CN108884029B - Lsd1抑制剂 - Google Patents
Lsd1抑制剂 Download PDFInfo
- Publication number
- CN108884029B CN108884029B CN201680077382.5A CN201680077382A CN108884029B CN 108884029 B CN108884029 B CN 108884029B CN 201680077382 A CN201680077382 A CN 201680077382A CN 108884029 B CN108884029 B CN 108884029B
- Authority
- CN
- China
- Prior art keywords
- phenylcyclopropyl
- piperidin
- amino
- alkyl
- ethyl
- 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
- 229940123628 Lysine (K)-specific demethylase 1A inhibitor Drugs 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 240
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 201000011510 cancer Diseases 0.000 claims abstract description 14
- -1 hydroxy, amino Chemical group 0.000 claims description 312
- 125000000623 heterocyclic group Chemical group 0.000 claims description 103
- 125000003118 aryl group Chemical group 0.000 claims description 89
- 229910052739 hydrogen Inorganic materials 0.000 claims description 71
- 239000001257 hydrogen Substances 0.000 claims description 71
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 150000002431 hydrogen Chemical class 0.000 claims description 53
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 150000003254 radicals Chemical class 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 37
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 125000002757 morpholinyl group Chemical group 0.000 claims description 25
- 125000004193 piperazinyl group Chemical group 0.000 claims description 25
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 25
- 125000001188 haloalkyl group Chemical group 0.000 claims description 23
- 125000003386 piperidinyl group Chemical group 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000002252 acyl group Chemical group 0.000 claims description 19
- 125000002393 azetidinyl group Chemical group 0.000 claims description 19
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 19
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 19
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000006413 ring segment Chemical group 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000003277 amino group Chemical group 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 11
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 claims description 10
- 125000005940 1,4-dioxanyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 206010025323 Lymphomas Diseases 0.000 claims description 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 8
- AQDXZWWFIDBZBT-FCHUYYIVSA-N 1-(2-phenoxyethyl)-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound O(C1=CC=CC=C1)CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 AQDXZWWFIDBZBT-FCHUYYIVSA-N 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- XSBCLHZKIOONKU-XZOQPEGZSA-N 1-(3-phenoxypropyl)-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound O(C1=CC=CC=C1)CCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 XSBCLHZKIOONKU-XZOQPEGZSA-N 0.000 claims description 7
- DWQDTYFREPNKJV-XGELLPRESA-N 1-phenoxy-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-2-ol Chemical compound O(C1=CC=CC=C1)CC(CN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)O DWQDTYFREPNKJV-XGELLPRESA-N 0.000 claims description 7
- 206010039491 Sarcoma Diseases 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- KKLUZIVFNCUJMR-LEWJYISDSA-N (1R,2S)-N-[[1-(2-phenoxyethyl)azetidin-3-yl]methyl]-2-phenylcyclopropan-1-amine Chemical compound O(C1=CC=CC=C1)CCN1CC(C1)CN[C@H]1[C@@H](C1)C1=CC=CC=C1 KKLUZIVFNCUJMR-LEWJYISDSA-N 0.000 claims description 6
- NXJWQHQMPDATAX-FCHUYYIVSA-N (1R,2S)-N-[[1-(3-phenoxypropyl)azetidin-3-yl]methyl]-2-phenylcyclopropan-1-amine Chemical compound O(C1=CC=CC=C1)CCCN1CC(C1)CN[C@H]1[C@@H](C1)C1=CC=CC=C1 NXJWQHQMPDATAX-FCHUYYIVSA-N 0.000 claims description 6
- DWQDTYFREPNKJV-ACIOBRDBSA-N (2S)-1-phenoxy-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-2-ol Chemical compound O(C1=CC=CC=C1)C[C@H](CN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)O DWQDTYFREPNKJV-ACIOBRDBSA-N 0.000 claims description 6
- OYELEBBISJGNHJ-UHFFFAOYSA-N 1,3-oxazinan-2-one Chemical compound O=C1NCCCO1 OYELEBBISJGNHJ-UHFFFAOYSA-N 0.000 claims description 6
- FIYQGBHJKUETFD-IZZNHLLZSA-N 1-[2-(4-morpholin-4-ylphenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound O1CCN(CC1)C1=CC=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=C1 FIYQGBHJKUETFD-IZZNHLLZSA-N 0.000 claims description 6
- 206010024612 Lipoma Diseases 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 6
- 201000011066 hemangioma Diseases 0.000 claims description 6
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 6
- WTFCSQDJTQTIQY-PYIJZYPVSA-N (E)-3-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]prop-2-enoic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=CC=C(C=C1)/C=C/C(=O)O WTFCSQDJTQTIQY-PYIJZYPVSA-N 0.000 claims description 5
- HJWAOTXDLZALED-XQFMJXHWSA-N 1-(2-methoxy-3-phenoxypropyl)-N-[(1S,2R)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound COC(COc1ccccc1)CN1CCC(CC1)N[C@H]1C[C@@H]1c1ccccc1 HJWAOTXDLZALED-XQFMJXHWSA-N 0.000 claims description 5
- GFYNGYAEQNESGD-ATTQYFOMSA-N 1-anilino-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-2-ol Chemical compound N(C1=CC=CC=C1)CC(CN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)O GFYNGYAEQNESGD-ATTQYFOMSA-N 0.000 claims description 5
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 5
- 125000005605 benzo group Chemical group 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- DWQDTYFREPNKJV-AKIFATBCSA-N (2R)-1-phenoxy-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-2-ol Chemical compound O(C1=CC=CC=C1)C[C@@H](CN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)O DWQDTYFREPNKJV-AKIFATBCSA-N 0.000 claims description 4
- HMGZTAWSZOCCBN-FCHUYYIVSA-N 1-[2-(2-methylpyridin-4-yl)oxyethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CC1=NC=CC(=C1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 HMGZTAWSZOCCBN-FCHUYYIVSA-N 0.000 claims description 4
- OBFRWIBANRMKNL-FCHUYYIVSA-N 1-[2-(3-fluorophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound FC=1C=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=CC=1 OBFRWIBANRMKNL-FCHUYYIVSA-N 0.000 claims description 4
- BSQSPVOXHMLTQY-QYAPWVIVSA-N 1-[2-(4-bromophenoxy)ethyl]-4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-2-one Chemical compound BrC1=CC=C(OCCN2C(CC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)=O)C=C1 BSQSPVOXHMLTQY-QYAPWVIVSA-N 0.000 claims description 4
- HCFBUBHFNFJNHC-VQTJNVASSA-N 1-morpholin-4-yl-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-1-one Chemical compound O1CCN(CC1)C(CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O HCFBUBHFNFJNHC-VQTJNVASSA-N 0.000 claims description 4
- RCLBQLRXGPHCPQ-YPURBLFUSA-N 1-phenoxy-3-[3-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]propan-2-ol Chemical compound O(C1=CC=CC=C1)CC(CN1CC(C1)CN[C@H]1[C@@H](C1)C1=CC=CC=C1)O RCLBQLRXGPHCPQ-YPURBLFUSA-N 0.000 claims description 4
- NYCJTYVDUWSFNJ-XAGPSQNTSA-N 2-methyl-1-phenoxy-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-2-ol Chemical compound CC(COC1=CC=CC=C1)(CN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)O NYCJTYVDUWSFNJ-XAGPSQNTSA-N 0.000 claims description 4
- MRZODRVNFUXRAU-BJKOFHAPSA-N 3-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]-1,3-oxazolidin-2-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=CC=C(C=C1)N1C(OCC1)=O MRZODRVNFUXRAU-BJKOFHAPSA-N 0.000 claims description 4
- QXGSPTWTTXBBQO-VUBBFULJSA-N COC(=O)/C=C/C1=CC=C(C=C1)OCC(CN2CCC(CC2)N[C@@H]3C[C@H]3C4=CC=CC=C4)O Chemical compound COC(=O)/C=C/C1=CC=C(C=C1)OCC(CN2CCC(CC2)N[C@@H]3C[C@H]3C4=CC=CC=C4)O QXGSPTWTTXBBQO-VUBBFULJSA-N 0.000 claims description 4
- RWEBWBGUJGIGHO-XZOQPEGZSA-N N,2-dimethyl-N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethyl]pyridin-4-amine Chemical compound CN(C1=CC(=NC=C1)C)CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 RWEBWBGUJGIGHO-XZOQPEGZSA-N 0.000 claims description 4
- PCUFVSHGTHPWDD-RBUKOAKNSA-N N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethyl]propane-2-sulfonamide Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNS(=O)(=O)C(C)C PCUFVSHGTHPWDD-RBUKOAKNSA-N 0.000 claims description 4
- VHLYSAMXJQKDAV-CXRLMVSZSA-N N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propyl]methanesulfonamide Chemical compound CS(=O)(=O)NCC(C)N1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 VHLYSAMXJQKDAV-CXRLMVSZSA-N 0.000 claims description 4
- XFKIGOCIXUBEIS-BJKOFHAPSA-N N-methoxy-2-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]acetamide Chemical compound CONC(CC1=CC=C(C=C1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O XFKIGOCIXUBEIS-BJKOFHAPSA-N 0.000 claims description 4
- 206010043276 Teratoma Diseases 0.000 claims description 4
- 239000008280 blood Substances 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 4
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 4
- 201000010260 leiomyoma Diseases 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- AYSVJNWKIRRHFG-YDUIRMPASA-N 1-(N-methylanilino)-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-2-ol Chemical compound CN(C1=CC=CC=C1)CC(CN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)O AYSVJNWKIRRHFG-YDUIRMPASA-N 0.000 claims description 3
- KSDULWWUAJTMEO-FCHUYYIVSA-N 1-[2-(4-bromophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound BrC1=CC=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=C1 KSDULWWUAJTMEO-FCHUYYIVSA-N 0.000 claims description 3
- NNTXKTQFAISUTJ-DLBZAZTESA-N 1-methyl-3-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethyl]urea Chemical compound CNC(=O)NCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 NNTXKTQFAISUTJ-DLBZAZTESA-N 0.000 claims description 3
- ZEBFHUSPYBVICS-KHMGXFTDSA-N 1-morpholin-4-yl-2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-1-one Chemical compound O1CCN(CC1)C(C(C)N1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O ZEBFHUSPYBVICS-KHMGXFTDSA-N 0.000 claims description 3
- VCYHCWGZNIZFKP-LHJLODMPSA-N 1-morpholin-4-yl-3-phenyl-2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-1-one Chemical compound O1CCN(CC1)C(C(CC1=CC=CC=C1)N1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O VCYHCWGZNIZFKP-LHJLODMPSA-N 0.000 claims description 3
- ZICZOSMNWHESCC-PHYMHCFQSA-N 1-phenoxy-3-[(1S,5R)-6-[[(1R,2S)-2-phenylcyclopropyl]amino]-3-azabicyclo[3.1.1]heptan-3-yl]propan-2-ol Chemical compound O(C1=CC=CC=C1)CC(CN1C[C@@H]2C([C@H](C1)C2)N[C@H]1[C@@H](C1)C1=CC=CC=C1)O ZICZOSMNWHESCC-PHYMHCFQSA-N 0.000 claims description 3
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 claims description 3
- 201000003076 Angiosarcoma Diseases 0.000 claims description 3
- 208000002927 Hamartoma Diseases 0.000 claims description 3
- 208000001258 Hemangiosarcoma Diseases 0.000 claims description 3
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims description 3
- JCKPXLBHLFMNTM-LOSJGSFVSA-N N,N-dimethyl-2-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]acetamide Chemical compound CN(C(CC1=CC=C(C=C1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O)C JCKPXLBHLFMNTM-LOSJGSFVSA-N 0.000 claims description 3
- 206010029260 Neuroblastoma Diseases 0.000 claims description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 201000008968 osteosarcoma Diseases 0.000 claims description 3
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 claims description 3
- 210000002307 prostate Anatomy 0.000 claims description 3
- 210000003932 urinary bladder Anatomy 0.000 claims description 3
- GTIYVRXRUMIRJA-RBUKOAKNSA-N (1R,2S)-2-phenyl-N-[[1-(2-pyridin-2-yloxyethyl)azetidin-3-yl]methyl]cyclopropan-1-amine Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NCC1CN(C1)CCOC1=NC=CC=C1 GTIYVRXRUMIRJA-RBUKOAKNSA-N 0.000 claims description 2
- DRQRIFCOQGVFGX-LOSJGSFVSA-N (1R,2S)-2-phenyl-N-[[1-[2-(4-piperazin-1-ylphenoxy)ethyl]azetidin-3-yl]methyl]cyclopropan-1-amine Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NCC1CN(C1)CCOC1=CC=C(C=C1)N1CCNCC1 DRQRIFCOQGVFGX-LOSJGSFVSA-N 0.000 claims description 2
- NZHUTHVNBHTIQV-AZUAARDMSA-N (1R,2S)-N-[[1-[2-(2,4-dichlorophenoxy)ethyl]azetidin-3-yl]methyl]-2-phenylcyclopropan-1-amine Chemical compound ClC1=C(OCCN2CC(C2)CN[C@H]2[C@@H](C2)C2=CC=CC=C2)C=CC(=C1)Cl NZHUTHVNBHTIQV-AZUAARDMSA-N 0.000 claims description 2
- ZSCPQOGJPMDJHN-AZUAARDMSA-N (1R,2S)-N-[[1-[2-(2,4-difluorophenoxy)ethyl]azetidin-3-yl]methyl]-2-phenylcyclopropan-1-amine Chemical compound FC1=C(OCCN2CC(C2)CN[C@H]2[C@@H](C2)C2=CC=CC=C2)C=CC(=C1)F ZSCPQOGJPMDJHN-AZUAARDMSA-N 0.000 claims description 2
- KSBMLEHIDMHUOK-LEWJYISDSA-N (1R,2S)-N-[[1-[2-(4-bromophenoxy)ethyl]azetidin-3-yl]methyl]-2-phenylcyclopropan-1-amine Chemical compound BrC1=CC=C(OCCN2CC(C2)CN[C@H]2[C@@H](C2)C2=CC=CC=C2)C=C1 KSBMLEHIDMHUOK-LEWJYISDSA-N 0.000 claims description 2
- IXFWRLRHZAWBJN-FCHUYYIVSA-N (1R,2S)-N-[[1-[2-(4-methylphenoxy)ethyl]azetidin-3-yl]methyl]-2-phenylcyclopropan-1-amine Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NCC1CN(C1)CCOC1=CC=C(C=C1)C IXFWRLRHZAWBJN-FCHUYYIVSA-N 0.000 claims description 2
- GQFASJWZLZIQOX-LEWJYISDSA-N (1R,2S)-N-[[1-[2-(6-methylpyridin-3-yl)oxyethyl]azetidin-3-yl]methyl]-2-phenylcyclopropan-1-amine Chemical compound CC1=CC=C(C=N1)OCCN1CC(C1)CN[C@H]1[C@@H](C1)C1=CC=CC=C1 GQFASJWZLZIQOX-LEWJYISDSA-N 0.000 claims description 2
- XYCLTABZKSZDBN-IZZNHLLZSA-N (1R,2S)-N-[[1-[2-[4-(4-methylpiperazin-1-yl)phenoxy]ethyl]azetidin-3-yl]methyl]-2-phenylcyclopropan-1-amine Chemical compound CN1CCN(CC1)C1=CC=C(OCCN2CC(C2)CN[C@H]2[C@@H](C2)C2=CC=CC=C2)C=C1 XYCLTABZKSZDBN-IZZNHLLZSA-N 0.000 claims description 2
- RZRZOMMLSJEFFS-RPWUZVMVSA-N (1S,2R)-N-[[1-[2-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]oxyethyl]azetidin-3-yl]methyl]-2-phenylcyclopropan-1-amine Chemical compound CN1CCN(CC1)C=1C=CC(=NC=1)OCCN1CC(C1)CN[C@@H]1[C@H](C1)C1=CC=CC=C1 RZRZOMMLSJEFFS-RPWUZVMVSA-N 0.000 claims description 2
- ZHDSXRLIXICBFX-ZWKOTPCHSA-N 1,1-dimethyl-3-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethyl]urea Chemical compound CN(C(=O)NCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)C ZHDSXRLIXICBFX-ZWKOTPCHSA-N 0.000 claims description 2
- MPYAKOBVALMKHY-FCHUYYIVSA-N 1-(2-anilinoethyl)-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound C1(=CC=CC=C1)NCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 MPYAKOBVALMKHY-FCHUYYIVSA-N 0.000 claims description 2
- CNGAWKKIQZLPRT-DLBZAZTESA-N 1-(2-methoxyethyl)-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound COCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 CNGAWKKIQZLPRT-DLBZAZTESA-N 0.000 claims description 2
- NQNKZBDVGJUWRQ-LEWJYISDSA-N 1-(4-methylpiperazin-1-yl)-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-1-one Chemical compound CN1CCN(CC1)C(CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O NQNKZBDVGJUWRQ-LEWJYISDSA-N 0.000 claims description 2
- IYFVTZWEFYQPEC-FCHUYYIVSA-N 1-(4-methylpiperazin-1-yl)-4-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]butan-1-one Chemical compound CN1CCN(CC1)C(CCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O IYFVTZWEFYQPEC-FCHUYYIVSA-N 0.000 claims description 2
- UZDXMBBAQSXUMM-GKJHBJHPSA-N 1-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-1-one Chemical compound C[C@@H]1O[C@@H](CN(C1)C(CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O)C UZDXMBBAQSXUMM-GKJHBJHPSA-N 0.000 claims description 2
- OMERYNLJLNJGOV-RBUKOAKNSA-N 1-[2-(1-methylpyrazol-3-yl)oxyethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CN1N=C(C=C1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 OMERYNLJLNJGOV-RBUKOAKNSA-N 0.000 claims description 2
- VHVHFAWUQJOZCW-PZJWPPBQSA-N 1-[2-(2,4-dichlorophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound ClC1=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=CC(=C1)Cl VHVHFAWUQJOZCW-PZJWPPBQSA-N 0.000 claims description 2
- ZDWNZFTWTFSEHO-PZJWPPBQSA-N 1-[2-(2,4-difluorophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound FC1=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=CC(=C1)F ZDWNZFTWTFSEHO-PZJWPPBQSA-N 0.000 claims description 2
- CLBDQRTXLDWBKD-VQTJNVASSA-N 1-[2-(2,5-dimethylpyrazol-3-yl)oxyethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CN1N=C(C=C1OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)C CLBDQRTXLDWBKD-VQTJNVASSA-N 0.000 claims description 2
- KCBIDBRYKQVZRY-LEWJYISDSA-N 1-[2-(2-methylpyrimidin-5-yl)oxyethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CC1=NC=C(C=N1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 KCBIDBRYKQVZRY-LEWJYISDSA-N 0.000 claims description 2
- UADVFXQLABFXCF-FCHUYYIVSA-N 1-[2-(3,5-dichlorophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound ClC=1C=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=C(C=1)Cl UADVFXQLABFXCF-FCHUYYIVSA-N 0.000 claims description 2
- ZHPRWNUQZBTACW-NZQKXSOJSA-N 1-[2-(3,5-difluoro-4-methylphenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound FC=1C=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=C(C=1C)F ZHPRWNUQZBTACW-NZQKXSOJSA-N 0.000 claims description 2
- YDFYCFRSGXPPCF-FCHUYYIVSA-N 1-[2-(3,5-difluorophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound FC=1C=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=C(C=1)F YDFYCFRSGXPPCF-FCHUYYIVSA-N 0.000 claims description 2
- IJACNUWWSHZSAE-JTHBVZDNSA-N 1-[2-(3-fluoro-4-methylphenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound FC=1C=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=CC=1C IJACNUWWSHZSAE-JTHBVZDNSA-N 0.000 claims description 2
- BZSBNIVSQZUMFZ-PZJWPPBQSA-N 1-[2-(4-bromo-2-fluorophenoxy)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound BrC1=CC(=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=C1)F BZSBNIVSQZUMFZ-PZJWPPBQSA-N 0.000 claims description 2
- QBGWWDQBYZTGKS-XZOQPEGZSA-N 1-[2-(4-bromo-N-methylanilino)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound BrC1=CC=C(C=C1)N(CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)C QBGWWDQBYZTGKS-XZOQPEGZSA-N 0.000 claims description 2
- VNOXGRAWDWRTEV-FCHUYYIVSA-N 1-[2-(4-bromoanilino)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound BrC1=CC=C(C=C1)NCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 VNOXGRAWDWRTEV-FCHUYYIVSA-N 0.000 claims description 2
- YNKXSRYLVHLTAG-IZZNHLLZSA-N 1-[2-(4-morpholin-4-ylanilino)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound O1CCN(CC1)C1=CC=C(C=C1)NCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 YNKXSRYLVHLTAG-IZZNHLLZSA-N 0.000 claims description 2
- JWAJGXPMRVJUCI-LEWJYISDSA-N 1-[2-(5-methylpyridin-2-yl)oxyethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CC=1C=CC(=NC=1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 JWAJGXPMRVJUCI-LEWJYISDSA-N 0.000 claims description 2
- IMRJZDXIPBRCBP-VQTJNVASSA-N 1-[2-(6-methylpyridazin-3-yl)oxyethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CC1=CC=C(N=N1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 IMRJZDXIPBRCBP-VQTJNVASSA-N 0.000 claims description 2
- KZDCRNMQFFIENF-LEWJYISDSA-N 1-[2-(6-methylpyridin-2-yl)oxyethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CC1=CC=CC(=N1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 KZDCRNMQFFIENF-LEWJYISDSA-N 0.000 claims description 2
- CUIKKMHOKDMTSR-FCHUYYIVSA-N 1-[2-(6-methylpyridin-3-yl)oxyethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CC1=CC=C(C=N1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 CUIKKMHOKDMTSR-FCHUYYIVSA-N 0.000 claims description 2
- GASSMUQUDOGXCK-XZOQPEGZSA-N 1-[2-(N-methylanilino)ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CN(CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)C1=CC=CC=C1 GASSMUQUDOGXCK-XZOQPEGZSA-N 0.000 claims description 2
- UPKFZFLCVPXIMH-ZWKOTPCHSA-N 1-[2-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CC1=NN=C(S1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 UPKFZFLCVPXIMH-ZWKOTPCHSA-N 0.000 claims description 2
- HZMWXMXAOYXTJB-RBUKOAKNSA-N 1-[2-[(5-methyl-1,3-thiazol-2-yl)oxy]ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CC1=CN=C(S1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 HZMWXMXAOYXTJB-RBUKOAKNSA-N 0.000 claims description 2
