。1H NMR(500MHz,CD3OD)δ1.25(s,9H),2.29(s,3H),4.87(s,1H),5.21(d,J=19.5Hz,1H),5.37(d,J=19.5Hz,1H),7.87(s,1H),8.23(s,1H)。对于C16H19N3O3,[M+H]计算值为302;测量值为302。
实施例87:(R)-1-(3,3-二甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-3,3-二甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酸(10mg,0.033mmol)、DMAP(6mg,0.05mmol)、4-甲基吗啉(0.015mL,0.13mmol)、EDC盐酸盐(10mg,0.050mmol)、HOBt水合物(8mg,0.050mmol)和氮杂环丁烷-3-甲腈盐酸盐(6mg,0.050mmol)溶解于DMF(2mL)中。将反应混合物在氮气下于室温搅拌3小时。将此溶液浓缩并经由制备HPLC(带有0.035%TFA的10-30% AcCN/H2O)纯化,以提供标题化合物(1.4mg,12%)。1H NMR(500MHz,CD3OD)δ1.18(s,9H),2.35(d,J=8.8Hz,3H)4.17-4.18(m,1H),4.29-4.31(m,2H),4.52-4.62(m,1H),4.64-4.69(m,1H),5.19-5.23(m,2H),5.45(s,1H),7.83(d,J=16.1Hz,3H),8.19(s,1H)。对于C20H23N5O2,[M+H]计算值为366;测量值为366。
实施例88:(R)-1-(3-甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈
将(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)氮杂环丁烷-3-甲腈(30mg,0.081mmol)、Pd(Ph3P)4(47mg,0.04mmol)和二噁烷(2mL)在5mL微波瓶中合并。将混合物用氮吹扫,并加入三甲基铝(2.0M/甲苯,0.24mL,0.48mmol)。将瓶密封,并将反应混合物在Biotage InitiatorTM微波炉中于120℃加热1小时。将反应以相同规模重复四次。将反应混合物合并,并将生成的混合物用水(0.5mL)淬灭、浓缩,并经由制备HPLC(带有0.035%TFA的10-30%AcCN/H2O)纯化,接着经由快速色谱法(5%MeOH/95%DCM)纯化,以提供淡黄色固体的标题化合物(41mg,29%)。1HNMR(500MHz,CD3OD)δ0.92(d,J=6.8Hz,3H),1.07(dd,J=15.9,6.1Hz,3H),2.42(d,J=6.35Hz,3H),3.69-3.77(m,1H),4.19-4.22(m,1H),4.32-4.34(m,1H),4.53-4.59(m,1H),4.68-4.72(m,1H),5.20-5.33(m,3H),7.98(d,J=19.5Hz,1H),8.27(s,1H)。对于C19H21N5O2,[M+H]计算值为352;测量值为352。
下面的表2列举对于实施例中所述的许多化合物的JAK3和JAK2抑制数据。根据说明书第38页描述的测定测试化合物。抑制数据报告为pIC50,即-log10(IC50),其中IC50为在50%抑制时的摩尔浓度。较大的pIC50数值代表较高的效力。
表2.JAK2和JAK3抑制
Claims (13)
1.一种式I的化合物
或其药学上可接受的盐,其中:
G1是CR8;
R1选自由任选取代的C3-6杂环烷基和任选取代的C1-6烷基组成的组;其中任选取代的C1-6烷基任选被1至7个取代基取代,该取代基独立地选自由C1-14酰胺、C1-5氧代羰基、氰基、C3-8环烷基、卤基、羟基、氧代、C1-8磺酰基和任选取代的C3-6杂环烷基组成的组;任选取代的C3-6杂环烷基各自在环碳原子上任选被1至4个取代基取代,该取代基独立地选自由任选取代的C1-4烷基、C1-4烷氧基、C1-8烷基氨基、C1-5氧代羰基、氰基、卤代、羟基、氧代和任选取代的苯基组成的组;任选取代的C3-6杂环烷基各自在任一环氮原子上任选被取代基取代,该取代基独立地选自由任选取代的C1-4烷基、C1-10杂芳基和C1-8磺酰基组成的组;任选取代的C1-4烷基各自任选被1至5个取代基取代,该取代基独立地选自由C1-4烷氧基、C1-5氧代羰基、氰基、C3-8环烷基、卤基、羟基、氧代、C1-8磺酰基、C3-6杂环烷基和C1-10杂芳基组成的组;并且任选取代的苯基各自任选被1至5个独立地选自卤素的取代基取代;
R2和R3各自是氢,或者R2、R3和它们所连接的碳原子形成羰基;
R4是氢;
R5是氢;
R6和R7各自是氢,或者R6、R7和它们所连接的碳原子形成羰基;以及
R8选自由氢、C1-6烷基和卤基组成的组;
附带条件是不多于一个羰基是由R2和R3及R6和R7形成。
2.根据权利要求1所述的化合物或药学上可接受的盐,其中R8选自氢、卤基和C1-4烷基。
3.根据权利要求1所述的化合物或药学上可接受的盐,其中R1为任选取代的C1-6烷基。
4.根据权利要求1所述的化合物或药学上可接受的盐,其中R2、R3和它们所连接的碳原子形成羰基。
5.根据权利要求4所述的化合物或药学上可接受的盐,其中R6和R7每一个为氢。
6.根据权利要求1所述的化合物或药学上可接受的盐,其中R6、R7和它们所连接的碳原子形成羰基。
7.根据权利要求6所述的化合物或药学上可接受的盐,其中R2和R3每一个为氢。
8.化合物,其选自:
4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯;
4-(哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
3-氧代-3-(4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)丙腈;
4-甲基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯;
4-(4-甲基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
3-(4-甲基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)-3-氧代丙腈;
4-乙基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯;
4-(4-乙基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
3-(4-乙基-4-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-基)-3-氧代丙腈;
4-(戊烷-3-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
4-(1-环丙基-3-羟丙基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
3-((5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)甲基)吡咯烷-1-羧酸叔丁酯;
4-(吡咯烷-3-基甲基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
3-(5-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)哌啶-1-羧酸叔丁酯;
4-(哌啶-3-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
4-(4-乙基-1-丙酰基哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
4-(4-乙基-1-(嘧啶-4-基)哌啶-4-基)-3,4-二氢吡咯并[4,3,2-de][2,6]萘啶-5(1H)-酮;
(S)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(3-甲基-1-氧代-1-(吡咯烷-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(4-甲基-1-氧代-1-(吡咯烷-1-基)戊烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(2R,3R)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺;
(2R,3S)-N-环戊基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)戊酰胺;
(R)-N-环戊基-2-环丙基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺;
(R)-N-环戊基-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N,2-二环戊基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)乙酰胺;
(R)-N-环戊基-4,4,4-三氟-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-环戊基-3-羟基-3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-氰基-N-环戊基丙酰胺;
N-环戊基-1-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)环戊烷甲酰胺;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(氰甲基)-3-甲基丁酰胺;
1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-3-甲腈;
(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)哌啶-4-甲腈;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(4-氰苯基)-3-甲基丁酰胺;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(3-氰苯基)-3-甲基丁酰胺;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((S)-1-氰基丁烷-2-基)-3-甲基丁酰胺;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((R)-1-氰基丁烷-2-基)-3-甲基丁酰胺;
(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)氮杂环丁烷-3-甲腈;
(R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-(2-氰乙基)-3,3-二甲基丁酰胺;
(R)-1-(2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3,3-二甲基丁酰基)氮杂环丁烷-3-甲腈;
(R)-1-(2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)氮杂环丁烷-3-甲腈;
(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酸;
(2R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(四氢呋喃-3-基)丁酰胺;
(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(1,1-二氧代四氢噻吩-3-基)丁酰胺;
(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基-N-(2-(甲基磺酰基)乙基)丁酰胺;
(R)-N-(1,1-二氧代四氢-2H-噻喃-4-基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺;
4-{(1R)-1-[(1,1-二氧代硫代吗啉-4-基)羰基]-2-甲基丙基}-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-N-(环丙基甲氧基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺;
(2R)-N-(3,3-二氟环戊基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺;
(R)-3-(氟甲基)-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
(R)-1-(2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)-3-甲基氮杂环丁烷-3-甲腈;
(R)-3-甲基-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
(R)-4-(1-吗啉基-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-(4-甲基哌嗪-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
4-((2R)-1-(3-羟基吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-N-环戊基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
4-((2R)-1-(3-(4-氟苯基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