- VRESGYDFPJSIEE-RRPNLBNLSA-N 1-[2-[4-(4-methylpiperazin-1-yl)anilino]ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CN1CCN(CC1)C1=CC=C(C=C1)NCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 VRESGYDFPJSIEE-RRPNLBNLSA-N 0.000 claims description 2
- LXEFFLNTPKQYSF-RRPNLBNLSA-N 1-[2-[4-(4-methylpiperazin-1-yl)phenoxy]ethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CN1CCN(CC1)C1=CC=C(OCCN2CCC(CC2)N[C@H]2[C@@H](C2)C2=CC=CC=C2)C=C1 LXEFFLNTPKQYSF-RRPNLBNLSA-N 0.000 claims description 2
- QCZOWADRAFFUEU-LOSJGSFVSA-N 1-[4-[2-[3-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]ethoxy]phenyl]piperidin-2-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NCC1CN(C1)CCOC1=CC=C(C=C1)N1C(CCCC1)=O QCZOWADRAFFUEU-LOSJGSFVSA-N 0.000 claims description 2
- QBBSZGBBPKFOLI-IZZNHLLZSA-N 1-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]piperidin-2-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=CC=C(C=C1)N1C(CCCC1)=O QBBSZGBBPKFOLI-IZZNHLLZSA-N 0.000 claims description 2
- NPACQEJRRFXZOO-LOSJGSFVSA-N 1-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]pyrrolidin-2-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=CC=C(C=C1)N1C(CCC1)=O NPACQEJRRFXZOO-LOSJGSFVSA-N 0.000 claims description 2
- YQHKIRWKLSCPON-IZZNHLLZSA-N 1-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethylamino]phenyl]piperidin-2-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNC1=CC=C(C=C1)N1C(CCCC1)=O YQHKIRWKLSCPON-IZZNHLLZSA-N 0.000 claims description 2
- VBPGIKQABFJECT-LOSJGSFVSA-N 1-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethylamino]phenyl]pyrrolidin-2-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNC1=CC=C(C=C1)N1C(CCC1)=O VBPGIKQABFJECT-LOSJGSFVSA-N 0.000 claims description 2
- REALYFMVJVJWSV-RRPNLBNLSA-N 1-[4-[4-[2-[3-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]ethoxy]phenyl]piperazin-1-yl]ethanone Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NCC1CN(C1)CCOC1=CC=C(C=C1)N1CCN(CC1)C(C)=O REALYFMVJVJWSV-RRPNLBNLSA-N 0.000 claims description 2
- UFYKOUXZFJZPLJ-WUFINQPMSA-N 1-[4-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]piperazin-1-yl]ethanone Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=CC=C(C=C1)N1CCN(CC1)C(C)=O UFYKOUXZFJZPLJ-WUFINQPMSA-N 0.000 claims description 2
- RRWGOMHXMSHIGO-WUFINQPMSA-N 1-[4-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethylamino]phenyl]piperazin-1-yl]ethanone Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNC1=CC=C(C=C1)N1CCN(CC1)C(C)=O RRWGOMHXMSHIGO-WUFINQPMSA-N 0.000 claims description 2
- VIJGORJGVOJEHF-LOSJGSFVSA-N 1-methyl-3-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]imidazolidin-2-one Chemical compound CN1C(N(CC1)C1=CC=C(C=C1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O VIJGORJGVOJEHF-LOSJGSFVSA-N 0.000 claims description 2
- DGIZEJIMLIRJCX-LOSJGSFVSA-N 1-methyl-3-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethylamino]phenyl]imidazolidin-2-one Chemical compound CN1C(N(CC1)C1=CC=C(C=C1)NCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O DGIZEJIMLIRJCX-LOSJGSFVSA-N 0.000 claims description 2
- MNBMPWLOVSVYLJ-LEWJYISDSA-N 1-morpholin-4-yl-4-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]butan-1-one Chemical compound O1CCN(CC1)C(CCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O MNBMPWLOVSVYLJ-LEWJYISDSA-N 0.000 claims description 2
- OVFPNRQAYDNFJT-VQTJNVASSA-N 2-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]pyridine-4-carboxylic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC=1C=C(C(=O)O)C=CN=1 OVFPNRQAYDNFJT-VQTJNVASSA-N 0.000 claims description 2
- GJXVHWNDTMJNKC-VQTJNVASSA-N 2-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethylamino]pyridine-4-carboxylic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNC=1C=C(C(=O)O)C=CN=1 GJXVHWNDTMJNKC-VQTJNVASSA-N 0.000 claims description 2
- YAOTZZKLDPOIDA-JTHBVZDNSA-N 2-[2-fluoro-4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]acetic acid Chemical compound FC1=C(C=CC(=C1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)CC(=O)O YAOTZZKLDPOIDA-JTHBVZDNSA-N 0.000 claims description 2
- CUAZMJBRZLKUCB-RBBKRZOGSA-N 2-[3-chloro-4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]acetic acid Chemical compound ClC=1C=C(C=CC=1OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)CC(=O)O CUAZMJBRZLKUCB-RBBKRZOGSA-N 0.000 claims description 2
- ZIRFGORGWGXHNT-RBBKRZOGSA-N 2-[3-fluoro-4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]acetic acid Chemical compound FC=1C=C(C=CC=1OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)CC(=O)O ZIRFGORGWGXHNT-RBBKRZOGSA-N 0.000 claims description 2
- CJLWVGVMDVIXLU-XZOQPEGZSA-N 2-[3-methyl-4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]acetic acid Chemical compound CC=1C=C(C=CC=1OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)CC(=O)O CJLWVGVMDVIXLU-XZOQPEGZSA-N 0.000 claims description 2
- XVMPKJAGCLJKPJ-YADHBBJMSA-N 2-[4-[2-[3-[[[(1S,2R)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]ethoxy]phenyl]acetic acid Chemical compound C1(=CC=CC=C1)[C@@H]1[C@H](C1)NCC1CN(C1)CCOC1=CC=C(C=C1)CC(=O)O XVMPKJAGCLJKPJ-YADHBBJMSA-N 0.000 claims description 2
- RYCHHNFPBJLGDF-XZOQPEGZSA-N 2-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]acetic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=CC=C(C=C1)CC(=O)O RYCHHNFPBJLGDF-XZOQPEGZSA-N 0.000 claims description 2
- WBWKPSKVIVTOKA-RPFBHVFUSA-N 2-[4-[2-hydroxy-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propoxy]phenyl]acetic acid Chemical compound OC(COC1=CC=C(C=C1)CC(=O)O)CN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 WBWKPSKVIVTOKA-RPFBHVFUSA-N 0.000 claims description 2
- CXQDEKXDWIRZRA-BJKOFHAPSA-N 2-[4-[3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propoxy]phenyl]acetic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCCOC1=CC=C(C=C1)CC(=O)O CXQDEKXDWIRZRA-BJKOFHAPSA-N 0.000 claims description 2
- FDTQLHKBHJKOQE-JKSUJKDBSA-N 2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethanol Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCO FDTQLHKBHJKOQE-JKSUJKDBSA-N 0.000 claims description 2
- PSDHVHFPINIMEQ-VQTJNVASSA-N 3-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]pyridine-4-carboxylic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=C(C(=O)O)C=CN=C1 PSDHVHFPINIMEQ-VQTJNVASSA-N 0.000 claims description 2
- NXZDXMHFUIQJLL-VQTJNVASSA-N 3-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethylamino]pyridine-4-carboxylic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNC1=C(C(=O)O)C=CN=C1 NXZDXMHFUIQJLL-VQTJNVASSA-N 0.000 claims description 2
- ZRAOJCOOPBYRKF-BJKOFHAPSA-N 3-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethylamino]phenyl]-1,3-oxazolidin-2-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNC1=CC=C(C=C1)N1C(OCC1)=O ZRAOJCOOPBYRKF-BJKOFHAPSA-N 0.000 claims description 2
- FXNQVFLYZFLKFS-VQTJNVASSA-N 3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]-1-piperazin-1-ylpropan-1-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCC(=O)N1CCNCC1 FXNQVFLYZFLKFS-VQTJNVASSA-N 0.000 claims description 2
- LNDJMWWJZRYBBL-JKSUJKDBSA-N 3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propanoic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCC(=O)O LNDJMWWJZRYBBL-JKSUJKDBSA-N 0.000 claims description 2
- OAQUWSNFVRKQIJ-LEWJYISDSA-N 4-[2-[3-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]ethoxy]benzoic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NCC1CN(C1)CCOC1=CC=C(C(=O)O)C=C1 OAQUWSNFVRKQIJ-LEWJYISDSA-N 0.000 claims description 2
- OKTLEWZLQNWLFE-SIKLNZKXSA-N 4-[2-[4-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]piperidin-1-yl]ethoxy]benzoic acid Chemical compound FC=1C=C(C=CC=1F)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=CC=C(C(=O)O)C=C1 OKTLEWZLQNWLFE-SIKLNZKXSA-N 0.000 claims description 2
- SMSAFPWDYUTZGX-FCHUYYIVSA-N 4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]benzoic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=CC=C(C(=O)O)C=C1 SMSAFPWDYUTZGX-FCHUYYIVSA-N 0.000 claims description 2
- RXWLIOSTOGKIMA-XGELLPRESA-N 4-[2-hydroxy-3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propoxy]benzoic acid Chemical compound OC(COC1=CC=C(C(=O)O)C=C1)CN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 RXWLIOSTOGKIMA-XGELLPRESA-N 0.000 claims description 2
- MYVPWFUQBXYFLP-XZOQPEGZSA-N 4-[3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propoxy]benzoic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCCOC1=CC=C(C(=O)O)C=C1 MYVPWFUQBXYFLP-XZOQPEGZSA-N 0.000 claims description 2
- AORFPAAZBAQLJW-BJKOFHAPSA-N 4-[4-[2-[3-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]ethoxy]phenyl]morpholin-3-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NCC1CN(C1)CCOC1=CC=C(C=C1)N1C(COCC1)=O AORFPAAZBAQLJW-BJKOFHAPSA-N 0.000 claims description 2
- UQJTZTMMRWZLHR-LOSJGSFVSA-N 4-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]morpholin-3-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=CC=C(C=C1)N1C(COCC1)=O UQJTZTMMRWZLHR-LOSJGSFVSA-N 0.000 claims description 2
- WYCCOAIMHSCXKU-LOSJGSFVSA-N 4-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethylamino]phenyl]morpholin-3-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNC1=CC=C(C=C1)N1C(COCC1)=O WYCCOAIMHSCXKU-LOSJGSFVSA-N 0.000 claims description 2
- YJFLUIISZQTKGQ-LEWJYISDSA-N 4-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]-1-piperazin-1-ylbutan-1-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCCC(=O)N1CCNCC1 YJFLUIISZQTKGQ-LEWJYISDSA-N 0.000 claims description 2
- OWIDNTIJYQSBGO-DLBZAZTESA-N 4-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]butanoic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCCC(=O)O OWIDNTIJYQSBGO-DLBZAZTESA-N 0.000 claims description 2
- QRCGFTXRXYMJOS-UHFFFAOYSA-N 4h-1,4-benzoxazin-3-one Chemical compound C1=CC=C2NC(=O)COC2=C1 QRCGFTXRXYMJOS-UHFFFAOYSA-N 0.000 claims description 2
- HMQWVKVFQCCFDI-JTHBVZDNSA-N 5-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]-1,3-dihydroindol-2-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC=1C=C2CC(NC2=CC=1)=O HMQWVKVFQCCFDI-JTHBVZDNSA-N 0.000 claims description 2
- WLSOJXIGTZCVTA-LADGPHEKSA-N 6-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC=1C=C2CCC(NC2=CC=1)=O WLSOJXIGTZCVTA-LADGPHEKSA-N 0.000 claims description 2
- ZXRASTGFWFYZCF-RBBKRZOGSA-N 7-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]-4H-1,4-benzoxazin-3-one Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC=1C=CC2=C(OCC(N2)=O)C=1 ZXRASTGFWFYZCF-RBBKRZOGSA-N 0.000 claims description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 2
- 206010073106 Bone giant cell tumour malignant Diseases 0.000 claims description 2
- 201000005262 Chondroma Diseases 0.000 claims description 2
- 208000005243 Chondrosarcoma Diseases 0.000 claims description 2
- 201000009047 Chordoma Diseases 0.000 claims description 2
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 2
- 206010053717 Fibrous histiocytoma Diseases 0.000 claims description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 2
- 208000007569 Giant Cell Tumors Diseases 0.000 claims description 2
- 206010019629 Hepatic adenoma Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 208000002260 Keloid Diseases 0.000 claims description 2
- 208000002404 Liver Cell Adenoma Diseases 0.000 claims description 2
- 206010027406 Mesothelioma Diseases 0.000 claims description 2
- AFOJZDKASRYIKT-XZOQPEGZSA-N N,6-dimethyl-N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethyl]pyridin-3-amine Chemical compound CN(C=1C=NC(=CC=1)C)CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 AFOJZDKASRYIKT-XZOQPEGZSA-N 0.000 claims description 2
- AGRLHLZEHASIMU-RBUKOAKNSA-N N-[(1R,2S)-2-phenylcyclopropyl]-1-(2-propan-2-yloxyethyl)piperidin-4-amine Chemical compound C(C)(C)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 AGRLHLZEHASIMU-RBUKOAKNSA-N 0.000 claims description 2
- AFFZAGUTOYIYFB-JKSUJKDBSA-N N-[2-[3-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]ethyl]methanesulfonamide Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NCC1CN(C1)CCNS(=O)(=O)C AFFZAGUTOYIYFB-JKSUJKDBSA-N 0.000 claims description 2
- QHJNZAMJXMRDAP-FCHUYYIVSA-N N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethyl]benzenesulfonamide Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNS(=O)(=O)C1=CC=CC=C1 QHJNZAMJXMRDAP-FCHUYYIVSA-N 0.000 claims description 2
- BEJXYCDQSZFBRW-RBUKOAKNSA-N N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethyl]cyclopropanesulfonamide Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNS(=O)(=O)C1CC1 BEJXYCDQSZFBRW-RBUKOAKNSA-N 0.000 claims description 2
- FTTOCGMZTPIGBM-DLBZAZTESA-N N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethyl]methanesulfonamide Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCNS(=O)(=O)C FTTOCGMZTPIGBM-DLBZAZTESA-N 0.000 claims description 2
- NSJHVNOZLRSHEW-XZOQPEGZSA-N N-methyl-1-[2-(6-methylpyridin-3-yl)oxyethyl]-N-[(1R,2S)-2-phenylcyclopropyl]piperidin-4-amine Chemical compound CN(C1CCN(CC1)CCOC=1C=NC(=CC=1)C)[C@H]1[C@@H](C1)C1=CC=CC=C1 NSJHVNOZLRSHEW-XZOQPEGZSA-N 0.000 claims description 2
- ISQINPHVGYDRGD-DLBZAZTESA-N N-methyl-N-[2-[3-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]azetidin-1-yl]ethyl]methanesulfonamide Chemical compound CN(S(=O)(=O)C)CCN1CC(C1)CN[C@H]1[C@@H](C1)C1=CC=CC=C1 ISQINPHVGYDRGD-DLBZAZTESA-N 0.000 claims description 2
- NZUSTUNVPZSRAQ-RBUKOAKNSA-N N-methyl-N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethyl]acetamide Chemical compound CN(C(C)=O)CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 NZUSTUNVPZSRAQ-RBUKOAKNSA-N 0.000 claims description 2
- DNLPPSCNPNUQAL-ZWKOTPCHSA-N N-methyl-N-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethyl]methanesulfonamide Chemical compound CN(S(=O)(=O)C)CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 DNLPPSCNPNUQAL-ZWKOTPCHSA-N 0.000 claims description 2
- 208000000035 Osteochondroma Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 208000005678 Rhabdomyoma Diseases 0.000 claims description 2
- 210000004100 adrenal gland Anatomy 0.000 claims description 2
- 239000003708 ampul Substances 0.000 claims description 2
- 208000001119 benign fibrous histiocytoma Diseases 0.000 claims description 2
- 210000003445 biliary tract Anatomy 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 claims description 2
- 208000003362 bronchogenic carcinoma Diseases 0.000 claims description 2
- 201000002143 bronchus adenoma Diseases 0.000 claims description 2
- 210000003679 cervix uteri Anatomy 0.000 claims description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 2
- 201000005217 chondroblastoma Diseases 0.000 claims description 2
- 201000010305 cutaneous fibrous histiocytoma Diseases 0.000 claims description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 2
- 210000003238 esophagus Anatomy 0.000 claims description 2
- 201000010175 gallbladder cancer Diseases 0.000 claims description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
- 208000006359 hepatoblastoma Diseases 0.000 claims description 2
- 201000002735 hepatocellular adenoma Diseases 0.000 claims description 2
- 210000001117 keloid Anatomy 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 210000002429 large intestine Anatomy 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 201000004593 malignant giant cell tumor Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 210000002418 meninge Anatomy 0.000 claims description 2
- 208000009091 myxoma Diseases 0.000 claims description 2
- 210000000653 nervous system Anatomy 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 210000001672 ovary Anatomy 0.000 claims description 2
- 210000000496 pancreas Anatomy 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- 210000003625 skull Anatomy 0.000 claims description 2
- 210000000813 small intestine Anatomy 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 210000001550 testis Anatomy 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 210000003708 urethra Anatomy 0.000 claims description 2
- 210000004291 uterus Anatomy 0.000 claims description 2
- 210000001215 vagina Anatomy 0.000 claims description 2
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 claims 1
- 101100455523 Drosophila melanogaster Lsd-1 gene Proteins 0.000 claims 1
- 208000000471 Dysplastic Nevus Syndrome Diseases 0.000 claims 1
- 206010023330 Keloid scar Diseases 0.000 claims 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 claims 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 claims 1
- 206010046798 Uterine leiomyoma Diseases 0.000 claims 1
- 230000000747 cardiac effect Effects 0.000 claims 1
- 210000000845 cartilage Anatomy 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 208000004649 neutrophil actin dysfunction Diseases 0.000 claims 1
- 208000003388 osteoid osteoma Diseases 0.000 claims 1
- 210000003101 oviduct Anatomy 0.000 claims 1
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 claims 1
- 210000000278 spinal cord Anatomy 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 20
- 230000000694 effects Effects 0.000 abstract description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 241
- 239000000203 mixture Substances 0.000 description 192
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 171
- 239000000243 solution Substances 0.000 description 79
- 238000005160 1H NMR spectroscopy Methods 0.000 description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
- 239000007787 solid Substances 0.000 description 62
- 239000011541 reaction mixture Substances 0.000 description 60
- 229910052938 sodium sulfate Inorganic materials 0.000 description 52
- 239000007832 Na2SO4 Substances 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 47
- 239000003921 oil Substances 0.000 description 46
- 235000019198 oils Nutrition 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- 239000004973 liquid crystal related substance Substances 0.000 description 37
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 34
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 33
- 238000001914 filtration Methods 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 30
- 101001050886 Homo sapiens Lysine-specific histone demethylase 1A Proteins 0.000 description 29
- 239000012267 brine Substances 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
- 239000012074 organic phase Substances 0.000 description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000003480 eluent Substances 0.000 description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
- 238000002953 preparative HPLC Methods 0.000 description 24
- 102100024985 Lysine-specific histone demethylase 1A Human genes 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 21
- 238000003818 flash chromatography Methods 0.000 description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 19
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 18
- 239000005977 Ethylene Substances 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000012230 colorless oil Substances 0.000 description 18
- 239000000463 material Substances 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- 238000001035 drying Methods 0.000 description 17
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 17
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- 238000012746 preparative thin layer chromatography Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 229910021529 ammonia Inorganic materials 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 13
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 10
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 10
- AELCINSCMGFISI-DTWKUNHWSA-N (1R,2S)-tranylcypromine Chemical compound N[C@@H]1C[C@H]1C1=CC=CC=C1 AELCINSCMGFISI-DTWKUNHWSA-N 0.000 description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 8
- 208000009956 adenocarcinoma Diseases 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- 108010033040 Histones Proteins 0.000 description 7
- 239000000908 ammonium hydroxide Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 235000018977 lysine Nutrition 0.000 description 7
- 150000004702 methyl esters Chemical class 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- HKDFRDIIELOLTJ-UHFFFAOYSA-N 1,4-dithianyl Chemical group [CH]1CSCCS1 HKDFRDIIELOLTJ-UHFFFAOYSA-N 0.000 description 6