4-((2R)-1-(3-(二甲基氨基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
4-((2R)-1-(3-(甲氧基甲基)吡咯烷-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
4-((2R)-1-(3-甲基哌啶-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-(4-(2-羟基丙烷-2-基)哌啶-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-(4-(甲基磺酰基)哌嗪-1-基)-1-氧代丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-氧代-1-(4-(吡啶-2-基)哌嗪-1-基)丁烷-2-基)-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-N-环丙基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-(环丙基甲基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-异丁基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-异丁基-N-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(2R)-N-(1-羟基丙烷-2-基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-(2-羟基-2-甲基丙基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-N-((S)-2,3-二羟丙基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(R)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-苯基丁酰胺;
(R)-N-(1-(甲基磺酰基)哌啶-4-基)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(2R)-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N-((四氢呋喃-2-基)甲基)丁酰胺;
(2R)-N-(1-氰乙基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰胺;
(R)-4-(1-(3,3-二氟氮杂环丁烷-1-基)-3-甲基-1-氧代丁烷-2-基)-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-4-(1-(1,1-二氧化噻唑烷-3-基)-3-甲基-1-氧代丁烷-2-基)-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N,3-二甲基-N-(2-(甲基磺酰基)乙基)丁酰胺;
(R)-N-(氰甲基)-2-(6-氟-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-N,3-二甲基丁酰胺;
(R)-4-(1-(3-(二氟甲基)氮杂环丁烷-1-基)-3-甲基-1-氧代丁烷-2-基)-6-氟-4,5-二氢吡咯并[4,3,2-de][2,6]萘啶-3(1H)-酮;
(R)-1-(3-甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
(R)-1-(3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
(R)-N-(氰甲基)-3,3-二甲基-2-(3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰胺;
(S)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-2-甲腈;
(R)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)吡咯烷-2-甲腈;
(2S,4S)-1-((R)-2-(6-氯-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)-3-甲基丁酰基)-4-氟吡咯烷-2-甲腈;
(R)-1-(3,3-二甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
(R)-1-(3-甲基-2-(6-甲基-3-氧代吡咯并[4,3,2-de][2,6]萘啶-4(1H,3H,5H)-基)丁酰基)氮杂环丁烷-3-甲腈;
任何上述化合物的立体异构体;以及
任何一种上述立体异构体或化合物的药学上可接受的盐类。
9.一种药物组合物,其包含如权利要求1~8任一项中所定义的化合物或药学上可接受的盐类、以及药学上可接受的赋形剂。
10.权利要求1~8任一项中所定义的化合物或药学上可接受的盐在制备药物中的用途,其中所述药物用于治疗选自如下的疾病、病症或症状:过敏性鼻炎、过敏性哮喘、特应性皮炎、类风湿性关节炎、多发性硬化、系统性红斑性狼疮、牛皮癣、免疫性血小板减少性紫癜、慢性阻塞性肺疾病以及血栓形成。
11.一种组合物,其含有权利要求1~8任一项中所定义的化合物或药学上可接受的盐,以及至少一种另外的药理学活性剂。
12.根据权利要求11所述的组合物,其中所述另外的药理学活性剂为缓解病情抗风湿药物。
13.根据权利要求12所述的组合物,其中所述缓解病情抗风湿药物为甲氨蝶呤。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18515709P | 2009-06-08 | 2009-06-08 | |
US61/185,157 | 2009-06-08 | ||
PCT/US2010/037822 WO2010144486A1 (en) | 2009-06-08 | 2010-06-08 | Dihydropyrrolonaphtyridinone compounds as inhibitors of jak |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102459267A CN102459267A (zh) | 2012-05-16 |
CN102459267B true CN102459267B (zh) | 2014-11-26 |
Family
ID=42805991
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201080032853.3A Active CN102459267B (zh) | 2009-06-08 | 2010-06-08 | 用作jak抑制剂的二氢吡咯并萘啶酮化合物 |
Country Status (15)
Country | Link |
---|---|
US (2) | US8420816B2 (zh) |
EP (1) | EP2440558B1 (zh) |
JP (1) | JP5719840B2 (zh) |
CN (1) | CN102459267B (zh) |
CA (1) | CA2764885C (zh) |
DK (1) | DK2440558T3 (zh) |
ES (1) | ES2540964T3 (zh) |
HK (1) | HK1167654A1 (zh) |
HR (1) | HRP20150701T1 (zh) |
HU (1) | HUE026518T2 (zh) |
PL (1) | PL2440558T3 (zh) |
PT (1) | PT2440558E (zh) |
SI (1) | SI2440558T1 (zh) |
SM (1) | SMT201500156B (zh) |
WO (1) | WO2010144486A1 (zh) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012078802A1 (en) | 2010-12-08 | 2012-06-14 | Takeda Pharmaceutical Company Limited | PREPARATION OF SUBSTITUTED-4,5-DIHYDROPYRROLO[4,3,2-de][2,6]NAPHTHYRIDIN-3(1H)-ONES |
KR101433057B1 (ko) * | 2012-03-07 | 2014-09-23 | 한국과학기술원 | 빛에 의해 rtk 신호전달을 활성화하는 융합단백질 및 그의 용도 |
KR101836822B1 (ko) * | 2016-10-17 | 2018-03-09 | 주식회사 엔지켐생명과학 | 모노아세틸디아실글리세롤 화합물을 함유하는 건선의 예방 또는 치료용 조성물 |
EP3305786A3 (de) | 2018-01-22 | 2018-07-25 | Bayer CropScience Aktiengesellschaft | Kondensierte bicyclische heterocyclen-derivate als schädlingsbekämpfungsmittel |
WO2020092015A1 (en) | 2018-11-02 | 2020-05-07 | University Of Rochester | Therapeutic mitigation of epithelial infection |
CN110016030B (zh) * | 2019-05-22 | 2021-02-09 | 南京合巨药业有限公司 | 一种5-氟-1H-吡咯-[2,3-b]吡啶-4-甲醛的制备方法 |
CN112390799B (zh) * | 2019-08-16 | 2022-04-29 | 科岭源生物科技(深圳)有限公司 | 一种含氮杂环类5-ht3受体调节剂及其制备方法和用途 |
WO2022110052A1 (zh) * | 2020-11-27 | 2022-06-02 | 科岭源生物科技(深圳)有限公司 | 一种含氮杂环类5-ht3受体调节剂及其制备方法和用途 |
US11561787B2 (en) | 2021-05-13 | 2023-01-24 | International Business Machines Corporation | Application invocation on specified operating system version |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007056155A1 (en) * | 2005-11-03 | 2007-05-18 | Chembridge Research Laboratories, Inc. | Heterocyclic compounds as tyrosine kinase modulators |
WO2007117494A1 (en) * | 2006-04-05 | 2007-10-18 | Vertex Pharmaceuticals Incorporated | Deazapurines useful as inhibitors of janus kinases |
WO2008079521A2 (en) * | 2006-11-01 | 2008-07-03 | Vertex Pharmaceuticals Incorporated | Tricyclic heteroaryl compounds useful as inhibitors of janus kinase |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3177299D1 (de) | 1980-04-11 | 1993-04-15 | Ampex | Bildverarbeitungssystem fuer raeumliche bildtransformation. |
US4437207A (en) | 1982-06-24 | 1984-03-20 | Ross Henry M | Magnetic, force-limited apparatus for tenderizing meat |
HU187583B (en) | 1983-04-14 | 1986-01-28 | Duna-Tisza Koezi Allami Epitoeipari Vallalat,Hu | Method and apparatus for in-situ producing non-uniform pile from monolithic concrete |
JPS6054356A (ja) | 1983-09-03 | 1985-03-28 | Taisho Pharmaceut Co Ltd | 3−ベンゾイル−2−メルカプトプロピオン酸誘導体 |
US4526290A (en) | 1983-10-19 | 1985-07-02 | Ball Corporation | Flanged container |
EP0193329A3 (en) * | 1985-02-22 | 1987-08-19 | Beecham Group Plc | Pyrazolopyridines, their preparation and pharmaceutical compositions containing them |
US6600028B1 (en) | 1997-04-02 | 2003-07-29 | Amersham Pharmacia Biotech Uk Limited | Tricyclic base analogues |
US6531475B1 (en) | 1998-11-12 | 2003-03-11 | Neurocrine Biosciences, Inc. | CRF receptor antagonists and methods relating thereto |