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 6
- 239000004472 Lysine Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 125000004043 oxo group Chemical group O=* 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 125000005551 pyridylene group Chemical group 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- JJFOBACUIRKUPN-UHFFFAOYSA-N 2-bromoethoxybenzene Chemical compound BrCCOC1=CC=CC=C1 JJFOBACUIRKUPN-UHFFFAOYSA-N 0.000 description 5
- NIDWUZTTXGJFNN-UHFFFAOYSA-N 3-bromopropoxybenzene Chemical compound BrCCCOC1=CC=CC=C1 NIDWUZTTXGJFNN-UHFFFAOYSA-N 0.000 description 5
- 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 description 5
- 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 125000003636 chemical group Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 5
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 4
- IITAGOPHHFGANB-UHFFFAOYSA-N 2-(phenoxymethyl)oxetane Chemical compound C1COC1COC1=CC=CC=C1 IITAGOPHHFGANB-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical class ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 4
- 102000006947 Histones Human genes 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- XTDYIOOONNVFMA-UHFFFAOYSA-N dimethyl pentanedioate Chemical compound COC(=O)CCCC(=O)OC XTDYIOOONNVFMA-UHFFFAOYSA-N 0.000 description 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 4
- VWWQXMAJTJZDQX-UYBVJOGSSA-N flavin adenine dinucleotide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1CO[P@](O)(=O)O[P@@](O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UYBVJOGSSA-N 0.000 description 4
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 description 4
- 239000011714 flavin adenine dinucleotide Substances 0.000 description 4
- 229940093632 flavin-adenine dinucleotide Drugs 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- XIMLAVRHZBUYBE-UHFFFAOYSA-N piperidin-2-one;hydrate;hydrochloride Chemical compound O.Cl.O=C1CCCCN1 XIMLAVRHZBUYBE-UHFFFAOYSA-N 0.000 description 4
- 238000013207 serial dilution Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- MBZAGPLGLMIZOL-NWDGAFQWSA-N tert-butyl n-[(1r,2s)-2-phenylcyclopropyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1C[C@H]1C1=CC=CC=C1 MBZAGPLGLMIZOL-NWDGAFQWSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UUFICZKIAFCDED-VQTJNVASSA-N 1-[2-(4-bromophenoxy)ethyl]-4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidine-2,6-dione Chemical compound BrC1=CC=C(OCCN2C(CC(CC2=O)N[C@H]2[C@@H](C2)C2=CC=CC=C2)=O)C=C1 UUFICZKIAFCDED-VQTJNVASSA-N 0.000 description 3
- SRGBSEMMGLSUMI-UHFFFAOYSA-N 1-bromo-4-(2-bromoethoxy)benzene Chemical compound BrCCOC1=CC=C(Br)C=C1 SRGBSEMMGLSUMI-UHFFFAOYSA-N 0.000 description 3
- GGZUSLXFZZJXNP-UHFFFAOYSA-N 2-(phenoxymethyl)oxirane Chemical compound C1OC1COC1=CC=CC=C1.C1OC1COC1=CC=CC=C1 GGZUSLXFZZJXNP-UHFFFAOYSA-N 0.000 description 3
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- 101100477411 Dictyostelium discoideum set1 gene Proteins 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- 208000032612 Glial tumor Diseases 0.000 description 3
- 206010018338 Glioma Diseases 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 206010016629 fibroma Diseases 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- VAVVRMCEAMQQQN-LADGPHEKSA-N methyl 2-[2-fluoro-4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]acetate Chemical compound FC1=C(C=CC(=C1)OCCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)CC(=O)OC VAVVRMCEAMQQQN-LADGPHEKSA-N 0.000 description 3
- SQNRRLUZFQWOAY-BJKOFHAPSA-N methyl 2-[4-[2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethoxy]phenyl]acetate Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCOC1=CC=C(C=C1)CC(=O)OC SQNRRLUZFQWOAY-BJKOFHAPSA-N 0.000 description 3
- VAUOPRZOGIRSMI-UHFFFAOYSA-N n-(oxiran-2-ylmethyl)aniline Chemical compound C1OC1CNC1=CC=CC=C1 VAUOPRZOGIRSMI-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012434 nucleophilic reagent Substances 0.000 description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ZPEFMSTTZXJOTM-OULXEKPRSA-N (1R,2S)-tranylcypromine hydrochloride Chemical compound Cl.N[C@@H]1C[C@H]1C1=CC=CC=C1 ZPEFMSTTZXJOTM-OULXEKPRSA-N 0.000 description 2
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 2
- IHQLGXMWCCIGAG-UHFFFAOYSA-N 1-(1-morpholin-4-yl-1-oxo-3-phenylpropan-2-yl)piperidin-4-one Chemical compound C(C1=CC=CC=C1)C(C(=O)N1CCOCC1)N1CCC(CC1)=O IHQLGXMWCCIGAG-UHFFFAOYSA-N 0.000 description 2
- LUOSNGFOANFUES-UHFFFAOYSA-N 1-(2,2,2-trifluoroacetyl)piperidin-4-one Chemical compound FC(F)(F)C(=O)N1CCC(=O)CC1 LUOSNGFOANFUES-UHFFFAOYSA-N 0.000 description 2
- PKYCWFICOKSIHZ-UHFFFAOYSA-N 1-(3,7-dihydroxyphenoxazin-10-yl)ethanone Chemical compound OC1=CC=C2N(C(=O)C)C3=CC=C(O)C=C3OC2=C1 PKYCWFICOKSIHZ-UHFFFAOYSA-N 0.000 description 2
- WTVZSVWFHNFRIO-UHFFFAOYSA-N 1-[2-(4-bromophenoxy)ethyl]piperidin-4-one Chemical compound C1=CC(Br)=CC=C1OCCN1CCC(=O)CC1 WTVZSVWFHNFRIO-UHFFFAOYSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- QXOGPTXQGKQSJT-UHFFFAOYSA-N 1-amino-4-[4-(3,4-dimethylphenyl)sulfanylanilino]-9,10-dioxoanthracene-2-sulfonic acid Chemical compound Cc1ccc(Sc2ccc(Nc3cc(c(N)c4C(=O)c5ccccc5C(=O)c34)S(O)(=O)=O)cc2)cc1C QXOGPTXQGKQSJT-UHFFFAOYSA-N 0.000 description 2
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 2
- PMDDXFGYBKIPKR-UHFFFAOYSA-N 2-(4-bromophenoxy)acetonitrile Chemical compound BrC1=CC=C(OCC#N)C=C1 PMDDXFGYBKIPKR-UHFFFAOYSA-N 0.000 description 2
- AIHSYDQJCKBJHB-UHFFFAOYSA-N 2-(4-bromophenoxy)ethanamine Chemical compound NCCOC1=CC=C(Br)C=C1 AIHSYDQJCKBJHB-UHFFFAOYSA-N 0.000 description 2
- VKXYJSKBUIWGSV-UHFFFAOYSA-N 2-(4-oxopiperidin-1-yl)-3-phenylpropanoic acid Chemical compound O=C1CCN(CC1)C(C(=O)O)CC1=CC=CC=C1 VKXYJSKBUIWGSV-UHFFFAOYSA-N 0.000 description 2
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- QAGATHCAVJHHGR-UHFFFAOYSA-N 2-chloro-1-morpholin-4-ylpropan-1-one Chemical compound CC(Cl)C(=O)N1CCOCC1 QAGATHCAVJHHGR-UHFFFAOYSA-N 0.000 description 2
- GAWAYYRQGQZKCR-UHFFFAOYSA-N 2-chloropropionic acid Chemical compound CC(Cl)C(O)=O GAWAYYRQGQZKCR-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 2
- DAOZBJCTEPJGES-UHFFFAOYSA-N 4-chloro-2-methylpyridine Chemical compound CC1=CC(Cl)=CC=N1 DAOZBJCTEPJGES-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 206010003571 Astrocytoma Diseases 0.000 description 2
- UHNRLQRZRNKOKU-UHFFFAOYSA-N CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O Chemical compound CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O UHNRLQRZRNKOKU-UHFFFAOYSA-N 0.000 description 2
- 206010007275 Carcinoid tumour Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- LRULVYSBRWUVGR-FCHUYYIVSA-N GSK2879552 Chemical compound C1=CC(C(=O)O)=CC=C1CN1CCC(CN[C@H]2[C@@H](C2)C=2C=CC=CC=2)CC1 LRULVYSBRWUVGR-FCHUYYIVSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 description 2
- CUDAWYGAFNDXAR-FCHUYYIVSA-N N-phenyl-2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]ethanesulfonamide Chemical compound C1(=CC=CC=C1)NS(=O)(=O)CCN1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1 CUDAWYGAFNDXAR-FCHUYYIVSA-N 0.000 description 2
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 2
- 201000004404 Neurofibroma Diseases 0.000 description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700584 Simplexvirus Species 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
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 208000008383 Wilms tumor Diseases 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 125000004419 alkynylene group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 125000000732 arylene group Chemical group 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 208000002458 carcinoid tumor Diseases 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940127113 compound 57 Drugs 0.000 description 2
- 229940125900 compound 59 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- WQSBZEAUVHWGEZ-UHFFFAOYSA-N ethyl 2-(4-oxopiperidin-1-yl)-3-phenylpropanoate Chemical compound O=C1CCN(CC1)C(C(=O)OCC)CC1=CC=CC=C1 WQSBZEAUVHWGEZ-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 125000004404 heteroalkyl group Chemical group 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical class Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 2
- UUBFEAJSPROQMF-UHFFFAOYSA-N methyl 2-(2-fluoro-4-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(O)C=C1F UUBFEAJSPROQMF-UHFFFAOYSA-N 0.000 description 2
- XGDZEDRBLVIUMX-UHFFFAOYSA-N methyl 2-(4-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(O)C=C1 XGDZEDRBLVIUMX-UHFFFAOYSA-N 0.000 description 2
- VSDUZFOSJDMAFZ-UHFFFAOYSA-N methyl 2-amino-3-phenylpropanoate Chemical compound COC(=O)C(N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-UHFFFAOYSA-N 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- WZXOEHYICZFQPQ-UHFFFAOYSA-N n'-methyl-n'-(2-methylpyridin-4-yl)ethane-1,2-diamine Chemical compound NCCN(C)C1=CC=NC(C)=C1 WZXOEHYICZFQPQ-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 125000000260 trans-2-phenylcyclopropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])[C@]1([H])C([H])([H])[C@@]1([H])* 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 1
- ZEBFHUSPYBVICS-LSTHTHJFSA-N (2R)-1-morpholin-4-yl-2-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propan-1-one Chemical compound O1CCN(CC1)C([C@@H](C)N1CCC(CC1)N[C@H]1[C@@H](C1)C1=CC=CC=C1)=O ZEBFHUSPYBVICS-LSTHTHJFSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 1
- LMWHOBWRSDUTTQ-CPBUKKLUSA-N (E)-3-[4-[3-[4-[[(1R,2S)-2-phenylcyclopropyl]amino]piperidin-1-yl]propoxy]phenyl]prop-2-enoic acid Chemical compound C1(=CC=CC=C1)[C@H]1[C@@H](C1)NC1CCN(CC1)CCCOC1=CC=C(C=C1)/C=C/C(=O)O LMWHOBWRSDUTTQ-CPBUKKLUSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 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
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- SRCZVHKTSLILCC-UHFFFAOYSA-N 1-(2-phenoxyethyl)piperidin-4-one Chemical compound C1CC(=O)CCN1CCOC1=CC=CC=C1 SRCZVHKTSLILCC-UHFFFAOYSA-N 0.000 description 1
- WLACLDJOIJWNRE-UHFFFAOYSA-N 1-(3-phenoxypropyl)piperidin-4-one Chemical compound C1CC(=O)CCN1CCCOC1=CC=CC=C1 WLACLDJOIJWNRE-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- RHQQHZQUAMFINJ-GKWSUJDHSA-N 1-[(3s,5s,8s,9s,10s,11s,13s,14s,17s)-3,11-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-hydroxyethanone Chemical group C1[C@@H](O)CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CC[C@H]21 RHQQHZQUAMFINJ-GKWSUJDHSA-N 0.000 description 1
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- 125000005955 1H-indazolyl group Chemical group 0.000 description 1
- PYHXGXCGESYPCW-UHFFFAOYSA-M 2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C(=O)[O-])C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-M 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- CHZXTOCAICMPQR-UHFFFAOYSA-N 2-(2-bromoethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCBr)C(=O)C2=C1 CHZXTOCAICMPQR-UHFFFAOYSA-N 0.000 description 1
- WNMSWTYGDNNRIM-UHFFFAOYSA-N 2-[4-(2-bromoethoxy)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(OCCBr)C=C1 WNMSWTYGDNNRIM-UHFFFAOYSA-N 0.000 description 1
- PAYROHWFGZADBR-UHFFFAOYSA-N 2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propane-1,3-diol Chemical compound C1=C(I)C(OC)=CC(C(C)C)=C1OC1=CN=C(NC(CO)CO)N=C1N PAYROHWFGZADBR-UHFFFAOYSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- VHCSBTPOPKFYIU-UHFFFAOYSA-N 2-chloroethanesulfonyl chloride Chemical compound ClCCS(Cl)(=O)=O VHCSBTPOPKFYIU-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- 125000001847 2-phenylcyclopropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 1
- XXUSNOSKULZSAG-UHFFFAOYSA-N 3-(methanesulfonamido)-2-methylpropane-1-sulfonic acid Chemical compound CC(CNS(C)(=O)=O)CS(O)(=O)=O XXUSNOSKULZSAG-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- GNHMRTZZNHZDDM-UHFFFAOYSA-N 3-chloropropionitrile Chemical compound ClCCC#N GNHMRTZZNHZDDM-UHFFFAOYSA-N 0.000 description 1
- RNJOKCPFLQMDEC-UHFFFAOYSA-N 4(R),8-dimethyl-trans-2-nonenoyl-CoA Chemical compound COC(=O)CC(=O)CC(=O)OC RNJOKCPFLQMDEC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- ANHQLUBMNSSPBV-UHFFFAOYSA-N 4h-pyrido[3,2-b][1,4]oxazin-3-one Chemical compound C1=CN=C2NC(=O)COC2=C1 ANHQLUBMNSSPBV-UHFFFAOYSA-N 0.000 description 1
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 1
- IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 241001251200 Agelas Species 0.000 description 1
- 102100032187 Androgen receptor Human genes 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006332 Choriocarcinoma 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
- 206010048832 Colon adenoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 208000007033 Dysgerminoma Diseases 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 208000007659 Fibroadenoma Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 101000904152 Homo sapiens Transcription factor E2F1 Proteins 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910020889 NaBH3 Inorganic materials 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 208000007256 Nevus Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000027067 Paget disease of bone Diseases 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 208000000097 Sertoli-Leydig cell tumor Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102100024026 Transcription factor E2F1 Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000009311 VIPoma Diseases 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 206010048214 Xanthoma Diseases 0.000 description 1
- 206010048215 Xanthomatosis Diseases 0.000 description 1
- BDHBBXZZAJWEMN-DTWKUNHWSA-N [(1r,2s)-2-phenylcyclopropyl]carbamic acid Chemical compound OC(=O)N[C@@H]1C[C@H]1C1=CC=CC=C1 BDHBBXZZAJWEMN-DTWKUNHWSA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- BBAWTPDTGRXPDG-UHFFFAOYSA-N [1,3]thiazolo[4,5-b]pyridine Chemical compound C1=CC=C2SC=NC2=N1 BBAWTPDTGRXPDG-UHFFFAOYSA-N 0.000 description 1
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- IHTYTYHXCRAMAV-UHFFFAOYSA-N acetic acid;dihydrochloride Chemical compound Cl.Cl.CC(O)=O IHTYTYHXCRAMAV-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 208000002718 adenomatoid tumor Diseases 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 1
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000005116 aryl carbamoyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000004931 azocinyl group Chemical group N1=C(C=CC=CC=C1)* 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000003181 biological factor Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 208000016738 bone Paget disease Diseases 0.000 description 1
- 201000009480 botryoid rhabdomyosarcoma Diseases 0.000 description 1
- 201000003149 breast fibroadenoma Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000005569 butenylene group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 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
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 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
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical group [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- JOXWSDNHLSQKCC-UHFFFAOYSA-N ethenesulfonamide Chemical class NS(=O)(=O)C=C JOXWSDNHLSQKCC-UHFFFAOYSA-N 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 1
- WUPBOSISFPJABC-UHFFFAOYSA-N ethyl 5-oxopentanoate Chemical compound CCOC(=O)CCCC=O WUPBOSISFPJABC-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 201000010934 exostosis Diseases 0.000 description 1
- 201000001343 fallopian tube carcinoma Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000004072 flavinyl group Chemical group 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 102000045213 human KDM1A Human genes 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 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
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 238000007422 luminescence assay Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 150000002669 lysines Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 201000000289 malignant teratoma Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- KQEVIFKPZOGBMZ-UHFFFAOYSA-N methyl 3-bromopropanoate Chemical compound COC(=O)CCBr KQEVIFKPZOGBMZ-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 208000010492 mucinous cystadenocarcinoma Diseases 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- NEKXUGUSHFDYLZ-UHFFFAOYSA-N n-methyl-n-(oxiran-2-ylmethyl)aniline Chemical compound C=1C=CC=CC=1N(C)CC1CO1 NEKXUGUSHFDYLZ-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 208000008798 osteoma Diseases 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- QNNHQVPFZIFNFK-UHFFFAOYSA-N oxazolo[4,5-b]pyridine Chemical compound C1=CC=C2OC=NC2=N1 QNNHQVPFZIFNFK-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical compound OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- RDNZDMDLRIQQAX-UHFFFAOYSA-N piperidine-2,4-dione Chemical compound O=C1CCNC(=O)C1 RDNZDMDLRIQQAX-UHFFFAOYSA-N 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 230000001855 preneoplastic effect Effects 0.000 description 1
- 230000001686 pro-survival effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- ZLSXAQXRLULEHI-UHFFFAOYSA-N prop-2-enoic acid;dihydrochloride Chemical compound Cl.Cl.OC(=O)C=C ZLSXAQXRLULEHI-UHFFFAOYSA-N 0.000 description 1
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 1
- DRINJBFRTLBHNF-UHFFFAOYSA-N propane-2-sulfonyl chloride Chemical compound CC(C)S(Cl)(=O)=O DRINJBFRTLBHNF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000006410 propenylene group Chemical group 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 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
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 description 1
- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000004548 serous cystadenocarcinoma Diseases 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- WGFBNQVDWQIIFQ-LOSJGSFVSA-N tert-butyl N-[1-[2-(2-methylpyridin-4-yl)oxyethyl]piperidin-4-yl]-N-[(1R,2S)-2-phenylcyclopropyl]carbamate Chemical compound CC1=NC=CC(=C1)OCCN1CCC(CC1)N(C(OC(C)(C)C)=O)[C@H]1[C@@H](C1)C1=CC=CC=C1 WGFBNQVDWQIIFQ-LOSJGSFVSA-N 0.000 description 1
- AISGXDCGIYRRSP-UHFFFAOYSA-N tert-butyl N-[2-[methyl-(2-methylpyridin-4-yl)amino]ethyl]carbamate Chemical compound CN(CCNC(OC(C)(C)C)=O)C1=CC(=NC=C1)C AISGXDCGIYRRSP-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 201000009657 thyroid sarcoma Diseases 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
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 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
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 208000022271 tubular adenoma Diseases 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 208000009540 villous adenoma Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000006648 viral gene expression Effects 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 229910009112 xH2O Inorganic materials 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- 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
-
- 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
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- 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
- A61P35/00—Antineoplastic 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
- C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及抑制LSD1活性的化合物。具体地,本发明涉及化合物、药物组合物和使用方法,例如,使用本发明的化合物和药物组合物治疗癌症的方法。
Description
交叉引用
本申请要求2015年12月29日提交的美国临时申请62/272,082和2016年2月15日提交的美国临时申请62/295,369的权益,在此将每一申请的全部内容通过引用的方式并入本文。
技术领域
本发明涉及抑制赖氨酸特异性脱甲基酶1(LSD1)的化合物。具体地,本发明涉及不可逆地抑制LSD1活性的化合物、包含所述化合物的药物组合物及其使用方法。
背景技术
赖氨酸特异性脱甲基酶1(“LSD1”),也称为KDM1A,是黄素依赖性赖氨酸脱甲基酶,其通过黄素腺嘌呤二核苷酸(FAD)依赖性酶促氧化从组蛋白H3蛋白的单和二甲基化赖氨酸4去除甲基(例如参见Shi等人,(2004)Cell119:941-953)。另外,LSD1将在前列腺癌细胞系中单甲基化和二甲基化的组蛋白H3赖氨酸9去甲基化,并且是由雄激素受体介导的转录调节所必需的(Metzger等,Nature(2005)437:436-439)。LSD1也去甲基化一些细胞蛋白质,如p53,E2F1和STAT3并调节它们的功能。
据报道,LSD1在多种癌症和组织中过表达,包括肺癌、膀胱癌、成神经细胞瘤、前列腺癌和乳腺癌。认为LSD1通过调节促存活基因表达和p53转录活性而在细胞增殖和癌细胞生长中发挥作用(例如,参见Suzuki和Miyata(2011)J.Med.Chem.54:8236-8250)。LSD1还通过使宿主中病毒基因表达所需的组蛋白H3赖氨酸9去甲基化而在调节病毒基因转录如单纯疱疹病毒(HSV)中发挥作用。
随着越来越多的证据表明LSD1在多种癌症和疾病中起关键作用,包括不可逆LSD1抑制剂在内的多种LSD1抑制剂已被报道并正在临床开发中。不可逆的含环丙胺的抑制剂,例如,Suzuki和Miyata综述如上,已被证明是LSD1酶的有效抑制剂;然而,这样的化合物倾向于缺乏稳健的细胞效力,具有较差的代谢稳定性且体内清除率高。
发明内容
本发明人认识到需要开发新的LSD1抑制剂,其显示出改善的细胞效力、功效、稳定性和安全性。本发明的化合物和组合物通过提供有效的、选择性的和口服活性的LSD1抑制剂有利地克服了这些缺点中的一个或多个。
在本发明的一个方面,提供了不可逆地抑制LSD1活性的化合物。在一些实施方案中,所述化合物由下式表示:
或其药学上可接受的盐,
R1为氢、C1-C4烷基或者C1-C4酰基;
L为-(CH2)s-CR2R3-(CH2)m-;
R2和R3各自独立地为氢、C1-C4烷基、-OR4或者芳烷基;
各个R4独立地为氢或者C1-C4烷基;
X为-W-R5或者Y-R6;
W为-NR4-或者-O-;
Y为-C(O)-、-S-、-SO-、-SO2-、-NR4SO2-、-SO2NR4-和-NR4C(O)-;
R5选自酰基、C1-C4烷基、环烷基、杂环基、芳基或者杂芳基,其中所述环烷基、杂环基、芳基或者杂芳基中的每个任选独立地取代有一个或者多个R8;
R6为C1-C6烷基、-NR4R7或者杂环基,其在一个或者多个碳原子上任选独立地取代有C1-C6烷基、卤素、氰基,或者卤代烷基,或者在一个或者多个氮原子上任选独立地取代有-C(O)C1-C6烷基;-C(O)OC1-C6烷基;-C(O)NR4C1-C6烷基,或者-S(O)2NR4C1-C6烷基;
R7为羟基、烷氧基、-SO2C1-C6烷基;-SO2环烷基,或者-SO2芳基,其中各个所述-SO2环烷基和-SO2芳基中的环烷基和芳基任选独立地取代有一个或者多个R8;
各个R8独立地为卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代烷基、烷氧基、烷基氨基、二烷基氨基、环烷基、芳基、杂芳基、杂环基、芳烷基、杂芳基烷基、-(CH2)nCOOR4、-(CH2)nC(O)NR4OC1-C6烷基、-(CH2)nC(O)NR4SO2C1-C6烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-C2-C6烯基C(O)OR4、-C2-C6烯基C(O)NR4SO2C1-C4烷基,或者-C2-C6烯基C(O)NR4SO2芳基,其中所述环烷基、芳基、杂芳基,和杂环基中的每个任选独立地取代有一个或者多个C1-C3烷基。
m为0或者1;
s为0或者1;
各个n为0、1,或者2;
各个p为0、1或者2;
各个RA独立地为氧代或者C1-C3烷基,或者在不同环原子上的两个RA基团一起形成C1-C3桥,其中所述桥碳中的一个任选被-NH-替代;
各个Q1、Q2和Q3独立地为氢、卤素、卤代烷基、C1-C4-烷基,或者C1-C4-烷氧基。
在本发明的另一方面,提供了药物组合物,其包含治疗有效量的式(I)或者式(II)的化合物和药学上可接受的赋形剂。
在本发明的又一方面,提供了在细胞中抑制LSD1活性的方法,其包括使所述细胞与式(I)或者式(II)的化合物接触。还提供了在患者中治疗癌症的方法,其包括将治疗有效量的式(I)或者式(II)的化合物或其药物组合物给药于需要的患者。
具体实施方式
本发明涉及LSD1抑制剂。具体地,本发明涉及不可逆地抑制LSD1活性的化合物、包含治疗有效量的所述化合物的药物组合物,及其使用方法。
定义
除非另外定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的技术人员通常理解的相同的含义。本文引用的所有专利、专利申请和出版物均以其与本公开一致的程度引入作为参考。术语和范围具有其通常定义的定义,除非另有明确定义。
为了简单起见,化学基团被定义并且主要被称为单价化学基团(例如烷基、芳基等)。尽管如此,这些术语也可用于在本领域技术人员清楚的适当结构环境下传递相应的多价基团。例如,虽然“烷基”基团通常是指一价基团(例如,CH3-CH2-),但是在某些情况下,二价连接基团可以是“烷基”,在这种情况下,本领域技术人员将理解该烷基是二价基团(例如,-CH2-CH2-),其等同于术语“亚烷基”。(类似地,在需要二价基团并且被描述为“芳基”的情况下,本领域技术人员将理解术语“芳基”是指相应的二价基团亚芳基。)所有原子被理解为具有它们用于键形成的正常化合价数(即,对于碳来说4,对于N来说3,对于O来说2,对于S来说2、4或6,取决于S的氧化态)。
如本文所用,“LSD1”是指哺乳动物赖氨酸特异性脱甲基酶(“LSD1”),其从组蛋白H3蛋白的单和二甲基化的赖氨酸4和赖氨酸9去除甲基。
如本文所用,“LSD1抑制剂”是指由本文所述的式(I)或(II)表示的本发明化合物。这些化合物能够负调节或抑制LSD1的全部或一部分酶活性。本发明的LSD1抑制剂通过以下过程不可逆地抑制LSD1活性:在一电子氧化和环丙基环开环后,在LSD1的活性位点中与FAD的黄素环形成共价加合物。
所述术语“氨基”是指-NH2。
本文中使用的术语"烷基"是指具有1至12个碳原子的直链和支链的脂族基团。因此,“烷基”涵盖C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12基团。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基,和己基。
本文中使用的术语"烯基"是指不饱和的直链或者支链的脂族基团,其具有一个或者多个碳-碳双键,具有2至12个碳原子。因此,“烯基”涵盖C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12基团。烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基,和己烯基。
本文中使用的术语"炔基"是指不饱和的直链或者支链的脂族基团,其具有一个或者多个碳-碳叁键,具有2至12个碳原子。因此,“炔基”涵盖C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12基团。炔基的实例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基,和己炔基。
"亚烷基"、"亚烯基"或者"亚炔基"是上文中限定的烷基、烯基,或者炔基,其位于两个其它化学基团之间并用于连接这两个其它化学基团。亚烷基的实例包括但不限于亚甲基、亚乙基、亚丙基,和亚丁基。示例性亚烯基包括但不限于亚乙烯基、亚丙烯基,和亚丁烯基。示例性亚炔基包括但不限于亚乙炔基、亚丙炔基,和亚丁炔基。
所述术语“烷氧基”是指-OC1-C6烷基。
所述术语“烷基硫基”是指-SC1-C6烷基。
所述术语“烷基氨基”是指-NR4C1-C6烷基。
所述术语“烷基磺酰基”是指-SO2C1-C6烷基。
本文中使用的术语"环烷基"是具有3至12个碳的饱和的和部分不饱和的环状烃基。因此,“环烷基”包括C3、C4、C5、C6、C7、C8、C9、C10、C11和C12环状烃基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基,和环辛基。
所述术语"杂烷基"是指上文限定的烷基,其中在链中的一个或者多个碳原子独立地被O、S,或者NR4替代,其中R4如本文中所限定。
"芳基"是包含1-3个芳环的C6-C14芳族基团。因此,“芳基”包括C6、C10、C13,和C14环状烃基。示例性芳基为C6-C10芳基。具体芳基包括但不限于苯基、萘基、蒽基,和芴基。
"芳烷基"或者"芳基烷基"包括与烷基共价连接的芳基,其中所述基团经由烷基连接至另一基团。示例性芳烷基为-(C1-C6)烷基(C6-C10)芳基,包括但不限于苄基、苯乙基,和萘基甲基。
"杂环基"或者"杂环"基团是具有3至12个原子(3、4、5、6、7、8、9、10、11或者12原子)如4-8个原子的单环或者二环(稠合或螺环)结构,其中一个或者多个环原子独立地为-C(O)-、NR4、O,或者S,以及其余的环原子为季碳或羰基碳。杂环基的实例包括但不限于环氧基、氮杂环丁烷基、氮杂环丙烷基、四氢呋喃基、四氢吡喃基、吡咯烷基、哌啶基、哌嗪基、咪唑烷基、噻唑烷基、二硫杂环己烷基、三硫杂环己烷基、二氧杂环戊烷基、噁唑烷基、噁唑烷酮基、十氢喹啉基、哌啶酮基、4-哌啶酮基、硫代吗啉基、二甲基吗啉基和吗啉基。特别排除在该术语范围之外的是具有相邻的环O和/或S原子的化合物。
术语“杂环基烷基”是指经由烷基连接基连接至分子的其余部分的如本文所定义的杂环基。
本文中使用的术语"杂芳基"是指具有5-14个环原子,优选5、6、10、13或者14个环原子;具有6、10,或者14个以环状排列共享的π电子;并且除了碳原子之外还具有1-3个杂原子的基团,所述杂原子各自独立地为N、O,或者S。“杂芳基”还包括稠合的多环(例如,二环)环系,其中所述稠合的环中的一个或者多个为非芳族的,条件是:至少一个环为芳族的和至少一个环含有N、O,或者S环原子。这种多环杂芳基环系的实例包括2H-苯并[b][1,4]噁嗪-3(4H)-酮和2H-吡啶并[3,2-b][1,4]噁嗪-3(4H)-酮。
杂芳基的实例包括吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并[d]噁唑-2(3H)-酮基、2H-苯并[b][1,4]噁嗪-3(4H)-酮基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、呋喃基、呋咱基、咪唑啉基、咪唑基、1H-吲唑基、indolenyl、吲哚啉基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异色满基、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、二氮萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑烷基、嘧啶基、菲啶基、二氮菲基、吩嗪基、吩噻嗪基、二苯并氧硫杂环己二烯(phenoxathiinyl)、吩噁嗪基、酞嗪基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡啶基、嘧啶基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹噁啉基、奎宁环基、四氢异喹啉基、四氢喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基,和氧杂蒽基。
"杂芳烷基"或者"杂芳基烷基"包括经由烷基连接基共价连接至另一基团的杂芳基。杂烷基的实例包括C1-C6烷基和具有5、6、9,或者10个环原子的杂芳基。杂芳烷基的实例包括吡啶基甲基、吡啶基乙基、吡咯基甲基、吡咯基乙基、咪唑基甲基、咪唑基乙基、噻唑基甲基、噻唑基乙基、苯并咪唑基甲基、苯并咪唑基乙基、喹唑啉基甲基、喹啉基甲基、喹啉基乙基、苯并呋喃基甲基、吲哚啉基乙基、异喹啉基甲基、异吲哚基甲基(isoinodylmethyl)、噌啉基甲基,和苯并噻吩基乙基。特别排除在该术语范围之外的是具有相邻的环O和/或S原子的化合物。
"亚芳基"、"亚杂芳基"或者"亚杂环基"分别为上文所限定的二价芳基、杂芳基,或者杂环基,其位于两个其它化学基团之间并且用于连接这两个其它化学基团。
当碳氢化合物(例如烷基或芳基)被描述为具有一定范围的碳原子数目(例如C1-C6烷基)时,应该理解的是它包括每个碳数在该范围内的碳氢化合物。因此,例如,“C1-C6烷基”表示基团“C1烷基、C2烷基、C3烷基、C4烷基、C5烷基,和C6烷基”。
如本文中所使用的,当基团(例如,环烷基、烃基、芳基、杂芳基、杂环、脲等)被描述为“任选取代的”而未明确陈述取代基时,其意指该基团任选具有1至4个,优选1至3个,更优选1个或2个非氢取代基。适合的取代基包括但不限于卤素、羟基、氧代(例如,取代有氧代的环-CH-为-C(O)-)、硝基、卤代烃基、烃基、芳基、芳烷基、烷氧基、芳基氧基、氨基、酰基氨基、烷基氨基甲酰基、芳基氨基甲酰基、氨基烷基、酰基、羧基、羟基烷基、烷基磺酰基、芳烃磺酰基、烷基磺酰氨基、芳烃磺酰氨基、芳烷基磺酰氨基、烷基羰基、酰基氧基、氰基,和脲基。本身不被进一步取代的示例性取代基(除非另有明确说明)是:
对于Q1、Q2和Q3:氢、卤素,具体为F、Cl或者Br,卤代烃基如CF3、烷基如C1-C4-烷基,或者烷氧基如C1-C4-烷氧基。
“任选独立地取代有”一个或者多个基团的基团为未取代的,取代有一个基团,或者取代有超过一个基团,其中所述基团中的每个被彼此独立地选择。例如,任选独立地取代有一个或者多个卤素、氰基,或者-OH基团的烷基包括乙基、三氟甲基,和1-氯,2-羟基丙基。
所述术语“卤代烷基”是指其中一个或多个氢被卤素替代的烷基链。示例性卤代烷基为三氟甲基、二氟甲基、氟氯甲基,和氟甲基。
本文中使用的术语"卤素"或者"卤代"是指氯、溴、氟,或者碘。
本文中使用的术语"酰基"是指烷基羰基或者芳基羰基取代基,其中所述烷基和芳基如本文中所限定。所述术语"酰基氨基"是指在氮原子处连接的酰胺基团(即,R-CO-NH-)。所述术语"氨基甲酰基"是指在羰基碳原子处连接的酰胺基团(即,NH2-CO-)。所述术语"磺酰氨基"是指通过硫或者氮原子连接的磺酰胺取代基。本文中使用的术语"脲基"是指取代的或者未取代的脲基团。
本文中使用的术语"基团"是指包含一个或者多个未成对电子的化学基团。
本文中使用的化合物的“有效量”是足以负调节或抑制LSD1的活性的量。
本文中使用的化合物的“治疗有效量”是足以改善或以某种方式减轻症状或停止或逆转病症的进展,或负调节或抑制LSD1的活性的量。这样的量可以作为单一剂量施用,或者可以根据方案施用,由此它是有效的。
本文中使用的“治疗”是指改善患者的病症、障碍或疾病的症状或病状或以其他方式有益地改变的任何方式。
如本文所用,通过施用特定化合物或药物组合物改善特定病症的症状是指可归因于施用组合物或与施用组合物相关的任何减轻,无论是永久的还是暂时的,持续的或短暂的。
化合物
在本发明的一个方面,提供由式(I)或者式(II)表示的化合物:
或其药学上可接受的盐。
R1为氢、C1-C4烷基或者C1-C4酰基;
L为-(CH2)s-CR2R3-(CH2)m-;
R2和R3各自独立地为氢、C1-C4烷基、-OR4或者芳烷基;
各个R4独立地为氢或者C1-C4烷基;
X为-W-R5或者Y-R6;
W为-NR4-或者-O-;
Y为-C(O)-、-S-、-SO-、-SO2-、-NR4SO2-、-SO2NR4-和-NR4C(O)-;
R5为酰基、C1-C4烷基、环烷基、杂环基、芳基或者杂芳基,其中所述环烷基、杂环基、芳基或者杂芳基中的每个任选独立地取代有一个或者多个R8;
R6为C1-C6烷基、芳基、-NR4R7或者杂环基,其在一个或者多个碳原子上任选独立地取代有C1-C6烷基、卤素、氰基,或者卤代烷基,或者在一个或者多个氮原子上任选独立地取代有-C(O)C1-C6烷基;-C(O)OC1-C6烷基;-C(O)NR4C1-C6烷基,或者-S(O)2NR4C1-C6烷基;
R7为羟基、烷氧基、-SO2C1-C6烷基;-SO2环烷基,或者-SO2芳基,其中各个所述-SO2环烷基和-SO2芳基中的环烷基和芳基任选独立地取代有一个或者多个R8;
各个R8独立地为卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代烷基、烷氧基、烷基氨基、二烷基氨基、环烷基、芳基、杂芳基、杂环基、芳烷基、杂芳基烷基、-(CH2)nCOOR4、-(CH2)nC(O)NR4OC1-C6烷基、-(CH2)nC(O)NR4SO2C1-C6烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-C2-C6烯基C(O)OR4、-C2-C6烯基C(O)NR4SO2C1-C4烷基,或者-C2-C6烯基C(O)NR4SO2芳基,其中所述环烷基、芳基、杂芳基,和杂环基中的每个任选独立地取代有一个或者多个C1-C3烷基或者-CH2NR4SO2芳基。
m为0或者1;
s为0或者1;
各个n为0、1,或者2;
各个p为0、1或者2;
各个RA独立地为氧代或者C1-C3烷基,或者在不同环原子上的两个RA基团一起形成C1-C3桥,其中所述桥碳中的一个任选被-NH-替代;
各个Q1、Q2和Q3独立地为氢、卤素、卤代烷基、C1-C4-烷基,或者C1-C4-烷氧基。
在本发明的一个方面,X为-W-R5和W为-O-,s为1和m为0。在该方面的一些实施方案中,R5为芳基,其任选独立地取代有一个或者多个R8。在一些这些实施方案中,芳基为苯基,其任选独立地取代有一个或者多个R8。在一些这些实施方案中,各个R8独立地为杂环基,其任选独立地取代有一个或者多个C1-C3烷基或者C1-C4酰基,和杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、四氢吡喃基、1,3-二氧杂环戊烷基、1,4-二氧杂环己烷基、吗啉基、二甲基-吗啉基、硫吗啉基、1,4-二硫杂环己烷基,或者1,3,5-三硫杂环己烷基。在其它这些实施方案中,杂环基为:
在该方面的其它实施方案中,R5为苯基,其任选独立地取代有一个或者多个R8,其中各个R8独立地为卤素、C1-C6烷基、-(CH2)nCOOR4、-(CH2)pC(O)NR4OC1-C4烷基、-(CH2)pC(O)NR4SO2C1-C4烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-CH=CHC(O)OR4、-CH=CHC(O)NR4SO2C1-C4烷基,或者-CH=CHC(O)NR4SO2芳基。在一些这些实施方案中,具有单一R8取代,其为-(CH2)nCOOR4。
在该方面的其它实施方案中,R5为杂芳基,其任选独立地取代有一个或者多个R8。在一些实施方案中,所述任选独立地取代有一个或者多个R8的杂芳基为吡啶基、6-甲基-吡啶基、4-羧基-吡啶基、二氢喹啉酮、二氢吲哚酮、喹唑啉基、喹啉基、嘧啶基、2-甲基-嘧啶基、哒嗪基、6-甲基-哒嗪基、吡唑基、1-甲基-吡唑基、5-甲基-吡唑基、1,3-二甲基-吡唑基、噻唑基、5-甲基-噻唑基、苯并[d]噁唑-2(3H)-酮基、2H-苯并[b][1,4]噁嗪-3(4H)-酮基、噻二唑基或者5-甲基-噻二唑基。
在其它实施方案中,杂芳基为吡啶基,其任选独立地取代有一个或者多个R8。对于一些这些实施方案,R8为杂环基,其任选独立地取代有一个或者多个C1-C3烷基或者C1-C4酰基。在一些实施方案中,所述任选独立地取代有一个或者多个C1-C3烷基或者C1-C4酰基的杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、四氢吡喃基、1,3-二氧杂环戊烷基、1,4-二氧杂环己烷基、吗啉基、二甲基-吗啉基、硫吗啉基、1,4-二硫杂环己烷基,或者1,3,5-三硫杂环己烷基。在其它实施方案中,所述R8杂环基为:
在该方面的其它实施方案中,R8为卤素、C1-C6烷基、-(CH2)nCOOR4、-(CH2)pC(O)NR4OC1-C4烷基、-(CH2)pC(O)NR4SO2C1-C4烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-CH=CHC(O)OR4、-CH=CHC(O)NR4SO2C1-C4烷基,或者-CH=CHC(O)NR4SO2芳基。
在式(II)化合物的该方面的其它实施方案中,RA为氧代和n为1或者2,由此形成哌啶-2-酮或者哌啶-2,6-二酮。在式(II)化合物的可选实施方案中,在不同哌啶环原子上具有两个RA基团,其形成C1-C3桥,其中所述桥的碳原子中的一个任选被-NH-替代。具有形成桥的两个RA基团的哌啶基团的实例包括但不限于3-氮杂二环[3.1.1]庚-3-基、1-氮杂二环[2.2.2]辛烷-3-基、1-氮杂二环[2.2.2]辛烷-4-基、1-氮杂二环[3.2.1]辛烷-6-基,和3,7-二氮杂二环[3.3.1]壬基。
在该方面的一些实施方案中,R1为氢、C1-C4烷基或者C1-C4酰基和R2和R3各自独立地为氢、C1-C4烷基、-OR4或者芳烷基,其中R4为氢或者烷基。在一些实施方案中,R2为羟基。在一些其它实施方案中,R2和R3各自独立地为氢、甲基和苄基。在一些其它示例性实施方案中,R4为氢或者甲基。
在该方面的一些其它实施方案中,R1为氢,L为亚乙基,W为-O-,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。
在该方面的一些其它实施方案中,R1为甲基,L为亚乙基,W为-O-,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。
在该方面的一些其它实施方案中,R1为氢,L为亚乙基,W为-O-,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为:
在该方面的一些其它实施方案中,R1为甲基,L为亚乙基,W为-O-,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为:
在该方面的一些其它实施方案中,R1为酰基,L为亚乙基,W为-O-,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为:
在本发明的另一方面,R1为氢,s和m各自为1,R2为羟基,R3为氢,W为-O-,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为:
在本发明的另一方面,R1为氢,L为亚乙基,W为-O-,R5为R8取代的亚吡啶基,和R8为杂环基,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。
在该方面的一些其它实施方案中,R1为甲基,L为亚乙基,W为-O-,R5为R8取代的亚吡啶基,和R8为杂环基,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。
在该方面的一些其它实施方案中,R1为氢,L为亚乙基,W为-O-,R5为R8取代的亚吡啶基,和R8为杂环基,其中所述杂环基为:
在一些实施方案中,其中W为-O-的式(I)和式(II)的化合物为
1-苯氧基-3-[4-[[反式-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇;
1-(2-甲氧基-3-苯氧基-丙基)-N-[反式-2-苯基环丙基]哌啶-4-胺;
2-甲基-1-苯氧基-3-(4-(((反式)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇;
1-苯氧基-3-[3-[[[(反式)-2-苯基环丙基]氨基]甲基]氮杂环丁烷-1-基]丙-2-醇;
(R)-1-苯氧基-3-(4-(((1S,2R)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇;
(S)-1-苯氧基-3-(4-(((1S,2R)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇;
1-苯氧基-3-[(1R,5S)-6-[[(反式)-2-苯基环丙基]氨基]-3-氮杂二环[3.1.1]庚-3-基]丙-2-醇;
(反式)-N-[[1-(2-苯氧基乙基)氮杂环丁烷-3-基]甲基]-2-苯基-环丙胺;
(反式)-N-[[1-(3-苯氧基丙基)氮杂环丁烷-3-基]甲基]-2-苯基-环丙胺;
1-[2-(4-溴苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺;
1-(3-苯氧基丙基)-N-((反式)-2-苯基环丙基)哌啶-4-胺;
1-(2-苯氧基乙基)-N-((反式)-2-苯基环丙基)哌啶-4-胺;
2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸;
N-(甲基磺酰基)-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酰胺;
2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)-N-(苯基磺酰基)乙酰胺;
N,N-二甲基-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酰胺;
N-甲氧基-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酰胺;
1-[2-(4-吗啉代苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺;
1-(2-(4-(4-甲基哌嗪-1-基)苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)噁唑烷-2-酮;
1-甲基-3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)咪唑烷-2-酮;
3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
4-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)吗啉-3-酮;
1-(4-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)哌嗪-1-基)乙-1-酮;
1-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)吡咯烷-2-酮;
1-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)哌啶-2-酮;
N-((1R,2S)-2-苯基环丙基)-1-(2-(4-(哌啶-1-基)苯氧基)乙基)哌啶-4-胺;
2-(4-(2-羟基-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)乙酸;
4-(2-羟基-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯甲酸;
(E)-3-(4-(2-羟基-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)丙烯酸;
2-(4-(3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)乙酸;
4-(3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯甲酸;
(E)-3-(4-(3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)丙烯酸;
(1R,2S)-N-((1-(2-(4-溴苯氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
1-(2-(2,4-二氯苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
(1R,2S)-N-((1-(2-(2,4-二氯苯氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
1-(2-(2,4-二氟苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
(1R,2S)-N-((1-(2-(2,4-二氟苯氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
(E)-3-(4-(2-羟基-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)-N-(甲基磺酰基)丙烯酰胺;
1-(2-((2-甲基吡啶-4-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
(1R,2S)-2-苯基-N-((1-(2-(对甲苯基氧基)乙基)氮杂环丁烷-3-基)甲基)环丙-1-胺;
(1R,2S)-2-苯基-N-((1-(2-(吡啶-2-基氧基)乙基)氮杂环丁烷-3-基)甲基)环丙-1-胺;
4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯甲酸;
N-(环丙基磺酰基)-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯甲酰胺;
4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)-N-(苯基磺酰基)苯甲酰胺;
(E)-N-(甲基磺酰基)-3-(4-(3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)丙烯酰胺;
3-(4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
4-(4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)吗啉-3-酮
1-(4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)哌啶-2-酮;
(1R,2S)-2-苯基-N-((1-(2-(4-(哌嗪-1-基)苯氧基)乙基)氮杂环丁烷-3-基)甲基)环丙-1-胺;
(1R,2S)-N-((1-(2-(4-(4-甲基哌嗪-1-基)苯氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
1-(4-(4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)哌嗪-1-基)乙-1-酮;
1-(2-((5-甲基吡啶-2-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((6-甲基吡啶-3-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
N-(甲基磺酰基)-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯甲酰胺;
N-(乙基磺酰基)-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯甲酰胺;
(1S,2R)-N-((1-(2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
2-(4-(2-(3-((((1S,2R)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)乙酸;
4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯甲酸
2-(4'-(2-(3-((((1S,2R)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)-[1,1'-二苯基]-4-基)-N-(苯基磺酰基)乙酰胺;
3-(6-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)吡啶-3-基)-1,3-氧杂氮杂环己烷-2-酮;
3-(5-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)吡啶-2-基)-1,3-氧杂氮杂环己烷-2-酮;
N-((1R,2S)-2-苯基环丙基)-1-(2-(对甲苯基氧基)乙基)哌啶-4-胺;
3-(4-(2-(4-(甲基((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
N-甲基-1-(2-((6-甲基吡啶-3-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
(1R,2S)-N-((1-(2-((6-甲基吡啶-3-基)氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
3-(5-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)吡啶-2-基)-1,3-氧杂氮杂环己烷-2-酮;
6-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)-3,4-二氢喹啉-2(1H)-酮;
5-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)二氢吲哚-2-酮;
1-(2-(3-氟-4-甲基苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
N-((1R,2S)-2-苯基环丙基)-1-(2-(喹唑啉-4-基氧基)乙基)哌啶-4-胺;
N-((1R,2S)-2-苯基环丙基)-1-(2-(喹啉-4-基氧基)乙基)哌啶-4-胺;
N-((1R,2S)-2-苯基环丙基)-1-(2-(嘧啶-5-基氧基)乙基)哌啶-4-胺;
1-(2-(3,5-二氟苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-(3,5-二氯苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((6-甲基哒嗪-3-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
(E)-3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)丙烯酸;
1-(2-(3-氟苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((6-甲基吡啶-2-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((2-甲基嘧啶-5-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-(4-溴苯氧基)乙基)-4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-2-酮;
2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙-1-醇;
N-(1-(2-(4-(2-氧代-1,3-氧杂氮杂环己烷-3-基)苯氧基)乙基)哌啶-4-基)-N-((1R,2S)-2-苯基环丙基)乙酰胺;
1-(2-甲氧基乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((1,3-二甲基-1H-吡唑-5-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((1-甲基-1H-吡唑-3-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
3-(4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
1-(2-异丙氧基乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
2-(2-氟-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸;
1-(2-(3,5-二氟-4-甲基苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((5-甲基-1,3,4-噻二唑-2-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
2-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)异烟酸;
3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)噁唑烷-2-酮;
1-(2-(4-溴苯氧基)乙基)-4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-2,6-二酮;
N-((1R,2S)-2-苯基环丙基)-1-(2-(吡啶-3-基氧基)乙基)哌啶-4-胺;
7-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮;
6-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯并[d]噁唑-2(3H)-酮;
1-(2-((5-甲基噻唑-2-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
3-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)异烟酸;
2-(3-氯-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸;
2-(3-氟-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸;
2-(3-甲基-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸;
4-(2-(4-(((1R,2S)-2-(3,4-二氟苯基)环丙基)氨基)哌啶-1-基)乙氧基)苯甲酸;
和上述化合物的药学上可接受的盐,包括但不限于二-盐酸盐。
在本发明的另一方面,X为-W-R5和W为-NR4-,s为1和m为0。在该方面的一些实施方案中,R5为芳基,其任选独立地取代有一个或者多个R8。在一些这些实施方案中,任选独立地取代有一个或者多个R8的芳基为苯基。在一些这些实施方案中,各个R8独立地为杂环基,其任选独立地取代有一个或者多个C1-C3烷基或者C1-C4酰基,和杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、四氢吡喃基、1,3-二氧杂环戊烷基、1,4-二氧杂环己烷基、吗啉基、二甲基-吗啉基、硫吗啉基、1,4-二硫杂环己烷基,或者1,3,5-三硫杂环己烷基。在其它这些实施方案中,杂环基为:
在该方面的其它实施方案中,R5为苯基,其任选独立地取代有一个或者多个R8,其中各个R8独立地为卤素、C1-C6烷基、-(CH2)nCOOR4、-(CH2)pC(O)NR4OC1-C4烷基、-(CH2)pC(O)NR4SO2C1-C4烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-CH=CHC(O)OR4、-CH=CHC(O)NR4SO2C1-C4烷基,或者-CH=CHC(O)NR4SO2芳基。在一些这些实施方案中,具有单一R8取代,其为-(CH2)nCOOR4。
在其它实施方案中,W为-NR4-,R5为杂芳基,其任选独立地取代有一个或者多个R8。在一些实施方案中,所述任选独立地取代有一个或者多个R8的杂芳基为吡啶基、6-甲基-吡啶基、4-羧基-吡啶基、二氢喹啉酮、二氢吲哚酮、喹唑啉基、喹啉基、嘧啶基、2-甲基-嘧啶基、哒嗪基、6-甲基-哒嗪基、吡唑基、1-甲基-吡唑基、5-甲基-吡唑基、1,3-二甲基-吡唑基、噻唑基、5-甲基-噻唑基、苯并[d]噁唑-2(3H)-酮基、2H-苯并[b][1,4]噁嗪-3(4H)-酮基、噻二唑基或者5-甲基-噻二唑基。在其它实施方案中,杂芳基为吡啶基,其任选独立地取代有一个或者多个R8。对于一些化合物,R8为杂环基,其任选独立地取代有一个或者多个C1-C3烷基。在一些实施方案中,所述任选独立地取代有一个或者多个C1-C3烷基的杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、四氢吡喃基、1,3-二氧杂环戊烷基、1,4-二氧杂环己烷基、吗啉基、二甲基-吗啉基、硫吗啉基、1,4-二硫杂环己烷基,或者1,3,5-三硫杂环己烷基。
在其它实施方案中,所述任选独立地取代有一个或者多个C1-C3烷基的杂环基为
在该方面的其它实施方案中,R5为吡啶基和各个R8独立地为卤素、烷基、-(CH2)nCOOR4、-(CH2)pC(O)NR4OC1-C4烷基、-(CH2)pC(O)NR4SO2C1-C4烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-CH=CHC(O)OR4、-CH=CHC(O)NR4SO2C1-C4烷基,或者-CH=CHC(O)NR4SO2芳基。
在式(II)化合物的该方面的其它实施方案中,在相同的碳上具有形成了氧代的两个RA和n为1或者2,由此形成哌啶-2-酮或者哌啶-2,6-二酮。在式(II)化合物的可选实施方案中,在不同哌啶环原子上具有两个RA基团,其形成C1-C3桥,其中所述桥的碳原子中的一个任选被-NH-取代。具有形成了桥的两个RA基团的哌啶基团的实例包括但不限于3-氮杂二环[3.1.1]庚-3-基、1-氮杂二环[2.2.2]辛烷-3-基、1-氮杂二环[2.2.2]辛烷-4-基、1-氮杂二环[3.2.1]辛烷-6-基,和3,7-二氮杂二环[3.3.1]壬基。
在该方面的一些实施方案中,R1为氢、C1-C4烷基或者C1-C4酰基和R2和R3各自独立地为氢、C1-C4烷基、-OR4或者芳烷基,其中R4为氢或者烷基。在一些实施方案中,R2为羟基。在一些其它实施方案中,R2和R3各自独立地为氢、甲基和苄基。在一些其它示例性实施方案中,R4为氢或者甲基。
在该方面的一些其它实施方案中,R1为氢,L为亚乙基,W为-NR4-,R4为氢,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。
在该方面的一些其它实施方案中,R1为甲基,L为亚乙基,W为-NR4-,R4为氢,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。
在该方面的一些其它实施方案中,R1为氢,L为亚乙基,W为-NR4-,R4为氢,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为:
在该方面的一些其它实施方案中,R1为甲基,L为亚乙基,W为-NR4-,R4为氢,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为:
在该方面的一些其它实施方案中,R1为酰基,L为亚乙基,W为-NR4-,R4为氢,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为:
在本发明的另一方面,R1为氢,s和m各自为1,R2为羟基,R3为氢,W为-NR4-,R4为氢,R5为R8取代的亚苯基,和R8为杂环基,其中所述杂环基为:
在该方面的一些其它实施方案中,R1为氢,L为亚乙基,W为-NR4-,R4为氢,R5为R8取代的亚苯基,和R8为杂芳基,其中所述杂芳基为吡啶基、二氢喹啉酮、二氢吲哚酮、喹唑啉基、喹啉基、嘧啶基、哒嗪基、吡唑基、吡唑基、1-甲基-吡唑基、5-甲基-吡唑基、噻唑基、苯并[d]噁唑酮、噻唑基或者5-甲基-噻唑基。
在本发明的另一方面,R1为氢,L为亚乙基,W为-NR4-,R4为氢,R5为R8取代的亚吡啶基,和R8为杂环基,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。
在该方面的一些其它实施方案中,R1为甲基,L为亚乙基,W为-NR4-,R4为氢,R5为R8取代的亚吡啶基,和R8为杂环基,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基或者硫吗啉基。
在该方面的一些其它实施方案中,R1为氢,L为亚乙基,W为-NR4-,R4为氢,R5为R8取代的亚吡啶基,和R8为杂环基,其中所述杂环基为:
在一些实施方案中,其中W为-NR4-的式(I)和式(II)的化合物为:
1-苯氨基-3-[4-[[反式-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇;
1-(N-甲基苯氨基)-3-[4-[[反式-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇;
1-(2-(苯基氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-(甲基(苯基)氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((4-溴苯基)氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)哌啶-2-酮;
3-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
4-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)吗啉-3-酮;
N-((1R,2S)-2-苯基环丙基)-1-(2-((4-(哌啶-1-基)苯基)氨基)乙基)哌啶-4-胺;
1-(2-((4-吗啉代苯基)氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)吡咯烷-2-酮;
3-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)噁唑烷-2-酮;
1-甲基-3-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)咪唑烷-2-酮;
1-(4-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)哌嗪-1-基)乙-1-酮;
3-(4-((2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙基)氨基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
N,6-二甲基-N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)吡啶-3-胺;
1-(2-((4-溴苯基)(甲基)氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
3-(4-(甲基(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
1-甲基-3-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)脲;
N-甲基-N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)乙酰胺;
N,2-二甲基-N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)吡啶-4-胺;
1-(2-(4-溴-2-氟苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
2-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)异烟酸;和
3-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)异烟酸。
和上述化合物的药学上可接受的盐,包括但不限于二盐酸盐。
在本发明的另一方面,提供了式(I)和式(II)的化合物,其中Y为-C(O)-,s为0,m为0,R2为C1-C4烷基或者芳烷基,和R6为杂环基,其中所述杂环基为哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。在该方面的一些实施方案中,Y为-C(O)-,s为0,m为0,R2为甲基,和R6为哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基或者硫吗啉基。在该方面的一些其它实施方案中,Y为-C(O)-,s为0,m为0,R2为苄基,和R6为哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基或者硫吗啉基。
在本发明的另一方面,提供了式(I)和式(II)的化合物,其中Y为-C(O)-,L为亚乙基,和R6为杂环基,其任选独立地取代有一个或者多个C1-C3烷基。在一些实施方案中,所述任选独立地取代有一个或者多个C1-C3烷基的杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、四氢吡喃基、1,3-二氧杂环戊烷基、1,4-二氧杂环己烷基、吗啉基、二甲基-吗啉基、硫吗啉基、1,4-二硫杂环己烷基,或者1,3,5-三硫杂环己烷基。在其它实施方案中,所述杂环基为:
在本发明的另一方面,提供了式(I)和式(II)的化合物,其中Y为-C(O)-,L为亚丙基,和R6为杂环基,其任选独立地取代有一个或者多个C1-C3烷基。在一些实施方案中,所述任选独立地取代有一个或者多个C1-C3烷基的杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、四氢吡喃基、1,3-二氧杂环戊烷基、1,4-二氧杂环己烷基、吗啉基、二甲基-吗啉基、硫吗啉基、1,4-二硫杂环己烷基,或者1,3,5-三硫杂环己烷基。在其它实施方案中,所述杂环基为:
在该方面的其它实施方案中,R6为-NR4R7。在一些实施方案中,R7为羟基、烷氧基、-SO2C1-C6烷基;-SO2环烷基,或者-SO2芳基,其中各个所述-SO2环烷基和-SO2芳基中的环烷基或者芳基任选独立地取代有一个或者多个R8。
在一些实施方案中,其中Y为-C(O)-的式(I)和式(II)的化合物为:
1-吗啉代-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮;
N-甲氧基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙酰胺;
1-吗啉代-3-苯基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮;
3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙酸;
1-吗啉代-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮;
N-(甲基磺酰基)-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙酰胺;
3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)-1-(哌嗪-1-基)丙-1-酮;
3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)-N-(苯基磺酰基)丙酰胺;
1-(4-甲基哌嗪-1-基)-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮;
N-(乙基磺酰基)-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙酰胺;
3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)-1-硫吗啉代丙-1-酮;
1-(4-甲基哌嗪-1-基)-4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁-1-酮;
4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)-1-(哌嗪-1-基)丁-1-酮;
1-吗啉代-4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁-1-酮;
4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)-N-(苯基磺酰基)丁酰胺;
4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁酸;
N-(环丙基磺酰基)-4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁酰胺;
N-(乙基磺酰基)-4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁酰胺;
N-(甲基磺酰基)-4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁酰胺;
1-(顺式-2,6-二甲基吗啉代)-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮;
和上述化合物的药学上可接受的盐,包括但不限于二盐酸盐。
在本发明的另一方面,Y为-NR4SO2-和R6为C1-C6烷基、环烷基或者芳基,其中所述环烷基或者芳基任选独立地取代有一个或者多个C1-C3烷基、卤素、卤代烷基、氨基或者氰基。
在一些实施方案中,其中Y为-NR4SO2-的式(I)和式(II)的化合物为:
N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)甲烷磺酰胺;
N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)苯磺酰胺;
N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)丙烷-2-磺酰胺;
N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙基)甲烷磺酰胺;
N-甲基-N-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙基)甲烷磺酰胺;
N-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙基)甲烷磺酰胺;
N-甲基-N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)甲烷磺酰胺;和
N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)环丙烷磺酰胺;
和上述化合物的药学上可接受的盐,包括但不限于二盐酸盐。
在本发明的另一方面,Y为-SO2NR4-和R6为C1-C6烷基或者芳基,其中所述芳基任选独立地取代有一个或者多个C1-C3烷基、卤素、卤代烷基、氨基或者氰基。
在本发明的该方面的一些实施方案中,其中Y为-SO2NR4-的式(I)和式(II)的化合物为
N-苯基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙烷-1-磺酰胺;
N-甲基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙烷-1-磺酰胺;
和上述化合物的药学上可接受的盐,包括但不限于二盐酸盐。
在本发明的另一方面,Y为-NR4C(O)NR4R4和各个R4为C1-C3烷基。其中Y为-NR4C(O)NR4R4的示例性化合物为1,1-二甲基-3-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)脲。
式(I)和式(II)的化合物可配制成药物组合物。
药物组合物
另一方面,本发明提供了药物组合物,其包含根据本发明的LSD1抑制剂和药学上可接受的载体、赋形剂或稀释剂。本发明的化合物可以通过本领域公知的任何方法配制,并且可以制备成通过任何途径给药,包括但不限于肠胃外,口服,舌下,透皮,局部,鼻内,气管内或直肠内。在某些实施方案中,本发明化合物在医院环境中静脉内施用。在某些其他实施方案中,施用可以优选通过口服途径。
载体的特征将取决于给药途径。如本文所用,术语“药学上可接受的”是指与生物系统如细胞、细胞培养物、组织或器官相容且不干扰活性成分的生物活性的有效性的无毒材料。因此,除了抑制剂之外,根据本发明的组合物还可以包含稀释剂、填料、盐、缓冲剂、稳定剂、增溶剂和本领域公知的其它材料。药学上可接受的制剂的制备描述于,例如,Remington's Pharmaceutical Sciences,18th Edition,ed.A.Gennaro,Mack PublishingCo.,Easton,Pa.,1990。
如本文所用,术语药学上可接受的盐是指保留上述化合物的所需生物学活性并且表现出最小或不具有不希望的毒理学作用的盐。这样的盐的实例包括但不限于与无机酸(例如盐酸、氢溴酸、硫酸、磷酸、硝酸等)形成的酸加成盐,以及与有机酸形成的盐,例如乙酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、扑酸、海藻酸、聚谷氨酸、萘磺酸、萘二磺酸和聚半乳糖醛酸。所述化合物还可以作为本领域技术人员已知的药学上可接受的季盐给药,所述季盐特别包括式-NR+Z-的季铵盐,其中R为氢、烷基或苄基,并且Z是抗衡离子,包括氯离子、溴离子、碘离子、-O-烷基、甲苯磺酸根、甲基磺酸根、磺酸根、磷酸根或羧酸根(如苯甲酸根、琥珀酸根、乙酸根、乙醇酸根、马来酸根、苹果酸根、柠檬酸根、酒石酸根、抗坏血酸根、苯甲酸根、肉桂酸根、扁桃酸根、苄酸根和二苯基乙酸根)。
活性化合物以足以将治疗有效量递送给患者的量包含在药学上可接受的载体或稀释剂中,而不会在所治疗的患者中引起严重的毒性效应。对于所有上述病症,活性化合物的剂量范围为约0.01至300mg/kg,优选每天0.1至100mg/kg,更通常每天0.5至约25mg每千克接受者体重。在合适的载体中典型的局部剂量范围为0.01-3%wt/wt。药学上可接受的衍生物的有效剂量范围可以基于待递送的母体化合物的重量来计算。如果衍生物本身表现出活性,则可以如上所述使用衍生物的重量或通过本领域技术人员已知的其他方式估计有效剂量。
包含本发明化合物的药物组合物可以用于本文所述的方法中。
使用方法
在另一方面,本发明提供了在细胞中抑制LSD1活性的方法,其包括使希望抑制LSD1活性的细胞与治疗有效量的式(I)化合物、其药学上可接受的盐或者含有所述化合物或其药学上可接受的盐的药物组合物接触。
本文中提供的组合物和方法特别被认为可用于抑制细胞中的LSD1活性。在一个实施方案中,使希望抑制LSD1活性的细胞与治疗有效量的式(I)化合物接触以负调节LSD1活性。在其它实施方案中,可使用治疗有效量的药学上可接受的盐或者含有式(I)化合物的药物组合物。
通过负调节LSD1的活性,特别是在过表达LSD1酶的细胞或激活LSD1酶的体细胞突变的情况下,设计所述方法以恢复正常的细胞转录表达模式,例如,通过改变H3K4的甲基化模式来抑制由细胞内LSD1活性增强引起的不希望的细胞增殖。根据特定的治疗方案,细胞可以以单剂量或多剂量接触,以实现期望的LSD1的负调节。可以使用众所周知的方法(包括下文实施例83中所述的方法)监测细胞中组蛋白H3K4的单和二甲基化程度,以评估治疗的有效性,并且剂量可以由主治医师相应地调整。
在另一方面,提供了治疗癌症的方法,其包括向癌症患者给药治疗有效量的式(I)化合物、其药学上可接受的盐或者包含所述化合物或其药学上可接受的盐的药物组合物。
本文提供的组合物和方法可用于治疗多种癌症,包括诸如前列腺癌、乳腺癌、脑癌、皮肤癌、宫颈癌、睾丸癌等的肿瘤。更特别地,可通过本发明的组合物和方法治疗的癌症包括但不限于诸如星形细胞瘤、乳腺癌、子宫颈癌、结肠直肠癌、子宫内膜癌、食道癌、胃癌、头颈癌、肝细胞癌、喉癌、肺癌、口腔癌、卵巢癌、前列腺癌和甲状腺癌和肉瘤的肿瘤类型。更具体地,这些化合物可用于治疗:心脏:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤;肺:支气管原癌(鳞状细胞癌、未分化小细胞癌、未分化大细胞癌、腺癌)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨错构瘤、间皮瘤;胃肠道:食道(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌、淋巴瘤、平滑肌肉瘤)、胰腺(导管腺癌、胰岛瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、舒血管肠肽瘤(vipoma))、小肠(腺癌、淋巴瘤、类癌瘤、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤);泌尿生殖道:肾(腺癌、威尔姆斯肿瘤(Wilm's tumor)(肾母细胞瘤)、淋巴瘤、白血病)、膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎性癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤、脂肪瘤);肝:肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞性腺瘤、血管瘤;胆道:胆囊癌、壶腹癌、胆管癌;骨:成骨性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨疣(osteocartilaginousexostose))、良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤(chondromyxofibroma)、骨样骨瘤和巨细胞瘤;神经系统:头骨(骨瘤、血管瘤、肉芽肿、黄色瘤、畸形性骨炎)、脑膜(脑膜瘤、脑膜肉瘤(meningiosarcoma)、神经胶质瘤病)、脑(星形细胞瘤、髓母细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性成胶质细胞瘤、少突神经胶质瘤(oligodendroglioma)、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤);妇科:子宫(子宫内膜癌)、宫颈(宫颈癌、肿瘤前宫颈病变(pre-tumor cervical dysplasia))、卵巢(卵巢癌(浆液性囊腺癌、粘液性囊腺癌、未分类癌(unclassified carcinoma))、颗膜细胞瘤(granulosa-thecal cell tumor)、塞-莱细胞瘤(Sertoli-Leydig cell tumor)、无性细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎型横纹肌肉瘤)、输卵管癌);血液方面:血液(髓细胞性白血病(急性和慢性)、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征(myelodysplastic syndrome))、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤);皮肤:恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、发育不良痣(moles dysplastic nevi)、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、牛皮癣;和肾上腺:神经母细胞瘤。在一些实施方案中,所述癌症为非小细胞肺癌。
向患者给药的浓度和途径将根据待治疗的癌症而变化。化合物,其药学上可接受的盐以及包含这些化合物和盐的药物组合物也可以与其他抗肿瘤化合物(例如化学疗法)共同施用,或者与其他治疗(例如辐射或手术介入)联合使用,作为手术前或手术后的辅助。可以使用众所周知的方法(包括下文实施例83中描述的那些方法)监测患者中组蛋白H3K4的单和二甲基化程度,以获得治疗的有效性以及其他预后或生物学因素,并且可以相应地由主治医师调整剂量。
反应方案和实施例
本发明的化合物可使用市售试剂使用本文所述的合成方法和反应方案或使用本领域技术人员熟知的其它试剂和常规方法来制备。
例如,本发明的化合物可以根据一般反应方案I-V制备。
方案Ia
方案Ib
方案Ia和Ib分别说明了式(I)或者式(II)的化合物的制备,其中W为NR4或者O,(或者Y为S、SO,或者SO2)和L为环氧氯丙烷衍生物。环氧氯丙烷A经亲核试剂W-R5取代得到中间体B(步骤1)。取代在诸如MeCN的溶剂中在碱如K2CO3存在下进行,通常在高温下进行。在Y为SO或SO2的情况下,用R6SH形式的亲核试剂进行初始取代,然后氧化成亚砜或者砜衍生物,得到Y-R6。B与胺C反应得到化合物D(步骤2)。环氧化物开环通常也在类似于步骤1的条件下进行。在步骤3中除去保护基得到化合物E典型地在诸如DCM的溶剂中用酸如TFA进行。
方案IIa
方案IIb
方案IIa和IIb分别说明了式(I)和式(II)的化合物的制备,其中W为NR4或者O,(或者Y为S、SO或者SO2),和L为烷基衍生物。试剂F经亲核试剂W-R5取代得到中间体G(步骤1)。在诸如K2CO3的碱的存在下,在溶剂(如丙酮)中进行取代。在Y为SO或SO2的情况下,用R6SH形式的亲核试剂进行初始取代,然后氧化成亚砜或者砜衍生物,得到Y-R6。G与胺C反应得到化合物H(步骤2)。这种取代通常在类似于步骤1的条件下进行。替代的碱和溶剂如Cs2CO3和MeCN也可为有效的。在步骤3中除去保护基得到化合物I通常在溶剂如DCM中用酸如TFA进行。
方案IIIa
方案IIIb
方案IIIa和方案IIIb分别说明了式(I)和式(II)的化合物的制备,其中Y为NR4SO2或者NR4C(O)。中间体C与腈衍生物进行烷基化反应,随后还原得到游离胺J。在一种情况下,用例如氯甲基乙腈在溶剂如丙酮中,用碱如K2CO3进行烷基化,得到中间体,该中间体可被还原得到胺,其中L为-CH2CH2-。替代地,胺J可以由中间体C与被保护的胺衍生物的烷基化反应产生。胺J的官能化将产生衍生物K,其将在脱保护后给出目标L。K的官能化将通过例如与磺酰氯或酰氯反应而进行。在最终步骤中除去Boc保护基在溶剂如DCM中用酸如TFA进行。
方案Iva
方案IVb
方案IVa和IVb分别说明了式(I)和式(II)的化合物的制备,其中Y为SO2NR4。中间体C例如用乙烯基磺酰胺衍生物M进行加成,得到化合物N。最后步骤中的Boc保护基团的脱除在溶剂如DCM中用酸如TFA进行,得到衍生物O。
方案Va
方案Vb
方案Va和Vb分别说明了式(I)和式(II)的化合物的制备,其中Y为-CO-。中间体C用卤素衍生物P烷基化,并将酯裂解,得到羧酸S。该取代在溶剂如DMF中用碱如TEA和碘化钾进行。用碱如NaOH在溶剂如THF中除去酯基。与物质R6形成酰胺键,然后除去保护基,得到化合物T。使用R6反应进行酰胺化,例如在二氯甲烷中用EDC/HOBt进行。例如,用二噁烷中的稀HCl溶液去除Boc基团。
以下实施例旨在进一步说明本发明的某些实施方式,而不是要限制本发明的范围。
实施例1
1-苯氧基-3-[4-[[反式-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇(5)
步骤1.2-(苯氧基甲基)氧杂环丙烷(2)
将2-(氯甲基)氧杂环丙烷(3.93g,42.5mmol,3.33mL,2.00当量)、苯酚(2.00g,21.3mmol,1.87mL,1.00当量)和K2CO3(8.81g,63.8mmol,3.00当量)在MeCN(40.0mL)中的溶液在80℃搅拌12小时。在完成之后,将混合物过滤并将滤液在真空下浓缩。残留物通过硅胶色谱法纯化(洗脱剂:PE/EA25/1),得到2-(苯氧基甲基)氧杂环丙烷(2.20g,13.9mmol,65.5%产率,95.0%纯度),其为无色油状物。LCMS[M+41+1]:192。
1H NMR(400MHz,甲醇-d4)δ=7.27-7.23(m,2H),6.94-6.91(m,3H),4.28-4.25(dd,J=11.2,2.4Hz,1H),3.86-3.81(dd,J=11.2,6.0Hz,1H),3.32-3.30(m,1H),2.86-2.83(dd,J=5.2,4.4Hz,1H),2.72-2.71(dd,J=5.2,2.8Hz,1H)。
步骤2.(1-(2-羟基-3-苯氧基丙基)哌啶-4-基)-N-(反式-2-苯基环丙基)氨基甲
酸叔丁基酯(4)
将2-(苯氧基甲基)氧杂环丙烷(200mg,1.33mmol,1.00当量)、N-[反式-2-苯基环丙基]-N-(4-哌啶基)氨基甲酸叔丁基酯(421mg,1.33mmol,1.00当量)和K2CO3(368mg,2.66mmol,2.00当量)在MeCN(5.00mL)中的悬浮液在80℃搅拌14小时。在完成之后,过滤混合物。将滤液在真空下浓缩。残留物通过硅胶色谱法纯化(PE/EA1/0至5/1),得到N-[1-(2-羟基-3-苯氧基-丙基)-4-哌啶基]-N-[反式-2-苯基环丙基]氨基甲酸叔丁基酯(400mg,857umol,64.5%产率),其为无色油状物。LCMS[M+1]:467。
1H NMR(400MHz,氯仿-d)δ=7.32-7.27(m,4H),7.22-7.18(m,1H),7.11-7.09(m,2H),6.95-6.93(m,3H),4.08-4.06(m,1H),4.00-3.98(m,2H),3.74-3.71(m,1H),3.09-2.92(m,2H),2.59-2.52(m,3H),2.39(m,1H),2.14-2.13(m,2H),2.08-2.06(m,2H),1.82-1.74(m,2H),1.45(m,9H),1.42-1.40(m,1H),1.27-1.16(s,1H)
步骤3.1-苯氧基-3-(4-(((反式)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇(5)
将N-[1-(2-羟基-3-苯氧基-丙基)-4-哌啶基]-N-[反式-2-苯基环丙基]氨基甲酸叔丁基酯(150mg,321umol,1.00当量)和TFA(366mg,3.21mmol,238uL,10.0当量)在DCM(5.00mL)中的溶液在28℃搅拌1小时。在完成之后,将饱和NaHCO3(10mL)添加至混合物。将混合物用DCM(3×20mL)萃取,将合并的有机相在真空下浓缩。残留物通过制备性HPLC纯化(仪器:GX-A;柱:PhenomenexGemini 150*25mm*10um;条件:水(0.05%氢氧化铵v/v)-ACN;开始B:55;结束B:85;梯度时间(min):12;100%B保持时间(min):2;流速(ml/min):25)。得到1-苯氧基-3-(4-(((反式)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇(5)(51.0mg,139umol,43.3%产率),其为黄色油状物。LCMS[M+1]:367
1H NMR(400MHz,甲醇-d4)δ=7.27-7.21(m,4H),7.14-7.12(m,1H),7.05-7.03(m,2H),6.94-6.92(m,3H),4.13(m,1H),4.12-3.91(m,2H),3.07(m,2H),2.65-2.60(m,3H),2.33-2.31(m,3H),1.95-1.90(m,3H),1.55-1.52(m,2H),1.09-1.03(m,2H)。
实施例2
1-(2-甲氧基-3-苯氧基-丙基)-N-[反式-2-苯基环丙基]哌啶-4-胺(7)
步骤1.N-[1-(2-甲氧基-3-苯氧基-丙基)-4-哌啶基]-N-[反式-2-苯基环丙基]氨基甲酸叔丁基酯(6)
在0℃向4(150mg,321umol,1.00当量)在THF(5.00mL)中的溶液添加NaH(15.4mg,6.4mmol,2.00当量)。在搅拌1小时之后,在0℃添加MeI(2.41g,17.0mmol,1.06mL,52.8当量)。将混合物在28℃搅拌2小时。在完成之后,将混合物倒入饱和NH4Cl水溶液(20mL)中,用DCM(3×30mL)萃取,并将合并的有机相在真空下浓缩。残留物通过制备性TLC纯化(PE/EA2/1,Rf=0.8)。得到N-[1-(2-甲氧基-3-苯氧基-丙基)-4-哌啶基]-N-[反式-2-苯基环丙基]氨基甲酸叔丁基酯(90.0mg,180umol,56.1%产率,96.2%纯度),其为黄色油状物。LCMS[M+1]:481
1H NMR(400MHz,甲醇-d4)δ=7.27-7.22(m,4H),7.12-7.10(m,3H),6.95-6.92(m,3H),4.09-4.08(m,1H),4.03-3.99(m,1H),3.75-3.70(m,2H),3.48(s,3H),3.20-3.02(m,2H),2.68-2.60(m,3H),2.28-2.08(m,5H),1.75(m,2H),1.42-1.39(m,10H),1.29-1.24(m,1H)。
步骤2.1-(2-甲氧基-3-苯氧基-丙基)-N-[反式-2-苯基环丙基]哌啶-4-胺(7)
以类似于实施例1的方式用TFA处理化合物6,得到标题化合物,其为黄色油状物(66.0mg,160umol,85.2%产率,92%纯度)。LCMS[M+1]:381
1H NMR(400MHz,甲醇-d4)δ=7.28-7.22(m,4H),7.15-7.09(m,1H),7.05-7.03(m,2H),6.94-6.91(m,3H),4.11-4.07(m,1H),4.02-3.98(m,1H),3.77(m,1H),3.48-3.47(m,3H),3.05(m,2H),2.68-2.66(m,3H),2.35-2.27(m,3H),1.95-1.91(m,3H),1.63-1.44(m,2H),1.09-1.03(m,2H)。
实施例3
1-苯氨基-3-[4-[[反式-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇(10)
遵循实施例1的一般操作,化合物10制备自化合物1:
步骤1.N-(环氧乙烷-2-基甲基)苯胺(8)
在完成之后,将混合物过滤并浓缩滤液。残留物通过制备性HPLC纯化(仪器:HPLC-D;柱:Phenomenex Synergi Max-RP 250*8010u;条件:水(0.1%TFA)-ACN;开始B:0;结束B:25%ACN;梯度时间(min):37MIN;52%;流速(ml/min):80)。得到化合物8(800mg,3.22mmol,15.0%产率,60.0%纯度),其为无色油状物。LCMS[M+1]:150。
1H NMR(400MHz,甲醇-d4)δ=7.36-7.07(m,1H),6.65-6.60(m,1H),3.42-3.39(m,1H),3.16-3.13(m,2H),2.77-2.75(m,1H),2.63-2.61(m,1H)
步骤2.N-[1-(3-苯氨基-2-羟基-丙基)-4-哌啶基]-N-[反式-2-苯基环丙基]氨基
甲酸叔丁基酯(9)
在完成之后,将混合物过滤并将滤液在真空下浓缩。残留物通过硅胶色谱法纯化(洗脱剂:PE/EA 1/0至5/1)。得到化合物9(250mg,537umol,53.2%产率),其为无色油状物。LCMS[M+1]:466。
1H NMR(400MHz,甲醇-d4)δ=7.29-7.20(m,2H),7.22-7.09(m,5H),6.66-6.61(m,3H),4.15-4.13(m,1H),3.96-3.71(m,2H),3.18-3.06(m,4H),2.63-2.60(m,3H),2.39-2.18(m,2H),2.13-2.09(m,2H),1.76(m,2H),1.42-1.37(m,10H),1.26-1.23(m,1H)。
步骤3.1-苯氨基-3-[4-[[反式-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇(10)
在完成之后,将饱和NaHCO3(10mL)添加至混合物中。将混合物用DCM(3×20mL)萃取,将合并的有机相在真空下浓缩。残留物通过制备性HPLC纯化(仪器:GX-I;柱:YMC-ActusODS-AQ 150*305u;条件:水(0.1%TFA)-ACN;开始B:8;结束B:38;梯度时间(min):11;100%B保持时间(min):2;流速(ml/min):25)。得到化合物10(83.0mg,189umol,35.3%产率,2HCl),其为黄色油状物。LCMS[M+1]:366。
1H NMR(400MHz,甲醇-d4)δ=7.31(m,2H),7.25-7.23(m,1H),7.18-7.14(m,4H),6.76-6.71(m,3H),4.25-4.23(dd,J=10.4,3.2Hz,1H),3.81-3.77(m,2H),3.67(m,1H),3.35(m,1H),3.25-3.19(m,5H),3.00-2.99(m,1H),2.49-2.39(m,3H),2.11(m,2H),1.55-1.51(m,1H),1.47-1.43(m,1H)
实施例4
1-(N-甲基苯氨基)-3-[4-[[反式-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇
遵循实施例1的一般操作,化合物13制备自化合物1:
步骤1.N-甲基-N-(环氧乙烷-2-基甲基)苯胺(11)。
在完成之后,将混合物过滤并将滤液在真空下浓缩。残留物通过制备性HPLC纯化(仪器:SFC-A;柱:Daiso 250*50mm,10um;条件:水(0.1%TFA)-ACN;开始B:0%ACN;结束B:20%ACN;梯度时间(min):34MIN;40%;流速(ml/min):80)。得到化合物11(300mg,1.58mmol,8.47%产率,86.0%纯度),其为无色油状物。
1H NMR(400MHz,甲醇-d4)δ=7.22-7.17(m,2H),6.81-6.79(d,J=8.0Hz,2H),6.70-6.67(m,1H),3.70-3.66(m,1H),3.36-3.31(m,2H),2.97(s,3H),2.77-2.75(m,1H),2.56-2.54(m,1H)。
步骤2.N-[1-[2-羟基-3-(N-甲基苯氨基)丙基]-4-哌啶基]-N-[反式-2-苯基环丙
基]氨基甲酸叔丁基酯(12)
在完成之后,将混合物冷却至28℃,将析出物过滤。将滤液在真空下浓缩。残留物通过制备性TLC纯化(PE/EA2/1,P1:Rf=0.6)。得到化合物12(200mg,414umol,45.0%产率,99.2%纯度),其为黄色油状物。LCMS[M+1]:480。
1H NMR(400MHz,甲醇-d4)δ=7.26-7.22(m,2H),7.16-7.10(m,5H),6.78-6.76(m,2H),6.65(m,1H),4.13(br.s.,1H),3.76-3.75(m,1H),3.39-3.31(m,4H),2.99(s,,3H),2.67-2.64(m,5H),2.13-2.11(m,3H),1.90-1.83(m,2H),1.42-1.37(m,10H),1.24-1.22(m,1H)
在完成之后,将混合物倒入饱和NaHCO3水溶液(20.0mL)中,然后用DCM(2×30.0mL)萃取。合并的有机相在真空下浓缩。残留物通过制备性TLC纯化(洗脱剂:DCM/MeOH20/1)。得到化合物13(60.0mg,148umol,35.6%产率,93.8%纯度),其为黄色油状物。LCMS[M+1]:380。
1H NMR(400MHz,甲醇-d4)δ=7.22-7.20(m,2H),7.16-7.12(m,3H),7.05-7.03(m,2H),6.77-6.75(d,J=8.8Hz,2H),6.64-6.63(m,1H),4.08-4.05(m,1H),3.44(m,1H),3.27(m,1H),3.15-3.02(m,2H),2.98(s,3H),2.78-2.67(m,1H),2.57-2.53(m,2H),2.33-2.31(m,3H),2.98-1.90(m,3H),1.54(m,2H),1.09-1.03(m,2H)。
实施例5
2-甲基-1-苯氧基-3-(4-(((反式)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇(16)
步骤1.N-[1-(2-氧代-3-苯氧基-丙基)-4-哌啶基]-N-[(反式)-2-苯基环丙基]氨
基甲酸叔丁基酯(14)。
向草酰氯(212mg,1.67mmol,146uL,3.00当量)在DCM(0.5mL)中的溶液添加在DCM(0.5mL)中的DMSO(304mg,3.90mmol,304uL,7.00当量),然后添加在DCM(1mL)中的N-[1-(2-羟基-3-苯氧基-丙基)-4-哌啶基]-N-[(反式)-2-苯基环丙基]氨基甲酸叔丁基酯(260mg,557.21umol,1.00当量),然后将混合物在-70℃搅拌1.5小时。在-70℃将TEA(845mg,8.36mmol,1.16mL,15.00当量)在DCM(0.5mL)中的溶液添加至该溶液中,将其在-70~-15℃搅拌30min。在完成之后,将混合物用水(10mL)淬灭,用DCM(2x 10mL)萃取,将合并的有机相用1N HCl(10mL)、饱和NaHCO3水溶液(10mL)、盐水(10mL)洗涤,干燥并浓缩,得到粗产物。得到化合物N-[1-(2-氧代-3-苯氧基-丙基)-4-哌啶基]-N-[(反式)-2-苯基环丙基]氨基甲酸叔丁基酯(240mg,479umol,86.12%产率,92.9%纯度),其为黄色固体。LCMS[M+1]:465.4。
步骤2.N-[1-(2-羟基-2-甲基-3-苯氧基-丙基)-4-哌啶基]-N-[(1S,2R)-2-苯基
环丙基]氨基甲酸叔丁基酯(15)。
在0℃向N-[1-(2-氧代-3-苯氧基-丙基)-4-哌啶基]-N-[(反式)-2-苯基环丙基]氨基甲酸叔丁基酯(240mg,516umol,1.00当量)在THF(3.00mL)中的溶液滴加CH3MgBr(3M,344uL,2.00当量),然后将混合物在0~20℃搅拌3小时。在完成之后,将混合物用水(5mL)淬灭,用EA(20mL)稀释,用饱和NaHCO3水溶液(10mL)、盐水(10mL)洗涤。将有机相经Na2SO4干燥,过滤,并在真空下浓缩。得到化合物15(240mg,499umol,96%产率),其为黄色固体,其不经进一步纯化就直接用于后续步骤。LCMS[M+1]:481.2。
步骤3.2-甲基-1-苯氧基-3-[4-[[(1S,2R)-2-苯基环丙基]氨基]-1-哌啶基]丙-
2-醇(16)。
在20℃一次性向N-[1-(2-羟基-2-甲基-3-苯氧基-丙基)-4-哌啶基]-N-[(反式)-2-苯基环丙基]氨基甲酸叔丁基酯(240mg,499umol,1.00当量)在DCM(4.00mL)中的混合物添加TFA(569mg,4.99mmol,369uL,10.0当量),然后将混合物在相同的温度搅拌1小时。在完成之后,将饱和NaHCO3水溶液(20mL)添加至混合物中,将混合物用DCM(3×20mL)萃取。将合并的有机相用盐水洗涤,干燥并在真空下浓缩。将残留物通过制备性HPLC纯化(仪器:GX-D;柱:Boston Green ODS 150*30 5u;条件:水(0.225%FA)-ACN;开始B:6;结束B:36,梯度时间(min):11;100%B保持时间(min):4;流速(ml/min):25),得到16,其为无色固体。LCMS[M+1]:381.1。
1H NMR(400MHz,甲醇-d4)δ=7.28-7.21(m,4H),7.11(d,J=7.2Hz,1H),7.01(d,J=7.2Hz,2H),6.93-6.90(m,3H),3.86-3.84(d,J=7.2Hz,1H),3.80-3.78(d,J=9.2Hz,1H),2.95-2.88(m,2H),2.58-2.54(m,1H),2.49(s,2H),2.29-2.22(m.,3H),1.89-1.79(m,3H),1.46-1.40(m,2H),1.25(s,3H),1.07-0.97(m,3H)
实施例6
1-苯氧基-3-[3-[[[(反式)-2-苯基环丙基]氨基]甲基]氮杂环丁烷-1-基]丙-2-醇(19)
步骤1.N-[[1-(2-羟基-3-苯氧基-丙基)氮杂环丁烷-3-基]甲基]-N-[(反式)-2-苯基环丙基]氨基甲酸叔丁基酯(18)。
向N-(氮杂环丁烷-3-基甲基)-N-[(反式)-2-苯基环丙基]氨基甲酸叔丁基酯(100mg,331umol,1.00当量)在MeCN(3.00mL)中的溶液添加2-(苯氧基甲基)氧杂环丙烷2(74.5mg,496umol,67.1uL,1.50当量)和K2CO3(45.7mg,331umol,1.00当量)。将混合物在80℃搅拌12小时。在完成之后,将混合物过滤并将滤液在真空下浓缩。将水(10mL)和HCl(1M,1mL)添加至混合物中。将所得混合物用DCM(3×20mL)萃取,将合并的有机相在真空下浓缩,得到化合物18(200mg,粗品),其为黄色油状物。所述粗品直接用于后续步骤。LCMS[M+1]:453。
步骤2.1-苯氧基-3-[3-[[[(反式)-2-苯基环丙基]氨基]甲基]氮杂环丁烷-1-基]
丙-2-醇(19)。
将N-[[1-(2-羟基-3-苯氧基-丙基)氮杂环丁烷-3-基]甲基]-N-[(反式)-2-苯基环丙基]氨基甲酸叔丁基酯(200mg,442umol,1.00当量)和TFA(50.4mg,442umol,32.7uL,1.00当量)在DCM(3.00mL)中的溶液在20℃搅拌1小时。在完成之后,将饱和NaHCO3水溶液(10mL)添加至混合物中,将混合物用DCM(3×20mL)萃取。合并的有机相在真空下浓缩。残留物通过制备性HPLC纯化(仪器:GX-D;柱:Boston Green ODS 150*305u;条件:水(0.225%FA)-ACN;开始B:6;结束B:36,梯度时间(min):11;100%B保持时间(min):4;流速(ml/min):25),得到1-苯氧基-3-[3-[[[(反式)-2-苯基环丙基]氨基]甲基]氮杂环丁烷-1-基]丙-2-醇(25.0mg,71.0umol,16.1%产率),其为黄色固体。LCMS[M+1]:353。
1H NMR(400MHz,甲醇-d4)δ=8.33(br.s,1H),7.30-7.22(m,4H),7.13(m,1H),7.08-7.06(m,2H),6.95-6.93(m,3H),4.24(br.s.,2H),4.14(br.s.,1H),4.01-3.95(m,4H),3.52-3.32(m,2H),3.13-3.07(m,3H),2.42(br.s.,1H),1.99(br.s.,1H),1.15-1.07(m,2H)
实施例7
(R)-1-苯氧基-3-(4-(((1S,2R)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇(23)
步骤1.(2R)-2-(苯氧基甲基)氧杂环丙烷(21)。
在20℃一次性向苯酚(1.00g,10.6mmol,935uL,1.00当量)在CH3CN(20.0mL)中的溶液添加K2CO3(4.41g,31.9mmol,3.00当量),然后添加(2R)-2-(氯甲基)氧杂环丙烷(1.97g,21.26mmol,1.67mL,2.00当量),然后将混合物加热至70~80℃并搅拌8小时。在完成之后,过滤混合物。将滤液在减压下浓缩,得到粗产物,其经柱色谱法纯化(PE/EA=50:1~20:1)。得到化合物(2R)-2-(苯氧基甲基)氧杂环丙烷(1.12g,7.35mmol,69%产率,98.5%纯度),其为无色油状物。
步骤2.N-[1-[(2R)-2-羟基-3-苯氧基-丙基]-4-哌啶基]-N-[(反式)-2-苯基环丙
基]氨基甲酸酯(22)。
在20℃一次性向(2R)-2-(苯氧基甲基)氧杂环丙烷(100mg,666umol,1.00当量)和N-[(反式)-2-苯基环丙基]-N-(4-哌啶基)氨基甲酸叔丁基酯(211mg,666umol,1.00当量)在CH3CN(5.0mL)中的溶液添加K2CO3(184mg,1.33mmol,2.00当量),然后将混合物加热至80℃并搅拌18小时。在完成之后,将混合物过滤,并将滤液浓缩,得到粗产物,其经柱色谱法纯化(PE/EA=5:1~2:1)。得到化合物22(200mg,407umol,61%产率),其为无色油状物。LCMS[M+1]:467.2。
步骤3.(2R)-1-苯氧基-3-[4-[[(反式)-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇
(23)。
在20℃一次性向22(200mg,428umol,1.00当量)在DCM(4.00mL)中的混合物添加TFA(831mg,7.28mmol,540uL,10.0当量),然后将混合物在相同的温度搅拌1小时。在完成之后,将饱和NaHCO3水溶液(20mL)添加至混合物中,将混合物用DCM(3×20mL)萃取。将合并的有机相用盐水洗涤,干燥并在真空下浓缩。残留物通过制备性HPLC纯化(仪器:GX-D;柱:Boston Green ODS 150*305u;条件:水(0.225%FA)-ACN;开始B:6;结束B:36,梯度时间(min):11;100%B保持时间(min):4;流速(ml/min):25),得到(2R)-1-苯氧基-3-[4-[[(反式)-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇23(90.8mg,185umol,43.2%产率,98.0%纯度),其为黄色固体。LCMS[M+1]:367.1。
1H NMR(400MHz,DMSO-d6)δ=7.30-7.22(m,4H),7.20-7.11(m,1H),7.03-7.01(m,2H),6.94-6.92(d,J=7.8Hz,3H),4.78-4.77(d,1H),3.97-3.94(m,1H),3.93-3.87(m,1H),3.85-3.81(m,1H),2.90-2.72(m,2H),2.45-2.36(m,1H),2.34(br.s.,2H),2.24-2.16(m,1H),2.08-1.94(m,2H),1.82-1.67(m,3H),1.41-1.19(m,2H),0.96-0.92(m,2H)。
实施例8
(S)-1-苯氧基-3-(4-(((1S,2R)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇(27)
遵循实施例7的一般操作,化合物27制备自化合物24。
步骤1.(2S)-2-(苯氧基甲基)氧杂环丙烷(25)。
在完成之后,将混合物过滤并将滤液浓缩,得到粗产物,其经柱色谱法纯化(PE/EA=50:1~20:1)。得到化合物25(1.12g,7.35mmol,69%产率,98.5%纯度),其为无色油状物。LCMS[M+1]:150。
步骤2.N-[1-[(2S)-2-羟基-3-苯氧基-丙基]-4-哌啶基]-N-[(反式)-2-苯基环丙
基]氨基甲酸叔丁基酯(26)。
得到化合物26(360mg,772umol,58%产率),其为无色油状物。LCMS[M+1]:467。
步骤3.(2S)-1-苯氧基-3-[4-[[(反式)-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇
(27)
残留物通过制备性HPLC纯化(仪器:GX-D;柱:Boston Green ODS150*305u;条件:水(0.225%FA)-ACN;开始B:6;结束B:36,梯度时间(min):11;100%B保持时间(min):4;流速(ml/min):25),得到(2S)-1-苯氧基-3-[4-[[(反式)-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇(27)(179mg,371umol,51%产率,99.7%纯度),其为黄色固体。LCMS[M+1]:367。
1H NMR(400MHz,DMSO-d6)δ=7.30-7.20(m,4H),7.12-7.08(m,1H),7.03-7.01(m,2H),6.94-6.92(d,J=7.6Hz,3H),4.79-4.78(m,1H),3.99-3.93(m,1H),3.93-3.87(m,1H),3.86-3.80(m,1H),2.90-2.72(m,2H),2.45-2.36(m,1H),2.34(br.s.,2H),2.24-2.16(m,1H),2.08-1.94(m,2H),1.82-1.67(m,3H),1.33-1.25(m,2H),0.95-0.93(m,2H)
实施例9
1-苯氧基-3-[(1R,5S)-6-[[(反式)-2-苯基环丙基]氨基]-3-氮杂二环[3.1.1]庚-3-基]丙-2-醇(31)。
步骤1.N-[(5S)-3-苄基-3-氮杂二环[3.1.1]庚-6-基]-N-[(反式)-2-苯基环丙
基]氨基甲酸叔丁基酯(29)。
向3-苄基-N-(2-苯基环丙基)-3-氮杂二环[3.1.1]庚-6-胺(50.0mg,157umol,1.00当量)在MeOH(2.00mL)中的溶液添加(Boc)2O(343mg,1.57mmol,361uL,10.0当量)。将混合物在50℃搅拌15小时。在完成之后,将混合物在真空下浓缩。将残留物通过硅胶色谱法纯化(PE/EA从100/1至5/1),得到N-[(5S)-3-苄基-3-氮杂二环[3.1.1]庚-6-基]-N-[(反式)-2-苯基环丙基]氨基甲酸叔丁基酯29(50.0mg,119umol,76.1%产率),其为黄色油状物。LCMS[M+1]:419。
步骤2.(5S)-N-[(反式)-2-苯基环丙基]-3-氮杂二环[3.1.1]庚-6-胺(30)。
向29(50.0mg,119umol,1.00当量)和K2CO3(144mg,1.43mmol,12.0当量)在DCM(3.00mL)中的溶液添加氯甲酸1-氯乙基酯(51.2mg,358umol,3.00当量)。在20℃搅拌1.5小时之后,将反应混合物过滤。将滤液在真空下浓缩。将残留物溶解在MeOH(3.00mL)中。将溶液回流(65℃)2小时。在完成之后,将混合物过滤并在真空下浓缩,得到(5S)-N-[(反式)-2-苯基环丙基]-3-氮杂二环[3.1.1]庚-6-胺30(27.0mg,粗品),其为黄色油状物。将粗物质直接用于后续步骤。
步骤3.1-苯氧基-3-[(1R,5S)-6-[[(反式)-2-苯基环丙基]氨基]-3-氮杂二环
[3.1.1]庚-3-基]丙-2-醇(31)。
在N2下将30(27.0mg,118.umol,1.00当量)、2-(苯氧基甲基)氧杂环丙烷(26.6mg,177umol,24.0uL,1.50当量)和K2CO3(32.7mg,237umol,2.00当量)在MeCN(5.00mL)中的混合物在80℃搅拌2小时。在完成之后,将混合物在真空下浓缩并通过制备性HPLC纯化(仪器:GX-B;柱:Welch Ultimate AQ-C18150*30mm*5um;条件:水(0.1%TFA)-ACN;开始B:22;结束B:52;梯度时间(min):12;100%B保持时间(min):2;流速(ml/min):25),得到1-苯氧基-3-[(1R,5S)-6-[[(反式)-2-苯基环丙基]氨基]-3-氮杂二环[3.1.1]庚-3-基]丙-2-醇31(2.80mg,7.07umol,8.92%产率,95.6%纯度),其为黄色油状物。LCMS[M+1]:379。
1H NMR(400MHz,甲醇-d4)δ=7.32-7.26(m,4H),7.24-7.22(m,1H),7.18-7.16(m,2H),6.96-6.94(m,3H),4.41(d,J=6.8Hz,1H),4.06-4.00(m,4H),3.76(br.s.,3H),3.53-3.48(m,2H),3.01(br.s.,1H),2.85(br.s.,3H),2.50(d,J=3.2Hz,1H),2.15-2.12(m,1H),1.56-1.51(m,1H),1.42-1.36(m,1H)。
实施例10
(反式)-N-[[1-(2-苯氧基乙基)氮杂环丁烷-3-基]甲基]-2-苯基-环丙胺(35)
步骤1.2-溴乙氧基苯(33).
将苯酚(200mg,2.13mmol,187uL,1.00当量)、1,2-二溴乙烷(2.40g,12.8mmol,962uL,6.00当量)和K2CO3(1.76g,12.8mmol,6.00当量)在丙酮(200mL)中的混合物在80℃在N2下搅拌15小时。在完成之后,将混合物过滤并将滤液在真空下浓缩。残留物通过制备性TLC纯化(PE/EA 10/1),得到2-溴乙氧基苯(160mg,738umol,35%产率,92.8%纯度),其为无色油状物。
1H NMR(400MHz,甲醇-d4)δ=7.29-7.25(m,2H),6.94-6.91(m,3H),4.30-4.27(m,2H),3.69-3.63(m,2H)。
步骤2.N-[[1-(2-苯氧基乙基)氮杂环丁烷-3-基]甲基]-N-[(反式)-2-苯基环丙
基]氨基甲酸叔丁基酯(34)。
将33(66.5mg,331umol,1.00当量)、17(100mg,331umol,1.00当量)和Cs2CO3(215mg,661umol,2.00当量)在MeCN(2.00mL)中的混合物在80℃在N2下搅拌2小时。在完成之后,将混合物过滤并将滤液在真空下浓缩,得到N-[[1-(2-苯氧基乙基)氮杂环丁烷-3-基]甲基]-N-[(反式)-2-苯基环丙基]氨基甲酸叔丁基酯34(150mg,粗品),其为黄色油状物。LCMS[M+1]:423。
步骤3.(反式)-N-[[1-(2-苯氧基乙基)氮杂环丁烷-3-基]甲基]-2-苯基-环丙胺
(35)。
将34(139mg,329umol,1.00当量)和TFA(375mg,3.29mmol,244uL,10.00当量)在DCM(2.00mL)中的混合物在10℃搅拌1小时。将混合物在真空下浓缩并通过制备性HPLC纯化(仪器:GX-E;柱:Phenomenex Synergi C18150*30mm*4um;条件:水(0.05%HCl)-ACN;开始B:16;结束B:36;梯度时间(min):7.8;100%B保持时间(min):2;流速(ml/min):25),得到(反式)-N-[[1-(2-苯氧基乙基)氮杂环丁烷-3-基]甲基]-2-苯基-环丙胺35(23.0mg,67.5umol,21%产率,94.6%纯度),其为白色固体。LCMS[M+1]:323。
1H NMR(400MHz,甲醇-d4)δ=7.35-7.29(m,4H),7.24-7.18(m,3H),7.01-6.97(m,3H),4.43(br.S.,2H),4.33-4.25(m,4H),3.70-3.57(m,4H),3.44-3.40(m,1H),3.01-3.00(d,J=3.2Hz,1H),2.61-2.58(m,1H),1.63-1.59(m,1H),1.43-1.29(m,1H)。
实施例11
(反式)-N-[[1-(3-苯氧基丙基)氮杂环丁烷-3-基]甲基]-2-苯基-环丙胺(38)
步骤1.3-溴丙氧基苯(36).
将苯酚(200mg,2.13mmol,187uL,1.00当量)、1,3-二溴丙烷(2.57g,12.8mmol,1.30mL,6.00当量)和K2CO3(1.76g,12.8mmol,6.00当量)在丙酮(200mL)中的混合物在80℃在N2下搅拌15小时。在完成之后,将混合物过滤并将滤液在真空下浓缩。残留物通过制备性TLC纯化(PE/EA10/1),得到3-溴丙氧基苯(260mg,1.21mmol,57%产率),其为无色油状物。
1H NMR(400MHz,甲醇-d4)δ=7.28-7.23(m,2H),6.93-6.90(m,3H),4.10-4.07(t,J=3.6Hz,2H),3.63-3.60(t,J=6.4Hz,2H),2.31-2.24(m,2H)。
步骤2.N-[[1-(3-苯氧基丙基)氮杂环丁烷-3-基]甲基]-N-[(反式)-2-苯基环丙
基]氨基甲酸叔丁基酯(37)。
将36(71.1mg,331umol,1.00当量)、17(100mg,331umol,1.00当量)和Cs2CO3(215mg,661umol,2.00当量)在MeCN(2.00mL)中的混合物在80℃在N2下搅拌2小时。在完成之后,将混合物过滤并将滤液在真空下浓缩,得到N-[[1-(3-苯氧基丙基)氮杂环丁烷-3-基]甲基]-N-[(反式)-2-苯基环丙基]氨基甲酸叔丁基酯37(200mg,粗品),其为黄色油状物。LCMS[M+1]:437。
步骤3.(反式)-N-[[1-(3-苯氧基丙基)氮杂环丁烷-3-基]甲基]-2-苯基-环丙胺
(38)。
将37(144mg,330umol,1.00当量)和TFA(376mg,3.30mmol,244uL,10.0当量)在DCM(2.00mL)中的混合物在10℃搅拌1小时。在完成之后,将混合物在真空下浓缩。残留物通过制备性HPLC纯化(仪器:GX-E;柱:Phenomenex Synergi C18150*30mm*4um;条件:水(0.05%HCl)-ACN;开始B:20;结束B:40;梯度时间(min):7.8;100%B保持时间(min):2;流速(ml/min):28),得到(反式)-N-[[1-(3-苯氧基丙基)氮杂环丁烷-3-基]甲基]-2-苯基-环丙胺38(10.0mg,29.0umol,9%产率,97.4%纯度),其为无色油状物。LCMS[M+1]:337。
1H NMR(400MHz,甲醇-d4)δ=7.32-7.18(m,7H),6.96-6.94(m,3H),4.30-4.29(m,3H),4.10-4.07(m,3H),3.67-3.58(m,2H),3.50-3.48(m,2H),3.39(m,1H),3.00-2.99(m,1H),2.60(br.s.,1H),2.09-2.07(d,J=6Hz,2H),1.64-1.58(m,1H),1.42-1.37(m,1H)
实施例12
1-[2-(4-溴苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺
步骤1.1-溴-4-(2-溴乙氧基)苯(40).
向4-溴苯酚(10.0g,57.8mmol,1.00当量)和1,2-二溴乙烷(65.2g,347mmol,26.2mL,6.00当量)在丙酮(200mL)中的溶液添加K2CO3(47.9g,347mmol,6.00当量)。将混合物在80℃搅拌15小时。在完成之后,将混合物过滤并在真空下浓缩。将残留物溶解在水(50mL)中并用DCM(2×100mL)萃取。将合并的有机相用盐水(80mL)洗涤,用无水Na2SO4干燥,过滤并在真空下浓缩,得到1-溴-4-(2-溴乙氧基)苯(13.0g,粗品),其为浅棕色固体。所述粗品直接用于后续步骤。
步骤2.1-[2-(4-溴苯氧基)乙基]哌啶-4-酮(41)。
向40(8.00g,28.6mmol,1.00当量)和哌啶-4-酮(7.75g,57.2mmol,2.00eq,HCl)在MeCN(120mL)中的混合物添加Cs2CO3(18.6g,57.2mmol,2.00当量)。将混合物在80℃在N2下搅拌15小时。在完成之后,将混合物过滤并将滤液在真空下浓缩。残留物通过硅胶色谱法纯化(PE/EA从10/1至1/1),得到1-[2-(4-溴苯氧基)乙基]哌啶-4-酮41(6.30g,16.5mmol,58%产率,78.0%纯度),其为黄色油状物。LCMS[M+1]:299。
步骤3.1-[2-(4-溴苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺(43)。
在-10℃向41(269mg,901umol,1.20当量)和(1R,2S)-2-苯基环丙胺42(100mg,751umol,1.00当量)在MeOH(3.00mL)中的溶液添加AcOH(45.1mg,751umol,42.9uL,1.00当量)。在搅拌1小时之后,将NaBH3CN(142mg,2.25mmol,3.00当量)添加至混合物中。将混合物在-10℃搅拌1小时。在完成之后,将混合物倒入饱和NH4Cl水溶液(20mL)中。将所得混合物用DCM(2×30mL)萃取。将合并的有机相在真空下浓缩,然后通过制备性HPLC纯化(仪器:gx-l;柱:Agela DuraShell 150mm_25mm_5um;条件:水(0.05%氢氧化铵v/v)-ACN;开始B:55;结束B:85;梯度时间(min):10;100%B保持时间(min):3;流速(ml/min):25),得到1-[2-(4-溴苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺43(44.0mg,96.2umol,13%产率,90.8%纯度),其为黄色油状物。LCMS[M+1]:417。
1H NMR(400MHz,甲醇-d4)δ=7.38-7.36(d,J=8.4Hz,2H),7.26-7.20(m,2H),7.12-7.11(m,1H),7.04-7.02(d,J=7.6Hz,2H),6.87-6.84(d,J=8.8Hz,2H),4.10-4.07(t,J=5.6Hz,2H),3.03-3.00(d,J=11.6Hz,2H),2.79-2.76(t,J=5.6Hz,2H),2.66(m,1H),2.31-2.30(m,1H),2.21-2.15(t,J=12.7Hz,2H),1.93-1.87(m,3H),1.53-1.48(m,2H),1.07-1.01(m,2H)。
实施例13
1-(3-苯氧基丙基)-N-((反式)-2-苯基环丙基)哌啶-4-胺(46)
方案13
步骤1.1-(3-苯氧基丙基)哌啶-4-酮(45)。
将苯氧基丙基溴(44)(0.3mL,1.90mmol,d=1.365)、哌啶酮盐酸盐水合物(0.44g,2.86mmol)、K2CO3(1.05g,7.62mmol)、无水Na2SO4(0.54g,3.81mmol)和KI(47mg,0.286mmol)在MeCN(20mL)中的悬浮液在回流条件下搅拌2.5小时,将混合物冷却至室温,用水稀释并用EA萃取。将萃取物经Na2SO4干燥,过滤,浓缩并将残留物通过快速柱色谱法纯化(洗脱剂5%MeOH/EA),得到标题化合物45(0.45g,定量产率),其为油状物。
1H NMR:500MHz,CDCl3,δ(ppm):7.30-7.26(m,2H),6.96-6.90(m 3H),4.06(t,J=6.3Hz,2H),2.78(t,J=6.1Hz,4H),2.66(t,J=7.1Hz,2H),2.46(t,J=6.8Hz,4H),2.04-1.99(m,2H)。MS:233.3(计算值),234.1(M+H+,实测值)。
步骤2.1-(3-苯氧基丙基)-N-((反式)-2-苯基环丙基)哌啶-4-胺(46)
将酮45(0.49g,2.10mmol)和(反式)-2-苯基环丙胺盐酸盐(0.43g,2.52mmol)在DCE(15mL)中的悬浮液在室温搅拌2.0小时,冷却至0℃,然后用硼氢化物(0.80g,7.78mmol)处理。历时4小时将混合物温热至室温并搅拌,用DCM稀释并用浓NaHCO3溶液洗涤。将有机相进一步用盐水洗涤,经无水Na2SO4干燥,过滤,浓缩并通过快速色谱法纯化(洗脱剂5然后10%MeOH/DCM)(MeOH含有2%氨)形成标题化合物46(0.29g,39%产率),其为蜂蜜状物质。
1H NMR:500MHz,CD3OD,δ(ppm):7.29-7.23(m,4H),7.16-7.05(m,1H),7.08-7.05(m,2H),6.94-6.90(m,3H),4.03(t,J=6.2Hz,2H),3.02(bd,J=11.7,2H),2.73-2.67(m,1H),2.60-2.57(m,2H),2.36-2.33(m,1H),2.16-2.10(m,2H),2.03-1.90(m,5H),1.56-1.48(m,2H),1.11-1.03(m,2H)。MS:350.5(计算值),351.1(M+H+,实测值)。
实施例14
1-(2-苯氧基乙基)-N-((反式)-2-苯基环丙基)哌啶-4-胺(49)
方案14
步骤1.1-(2-苯氧基乙基)哌啶-4-酮(48)。
将苯氧基乙基溴(47)(0.30g,1.49mmol)、哌啶酮盐酸盐水合物(0.34g,2.24mmol)、K2CO3(0.83g,5.97mmol)、无水Na2SO4(0.42g,2.98mmol)和KI(37mg,0.224mmol)在MeCN(15mL)中的悬浮液在回流条件下搅拌2.5小时,将混合物冷却至室温,用水稀释并用EA萃取。将萃取物经Na2SO4干燥,过滤,浓缩并对残留物实施快速色谱法(洗脱剂5%MeOH/DCM),得到标题化合物48(0.20g,60%产率),其为液体。
1H NMR:500MHz,CDCl3,δ(ppm):7.31-7.28(m,2H),6.98-6.91(m 3H),4.15(t,J=5.6Hz,2H),2.95(t,J=5.6Hz,2H),2.91(t,J=6.1Hz,4H),2.49(t,J=6.3Hz,4H)。MS:219.3(计算值),219.9(M+H+,实测值)。
步骤2.1-(2-苯氧基乙基)-N-((反式)-2-苯基环丙基)哌啶-4-胺(49)
将酮48(0.19g,0.866mmol)和(反式)-2-苯基环丙胺盐酸盐(0.18g,1.04mmol)在DCE(10mL)中的悬浮液在室温搅拌2.0小时,冷却至0℃,然后用硼氢化物(0.33g,1.56mmol)处理。历时4小时将混合物温热至室温并搅拌。然后将混合物用DCM稀释并用浓NaHCO3溶液洗涤。将有机相进一步用盐水洗涤,经无水Na2SO4干燥,过滤,浓缩并通过快速色谱法纯化(洗脱剂5然后10%MeOH/DCM)(MeOH含有2%氨),得到标题化合物49(0.19g,65%产率),其为蜂蜜状物质。
1H NMR:500MHz,CD3OD,δ(ppm):7.30-7.23(m,4H),7.16-7.12(m,1H),7.07-7.05(m,2H),6.96-6.92(m,3H),4.14(t,J=5.7Hz,2H),3.07(bd,J=12.2,2H),2.83(t,J=5.6Hz,2H),2.73-2.67(m,1H),2.36-2.33(m,1H),2.27-2.19(m,2H),2.01-1.90(m,3H),1.58-1.50(m,2H),1.11-1.03(m,2H)。MS:336.5(计算值),337.1(M+H+,实测值)。
实施例15
2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸二-盐酸盐(56)
方案15
步骤1.2-(4-(2-溴乙氧基)苯基)乙酸甲基酯(51)。
将2-(4-羟基苯基)乙酸甲基酯(50)(5.0g,30.1mmol)、1,2-二溴乙烷(16mL,186mmol,d=2.18)、K2CO3(11.50g,84.4mmol)和KI(200mg,1.20mmol)在MeCN(90mL)中的悬浮液在回流条件下搅拌24小时。将混合物用水稀释并用EA萃取。将萃取物经无水Na2SO4干燥,过滤并在40℃真空浓缩。将所得油状物进一步在60℃保持在较高真空中以尽可能地除去过量的二溴乙烷,然后通过快速色谱法纯化(洗脱剂DCM-己烷(1:1),然后EA-己烷(8:17)),得到标题化合物51(5.05g,62%产率)。
1H NMR:500MHz,CDCl 3,δ(ppm):7.20(d,J=8.7Hz,2H),6.87(d,J=8.7Hz,2H),4.28(t,J=6.3Hz,2H),3.69(s,3H),3.63(t,J=6.3Hz,2H),3.53(s,2H)。
步骤2.2-(4-(2-(4-氧代哌啶-1-基)乙氧基)苯基)乙酸甲基酯(52)。
将溴化物51(5.05g,18.49mmol)、哌啶酮盐酸盐水合物(4.54g,29.6mmol)、K2CO3(10.22g,74.0mmol)、无水Na2SO4(5.25g,37.0mmol)和KI(153mg,0.924mmol)在MeCN(100mL)中的悬浮液在回流条件下搅拌18小时,将混合物冷却至室温,用水稀释并用EA萃取。将萃取物经Na2SO4干燥,过滤并浓缩。残留物通过快速色谱法纯化(洗脱剂10%MeOH/DCM)(MeOH含有2%氨),得到标题化合物52(5.19g,96%产率),其为油状物。
1H NMR:500MHz,CD3OD,δ(ppm):7.19(d,J=8.7Hz,2H),6.87(d,J=8.7Hz,2H),4.13(t,J=5.6Hz,2H),3.68(s,3H),3.56(s,2H),2.93(t,J=5.6Hz,2H),2.89(t,J=6.1Hz,4H),2.48(t,J=6.2Hz,4H)。MS:291.3(计算值),292.0(M+H+,实测值)。
步骤3.2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙
酸甲基酯(53)。
将酮52(2.5g,8.58mmol)、(1R,2S)-2-苯基环丙胺(2R,3R)-酒石酸盐(3.16g,11.16mmol)和数滴6N HCl溶液在溶剂混合物DCE(10mL)和DCM(5mL)中的悬浮液在室温搅拌3.0小时,冷却至0℃,然后用硼氢化物(3.27g,15.45mmol)处理。历时14小时将混合物温热至室温并搅拌。然后将混合物用DCM稀释并用NaHCO3溶液洗涤。将有机相用盐水洗涤,经无水Na2SO4干燥,过滤,浓缩并通过快速色谱法纯化(洗脱剂10%MeOH/DCM)(MeOH含有2%氨),得到标题化合物53(1.65g,47%产率),其为蜂蜜状物质,估计的纯度约为90%。将所述物质不经另外纯化就用于后续步骤。MS:408.5(计算值),409.0(M+H+,实测值)。
步骤4.2-(4-(2-(4-((叔丁氧基羰基)((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)
乙氧基)苯基)乙酸甲基酯(54)。
向胺53(1.65g,4.04mmol)在DCM(20mL)中的溶液添加TEA(1.69mL,12.12mmol,d=0.726)。将混合物通过冰浴冷却,然后用Boc-酸酐(1.763g,8.08mmol)在DCM(20mL)中的溶液处理。将混合物在0-5℃搅拌30min,然后在环境温度搅拌4小时,用DCM稀释,用稀释的盐水洗涤,经无水Na2SO4干燥,过滤并浓缩。残留物通过快速色谱法纯化(洗脱剂EA-己烷(1:1)),得到标题化合物54(1.50g,73%产率),其为蜂蜜状物质。所述物质含有一些残留EA。
1H NMR:500MHz,CD3OD,δ(ppm):7.29-7.25(m,2H),7.22-7.14(m,5H),6.91(d,J=8.7Hz,2H),4.13(t,J=5.6Hz,2H),3.78-3.71(m,1H),3.69(s,3H),3.60(s,2H),3.17-3.09(m,2H),2.82(t,J=5.6Hz,2H),2.64-2.61(m,1H),2.28-2.12(m,4H),2.06-2.03(m,1H),1.85-1.82(m,1H),1.78-1.75(m,1H),1.46-1.42(m,10H),1.28-1.24(m,1H)。MS:508.7(计算值),509.2(M+H+,实测值)。
步骤5.2-(4-(2-(4-((叔丁氧基羰基)((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)
乙氧基)苯基)乙酸(55)。
向酯54(1.50g,2.95mmol)在70%EtOH水溶液(35mL)中的溶液添加LiOH x H2O(0.25g,5.90mmol)在水(9mL)中的溶液。将反应混合物在室温搅拌1小时,用HCl酸化至pH5-6,然后最大程度地蒸发。将残留物用盐水处理并用DCM萃取。将萃取物经无水Na2SO4干燥,过滤并将滤液蒸发形成泡沫体,将其真空干燥过夜,得到标题化合物55(1.42g,97%产率)。将所述物质不另外纯化就用于后续步骤。MS:494.6(计算值),495.2(M+H+,实测值)。
步骤6.2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙
酸二-盐酸盐(56)
在室温将HCl在二噁烷(2ml,8.00mmol)中的4M溶液添加至化合物55(0.200g,0.404mmol)在二噁烷(2mL)中的悬浮液,并将反应混合物在环境温度搅拌3小时。将混合物蒸发至干,并将所得白色析出物用MeOH和丙酮的混合物研磨,通过过滤收集并干燥,得到标题化合物56(0.17g,90%产率),其为白色固体。
1H NMR:500MHz,DMSO-d6,δ(ppm):12.25(bs,1H),10.74(bs,1H),9.99(bs,2H),7.32-7.29(m,2H),7.24-7.18(m,5H),6.94(d,J=8.6Hz,2H),4.37(bt,2H),3.66(bs,2H),3.50(s,2H),3.46(bs,3H),3.46(bs,2H),2.96(bs,1H),2.58-2.54(m,1H),2.31(bs,2H),2.10(bs,2H),1.60-1.56(m,1H),1.31-1.27(m,1H)。MS:394.5(计算值),395.0(M+H+,实测值)。
实施例16和17
N-(甲基磺酰基)-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酰胺二-盐酸盐(58)和
2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)-N-(苯基磺酰基)乙酰胺二-盐酸盐(60)
方案16
步骤1.(1-(2-(4-(2-(甲基磺酰氨基)-2-氧代乙基)苯氧基)乙基)哌啶-4-基)
((1R,2S)-2-苯基环丙基)氨基甲酸叔丁基酯(57)。
在0℃向酸55(200mg,0.404mmol)在DCM(5mL)中的溶液添加CDI(72mg,0.445mmol)。将反应混合物在0℃搅拌5min,然后在环境温度再搅拌1小时。向混合物添加甲基磺酰胺(42mg,0.445mmol)和DBU(0.121mL,0.809mmol,d=1.018)。将合并的混合物搅拌过夜,用更多DCM稀释并先后用10%NaH2PO4水溶液和盐水洗涤。将有机相经Na2SO4干燥,过滤并蒸发。将残留物通过快速色谱法纯化(洗脱剂10然后15%MeOH/DCM)(MeOH含有2%氨),得到标题化合物57(0.208mg,90%产率),其为灰白色固体。
1H NMR:500MHz,DMSO-d6,δ(ppm):7.27-7.24(m,2H),7.17-7.10(m,5H),6.88(d,J=8.7Hz,2H),4.06(t,J=5.7Hz,2H),3.61-3.54(m,1H),3.47(s,2H),3.14(s,3H),3.07-3.03(m,2H),2.77(bt,2H),2.59-2.56(m,1H),2.23-2.16(m,2H),2.08-1.99(m,2H),1.93-1.85(m,1H),1.72-1.64(m,2H),1.35-1.32(m,10H),1.22-1.18(m,1H)。MS:571.7(计算值),572.2(M+H+,实测值)。
步骤2.N-(甲基磺酰基)-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-
基)乙氧基)苯基)乙酰胺二-盐酸盐(58)。
在室温将HCl在二噁烷中的4M溶液(3ml,12mmol)添加至化合物57(205mg,0.359mmol)在二噁烷(2mL)中的溶液。将混合物在环境温度搅拌3小时,蒸发至干并将所得白色析出物用丙酮和MeOH的混合物研磨,通过过滤收集并干燥,得到标题化合物58(146mg,75%产率),其为白色固体。
1H NMR:500MHz,DMSO-d6,δ(ppm):11.92(bs,1H),10.65(bs,1H),9.91(bs,2H),7.33-7.30(m,2H),7.24-7.18(m,5H),6.96(d,J=8.6Hz,2H),4.37(bt,2H),3.67(bs,2H),3.55(s,2H),3.46(bs,3H),3.22(s,3H),3.12(bs,2H),2.97(bs,1H),2.55(bs,1H),2.30(bs,2H),2.08(bs,2H),1.57(bs,1H),1.32-1.28(m,1H)。MS:471.6(计算值),472.1(M+H+,实测值)。
步骤1.(1-(2-(4-(2-氧代-2-(苯基磺酰氨基)乙基)苯氧基)乙基)哌啶-4-基)
((1R,2S)-2-苯基环丙基)氨基甲酸叔丁基酯(59)。
在室温向酸55(200mg,0.404mmol)和苯磺酰胺(95mg,0.607mmol)在DCM(7mL)中的溶液添加EDC x HCl(155mg,0.809mmol)和DMAP(99mg,0.809mmol)。将反应混合物在相同的条件搅拌过夜,用更多DCM稀释,然后用NaHCO3溶液、水和盐水洗涤。将有机相经Na2SO4干燥,过滤并蒸发。残留物通过快速色谱法纯化(洗脱剂10%MeOH/DCM)(MeOH含有2%氨)。所述物质需要通过快速色谱法的第二纯化(洗脱剂5%MeOH(含有2%氨)/DCM),得到标题化合物59(86mg,34%产率),其为白色固体。MS:633.8(计算值),634.2(M+H+,实测值)。
步骤2.2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)-
N-(苯基磺酰基)乙酰胺二-盐酸盐(60)。
在室温将HCl在二噁烷中的4M溶液(1.0ml,4mmol)添加至化合物59(86mg,0.136mmol)在二噁烷(1.5mL)中的溶液。将混合物在环境温度搅拌3小时,蒸发至干,并将所得的白色固体用丙酮研磨,通过过滤收集,重新溶解在水中,冷冻并冻干,得到标题化合物60(59mg,72%产率),其为白色固体。
1H NMR:500MHz,DMSO-d6,δ(ppm):12.35(bs,1H),10.73(bs,1H),9.97(bs,2H),7.90-7.88(m,2H),7.72-7.69(m,1H),7.62-7.59(m,2H),7.33-7.29(m,2H),7.24-7.18(m,3H),7.11(d,J=8.7Hz,2H),6.91(d,J=8.7Hz,2H),4.35(bt,2H),3.64(bd,2H),3.50(s,2H),3.44(bs,3H),3.10(bs,2H),2.96(bs,1H),2.55(bs,1H),2.29(bs,2H),2.09(bs,2H),1.59(bs,1H),1.31-1.27(m,1H)。MS:533.7(计算值),534.2(M+H+,实测值)。
实施例18和19
N,N-二甲基-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酰胺二盐酸盐(62)和N-甲氧基-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酰胺(64)
方案17
步骤1.(1-(2-(4-(2-(二甲基氨基)-2-氧代乙基)苯氧基)乙基)哌啶-4-基)((1R,
2S)-2-苯基环丙基)氨基甲酸叔丁基酯(61)。
向酸55(200mg,0.404mmol)在DMF(4mL)中的溶液添加HOBT xH2O(124mg,0.809mmol),然后添加EDC x HCl(233mg,1.213mmol)。将反应混合物在室温搅拌2小时,然后添加Me2NH x HCl(165mg,2.200mmol),然后添加TEA(0.282mL,2.022mmol,d=0.726)。将所得的混合物搅拌过夜,然后用盐水稀释。形成粘性析出物,将其通过过滤收集并重新溶解在丙酮中。将溶液经Na2SO4干燥,过滤并浓缩。残留物通过快速色谱法纯化(洗脱剂5%MeOH/DCM)(MeOH含有2%氨),得到标题化合物61(144mg,68%产率),其为玻璃状固体。MS:521.7(计算值),522.3(M+H+,实测值)。
步骤2.N,N-二甲基-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙
氧基)苯基)乙酰胺二盐酸盐(62)。
在室温将HCl在二噁烷中的4M溶液(2ml,8mmol)添加至化合物61(144mg,0.276mmol)在二噁烷(2mL)中的溶液。将混合物在环境温度搅拌3小时,蒸发至干并将所得的微黄色粘性析出物溶解在MeOH中并过滤。将滤液几乎彻底蒸发并用过量丙酮处理。形成白色析出物,将其通过过滤收集,重新溶解在水中,冷冻并冻干,得到标题化合物62(113mg,83%产率),其为灰白色固体。
1H NMR:500MHz,DMSO-d6,δ(ppm):10.83(bs,1H),10.03(bs,2H),7.33-7.29(m,2H),7.24-7.15(m,5H),6.93(d,J=8.6Hz,2H),4.37(bt,2H),3.67(bd,2H),3.61(s,2H),3.46(bs,3H),3.14(bs,2H),2.98(s,3H),2.97(bs,1H),2.81(s,3H),2.59-2.56(m,1H),2.32(bs,2H),2.11(bs,2H),1.61-1.57(m,1H),1.31-1.26(m,1H)。MS:421.6(计算值),422.3(M+H+,实测值)。
步骤1.(1-(2-(4-(2-(甲氧基氨基)-2-氧代乙基)苯氧基)乙基)哌啶-4-基)((1R,
2S)-2-苯基环丙基)氨基甲酸叔丁基酯(63)。
向酸55(185mg,0.374mmol)在DCM(5mL)中的溶液添加TEA(0.21mL,1.496mmol,d=0.726)、EDC x HCl(143mg,0.748mmol),和NH2OMe xHCl(66mg,0.785mmol)。将混合物搅拌过夜,用DCM稀释并用稀释的盐水洗涤,经无水Na2SO4干燥,过滤并在减压下浓缩。残留物通过快速色谱法纯化(洗脱剂5%MeOH(含有2%氨)/DCM),得到标题化合物63(73mg,37%产率),其为白色泡沫状物。MS:523.7(计算值),524.2(M+H+,实测值)。
步骤2.N-甲氧基-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧
基)苯基)乙酰胺(64)。
在室温将HCl在二噁烷中的4M溶液(1.0ml,4mmol)添加至化合物63(73mg,0.139mmol)在二噁烷(1mL)中的溶液。将混合物在环境温度搅拌3小时,蒸发至干,并将所得的白色析出物用丙酮研磨,通过过滤收集,重新溶解在水中,冷冻并冻干,得到标题化合物64(67mg,93%产率),其为白色固体。
1H NMR:500MHz,DMSO-d6,δ(ppm):11.34(bs,1H),10.89(bs,1H),10.08(bs,2H),7.32-7.29(m,2H),7.24-7.18(m,5H),6.94(d,J=8.6Hz,2H),4.37(bt,2H),3.66(bd,2H),3.56(s,3H),3.45(bs,3H),3.23(s,2H),3.14(bs,2H),2.95(bs,1H),2.60-2.56(m,1H),2.32(bs,2H),2.12(bs,2H),1.62-1.58(m,1H),1.30-1.26(m,1H)。MS:423.6(计算值),424.2(M+H+,实测值)。
实施例20
1-[2-(4-吗啉代苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺(66)
方案18
步骤1.N-[1-[2-(4-溴苯氧基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨
基甲酸叔丁基酯(65)
将1-[2-(4-溴苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺(43,实施例12)(7.20g,17.3mmol,1.00当量)和(Boc)2O(7.57g,34.7mmol,7.96mL,2.00当量)在DCM(10.0mL)中的混合物在50℃搅拌5小时。在完成之后,将混合物在真空下浓缩。残留物通过硅胶色谱法纯化(PE/EA从10/1至0/1),得到N-[1-[2-(4-溴苯氧基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(6.00g,9.89mmol,57%产率,85.0%纯度),其为黄色油状物,将其通过制备性HPLC再次纯化(仪器:HPLC-A;柱:Phenomenex GeminiC18250*50mm*10um;条件:水(0.05%氢氧化铵v/v)-ACN;开始B:70;结束B:95;梯度时间(min):31,85%;100%B保持时间(min):5;流速(ml/min):80),得到N-[1-[2-(4-溴苯氧基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(1.9g纯度98.5%),其为白色固体。LCMS[M+1]:517
1H NMR(400MHz,甲醇-d4)δ=7.42-7.40(m,2H),7.24-7.22(m,2H),7.15-7.10(m,3H),6.92-6.90(m,2H),4.23-4.21(m,2H),3.82-3.79(m,1H),3.42-3.31(m,2H),3.24-3.22(m,2H),2.67-2.66(m,2H),2.59(m,1H),2.44-2.17(m,3H),2.12-2.11(m,1H),1.98-1.84(m,2H),1.40-1.38(m,9H),1.25-1.22(m,1H)
步骤2.1-[2-(4-吗啉代苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺
(66)
向N-[1-[2-(4-溴苯氧基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(100mg,194umol,1.00当量)和吗啉(33.8mg,388umol,34.1uL,2.00当量)在DMAC(1.00mL)中的溶液添加RuPhos(9.05mg,19.4umol,0.10当量)、Pd2(dba)3(8.88mg,9.70umol,0.05当量)和Cs2CO3(190mg,582umol,3.00当量)。将混合物在85℃在N2下搅拌5小时。在完成之后,将水(10mL)添加至混合物中。将所得混合物用DCM(3×20mL)萃取。将合并的有机相在真空下浓缩。残留物通过制备性TLC纯化(DCM/MeOH 20/1),得到1-[2-(4-吗啉代苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺(100mg,83.3%纯度,82.4%产率),其为黄色油状物。LCMS[M+1]:522
步骤3.1-[2-(4-吗啉代苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺
(67,实施例20)
将N-[1-[2-(4-吗啉代苯氧基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(100mg,192umol,1.00当量)和TFA(219mg,1.92mmol,142uL,10.0当量)在DCM(1.00mL)中的混合物在15℃搅拌1小时。在完成之后,将反应混合物在真空下浓缩。将残留物通过制备性HPLC纯化(仪器:LC-E;柱:Phenomenex Synergi C18 150*30mm*4um;条件:水(0.05%氢氧化铵v/v)-ACN;开始B:1;结束B:21;梯度时间(min):10.5;100%B保持时间(min):2;流速(ml/min):25)。将希望的级份收集并冻干,得到1-[2-(4-吗啉代苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺(40mg,75.34umol,39.30%产率,3HCl),其为白色固体。LCMS[M+1]:422
1H NMR(400MHz,甲醇-d4)δ=7.77(d,J=8.8Hz,2H),7.33-7.19(m,7H),4.52-4.49(m,2H),4.16-4.12(m,4H),3.87-3.67(m,9H),3.34(m,2H),3.05-3.04(m,,1H),2.60-2.59(m,1H),2.48-2.45(m,2H),2.25-2.22(m,2H),1.62-1.60(m,1H),1.45-1.29(m,1H)。
遵循本文所述的反应方案和合成路线的教导,制备以下化合物:
表1
示例性式(I)和式(II)的化合物
实施例35
(E)-3-(4-(2-羟基-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)丙烯酸(73)
步骤1.2-[(4-溴苯氧基)甲基]氧杂环丙烷
一次性地向4-溴苯酚(10.0g,57.8mmol,2.00当量)和2-(氯甲基)氧杂环丙烷(12.9g,140mmol,11.0mL,4.85当量)在MeCN(200mL)中的混合物添加K2CO3(11.9g,86.7mmol,3.00当量)。将混合物在90℃搅拌12小时。在完成之后,将混合物浓缩,用DCM(150mL)稀释,然后用H2O(150mL)洗涤。将有机相用盐水(150mL×2)洗涤,经Na2SO4干燥,过滤并浓缩。残留物通过硅胶色谱法纯化(石油醚/乙酸乙酯=100/1~50/1),得到2-[(4-溴苯氧基)甲基]氧杂环丙烷(9.10g,粗品),其为白色固体
1H NMR(400MHz,氯仿-d)δ7.46-7.36(m,1H),6.88-6.79(m,1H),4.25-4.22(m,1H),3.95-3.91(m,1H),3.41-3.31(m,1H),3.00-2.87(m,1H),2.82-2.72(m,1H)。
步骤2.N-[1-[3-(4-溴苯氧基)-2-羟基-丙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环
丙基]氨基甲酸叔丁基酯
向2-[(4-溴苯氧基)甲基]氧杂环丙烷(3.00g,13.10mmol,1.00当量)和N-[(1R,2S)-2-苯基环丙基]-N-(4-哌啶基)氨基甲酸叔丁基酯(4.56g,14.4mmol,1.10当量)在MeCN(50.0mL)中的混合物添加K2CO3(3.62g,26.2mmol,2.00当量),并将反应在85℃搅拌12小时。在完成之后,将反应添加水(80mL),然后用EA(60mL×2)萃取,将合并的有机层经Na2SO4干燥,过滤并浓缩。残留物通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=10/1-3/1),得到产物N-[1-[3-(4-溴苯氧基)-2-羟基-丙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(5.50g,9.79mmol,74.7%产率,97.1%纯度),其为黄色固体。LCMS[M+1]:545,547
1H NMR(400MHz,氯仿-d)δ7.29(d,J=8.8Hz,2H),7.24-7.17(m,2H),7.15-7.07(m,1H),7.01(d,J=7.2Hz,2H),6.73(d,J=8.8Hz,2H),4.02-3.91(m,1H),3.88-3.85(m,2H),3.70-3.39(m,2H),3.07-2.92(m,1H),2.85-2.78(m,1H),2.57-2.36(m,3H),2.35-2.21(m,1H),2.14-1.83(m,4H),1.77-1.61(m,2H),1.47-1.24(m,10H),1.21-1.14(m,1H)。
步骤3.(E)-3-[4-[3-[4-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶
基]-2-羟基-丙氧基]苯基]丙-2-烯酸酯
化合物71:向N-[1-[3-(4-溴苯氧基)-2-羟基-丙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(800mg,1.47mmol,1.00当量)和丙-2-烯酸甲基酯(470mg,5.46mmol,489uL,3.71当量)在DMF(15.0mL)中的混合物添加KOAc(158mg,1.61mmol,1.10当量)、Pd(OAc)2(32.9mg,147umol,0.10当量)和三(邻甲基苯基)磷(tris-o-tolylphosphane)(44.6mg,147umol,0.10当量),将反应在120℃搅拌12小时。在完成之后,将反应添加水(30mL),用EA(25mL×2)萃取,将合并的有机层经Na2SO4干燥,过滤并浓缩。残留物通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=10/1~1/1),得到产物(E)-3-[4-[3-[4-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]-2-羟基-丙氧基]苯基]丙-2-烯酸酯(400mg,719umol,48.9%产率,99%纯度),其为黄色油状物。LCMS[M+1]:551
步骤4.(E)-3-[4-[3-[4-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶
基]-2-羟基-丙氧基]苯基]丙-2-烯酸
向(E)-3-[4-[3-[4-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]-2-羟基-丙氧基]苯基]丙-2-烯酸甲基酯(200mg,363umol,1.00当量)在MeOH(3.00mL)和H2O(1.00mL)中的混合物添加NaOH(58.1mg,1.45mmol,4.00当量),并将反应在15℃搅拌12小时。在完成之后,将反应添加水(10mL),然后用DCM(15mL×2)萃取,将合并的有机层经Na2SO4干燥,过滤并浓缩,得到(E)-3-[4-[3-[4-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]-2-羟基-丙氧基]苯基]丙-2-烯酸(150mg,254umol,69.9%产率,90.8%纯度),其为黄色固体,其不经进一步纯化就用于后续步骤。LCMS[M+1]:537
步骤5.E)-3-[4-[2-羟基-3-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]丙氧
基]苯基]丙-2-烯酸
向(E)-3-[4-[3-[4-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]-2-羟基-丙氧基]苯基]丙-2-烯酸(150mg,279umol,1.00当量)在DCM(1.00mL)中的混合物添加TFA(1.54g,13.5mmol,1.00mL,48.3当量),将反应在15℃搅拌1小时。在完成之后,将反应混合物浓缩,用CH3CN(3mL)稀释,然后将混合物用Na2CO3固体调节至pH 6~7,将固体过滤。将滤液通过制备性HPLC纯化(仪器:GX-B;柱:Welch Ultimate AQ-C18150*30mm*5um;条件:水(0.1%TFA)-ACN;开始B:20;结束B:43;梯度时间(min):10;100%B保持时间(min):3;流速(ml/min):25),得到(E)-3-[4-[2-羟基-3-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]丙氧基]苯基]丙-2-烯酸(64.0mg,96.1umol,34.4%产率,99.8%纯度,2TFA),其为白色固体。LCMS[M+1]:437
1H NMR(400MHz,甲醇-d4)δ7.64(d,J=16.0Hz,1H),7.60-7.57(m,2H),7.39-7.31(m,2H),7.30-7.17(m,3H),7.02(d,J=8.8Hz,2H),6.37(d,J=16.0Hz,1H),4.46-4.42(m,1H),4.16-4.03(m,2H),3.88-3.84(m,2H),3.75-3.69(m,1H),3.41-3.48(m,2H),3.32-3.15(m,2H),3.03-3.01(m,1H),2.58-2.35(m,3H),2.25-2.01(m,2H),1.61-1.43(m,2H)。
实施例36
合成中间体79:
((1R,2S)-2-苯基环丙基)(哌啶-4-基)氨基甲酸叔丁基酯
化合物79制备自化合物74和42。
化合物75:向4-氧代哌啶-1-甲酸叔丁基酯(100g,502mmol,1.00当量)在二噁烷(750mL)中的混合物添加HCl/二噁烷(750mL),并将反应在15℃搅拌12小时。在完成之后,将析出的固体过滤,用二噁烷(400mL)洗涤,然后将固体在真空下干燥。得到产物哌啶-4-酮(66.0g,487mmol,97.0%产率,HCl),其为白色固体。
1H NMR(400MHz,氘氧化物)δ3.20(t,J=5.8Hz,4H),1.92(t,J=5.8Hz,4H)
化合物76:在0℃向75(66.0g,487mmol,1.00eq,HCl)在DCM(600mL)中的混合物滴加TEA(197g,1.95mol,270mL,4.00当量)和(CF3CO)2O(307g,1.46mol,203mL,3.00当量),在N2下将混合物在0-15℃搅拌12小时。在完成之后,将反应混合物用水(2×800mL)洗涤、先后用HCl水溶液(0.5N,2×800mL)、饱和NaHCO3水溶液(2×800mL)稀释,将有机层经Na2SO4干燥,过滤并浓缩。将残留物用石油醚(200mL)研磨,将析出的固体过滤并在真空下干燥,得到1-(2,2,2-三氟乙酰基)哌啶-4-酮(34.5g,177mmol,36.3%产率),其为黄色固体。
1H NMR(400MHz,氯仿-d)δ4.01-3.89(m,4H),2.62-2.56(m,4H)
化合物77:向(1R,2S)-2-苯基环丙胺(23.0g,173mmol,1.00当量)和1-(2,2,2-三氟乙酰基)哌啶-4-酮(35.4g,181mmol,1.05当量)在MeOH(500mL)中的混合物添加AcOH(31.1g,518mmol,29.6mL,3.00当量),将反应在15℃搅拌0.5小时,然后将混合物冷却至-10℃并将NaBH3CN(32.6g,518mmol,3.00当量)添加至混合物,并将混合物在-10~15℃搅拌11.5小时。在完成之后,将反应混合物添加至H2O(500mL)并浓缩。将残留物用DCM(2×400mL)萃取,将合并的有机层经Na2SO4干燥,过滤并浓缩。得到产物2,2,2-三氟-1-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]乙酮(59.2g,粗品),其为黄色固体,其不经进一步纯化就用于后续步骤。LCMS[M+1]:313
化合物78:向2,2,2-三氟-1-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]乙酮(59.2g,189mmol,1.00当量)在MeOH(200mL)中的混合物添加(Boc)2O(82.7g,379mmol,87.1mL,2.00当量)和TEA(57.5g,568mmol,78.8mL,3.00当量),将混合物在50℃搅拌12小时。在完成之后,将反应混合物浓缩。残留物通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=100/1至5/1),得到N-[(1R,2S)-2-苯基环丙基]-N-[1-(2,2,2-三氟乙酰基)-4-哌啶基]氨基甲酸叔丁基酯(42.3g,79.8mmol,42.1%产率,77.8%纯度),其为无色油状物。LCMS[M-99]:313
化合物79:向N-[(1R,2S)-2-苯基环丙基]-N-[1-(2,2,2-三氟乙酰基)-4-哌啶基]氨基甲酸叔丁基酯(40.0g,96.9mmol,1.00当量)在MeOH(200mL)和H2O(50.0mL)中的混合物添加K2CO3(53.6g,388mmol,4.00当量),将混合物在15℃搅拌12小时。在完成之后,将反应混合物添加水(500mL),然后用DCM(3×400mL)萃取,将合并的有机层经Na2SO4干燥,过滤并浓缩,得到N-[(1R,2S)-2-苯基环丙基]-N-(4-哌啶基)氨基甲酸叔丁基酯(27.3g,65.4mmol,88.9%产率,75.8%纯度),其为黄色固体。LCMS[M+1]:317。
1H NMR(400MHz,甲醇-d4)δ7.32-7.22(m,2H),7.19-7.11(m,3H),3.82-3.73(m,1H),3.16-3.03(m,2H),2.67-2.57(m,3H),2.16-2.11(m,1H),2.08-1.71(m,4H),1.46-1.39(m,10H),1.34-1.20(m,1H)。
1-[2-[(2-甲基-4-吡啶基)氧基]乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺
实施例36制备自化合物79:
化合物80:向N-[(1R,2S)-2-苯基环丙基]-N-(4-哌啶基)氨基甲酸叔丁基酯(300mg,948umol,1.00当量)和2-溴乙醇(237mg,1.90mmol,135uL,2.00当量)在MeCN(6.00mL)中的溶液添加K2CO3(262mg,1.90mmol,2.00当量)。将混合物在85℃搅拌5小时。在完成之后,将析出物过滤并将滤液在真空下浓缩。将残留物通过硅胶纯化(DCM/MeOH从100/1至10/1),并将合并的级份浓缩。得到N-[1-(2-羟基乙基)-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯80(300mg,798umol,84.1%产率,95.8%纯度),其为黄色油状物。LCMS[M-55]:305
化合物81:向N-[1-(2-羟基乙基)-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(100mg,277umol,1.00当量)在DMF(2.00mL)中的溶液添加NaH(22.2mg,555umol,60%纯度,2.00当量)。在15℃搅拌1小时之后,添加2-甲基-4-氯吡啶(76.6mg,555umol,2.00当量)。将混合物在85℃搅拌15小时。将析出物过滤并将滤液在真空下浓缩并通过制备性TLC纯化(DCM/MeOH 10/1,Rf:0.3)。
得到N-[1-[2-[(2-甲基-4-吡啶基)氧基]乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(200mg,213umol,76.6%产率,48.0%纯度),其为黄色油状物。LCMS[M+1]:452
化合物82,实施例36:将N-[1-[2-[(2-甲基-4-吡啶基)氧基]乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(200mg,443umol,1.00当量)和TFA(1.51g,13.3mmol,984uL,30.00当量)在DCM(2.00mL)中的混合物在15℃搅拌1小时。在完成之后,将反应混合物在真空下浓缩。残留物通过制备性HPLC纯化(柱:Phenomenex Gemini 150*25mm*10um;流动相:[水(0.05%氢氧化铵v/v)-ACN];B%:35%-65%,10min)。将希望的级份收集并冻干,得到1-[2-[(2-甲基-4-吡啶基)氧基]乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺(39.0mg,111umol,25.1%产率),其为无色油状物。LCMS[M+1]:352。
1H NMR(400MHz,甲醇-d4)δ=8.19-8.18(d,J=6Hz,1H),7.23-7.20(m,2H),7.11(m,1H),7.04-7.02(m,2H),6.86(,1H),6.86-6.80(m,1H),4.20-4.18(t,J=5.2Hz,2H),3.02-2.99(br d,J=11.6Hz,2H),2.81-2.79(br t,J=5.6Hz,2H),2.66(m,1H),2.46(s,3H),2.30-2.29(m,1H),2.19-2.18(m,2H),1.94-1.88(m,3H),1.50(m,2H),1.07-1.01(m,2H)
实施例37
1-吗啉代-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮
化合物85,实施例37,制备自2-氯丙酸:
化合物83:向2-氯丙酸(1.00g,9.20mmol)在二氯甲烷(30.0ml)中的搅拌的冰冷的溶液添加N-甲基吗啉(1.50ml,13.8mmol),然后添加1-羟基苯并三唑(1.48g,11.0mmol)和1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(2.31g,12.0mmol)。将所得溶液在0℃搅拌约45分钟。然后添加吗啉(2.40ml,27.6mmol),移除冷却浴,并将反应混合物在20℃搅拌12小时。将残留物在乙酸乙酯(50.0mL)和水(30.0mL)之间分配,然后分离有机相并用盐水(30.0mL)洗涤,经硫酸钠干燥,并在减压下蒸发,得到残留物。残留物通过制备性TLC纯化(二氯甲烷/甲醇10/1),得到2-氯-1-吗啉代丙-1-酮(500mg,2.81mmol,30.5%产率),其为无色油状物。
1H NMR(400MHz,甲醇-d4)δ=4.91(q,J=6.4Hz,1H),3.75-3.50(m,8H),1.62(d,J=6.4Hz,3H)。
化合物84:向2-氯-1-吗啉代-丙-1-酮(100mg,562umol,1.00eq.)在DMF(5.00mL)中的溶液添加DIEA(291mg,2.25mmol,393uL,4.00当量)、N-[(1R,2S)-2-苯基环丙基]-N-(4-哌啶基)氨基甲酸叔丁基酯(356mg,1.13mmol,2.00当量)和碘化钾(18.6mg,112umol,0.20当量)。将反应混合物在50℃搅拌12小时,然后将反应混合物在水(30.0mL)和乙酸乙酯(50.0mL)之间分配。将有机相分离,用盐水(30.0mL)洗涤,经无水硫酸钠干燥,过滤并在减压下浓缩,得到残留物。将残留物通过制备性TLC纯化(SiO2,石油醚/乙酸乙酯1/1),得到N-[1-[(1R)-1-甲基-2-吗啉代-2-氧代-乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(120mg,262umol,46.5%产率),其为白色固体。LCMS[M+1]:458。
化合物85:将N-[1-[(1R)-1-甲基-2-吗啉代-2-氧代-乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(120mg,262umol,1.00当量)在HCl/二噁烷(4M,2mL)中的溶液在0℃搅拌2小时。形成白色固体。将反应混合物过滤并将滤饼浓缩,得到(2R)-1-吗啉代-2-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]丙-1-酮(70.0mg,195umol,74.7%产率),其为白色固体。LCMS[M+1]:358。
1H NMR(400MHz,甲醇-d4)δ=7.37-7.30(m,2H),7.29-7.17(m,3H),4.61(br d,J=6.4Hz,1H),3.93(br d,J=10.8Hz,1H),3.81-3.50(m,10H),3.31-3.17(m,2H),3.09-3.01(m,1H),2.66-2.37(m,3H),2.31-1.99(m,2H),1.67-1.59(m,1H),1.57(d,J=6.4Hz,3H),1.52-1.37(m,1H)。
实施例38
1-甲基-3-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)脲
化合物90,实施例38,制备自化合物79。
化合物86:向N-[(1R,2S)-2-苯基环丙基]-N-(4-哌啶基)氨基甲酸叔丁基酯(5.00g,15.8mmol,1.00当量)和2-(2-溴乙基)异二氢吲哚-1,3-二酮(6.02g,23.7mmol,1.50当量)在乙腈(50.0mL)中的混合物添加碳酸钾(8.74g,63.2mmol,4.00当量)和碘化钾(263mg,1.58mmol,0.1当量),然后在90℃加热至回流18小时。完成后,将反应混合物真空浓缩除去溶剂,添加水(40mL),并将水层用DCM(50.0mL×3)萃取。将合并的有机级份经无水硫酸钠干燥,并真空浓缩,得到残留物。残留物通过柱色谱法纯化(石油醚:乙酸乙酯10:1至2:1),得到(1-(2-(1,3-二氧代异二氢吲哚-2-基)乙基)哌啶-4-基)((1R,2S)-2-苯基环丙基)氨基甲酸叔丁基酯(4.50g,9.19mmol,58.2%产率),其为黄色油状物。
1H NMR(400MHz,CD3Cl)δ=7.88-7.81(m,2H),7.76-7.69(m,2H),7.24-7.12(m,3H),7.06-7.01(m,2H),3.85-3.75(m,2H),3.74-3.62(m,1H),3.12-2.94(m,2H),2.67-2.55(m,2H),2.54-2.47(m,1H),2.12-2.06(m,2H),1.95(dq,J=3.6,12.0Hz,1H),1.83(dq,J=4.0,12.0Hz,1H),1.77-1.70(m,1H),1.66(br s,2H),1.40(s,9H),1.37-1.30(m,1H),1.20(q,J=6.4Hz,1H)。
化合物87:向N-[1-[2-(1,3-二氧代异二氢吲哚-2-基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(4.40g,8.99mmol,1.00当量)在乙醇(50.0mL)中的溶液添加肼一水合物(4.59g,89.9mmol,4.46mL,98.0%纯度,10.0当量)。将混合物在90℃搅拌1小时。一旦完成,将反应混合物真空浓缩除去溶剂;添加水(50mL),并将水相用乙酸乙酯(40.0mL×2)萃取。将合并的有机层经无水硫酸钠干燥并真空浓缩,得到(1-(2-氨基乙基)哌啶-4-基)((1R,2S)-2-苯基环丙基)氨基甲酸叔丁基酯(3.40g,8.61mmol,95.7%产率,91%纯度),其为浅黄色油状物。LCMS[M+1]:360
化合物88:向N-[1-(2-氨基乙基)-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(200mg,556umol,1.00当量)在DCM(10mL)中的混合物添加TEA(169mg,1.67mmol,231uL,3.00当量)和氯甲酸苯酯(104mg,668umol,83.6uL,1.20当量)在DCM(5mL)中的溶液。将反应在N2下在-10-0℃搅拌3小时。在完成之后,将反应用DCM(10mL)稀释,然后用H2O(3×25mL)洗涤,将有机层经Na2SO4干燥,过滤并浓缩,得到产物N-[1-[2-(苯氧基羰基氨基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(200mg,粗品),其为黄色固体,其不经进一步纯化就用于后续步骤。
化合物89:将N-[1-[2-(苯氧基羰基氨基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(200mg,417umol,1.00当量)在甲基胺(2M,4.62mL,22.1当量)(在THF中)中的混合物在15℃在N2下再搅拌3小时。在完成之后,将反应用DCM(15mL)稀释,然后用H2O(3×20mL)洗涤,将有机层经Na2SO4干燥,过滤并浓缩。残留物通过制备性TLC纯化(二氯甲烷:甲醇=10:1)。得到产物N-[1-[2-(甲基氨基甲酰基氨基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(130mg,312umol,74.8%产率,100%纯度),其为白色固体。LCMS[M+1]:417
化合物90:向N-[1-[2-(甲基氨基甲酰基氨基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(130mg,312umol,1.00当量)在DCM(1.00mL)中的混合物添加TFA(1.54g,13.5mmol,1.00mL,43.3当量),并将反应在15℃搅拌1小时。在完成之后,将反应混合物浓缩,用CH3CN(3mL)稀释,然后将混合物用Na2CO3固体调节至pH 7~8,并将剩余固体通过过滤除去。将滤液通过制备性HPLC纯化(仪器:GX-A;柱:Phenomenex Gemini 150*25mm*10um;条件:水(0.05%氢氧化铵v/v)-ACN;开始B:28;结束B:50;梯度时间(min):10;100%B保持时间(min):2;流速(ml/min):25),将得到的产物浓缩,然后冻干,得到1-甲基-3-[2-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]乙基]脲(92.7mg,291umol,93.2%产率,99.2%纯度),其为无色油状物。LCMS[M+1]:317
1H NMR(400MHz,甲醇-d4)δ7.27-7.17(m,2H),7.13-7.08(m,1H),7.07-6.99(m,2H),3.24(t,J=6.6Hz,2H),2.94-2.91(m,2H),2.72-2.59(m,4H),2.44(t,J=6.8Hz,2H),2.34-2.24(m,1H),2.13-2.00(m,2H),1.98-1.84(m,3H),1.53-1.39(m,2H),1.09-0.99(m,2H)。
实施例39
N-[2-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]乙基]丙烷-2-磺酰胺
化合物92,实施例39,制备自化合物87:
化合物91:在0℃向N-[1-(2-氨基乙基)-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(500mg,1.39mmol,1.00当量)在DCM(20.0mL)中的混合物添加TEA(422mg,4.17mmol,578uL,3.00当量)和丙烷-2-磺酰氯(396mg,2.78mmol,310uL,2.00当量)。将混合物缓慢温热至25℃并在25℃搅拌15小时。一旦完成,将反应混合物倒入饱和碳酸氢钠(30.0mL)中,并用DCM(40.0mL×2)萃取。将合并的有机层经无水硫酸钠干燥并在减压下浓缩除去溶剂,得到(1-(2-(1-甲基乙基磺酰氨基)乙基)哌啶-4-基)((1R,2S)-2-苯基环丙基)氨基甲酸叔丁基酯(700mg,粗品),其为橙色油状物,其不经进一步纯化就用于后续步骤。LCMS[M+1]:466
化合物92:在0℃向N-[1-[2-(异丙基磺酰基氨基)乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(700mg,1.50mmol,1.00当量)在DCM(10.0mL)中的溶液添加TFA(10.0mL),并将所得混合物在0-25℃搅拌1小时。一旦完成,将反应混合物真空浓缩除去溶剂,用乙腈(3.00mL)稀释,并将pH用氢氧化钠(1M)调节至pH=7-8。将固体通过过滤除去,并将残留物通过制备性HPLC纯化(碱性条件),得到化合物N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)丙烷-2-磺酰胺(260mg,680umol,两个步骤48.9%产率,95.6%纯度),其为黄色油状物。LCMS[M+1]:366。
1H NMR(400MHz,CD3OD)δ=7.25-7.18(m,2H),7.14-7.08(m,1H),7.05-7.00(m,2H),3.29-3.22(m,1H),3.18(t,J=6.8Hz,2H),2.93(d,J=11.6Hz,2H),2.64(m,J=4.0,10.8Hz,1H),2.50(t,J=6.8Hz,2H),2.34-2.26(m,1H),2.15-2.01(m,2H),1.98-1.84(m,3H),1.52-1.39(m,2H),1.32(d,J=6.8Hz,6H),1.10-0.97(m,2H)。
实施例40
(E)-3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)丙烯酸(98)
步骤1.(E)-3-(4-(2-(4-氧代哌啶-1-基)乙氧基)苯基)丙烯酸甲基酯(94)
将(E)-3-(4-(2-溴乙氧基)苯基)丙烯酸甲基酯(93)(3.00g,10.52mmol,描述在WO2008/033747中)、4-哌啶酮盐酸盐水合物(1.697g,11.05mmol)、K2CO3(4.36g,31.6mmol)、KI(105mg,0.631mmol)和无水Na2SO4(2.99g,21.04mmol)在DMF(25mL)中的悬浮液在90℃搅拌过夜,冷却至室温,用盐水稀释并用EA萃取。将萃取物用盐水洗涤并经无水Na2SO4干燥,过滤并蒸发。将剩余油状物通过快速柱色谱法纯化(洗脱剂10%己烷/EA,然后纯的EA),得到标题化合物94(1.65g,52%产率),其为白色固体。
1H NMR:500MHz,CDCl3,δ(ppm):7.65(d,J=16.0Hz,1H),7.48(d,J=8.6Hz,2H),6.92(d,J=8.8Hz,2H),6.32(d,J=16.0Hz,1H),4.17(t,J=5.6Hz,2H),3.79(s,3H),2.95(t,J=5.6Hz,2H),2.90(t,J=6.1Hz,4H),2.49(t,J=6.2Hz,4H)。MS:303.4(计算值),304.2(M+H+)和322.1(M+H2O+H+)(实测值)。
步骤2.(E)-3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯
基)丙烯酸甲基酯(95)
向(1R,2S)-2-苯基环丙胺(2R,3R)-酒石酸盐(2.03g,7.07mmol)和酮94(1.65g,5.44mmol)在DCM(10mL)和DCE(10mL)的混合物中的悬浮液添加4A分子筛(2g)和冰乙酸(0.5mL)。将所得的混合物在室温搅拌6小时,冷却至0℃并用硼氢化物(2.075g,9.79mmol)处理。将混合物在0℃搅拌30min,温热至室温并一起搅拌18小时。然后将混合物用DCM稀释并通过celite垫过滤。将滤液先后用NaHCO3溶液和盐水洗涤,经无水Na2SO4干燥,过滤,浓缩并将残留物通过快速柱色谱法纯化(洗脱剂10%MeOH/DCM)(MeOH含有2%氨),得到标题化合物95(1.27g,56%产率),其为油状物,其在真空中固化。MS:420.5(计算值),421.2(M+H+,实测值)。
步骤3.(E)-3-(4-(2-(4-((叔丁氧基羰基)((1R,2S)-2-苯基环丙基)氨基)哌啶-
1-基)乙氧基)苯基)丙烯酸甲基酯(96)
向胺95(1.27g,3.02mmol)在DCM(10mL)中的溶液添加TEA(2.53mL,18.12mmol)。将混合物通过冰浴冷却,然后用Boc-酸酐(2.64g,12.08mmol)在DCM(15mL)中的溶液处理。将混合物在0-5℃搅拌30min,然后在环境温度搅拌8小时,用DCM稀释,用水洗涤,经无水Na2SO4干燥,过滤并浓缩。将残留物通过快速柱色谱法纯化(洗脱剂EA-己烷(4:1)),得到标题化合物96(1.189g,76%产率),其为蜂蜜状物质,其含有约0.7M EA(NMR)。将产物按原样用于后续步骤。
1H NMR:500MHz,MeOD,δ(ppm):7.64(d,J=16.0Hz,1H),7.55(d,J=8.8Hz,2H),7.26-7.23(m,2H),7.16-7.11(m,3H),6.97(d,J=8.8Hz,2H),6.39(d,J=16.0Hz,1H),4.16(t,J=5.6Hz,2H),3.77(s,3H),3.75-3.68(m,1H),3.15-3.11(m,1H),3.10-3.06(m,1H),2.81(t,J=5.5Hz,2H),2.62-2.59(m,1H),2.25-2.09(m,4H),2.06-1.98(m,1H),1.82-1.79(m,1H),1.76-1.72(m,1H),1.43-1.39(m,10H),1.25-1.21(m,1H)。MS:520.7(计算值),521.3(M+H+,实测值)。
步骤4.(E)-3-(4-(2-(4-((叔丁氧基羰基)((1R,2S)-2-苯基环丙基)氨基)哌啶-
1-基)乙氧基)苯基)丙烯酸(97)
向酯96(1.189g,2.284mmol)在THF(15mL)中的溶液添加LiOH xH2O(422mg,10.05mmol)在水(15mL)中的溶液。将反应混合物在室温搅拌48小时,用HCl酸化至pH 4,然后最大程度地蒸发以除去THF。将残留水溶液用盐水稀释并用DCM萃取。将萃取物经无水Na2SO4干燥,过滤并将滤液真空蒸发,得到标题化合物97(1.014g,88%产率),其为白色蓬松物质。MS:506.6(计算值),507.3(M+H+,实测值)。
步骤5.(E)-3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯
基)丙烯酸二-盐酸盐(98)
在室温向化合物97(200mg,0.395mmol)在二噁烷(3.0mL)中的溶液添加HCl在二噁烷中的4M溶液(3.0ml,11.84mmol)。将混合物在环境温度搅拌3小时,真空蒸发至干;并将所得的白色析出物用丙酮研磨,通过过滤收集并干燥,得到标题化合物98(169mg 89%产率),其为白色固体。
1H NMR:500MHz,DMSO-d6,δ(ppm):12.25(bs,1H),10.85(bs,1H),10.01(bs,2H),7.67(d,J=8.8Hz,2H),7.55(d,J=15.9Hz,1H),7.32-7.29(m,2H),7.24-7.18(m,3H),7.04(d,J=8.8Hz,2H),6.41(d,J=16.0Hz,1H),4.45(bt,2H),3.68(bs,2H),3.66(bs,1H),3.48(bs,3H),3.14(bs,2H),2.97(bs,1H),2.57(m,1H),2.32(bs,2H),2.12(bs,1H),1.61-1.57(m,1H),1.31-1.27(m,1H)。MS:406.5(计算值),407.3(M+H+,实测值)。
实施例41
N-[2-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]丙基]甲烷磺酰胺
化合物102,实施例41,制备自化合物99:
化合物100:在0℃向1-氨基丙-2-醇(1.00g,13.3mmol,1.04mL,1.00当量)在吡啶(1.70mL)中的溶液添加DMAP(48.8mg,399umol,0.03当量)。将MsCl(3.05g,26.6mmol,2.06mL,2.00当量)滴加至混合物中。将反应混合物在0-10℃搅拌1小时。在完成之后,将水(10mL)和HCl(1M,10mL)添加至混合物中。将所得混合物用DCM(3×30mL)萃取。将合并的有机相用无水Na2SO4干燥,过滤并将滤液在真空下浓缩,得到[2-(甲烷磺酰氨基)-1-甲基-乙基]甲烷磺酸盐(700mg,3.03mmol,22.7%产率),其为黄色油状物。
1H NMR(400MHz,氯仿-d)δ=5.13-5.11(m,1H),4.92-4.87(m,1H),3.48-3.40(s,1H),3.30-3.32(s,1H),3.09(s,3H),3.02(m,3H),1.46(s,3H)。
化合物101:向N-[(1R,2S)-2-苯基环丙基]-N-(4-哌啶基)氨基甲酸叔丁基酯(100mg,316umol,1.00当量)和[2-(甲烷磺酰氨基)-1-甲基-乙基]甲烷磺酸盐(73.1mg,316umol,1.00当量)在MeCN(3.00mL)中的溶液添加K2CO3(87.4mg,632umol,2.00当量)。将反应混合物在85℃搅拌3小时。在完成之后,将析出物过滤并将滤液在真空下浓缩。残留物通过制备性TLC纯化(DCM/MeOH=10/1)。得到N-[1-[2-(甲烷磺酰氨基)-1-甲基-乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(80.0mg,177umol,56.1%产率),其为黄色油状物。LCMS[M+1]:452。
化合物102:向N-[1-[2-(甲烷磺酰氨基)-1-甲基-乙基]-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(50.0mg,111umol,1.00当量)在DCM(1.00mL)中的溶液添加TFA(379mg,3.32mmol,246uL,30.0当量)。将反应混合物在25℃搅拌1小时。在完成之后,将反应混合物在真空下浓缩。残留物通过制备性HPLC纯化(柱:Phenomenex SynergiC18150*25*10um;流动相:[水(0.05%HCl)-ACN];B%:5%-25%,7.8min)。将希望的级份收集并冻干,得到N-[2-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]丙基]甲烷磺酰胺(12.0mg,28.3umol,25.5%产率,2HCl),其为白色固体。LCMS[M+1]:352。
1H NMR(400MHz,氘氧化物)δ=7.33-7.22(m,3H),7.14-7.12(m,2H),3.97(br s,2H),3.67-3.63(m,2H),3.15(m,3H),3.09(s,3H),2.94(m,1H),2.92(m,1H),2.46-2.39(m,3H),2.08(m,1H),1.93(m,1H),1.48-1.30(m,2H),1.23(m,3H)。
实施例42
1-[2-(4-溴苯氧基)乙基]-4-[[(1R,2S)-2-苯基环丙基]氨基]哌啶-2-酮
化合物106,实施例42,制备自化合物42:
化合物103:在25℃向哌啶-2,4-二酮(84.9mg,751umol,1.00当量)在MeOH(4.00mL)中的混合物添加(1R,2S)-2-苯基环丙胺(100mg,751umol,1.00当量)。在25℃搅拌1小时之后,添加AcOH(90.2mg,1.50mmol,85.9uL,2.00当量)。将所得混合物在25℃搅拌2小时。在完成之后,将水(20mL)添加至合并的混合物中。将所得混合物用DCM(3×30mL)萃取。将合并的有机相用无水Na2SO4干燥,过滤并在真空下浓缩。得到4-[[(1R,2S)-2-苯基环丙基]氨基]哌啶-2-酮(200mg,粗品),其为黄色油状物。所述粗品直接用于后续步骤。
化合物104:向4-[[(1R,2S)-2-苯基环丙基]氨基]哌啶-2-酮(340mg,1.48mmol,1.00当量)在MeOH(2.00mL)中的溶液添加Boc2O(644mg,2.95mmol,678uL,2.00当量)和Et3N(299mg,2.95mmol,409uL,2.00当量)。将反应混合物在60℃搅拌2小时。在完成之后,将反应混合物在真空下浓缩。残留物通过硅胶色谱法纯化(DCM/MeOH从50/1至20/1)。得到N-(2-氧代-4-哌啶基)-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(200mg,551umol,37.2%产率,91.0%纯度),其为黄色油状物。LCMS[M-55]:275。
化合物105:在0℃向N-(2-氧代-4-哌啶基)-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(150mg,454umol,1.00当量)在DMF(2.00mL)中的溶液添加NaH(36.3mg,908umol,60%纯度,2.00当量)。在0℃搅拌1小时之后,添加1-溴-4-(2-溴乙氧基)苯(254mg,908umol,2.00当量)。将反应混合物在0-10℃搅拌1小时。在完成之后,将水(10mL)添加至混合物中。将所得混合物用DCM(3×30mL)萃取。将合并的有机相用无水Na2SO4干燥,过滤并在真空下浓缩。残留物通过制备性TLC纯化(DCM/MeOH=10/1)。得到N-[1-[2-(4-溴苯氧基)乙基]-2-氧代-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(40.0mg,75.6umol,16.6%产率),其为黄色油状物。LCMS[M+1,M+3]:529,531。
化合物106:向N-[1-[2-(4-溴苯氧基)乙基]-2-氧代-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(40.0mg,75.6umol,1.00当量)在二噁烷(2.00mL)中的溶液添加HCl/二噁烷(4M,2.00mL,105.9当量)。将反应混合物在28℃搅拌1小时。在完成之后,将反应混合物在真空下浓缩,得到1-[2-(4-溴苯氧基)乙基]-4-[[(1R,2S)-2-苯基环丙基]氨基]哌啶-2-酮(27.0mg,52.5umol,69.5%产率,97.6%纯度,2HCl),其为黄色固体。LCMS[M+1,M+23]:429,451。
1H NMR(400MHz,甲醇-d4)δ=7.38-7.23(m,5H),7.13-7.11(m,2H),6.83-6.81(m,2H),4.16(br s,2H),3.70-3.44(m,5H),2.85-2.83(m,2H),2.45-2.40(m,2H),2.26(br s,1H),1.92-1.74(m,1H),1.45-1.39(m,2H)。
实施例43
2-(2-氟-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸二-盐酸盐(113)
步骤1.2-(4-(2-溴乙氧基)-2-氟苯基)乙酸甲基酯(108)
将2-(2-氟-4-羟基苯基)乙酸甲基酯(107)(4.0g,21.72mmol,WO2012/138845)、1,2-二溴乙烷(12.0mL,139mmol)、K2CO3(8.41g,60.8mmol)和KI(100mg,0.602mmol)在MeCN(70mL)中的悬浮液在回流条件下搅拌24小时。然后将混合物冷却至室温,用水稀释并用EA萃取。将萃取物经无水Na2SO4干燥,过滤并真空浓缩。对所得油状物实施快速柱色谱法(洗脱剂EA-己烷(1:4)),得到标题化合物108(4.65g,74%产率),其为微黄色油状物。
1H NMR:500MHz,CDCl3,δ(ppm):7.16(t,J=8.5Hz,1H),6.69-6.63(m,2H),4.26(t,J=6.3Hz,2H),3.70(s,3H),3.62,(t,J=6.2Hz,2H),3.61(s,2H)。
步骤2.2-(2-氟-4-(2-(4-氧代哌啶-1-基)乙氧基)苯基)乙酸甲基酯(109)
将溴化物108(4.65g,15.97mmol)、哌啶酮盐酸盐水合物(3.68g,23.96mmol)、K2CO3(8.83g,63.9mmol)、无水Na2SO4(4.54g,31.9mmol)和KI(265mg,1.597mmol)在MeCN(90mL)中的悬浮液在回流条件下搅拌18小时。将混合物冷却至室温,用水稀释并用EA萃取。将萃取物经无水Na2SO4干燥,过滤并浓缩。残留物通过快速柱色谱法纯化(洗脱剂10%MeOH/DCM)(MeOH含有2%氨),得到标题化合物109(4.60g,93%产率),其为油状物。
1H NMR:500MHz,CDCl3,δ(ppm):7.15(t,J=8.6Hz,1H),6.69-6.63(m,2H),4.11(t,J=5.6Hz,2H),3.70(s,3H),3.60(s,2H),2.92(t,J=5.6Hz,2H),2.89(t,J=6.1Hz,4H),2.48(t,J=6.2Hz,4H)。MS:309.3(计算值),310.2(M+H+,实测值)。
步骤3.2-(2-氟-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯
基)乙酸甲基酯(110)
向(1R,2S)-2-苯基环丙胺(2R,3R)-酒石酸盐(3.36g,11.85mmol)和酮109(2.82g,9.12mmol)在DCE(20mL)和DCM(20mL)的混合物中的悬浮液添加4A分子筛(3g)和冰乙酸(0.5mL)。将所得的混合物在室温搅拌16小时,冷却至0℃,然后用硼氢化物(3.48g,16.41mmol)处理。将混合物在0℃搅拌30min,然后温热至室温,一起搅拌3小时,用DCM稀释并通过celite垫过滤。将滤液先后用10%NaHCO3溶液和盐水洗涤,经无水Na2SO4干燥,过滤并浓缩。残留物通过快速柱色谱法纯化(洗脱剂10%MeOH/DCM)(MeOH含有2%氨),得到标题化合物110(4.07g,105%产率),其为油状物。将所述物质不另外纯化就用于后续步骤。MS:426.5(计算值),427.2(M+H+,实测值)。
步骤4.2-(4-(2-(4-((叔丁氧基羰基)((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)
乙氧基)-2-氟苯基)乙酸甲基酯(111)
向胺110(4.07g,9.54mmol)在DCM(40mL)中的溶液添加TEA(4.0ml,28.7mmol)。将混合物通过冰浴冷却,然后用Boc-酸酐(4.17g,19.08mmol)在DCM(40mL)中的溶液处理。将混合物在0-5℃搅拌30min,然后在环境温度搅拌过夜,用DCM稀释,用稀释盐水洗涤,经无水Na2SO4干燥,过滤并浓缩。残留物通过快速柱色谱法纯化(洗脱剂EA-己烷(1:1,然后4:1)),得到标题化合物111(3.72g,74%产率),其为蜂蜜状物质。所述产物含有约0.5M EA并按原样用于后续步骤。
1H NMR:500MHz,CDCl3,δ(ppm):7.28-7.25(m,2H,与残留溶剂信号重叠),7.18-7.11(m,2H),7.09-7.07(m,2H),6.67-6.61(m,2H),4.04(t,J=5.9Hz,2H),3.79-3.73(m,1H),3.70(s,3H),3.60(s,2H),3.05-2.97(m,2H),2.76(t,J=5.9Hz,2H),2.56-2.53(m,1H),2.20-2.05(m,4H),1.97-1.89(m,1H),1.80-1.71(m,2H),1.42(s,9H),1.40-1.37(m,1H),1.23-1.19(m,1H)。MS:526.6(计算值),527.4(M+H+,实测值)。
步骤5.2-(4-(2-(4-((叔丁氧基羰基)((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)
乙氧基)-2-氟苯基)乙酸(112)
向酯111(3.72g,7.06mmol)在THF(35mL)中的溶液添加LiOH水合物(741mg,17.66mmol)在35mL水中的溶液。将反应混合物在室温搅拌2小时,酸化至pH 6-7,然后最大程度地蒸发。将残留物用盐水处理并用DCM萃取。将萃取物经无水Na2SO4干燥,过滤并将滤液蒸发,得到标题化合物112(3.57g,99%产率),其为白色蓬松固体。MS:512.6(计算值),513.3(M+H+,实测值)。
步骤6.2-(2-氟-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯
基)乙酸二-盐酸盐(113)
在室温向化合物112(3.57g,6.96mmol)在二噁烷(20mL)中的溶液添加HCl在二噁烷(40ml,160mmol)中的4M溶液。将混合物搅拌3小时,用丙酮稀释并几乎完全蒸发。将所得的白色析出物用丙酮研磨,通过过滤收集并真空干燥,得到标题化合物113(2.908g,86%产率),其为白色固体。
1H NMR:500MHz,DMSO6,δ(ppm):12.39(bs,1H),11.05和10.86(两个bs,1H),10.05(bs,2H),7.33-7.19(m,6H),6.90(dd,J=2.4和11.7Hz,1H),6.81(dd,J=2.2和8.4Hz,1H),4.42(bt,2H),3.68(bs,1H),3.66(bs,1H),3.55(s,2H),3.46(bs,3H),3.13(bs,2H),2.97(bs,1H),2.58(m,1H),2.33(bs,2H),2.11(bs,2H),1.62-1.58(m,1H),1.31-1.28(m,1H)。MS:412.5(计算值),413.2(M+H+,实测值)。
实施例44
N,2-二甲基-N-[2-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]乙基]吡啶-4-胺
化合物118,实施例44,制备自化合物114:
化合物115:向4-氯-2-甲基-吡啶(1.00g,7.84mmol,1.00当量)和N-[2-(甲基氨基)乙基]氨基甲酸叔丁基酯(1.37g,7.84mmol,1.00当量)在DMAC(20.0mL)中的溶液添加K2CO3(2.17g,15.7mmol,2.00当量)、RuPhos(366mg,784umol,0.10当量)和Pd2(dba)3(359mg,392umol,0.05当量)。将反应混合物在90℃在N2下搅拌12小时。在完成之后,将水(15mL)添加至混合物中。将所得混合物用EA(3×20mL)萃取。将合并的有机相在真空下浓缩。残留物通过硅胶色谱法纯化(DCM/MeOH从30/1至5/1),得到N-[2-[甲基-(2-甲基-4-吡啶基)氨基]乙基]氨基甲酸叔丁基酯(1.80g,5.83mmol,74.3%产率,85.9%纯度),其为黄色油状物。LCMS[M+1]:266。
1H NMR(400MHz,甲醇-d4)δ=7.94-7.93(d,J=6.0Hz,1H),6.56-6.54(m,2H),3.52-3.48(t,J=6.4Hz,2H),3.26-3.24(m,2H),3.02(s,3H),2.38(s,3H),1.39(s,9H)。
化合物116:向N-[2-[甲基-(2-甲基-4-吡啶基)氨基]乙基]氨基甲酸叔丁基酯(1.30g,4.90mmol,1.00当量)在MeOH(10.0mL)中的混合物添加HCl/二噁烷(4.90mmol,10.0mL,1.00当量)。将反应混合物在25℃搅拌2小时。在完成之后,将反应混合物在真空下浓缩。将残留物溶解在MeOH(20mL)中并将碱性离子交换树脂添加至混合物中。将所得混合物在25℃搅拌5小时。将固体通过过滤除去并将滤液在真空下浓缩,得到N'-甲基-N'-(2-甲基-4-吡啶基)乙烷-1,2-二胺(500mg,2.23mmol,45.5%产率,90.0%纯度,HCl),其为黄色油状物。
化合物117:在90℃向N'-甲基-N'-(2-甲基-4-吡啶基)乙烷-1,2-二胺(1.00g,6.05mmol,1.00当量)和K2CO3(125mg,908umol,0.150当量)在EtOH(14.0mL)中的混合物添加1-苄基-1-甲基-1-氮杂环己烷-4-酮(3.01g,9.08mmol,1.50当量)在H2O(4.00mL)中的混合物,历时0.5小时。将反应混合物在90℃另外搅拌1小时。在完成之后,将反应混合物在真空下浓缩。残留物通过硅胶色谱法纯化(DCM/MeOH从30/1至10/1)。然后通过制备性HPLC纯化(柱:Phenomenex Synergi Max-RP 250*50mm*10um;流动相:[水(0.05%氢氧化铵v/v)-ACN];B%:15%-40%,25MIN;69%min),得到1-[2-[甲基-(2-甲基-4-吡啶基)氨基]乙基]哌啶-4-酮(350mg,1.35mmol,22.4%产率,95.6%纯度),其为无色油状物。LCMS[M+1]:248。
1H NMR(400MHz,甲醇-d4)δ=7.97-7.95(m,1H),6.56-6.51(m,2H),3.65-3.55(m,2H),3.07-3.03(d,J=16.4Hz,3H),2.86-2.85(m,2H),2.72-2.71(m,1H),2.57(m,3H),2.46-2.44(m,2H),2.39(s,3H),1.79(m,2H)。
化合物118:在-10℃向(1R,2S)-2-苯基环丙胺(20.0mg,150umol,1.00当量)在MeOH(3.00mL)中的溶液添加1-[2-[甲基-(2-甲基-4-吡啶基)氨基]乙基]哌啶-4-酮(44.6mg,180umol,1.20当量),然后添加AcOH(18.0mg,300umol,17.2uL,2.00当量)。在1小时后,添加NaBH(OAc)3(95.5mg,451umol,3.00当量)。将反应混合物在-10-25℃搅拌2小时。在完成之后,将水(10mL)添加至混合物中。将所得混合物用DCM(3×20mL)萃取。将合并的有机相在真空下浓缩。残留物通过制备性HPLC纯化(柱:Phenomenex Synergi C18150*25*10um;流动相:[水(0.05%HCl)-ACN];B%:0%-20%,7.8min)。
将希望的级份收集并冻干,得到N,2-二甲基-N-[2-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]乙基]吡啶-4-胺(32.0mg,67.2umol,44.7%产率,99.5%纯度,3HCl),其为黄色油状物。LCMS[M+1]:365。
1H NMR(400MHz,D2O)δ=7.98-7.96(d,J=7.6Hz,1H),7.39-7.35(m,2H),7.32-7.30(m,1H),7.20-7.18(m,2H),6.85(d,J=6.8Hz,1H),6.80-6.79(m,1H),4.01-3.97(m,2H),3.77-3.74(m,3H),3.46-3.42(m,2H),3.23(m,2H),3.17(s,3H),3.01-2.99(m,1H),2.52-2.49(m,6H),2.07-1.94(m,2H),1.55-1.47(m,2H)。
实施例45
N-苯基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙烷磺酰胺
化合物121,实施例45,制备自119:
化合物120:在20℃向2-氯乙烷磺酰氯(70.0mg,429umol,44.8uL,1.00当量)在DCM(5.00mL)中的溶液添加TEA(108mg,1.07mmol,148uL,2.50当量)和苯胺(31.9mg,343umol,31.3uL,0.80当量)。在搅拌2小时之后,添加((1R,2S)-2-苯基环丙基)(哌啶-4-基)氨基甲酸叔丁基酯(163mg,515umol,1.20当量),并再搅拌0.5小时。将反应混合物浓缩。残留物通过制备性TLC纯化,得到((1R,2S)-2-苯基环丙基)(1-(2-(N-苯基氨磺酰基)乙基)哌啶-4-基)氨基甲酸叔丁基酯(60.0mg,273umol,63.6%产率),其为黄色固体。LCMS[M+1]:500。
化合物121:在0℃向((1R,2S)-2-苯基环丙基)(1-(2-(N-苯基氨磺酰基)乙基)哌啶-4-基)氨基甲酸叔丁基酯(60.0mg,120umol,1.00当量)在DCM(3.00mL)中的溶液添加TFA(1.85g,16.2mmol,1.20mL,134当量)。然后将反应混合物在20℃搅拌12小时。将反应混合物用饱和碳酸氢钠中和至7-8,然后浓缩。将固体通过过滤除去并将滤液浓缩,得到残留物,其通过制备性HPLC(甲酸)纯化,得到N-苯基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙烷磺酰胺(10.0mg,25.0umol,20.8%产率),其为白色固体。LCMS[M+1]:400。
1H NMR(400MHz,甲醇-d4)δ=8.23(br s,2H),7.36-7.29(m,2H),7.27-7.20(m,4H),7.11(td,J=7.2,11.2Hz,2H),7.03(d,J=7.6Hz,2H),3.27-3.19(m,2H),2.73-2.63(m,4H),2.62-2.55(m,1H),2.35-2.26(m,1H),1.97-1.82(m,3H),1.73(br d,J=11.2Hz,2H),1.34-1.21(m,2H),1.07-0.94(m,2H)。
实施例46
1-吗啉代-3-苯基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮
化合物127,实施例46,制备自化合物122。
化合物123:在0℃分批向2-氨基-3-苯基-丙酸(2.00g,12.1mmol,1.00当量)在MeOH(30.0mL)中的混合物添加SOCl2(4.32g,36.3mmol,2.63mL,3.00当量)。将反应混合物在0℃搅拌0.5小时,然后将混合物加热至70℃并在70℃搅拌2.5小时。在完成之后,将反应混合物浓缩。将残留物用EA(30mL)稀释,用饱和NaHCO3水溶液(2×30mL)洗涤,将有机层用盐水(2×30mL)洗涤,经Na2SO4干燥,过滤并浓缩。得到产物2-氨基-3-苯基-丙酸甲基酯(1.80g,10.0mmol,82.9%产率),其为黄色油状物。
1H NMR(400MHz,氯仿-d)δ7.36-7.20(m,5H),3.79-3.73(m,4H),3.12(dd,J=5.2,13.6Hz,1H),2.88(dd,J=8.0,13.6Hz,1H)
化合物124:在78℃分批向2-氨基-3-苯基-丙酸甲基酯(1.80g,10.0mmol,1.00当量)和K2CO3(208mg,1.51mmol,0.15当量)在EtOH(20.0mL)中的混合物添加1-苄基-1-碘代-1-甲基-2,3,5,6-四氢吡啶-4-酮(4.99g,15.1mmol,1.50当量)在H2O(10.0mL)中的混合物,然后将混合物加热至90℃并在90℃搅拌3小时。在完成之后,将反应混合物用水(30mL)稀释并用EA(3×30mL)萃取。将合并的有机层经Na2SO4干燥,过滤并浓缩。残留物通过柱色谱法纯化(石油醚/乙酸乙酯=10/1~5/1),得到2-(4-氧代-1-哌啶基)-3-苯基-丙酸乙基酯(2.00g,6.73mmol,67.1%产率,92.7%纯度),其为黄色油状物。
1H NMR(400MHz,氯仿-d)δ7.33-7.21(m,5H),4.15-4.07(m,2H),3.63(dd,J=6.8,8.8Hz,1H),3.17-2.97(m,4H),2.95-2.84(m,2H),2.51-2.37(m,4H),1.19(t,J=7.2Hz,3H)
化合物125:向2-(4-氧代-1-哌啶基)-3-苯基-丙酸乙基酯(500mg,1.82mmol,1.00当量)在MeOH(10.0mL)和H2O(2.00mL)中的混合物添加NaOH(291mg,7.28mmol,4.00当量),将反应混合物在20℃搅拌3小时。在完成之后,将反应混合物调节至pH~6,然后浓缩。将固体用MeOH(10mL)溶解,浓缩,将残留物用DCM(15mL)研磨,将固体过滤并干燥。得到产物2-(4-氧代-1-哌啶基)-3-苯基-丙酸(380mg,1.34mmol,73.6%产率,HCl),其为灰色固体。
1H NMR(400MHz,DMSO-d6)δ7.34-7.16(m,5H),3.55(dd,J=6.8,8.0Hz,1H),3.04-2.76(m,6H),2.46-2.21(m,4H)
化合物126:在0℃向2-(4-氧代-1-哌啶基)-3-苯基-丙酸(200mg,809umol,1.00当量)在DMF(8.00mL)中的混合物添加HATU(615mg,1.62mmol,2.00当量)和DIPEA(209mg,1.62mmol,282uL,2.00当量)。将所得混合物在0℃搅拌0.5小时,添加吗啉(141mg,1.62mmol,142uL,2.00当量),并将混合物在0-15℃搅拌11.5小时。在完成之后,将反应混合物用水(30mL)稀释,然后用DCM(2×15mL)萃取,将合并的有机层用盐水(2×40mL)洗涤,经Na2SO4干燥,过滤并浓缩。残留物通过制备性TLC纯化(石油醚:乙酸乙酯=1:1),得到1-(1-苄基-2-吗啉代-2-氧代-乙基)哌啶-4-酮(140mg,442umol,54.7%产率,100%纯度),其为黄色固体。LCMS[M+1]:317。
1H NMR(400MHz,氯仿-d)δ7.32-7.20(m,5H),3.85(dd,J=4.0,10.0Hz,1H),3.62-3.41(m,6H),3.29-3.02(m,5H),2.99-2.92(m,3H),2.46(t,J=6.0Hz,4H)
化合物127:在-10℃向1-(1-苄基-2-吗啉代-2-氧代-乙基)哌啶-4-酮(140mg,442umol,1.00当量)在MeOH(10.0mL)中的混合物添加(1R,2S)-2-苯基环丙胺(58.9mg,442umol,1.00当量)和AcOH(53.1mg,885umol,50.6uL,2.00当量)。将所得混合物在-10℃搅拌0.5小时,分批添加NaBH3CN(83.4mg,1.33mmol,3.00当量),并将混合物在0-15℃搅拌11.5小时。在完成之后,将反应混合物用水(15mL)稀释,然后用DCM(2×15mL)萃取,将有机层经Na2SO4干燥,过滤并浓缩。残留物通过制备性HPLC纯化(仪器:GX-F;柱:PhenomenexGemini 150*25mm*10um;条件:水(0.05%HCl)-ACN;开始B:5;结束B:29;梯度时间(min):8;100%B保持时间(min):2;流速(ml/min):25),将得到的产物浓缩,然后冻干。得到产物1-吗啉代-3-苯基-2-[4-[[(1R,2S)-2-苯基环丙基]氨基]-1-哌啶基]丙-1-酮(85.0mg,168umol,37.9%产率,100%纯度,2HCl),其为白色固体。LCMS[M+1]:434。
1H NMR(400MHz,氘氧化物)δ7.41-7.29(m,5H),7.28-7.18(m,3H),7.15(d,J=8.0Hz,2H),4.16-3.92(m,1H),3.75-3.71(m,1H),3.62-3.45(m,4H),3.41-3.06(m,7H),3.04-2.90(m,2H),2.85-2.62(m,1H),2.56-2.33(m,3H),2.33-2.20(m,1H),2.16-1.91(m,2H),1.53-1.39(m,2H)
实施例47
1-(2-(4-溴苯氧基)乙基)-4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-2,6-二酮
化合物138,实施例47,制备自化合物128。
化合物129:向4-溴苯酚(2.00g,11.6mmol,1.00当量)和2-溴乙腈(1.66g,13.9mmol,924uL,1.20当量)在MeCN(30.0mL)中的混合物添加K2CO3(3.99g,28.9mmol,2.50当量),并将混合物在80℃搅拌3小时。在完成之后,将固体通过过滤除去并将滤液浓缩。残留物通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=1/0至10:1),得到2-(4-溴苯氧基)乙腈(2.10g,9.83mmol,85.1%产率,99.3%纯度),其为白色固体。
1H NMR(400MHz,氯仿-d)δ7.49(d,J=9.2Hz,2H),6.90(d,J=9.2Hz,2H),4.77(s,2H)。
化合物130:在0℃分批向2-(4-溴苯氧基)乙腈(1.90g,8.96mmol,1.00当量)在THF(20.0mL)中的混合物添加BH3.THF(1M,26.9mL,3.00当量),将反应在0℃搅拌2小时,然后将反应混合物加热至80℃并在80℃搅拌12小时。在完成之后,将反应混合物用MeOH(30mL)淬灭,直到无气体形成,然后浓缩。残留物通过柱色谱法纯化(SiO2,石油醚:乙酸乙酯=5:1至二氯甲烷:甲醇=10:1),得到2-(4-溴苯氧基)乙胺(1.60g,7.26mmol,80.9%产率,97.9%纯度),其为黄色油状物。LCMS[M+1,M+3]:216,218。
化合物132:在-10℃向3-氧代戊烷二酸二甲基酯(686mg,3.94mmol,567uL,1.05当量)和(1R,2S)-2-苯基环丙胺(500mg,3.75mmol,1.00当量)在MeOH(15.0mL)中的混合物添加AcOH(450mg,7.50mmol,429uL,2.00当量)。将混合物在-10℃搅拌1小时,然后在-10℃分批将NaBH3CN(707mg,11.3mmol,3.00当量)添加至混合物,并将反应在-10~0℃搅拌2小时。在完成之后,将反应混合物添加至水(20mL),然后用DCM(2×20mL)萃取。将合并的有机层经Na2SO4干燥,过滤并浓缩,得到3-[[(1R,2S)-2-苯基环丙基]氨基]戊烷二酸二甲基酯(1.00g,粗品),其为黄色油状物。LCMS[M+1]:292。
化合物133:将3-[[(1R,2S)-2-苯基环丙基]氨基]戊烷二酸二甲基酯(900mg,3.09mmol,1.00当量)在(Boc)2O(9.50g,43.5mmol,10.0mL,14.1当量)中的混合物在15℃搅拌12小时。在完成之后,将混合物通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=100/1至5/1),得到3-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]戊烷二酸二甲基酯(500mg,1.20mmol,38.7%产率,93.7%纯度),其为无色油状物。LCMS[M-99]:292
1H NMR(400MHz,氯仿-d)δ7.31-7.25(m,2H),7.22-7.08(m,3H),4.38-4.29(m,1H),3.71(s,3H),3.64(s,3H),3.10-2.93(m,2H),2.77-2.63(m,3H),2.18-2.14(m,1H),1.48-1.35(m,10H),1.31-1.14(m,1H)。
化合物134:向3-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]戊烷二酸二甲基酯(400mg,1.02mmol,1.00当量)在EtOH(15.0mL)中的混合物添加KOH(80.8mg,1.22mmol,85%纯度,1.20当量),并将反应在15℃搅拌4小时。在完成之后,将反应混合物用1M HCl调节至pH~6,然后用DCM(2×15mL)萃取。将合并的有机层经Na2SO4干燥,过滤并浓缩,得到3-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-5-乙氧基-5-氧代-戊酸(270mg,684umol,67.1%产率,99.2%纯度),其为黄色油状物。LCMS[M-99]:292。
化合物135:在0℃向3-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-5-乙氧基-5-氧代-戊酸(330mg,843umol,1.00当量)在DMF(10.0mL)中的混合物添加HATU(641mg,1.69mmol,2.00当量)和DIPEA(218mg,1.69mmol,294uL,2.00当量)。在将反应在0℃搅拌0.5小时之后,添加2-(4-溴苯氧基)乙胺(237mg,1.10mmol,1.30当量),并将混合物在0-15℃搅拌11.5小时。在完成之后,将反应混合物添加至水(15mL),然后用DCM(2×15mL)萃取,将合并的有机层经Na2SO4干燥,过滤并浓缩。残留物通过柱色谱法纯化(石油醚:乙酸乙酯=50:1~3:1),得到5-[2-(4-溴苯氧基)乙基氨基]-3-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-5-氧代-戊酸乙基酯(330mg,515umol,61.1%产率,92%纯度),其为黄色油状物。LCMS[M-99]:489,491。
化合物136:向5-[2-(4-溴苯氧基)乙基氨基]-3-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-5-氧代-戊酸乙基酯(250mg,424umol,1.00当量)在MeOH(2.00mL)和H2O(500uL)中的混合物添加NaOH(67.9mg,1.70mmol,4.00当量),并将混合物在15℃搅拌3小时。在完成之后,将反应混合物用0.5M HCl水溶液稀释至pH~7,然后将混合物添加至水(10mL),并用DCM(2×10mL)萃取。将合并的有机层经Na2SO4干燥,过滤并浓缩,得到5-[2-(4-溴苯氧基)乙基氨基]-3-[叔丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-5-氧代-戊酸(180mg,306umol,72.1%产率,95.4%纯度),其为黄色固体。LCMS[M-99,M+23]:463,585。
化合物137:向5-[2-(4-溴苯氧基)乙基氨基]-3-[叔-丁氧基羰基-[(1R,2S)-2-苯基环丙基]氨基]-5-氧代-戊酸(120mg,214umol,1.00当量)在THF(4.00mL)中的混合物添加Ac2O(43.6mg,427umol,40.0uL,2.00当量),并将反应在70℃在N2下搅拌12小时。在完成之后,将反应混合物浓缩。残留物通过制备性TLC纯化(石油醚:乙酸乙酯=3:1),得到N-[1-[2-(4-溴苯氧基)乙基]-2,6-二氧代-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(60.0mg,109umol,51.4%产率,99.5%纯度),其为白色固体。LCMS[M-55,M+23]:487,567。
1H NMR(400MHz,氯仿-d)δ7.40-7.19(m,5H),7.11-7.04(m,2H),6.81-6.74(m,2H),4.18(t,J=6.2Hz,2H),4.13-4.03(m,3H),3.45-3.30(m,2H),2.93-2.82(m,2H),2.74-2.67(m,1H),2.19-2.06(m,1H),1.42(s,9H),1.33-1.25(m,2H)。
化合物138:向N-[1-[2-(4-溴苯氧基)乙基]-2,6-二氧代-4-哌啶基]-N-[(1R,2S)-2-苯基环丙基]氨基甲酸叔丁基酯(60.0mg,110umol,1.00当量)在DCM(500uL)中的混合物添加TFA(770mg,6.75mmol,500uL,61.2当量),并将反应在15℃搅拌1小时。在完成之后,将反应混合物浓缩。残留物通过制备性HPLC纯化((仪器:GX-E;柱:Phenomenex SynergiC18150*25*10um;条件:水(0.05%HCl)-ACN;开始B:35;结束B:55;梯度时间(min):7.8;100%B保持时间(min):2;流速(ml/min):28)。将得到的产物浓缩,然后冻干。得到产物1-[2-(4-溴苯氧基)乙基]-4-[[(1R,2S)-2-苯基环丙基]氨基]哌啶-2,6-二酮(30.8mg,63.9umol,57.9%产率,99.8%纯度,HCl),其为黄色油状物。LCMS[M+1]:443,445。
1H NMR(400MHz,甲醇-d4)δ7.41-7.31(m,4H),7.29-7.17(m,3H),6.85(d,J=8.4Hz,2H),4.20-4.06(m,5H),3.32-3.22(m,2H),3.18-3.01(m,3H),2.65-2.54(m,1H),1.68-1.56(m,1H),1.53-1.43(m,1H)。
实施例48
1-吗啉代-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮二-盐酸盐(142)
步骤1.3-(4-((叔丁氧基羰基)((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙酸甲
基酯(139)
向中间体79(1.00g,3.16mmol)在DMF(8mL)中的溶液添加TEA(1.189mL,8.53mmol)、KI(131mg,0.790mmol)和3-溴丙酸甲基酯(0.345mL,3.16mmol)。将反应混合物在室温搅拌4小时,用盐水稀释并用EA萃取。将萃取物用盐水洗涤,经无水Na2SO4干燥,过滤并浓缩。对残留物实施快速柱色谱法(洗脱剂EA-己烷(4:1)),得到标题化合物65(1.027g,81%产率),其为胶状物。产物含有每1M希望的化合物0.18M EA。
1H NMR:500MHz,丙酮-d6,δ(ppm):7.32-7.28(m,2H),7.21-7.18(m,3H),3.68-3.62(m,1H),3.65(s,3H),3.00-2.93(m,2H),2.65-2.61(m,3H),2.48(t,J=7.2Hz,2H),2.19-2.10(m,3H),2.06-2.00(m,2H),1.76-1.67(m,2H),1.43(s,9H),1.42-1.38(m,1H),1.29-1.25(m,1H)。MS:402.5(计算值),403.3(M+H+,实测值)。
步骤2.3-(4-((叔丁氧基羰基)((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙酸
(140)
向酯139(1.027g,2.55mmol)在THF(20mL)中的溶液添加NaOH(153mg,3.83mmol)在水(10mL)中的溶液。将反应混合物在室温搅拌2小时,然后用HCl酸化至pH 5。将酸性溶液真空蒸发,形成玻璃状固体。然后将所述物质悬浮在DCM中,用己烷处理并蒸发,得到标题化合物140(1.13g,99%产率),其为白色蓬松固体,其含有1.5当量NaCl。将所述物质按原样用于后续步骤。MS:388.5(计算值),389.7(M+H+,实测值)。
步骤3.(1-(3-吗啉代-3-氧代丙基)哌啶-4-基)((1R,2S)-2-苯基环丙基)氨基甲
酸叔丁基酯(141)
向酸140(800mg,1.79mmol)在DCM(30mL)中的悬浮液添加HOBt水合物(548mg,3.58mmol)、EDC盐酸盐(1.029g,5.37mmol)和吗啉(0.627mL,7.16mmol)。将反应混合物在室温搅拌过夜,用更多DCM稀释并用盐水洗涤。将有机相经Na2SO4干燥,过滤并浓缩。残留物通过快速柱色谱法纯化(洗脱剂5然后10%MeOH(含有2%氨)/DCM),得到标题化合物141(748mg,91%产率),其为蜂蜜状物质,其含有每1M产物约0.6M DCM。将所述物质按原样用于后续步骤。
1H NMR:500MHz,CD3OD,δ(ppm):7.26-7.23(m,2H),7.16-7.10(m,3H),3.72-3.68(m,1H),3.67-3.62(m,4H),3.57-3.53(m,4H),3.05-2.98(m,2H),2.69-2.66(m,2H),2.62-2.56(m,3H),2.13-2.09(m,4H),2.02-1.94(m,1H),1.82-1.79(m,1H),1.75-1.72(m,1H),1.41(s,9H),1.40-1.38(m,1H),1.25-1.21(m,1H)。MS:457.6(计算值),458.4(M+H+,实测值)。
步骤4.1-吗啉代-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮二-
盐酸盐(142)
在室温向化合物141(748mg,1.635mmol)在二噁烷(7.0mL)中的溶液添加在二噁烷中的4M HCl溶液(12.0ml,48mmol)。将混合物在环境温度搅拌3小时,然后真空蒸发至干。将所得的白色析出物用丙酮研磨,得到标题化合物142(637mg,91%产率),其为白色固体(实施例48)。
1H NMR:500MHz,DMSO-d6,δ(ppm):10.71和10.52(两个bs,1H,旋转异构体的混合物),10.18和10.02(2bs,2H,旋转异构体的混合物),7.32-7.29(m,2H),7.24-7.17(m,3H),3.61-3.59(m,4H),3.56-3.54(m,2H),3.45-3.44(m,5H),3.24(bt,2H),3.03-2.94(m,3H),2.89(t,J=7.6Hz,2H),2.68-2.65和2.59-2.55(两个m,1H,旋转异构体的混合物),2.32-2.21(bs,2H),2.11-2.01(m,2H),1.66和1.60-1.56(bs和m,1H,旋转异构体的混合物),1.31-1.27(m,1H)。MS:357.5(计算值),358.7(M+H+,实测值)。
遵循本文所述的反应方案和特定合成路线的一般教导,制备另外的下列化合物:
表2
其它示例性式(I)和式(II)的化合物
本发明的化合物具有两个或更多个手性中心并且被合成为立体异构体混合物,在空间中的原子排列不同的具有相同构造的异构体。所述化合物可以作为混合物使用,或者可以使用市售试剂和本领域技术人员熟知的用于分离立体异构体和对映异构体的常规方法分离各个组分/异构体,例如,根据制造商的说明使用(Sigma-Aldrich)或者(DiacelCorp)手性色谱HPLC柱。或者,可以使用光学纯的手性试剂和中间体合成本发明的化合物以制备单个异构体或对映异构体,如例如实施例7和8中所述。除非另有说明,否则所有手性(对映体和非对映体)和外消旋形式都在本发明的范围内。
实施例A
该实施例说明本发明的示例性化合物抑制LSD1酶活性。
表3中所示化合物的10点剂量-应答曲线使用荧光偶联酶促测定来确定,所述测定使用纯化的N端截短的人LSD1酶(氨基酸151-852;Genbank登录号NM015013),其含有N端His标签(Reaction Biology Corp)。在该测定中,使用辣根过氧化物酶/Amplex Red偶联反应通过LSD1FAD依赖性脱甲基酶活性产生过氧化氢,导致产生高荧光化合物试卤灵,其在590nM处被检测到。
简而言之,将本发明化合物溶于DMSO中,并对15%DMSO中的每种化合物进行一系列(10)3倍系列稀释。每种化合物的系列稀释物的初始起始浓度为10μM。还制备了缺乏化合物、LSD1酶或各种反应组分的对照样品并与化合物测试样品平行处理。
将各化合物的连续稀释液的等份试样加入到96孔板,其含有在10微升反应体积中的50nM纯化的N-截短的LSD1酶(RBC Cat#PDM-11-350),50mM Tris-HCl,pH7.5,0.05%CHAPS和1%DMSO。将板在室温预培养30分钟,向其中加入10μM组蛋白3.3肽(氨基酸1-21)以引发酶促反应。将反应混合物在室温培养1小时。在1小时后,加入辣根过氧化物酶(SigmaCat#P8375)和Amplex Red(InVitrogen A36006)的10μl检测混合物,并使用EnvisionMultiplate Reader(PerkinElmer;在535nM激发和在590nM读取发射)以5分钟间隔读取动力学测量值30分钟。每种化合物的IC50值从每个10点剂量-应答曲线使用GraphPad Prism 4软件以sigmodial剂量应答测定。示例性的式(I)和式(II)化合物的结果示于表3中。
表3
示例性的式(I)化合物对LSD1活性的抑制
实施例B
该实施例说明本发明的示例性化合物抑制表达LSD1的肿瘤细胞系的生长。
MV4-11细胞系由患有双表型B-骨髓单核细胞白血病的10岁男性的原始细胞建立。该细胞系表达白血病融合蛋白(MLL-AF9+),LSD1,并已显示对LSD1的抑制剂敏感。
在CellTiter Glo发光测定法(Promega Corp)中测量式(I)或式(II)化合物对LSD1介导的细胞增殖的抑制,其通过使用BMG LabTech CLARIOStar仪器根据制造商的说明定量ATP量来确定活细胞的数量。简而言之,将MV4-11细胞在96孔培养板中以1000细胞/90μl/孔的密度铺板并在补充有10%胎牛血清(FBS)和1%青霉素和1%链霉素的IMDM培养基(Gibco)中在37℃培养。在缺乏FBS的IMDM培养基中制备各种式(I)测试化合物的一系列3倍系列稀释液,并以1μM至0.01nM的终浓度添加至细胞。平行处理缺乏测试化合物或细胞的对照样品。将板在37℃培养4天,然后加入50μl含有相同浓度测试化合物的新鲜培养基。将板再培养3天(第7天)。如下所述,时间零点的基线测量在第0天进行。
在第7天,通过抽吸除去上清液,并使板平衡至室温(约15分钟)。使用45μl(30μl,第0天)Cell Titer Glo试剂(Promega Corp)裂解细胞。将板振荡2分钟并在室温培养30分钟。通过测量340nm处的发光,使用分光光度读数测定细胞活力的抑制程度,并使用GraphPad Prism 4软件计算每种化合物的EC50浓度。结果如表4所示。注解:N/D=未测定。
表4
式(I)和式(II)的示例性化合物抑制LSD1介导的细胞增殖
如实施例A和B中所证实,本发明的许多式(I)和式(II)的化合物的效力是LSD1抑制剂GSK2879552的至少10倍、至少20倍、至少30倍、至少40倍或者高达至少50倍,所述GSK2879552为
目前正在进行I期临床试验(临床试验政府标识符:NCT02177812)。
虽然已经结合其具体实施例描述了本发明,但应该理解的是,它能够进行进一步的修改,并且本申请旨在覆盖本发明的任何变型、用途或修改,大体上,遵循本发明的原则并包括从本发明的偏离,这些偏离在本发明所属领域内的已知或惯例实践中,并且可以应用于前面阐述的基本特征,并且如下在所附权利要求的范围内。
Claims (68)
1.式(I)或者式(II)的化合物:
或其药学上可接受的盐:
其中:
R1为氢、C1-C4烷基或者C1-C4酰基;
L为-(CH2)s-CR2R3-(CH2)m-;
R2和R3各自独立地为氢、C1-C4烷基、-OR4或者芳烷基;
各个R4独立地为氢或者C1-C4烷基;
X为-W-R5或者Y-R6;
W为-NR4-或者-O-;
Y为-C(O)-、-S-、-SO-、-SO2-、-NR4SO2-、-SO2NR4-或者-NR4C(O)-;
R5为酰基、C1-C4烷基、环烷基、杂环基、芳基或者杂芳基,其中所述环烷基、杂环基、芳基或者杂芳基中的每个任选独立地取代有一个或者多个R8;
R6为C1-C6烷基、芳基、-NR4R7或者杂环基,其在一个或者多个碳原子上任选独立地取代有C1-C6烷基、卤素、氰基、卤代烷基或者在一个或者多个氮原子上任选独立地取代有-C(O)C1-C6烷基、-C(O)OC1-C6烷基、-C(O)NR4C1-C6烷基,或者-S(O)2NR4C1-C6烷基;
R7为羟基、烷氧基、-SO2C1-C6烷基、-SO2环烷基,或者-SO2芳基,其中各个所述-SO2环烷基和-SO2芳基中的环烷基或者芳基任选独立地取代有一个或者多个R8;
各个R8为卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代烷基、烷氧基、烷基氨基、二烷基氨基、环烷基、芳基、杂芳基、杂环基、芳烷基、杂芳基烷基、-(CH2)nCOOR4、-(CH2)nC(O)NR4OC1-C6烷基、-(CH2)nC(O)NR4SO2C1-C6烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-C2-C6烯基C(O)OR4、-C2-C6烯基C(O)NR4SO2 C1-C4烷基,或者-C2-C6烯基C(O)NR4SO2芳基,其中所述环烷基、芳基、杂芳基、杂环基中的每个任选独立地取代有一个或者多个C1-C3烷基或者-CH2NR4SO2芳基;
m为0或者1;
s为0或者1;
各个n为0、1,或者2;
各个p为0、1或者2;
各个RA基团独立地为氧代或者C1-C3烷基,或者在不同环原子上的两个RA基团一起形成C1-C3桥,其中所述桥碳中的一个任选被-NH-替代;和
各个Q1、Q2和Q3独立地为氢、卤素、卤代烷基、C1-C4-烷基,或者C1-C4-烷氧基。
2.权利要求1的化合物,其中W为-O-和s为1和m为0。
3.权利要求2的化合物,其中R5为芳基,其任选独立地取代有一个或者多个R8。
4.权利要求3的化合物,其中所述芳基为苯基,其任选独立地取代有一个或者多个R8。
5.权利要求4的化合物,其中R8为杂环基,其任选独立地取代有一个或者多个C1-C3烷基。
6.权利要求5的化合物,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、四氢吡喃基、1,3-二氧杂环戊烷基、1,4-二氧杂环己烷基、吗啉基、二甲基-吗啉基、硫吗啉基、1,4-二硫杂环己烷基,或者1,3,5-三硫杂环己烷基。
8.权利要求4的化合物,其中R8为卤素、C1-C6烷基、-(CH2)nCOOR4、-(CH2)nC(O)NR4SO2C1-C4烷基、-(CH2)nC(O)NR4OC1-C4烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-CH=CHC(O)OR4、-CH=CHC(O)NR4SO2C1-C4烷基,或者-CH=CHC(O)NR4SO2芳基。
9.权利要求2的化合物,其中R5为杂芳基,其任选独立地取代有一个或者多个R8。
10.权利要求9的化合物,其中所述杂芳基为吡啶基、6-甲基-吡啶基、4-羧基-吡啶基、二氢喹啉酮、二氢吲哚酮、喹唑啉基、喹啉基、嘧啶基、2-甲基-嘧啶基、哒嗪基、6-甲基-哒嗪基、吡唑基、1-甲基-吡唑基、5-甲基-吡唑基、1,3-二甲基-吡唑基、噻唑基、5-甲基-噻唑基、苯并[d]噁唑-2(3H)-酮、2H-苯并[b][1,4]噁嗪-3(4H)-酮基、噻二唑基或者5-甲基-噻二唑基。
11.权利要求9的化合物,其中所述杂芳基为吡啶基,其任选独立地取代有一个或者多个R8。
12.权利要求11的化合物,其中R8为杂环基,其任选独立地取代有一个或者多个C1-C3烷基。
13.权利要求12的化合物,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、四氢吡喃基、1,3-二氧杂环戊烷基、1,4-二氧杂环己烷基、吗啉基、二甲基-吗啉基、硫吗啉基、1,4-二硫杂环己烷基,或者1,3,5-三硫杂环己烷基。
15.权利要求9的化合物,其中R8为卤素、C1-C6烷基、-(CH2)nCOOR4、-(CH2)nC(O)NR4OC1-C4烷基、-(CH2)nC(O)NR4SO2C1-C4烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-CH=CHC(O)OR4、-CH=CHC(O)NR4SO2C1-C4烷基,或者-CH=CHC(O)NR4SO2芳基。
16.权利要求2的式(II)化合物,其中RA为氧代和n为1或者2。
17.权利要求2的式(II)化合物,其中在不同环原子上的两个RA基团一起形成C1-C3桥,其中所述桥碳中的一个任选被-NH-替代。
18.权利要求2的化合物,其中所述化合物为
1-苯氧基-3-[4-[[反式-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇;
1-(2-甲氧基-3-苯氧基-丙基)-N-[反式-2-苯基环丙基]哌啶-4-胺;
2-甲基-1-苯氧基-3-(4-(((反式)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇;
1-苯氧基-3-[3-[[[(反式)-2-苯基环丙基]氨基]甲基]氮杂环丁烷-1-基]丙-2-醇;
(R)-1-苯氧基-3-(4-(((1S,2R)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇;
(S)-1-苯氧基-3-(4-(((1S,2R)-2-苯基环丙基)氨基)哌啶-1-基)丙-2-醇;
1-苯氧基-3-[(1R,5S)-6-[[(反式)-2-苯基环丙基]氨基]-3-氮杂二环[3.1.1]庚-3-基]丙-2-醇;
(反式)-N-[[1-(2-苯氧基乙基)氮杂环丁烷-3-基]甲基]-2-苯基-环丙胺;
(反式)-N-[[1-(3-苯氧基丙基)氮杂环丁烷-3-基]甲基]-2-苯基-环丙胺;
1-[2-(4-溴苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺;
1-(3-苯氧基丙基)-N-((反式)-2-苯基环丙基)哌啶-4-胺;
1-(2-苯氧基乙基)-N-((反式)-2-苯基环丙基)哌啶-4-胺;
2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸;
N-(甲基磺酰基)-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酰胺;
2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)-N-(苯基磺酰基)乙酰胺;
N,N-二甲基-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酰胺;
N-甲氧基-2-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酰胺;
1-[2-(4-吗啉代苯氧基)乙基]-N-[(1R,2S)-2-苯基环丙基]哌啶-4-胺;
1-(2-(4-(4-甲基哌嗪-1-基)苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)噁唑烷-2-酮;
1-甲基-3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)咪唑烷-2-酮;
3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
4-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)吗啉-3-酮;
1-(4-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)哌嗪-1-基)乙-1-酮;
1-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)吡咯烷-2-酮;
1-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)哌啶-2-酮;
N-((1R,2S)-2-苯基环丙基)-1-(2-(4-(哌啶-1-基)苯氧基)乙基)哌啶-4-胺;
2-(4-(2-羟基-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)乙酸;
4-(2-羟基-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯甲酸;
(E)-3-(4-(2-羟基-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)丙烯酸;
2-(4-(3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)乙酸;
4-(3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯甲酸;
(E)-3-(4-(3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)丙烯酸;
(1R,2S)-N-((1-(2-(4-溴苯氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
1-(2-(2,4-二氯苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
(1R,2S)-N-((1-(2-(2,4-二氯苯氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
1-(2-(2,4-二氟苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
(1R,2S)-N-((1-(2-(2,4-二氟苯氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
(E)-3-(4-(2-羟基-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)-N-(甲基磺酰基)丙烯酰胺;
1-(2-((2-甲基吡啶-4-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
(1R,2S)-2-苯基-N-((1-(2-(对甲苯基氧基)乙基)氮杂环丁烷-3-基)甲基)环丙-1-胺;
(1R,2S)-2-苯基-N-((1-(2-(吡啶-2-基氧基)乙基)氮杂环丁烷-3-基)甲基)环丙-1-胺;
4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯甲酸;
N-(环丙基磺酰基)-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯甲酰胺;
4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)-N-(苯基磺酰基)苯甲酰胺;
(E)-N-(甲基磺酰基)-3-(4-(3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙氧基)苯基)丙烯酰胺;
3-(4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
4-(4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)吗啉-3-酮
1-(4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)哌啶-2-酮;
(1R,2S)-2-苯基-N-((1-(2-(4-(哌嗪-1-基)苯氧基)乙基)氮杂环丁烷-3-基)甲基)环丙-1-胺;
(1R,2S)-N-((1-(2-(4-(4-甲基哌嗪-1-基)苯氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
1-(4-(4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)哌嗪-1-基)乙-1-酮;
1-(2-((5-甲基吡啶-2-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((6-甲基吡啶-3-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
N-(甲基磺酰基)-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯甲酰胺;
N-(乙基磺酰基)-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯甲酰胺;
(1S,2R)-N-((1-(2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
2-(4-(2-(3-((((1S,2R)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)乙酸;
4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯甲酸
2-(4'-(2-(3-((((1S,2R)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)-[1,1'-联苯]-4-基)-N-(苯基磺酰基)乙酰胺;
3-(6-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)吡啶-3-基)-1,3-氧杂氮杂环己烷-2-酮;
3-(5-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)吡啶-2-基)-1,3-氧杂氮杂环己烷-2-酮;
N-((1R,2S)-2-苯基环丙基)-1-(2-(对甲苯基氧基)乙基)哌啶-4-胺;
3-(4-(2-(4-(甲基((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
N-甲基-1-(2-((6-甲基吡啶-3-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
(1R,2S)-N-((1-(2-((6-甲基吡啶-3-基)氧基)乙基)氮杂环丁烷-3-基)甲基)-2-苯基环丙-1-胺;
3-(5-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)吡啶-2-基)-1,3-氧杂氮杂环己烷-2-酮;
6-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)-3,4-二氢喹啉-2(1H)-酮;
5-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)二氢吲哚-2-酮;
1-(2-(3-氟-4-甲基苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
N-((1R,2S)-2-苯基环丙基)-1-(2-(喹唑啉-4-基氧基)乙基)哌啶-4-胺;
N-((1R,2S)-2-苯基环丙基)-1-(2-(喹啉-4-基氧基)乙基)哌啶-4-胺;
N-((1R,2S)-2-苯基环丙基)-1-(2-(嘧啶-5-基氧基)乙基)哌啶-4-胺;
1-(2-(3,5-二氟苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-(3,5-二氯苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((6-甲基哒嗪-3-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
(E)-3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)丙烯酸;
1-(2-(3-氟苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((6-甲基吡啶-2-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((2-甲基嘧啶-5-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-(4-溴苯氧基)乙基)-4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-2-酮;
2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙-1-醇;
N-(1-(2-(4-(2-氧代-1,3-氧杂氮杂环己烷-3-基)苯氧基)乙基)哌啶-4-基)-N-((1R,2S)