IL142893A0 (en) | 1998-11-12 | 2002-04-21 | Neurocrine Biosciences Inc | Fused polyclic heterocyclic compounds and pharmaceutical compositions containing the same |
CN1512883A (zh) | 2001-04-30 | 2004-07-14 | Crf受体拮抗剂 | |
CA2450535A1 (en) | 2001-05-21 | 2002-11-28 | Neurocrine Biosciences Inc. | Tri-and tetraaza-acenaphthylen derivatives as crf receptor antagonists |
US7273871B2 (en) | 2001-07-17 | 2007-09-25 | Sb Pharmco Puerto Rico Inc. | Phenyl-5,6,6A,7,8,9-hexahydro-4H-1,4,9-triaza-phenalene derivatives as CRF antagonists |
GB0117395D0 (en) | 2001-07-17 | 2001-09-05 | Glaxo Group Ltd | Chemical compounds |
US7049303B2 (en) * | 2001-11-07 | 2006-05-23 | Medical Research Council | Inhibition of viruses |
WO2003061385A1 (en) | 2002-01-17 | 2003-07-31 | Ribapharm Inc. | Tricyclic nucleoside library compounds, synthesis, and use as antiviral agents |
EP1495016A2 (en) | 2002-04-09 | 2005-01-12 | Astex Technology Limited | Heterocyclic compounds and their use as modulators of p38 map kinase |
CA2548283A1 (en) | 2003-12-19 | 2005-07-21 | Koronis Pharmaceuticals, Inc. | Mutagenic heterocycles |
PT1696920E (pt) | 2003-12-19 | 2015-01-14 | Plexxikon Inc | Compostos e métodos para o desenvolvimento de moduladores de ret |
GB0420719D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
EP2251341A1 (en) | 2005-07-14 | 2010-11-17 | Astellas Pharma Inc. | Heterocyclic Janus kinase 3 inhibitors |
ES2611588T3 (es) | 2005-12-13 | 2017-05-09 | Incyte Holdings Corporation | Pirrolo[2,3-b]piridinas y pirrolo[2,3-b]pirimidinas sustituidas con heteroarilo como inhibidores de quinasas Janus |
GB0619926D0 (en) | 2006-10-09 | 2006-11-15 | Koolmill Systems Ltd | Surface abrasion of objects |
CN101578285A (zh) | 2007-01-12 | 2009-11-11 | 安斯泰来制药株式会社 | 稠合吡啶化合物 |
WO2008100447A2 (en) | 2007-02-09 | 2008-08-21 | Gilead Sciences, Inc. | Nucleoside analogs for antiviral treatment |
CA2679694A1 (en) * | 2007-03-13 | 2008-09-18 | Merck & Co., Inc. | Inhibitors of janus kinases and/or 3-phosphoinositide-dependent protein kinase-1 |
CN101679440A (zh) * | 2007-04-02 | 2010-03-24 | 帕劳制药股份有限公司 | 作为jak3抑制剂的吡咯并嘧啶衍生物 |
TW200908968A (en) | 2007-05-29 | 2009-03-01 | Sgx Pharmaceuticals Inc | Substituted pyrrolopyridines and pyrazolopyridines as kinase modulators |
EP2002836B1 (en) | 2007-05-31 | 2010-10-20 | Nerviano Medical Sciences S.r.l. | Cyclocondensed azaindoles active as kinase inhibitors |
CA2698256A1 (en) * | 2007-09-11 | 2009-03-19 | Merck Sharp & Dohme Corp. | Inhibitors of janus kinases |
US8183245B2 (en) * | 2007-10-25 | 2012-05-22 | Merck Sharp & Dohme Corp. | Pyrazine substituted pyrrolopyridines as inhibitors of JAK and PDK1 |
-
2010
- 2010-06-08 DK DK10725338.7T patent/DK2440558T3/en active
- 2010-06-08 JP JP2012514236A patent/JP5719840B2/ja active Active
- 2010-06-08 CA CA2764885A patent/CA2764885C/en active Active
- 2010-06-08 SI SI201030965T patent/SI2440558T1/sl unknown
- 2010-06-08 EP EP10725338.7A patent/EP2440558B1/en active Active
- 2010-06-08 HU HUE10725338A patent/HUE026518T2/en unknown
- 2010-06-08 US US12/796,583 patent/US8420816B2/en active Active
- 2010-06-08 PL PL10725338T patent/PL2440558T3/pl unknown
- 2010-06-08 CN CN201080032853.3A patent/CN102459267B/zh active Active
- 2010-06-08 PT PT107253387T patent/PT2440558E/pt unknown
- 2010-06-08 ES ES10725338.7T patent/ES2540964T3/es active Active
- 2010-06-08 WO PCT/US2010/037822 patent/WO2010144486A1/en active Application Filing
-
2012
- 2012-08-29 HK HK12108435.2A patent/HK1167654A1/zh unknown
-
2013
- 2013-03-06 US US13/787,514 patent/US8785429B2/en active Active
-
2015
- 2015-06-30 HR HRP20150701TT patent/HRP20150701T1/hr unknown
- 2015-07-01 SM SM201500156T patent/SMT201500156B/xx unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007056155A1 (en) * | 2005-11-03 | 2007-05-18 | Chembridge Research Laboratories, Inc. | Heterocyclic compounds as tyrosine kinase modulators |
WO2007117494A1 (en) * | 2006-04-05 | 2007-10-18 | Vertex Pharmaceuticals Incorporated | Deazapurines useful as inhibitors of janus kinases |
WO2008079521A2 (en) * | 2006-11-01 | 2008-07-03 | Vertex Pharmaceuticals Incorporated | Tricyclic heteroaryl compounds useful as inhibitors of janus kinase |
Also Published As
Publication number | Publication date |
---|---|
EP2440558B1 (en) | 2015-04-01 |
PT2440558E (pt) | 2015-08-27 |
HRP20150701T1 (hr) | 2015-08-28 |
DK2440558T3 (en) | 2015-07-06 |
JP5719840B2 (ja) | 2015-05-20 |
SMT201500156B (it) | 2015-09-07 |
WO2010144486A1 (en) | 2010-12-16 |
JP2012529437A (ja) | 2012-11-22 |
US8785429B2 (en) | 2014-07-22 |
PL2440558T3 (pl) | 2015-10-30 |
EP2440558A1 (en) | 2012-04-18 |
CA2764885A1 (en) | 2010-12-16 |
SI2440558T1 (sl) | 2015-10-30 |
HK1167654A1 (zh) | 2012-12-07 |
ES2540964T3 (es) | 2015-07-15 |
CN102459267A (zh) | 2012-05-16 |
US8420816B2 (en) | 2013-04-16 |
US20110136780A1 (en) | 2011-06-09 |
CA2764885C (en) | 2018-05-15 |
HUE026518T2 (en) | 2016-06-28 |
US20130184252A1 (en) | 2013-07-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102459267B (zh) | 用作jak抑制剂的二氢吡咯并萘啶酮化合物 | |
JP6688352B2 (ja) | 補体媒介障害の治療のためのアリール化合物、ヘテロアリール化合物及び複素環式化合物 | |
TWI647214B (zh) | 雙環稠合之雜芳基或芳基化合物類 | |
CN102753548B (zh) | 作为syk抑制剂的稠合的杂芳族吡咯烷酮 | |
CN110003209B (zh) | 作为trk激酶抑制剂的大环化合物 | |
JP2022174122A (ja) | 医学的障害の治療のためのアリール、ヘテロアリール及び複素環式医薬化合物 | |
CN114667167A (zh) | 用于治疗癌症的杂环化合物 | |
CN114401971A (zh) | 用作nlrp3抑制剂的大环磺酰脲衍生物 | |
WO2021028854A1 (en) | Piperidinyl-methyl-purineamines as nsd2 inhibitors and anti-cancer agents | |
TW201639842A (zh) | 作為pi3k抑制劑之雜環基胺 | |
WO2019060850A1 (en) | CYANO-SUBSTITUTED N- (BENZYL OR PYRIDINYLMETHYL) DERIVATIVES-3-HYDROXYPICOLINAMIDE USEFUL AS INHIBITORS OF HIF PROLYL HYDROXYLASE | |
CN104619708A (zh) | 氮杂吲哚衍生物 | |
JP2017523213A (ja) | 抗菌薬としてのキノロン誘導体 | |
CN111527090B (zh) | 作为p2x3抑制剂的吡唑并-吡咯并-嘧啶-二酮衍生物 | |
WO2019120194A1 (zh) | 一种取代的吡唑并[1,5-a]嘧啶化合物及其药物组合物及用途 | |
WO2015106012A1 (en) | Azaindole derivatives | |
TW202102498A (zh) | 作為ripk2 抑制劑之吡啶稠合咪唑及吡咯衍生物 | |
TW202200589A (zh) | Mll1抑制劑及抗癌劑 | |
TW201215606A (en) | Dihydropyrrolonaphthyridinone compounds as inhibitors of JAK | |
TW202332429A (zh) | 治療性化合物及其使用方法 | |
CN114981270A (zh) | Mll1抑制剂和抗癌剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |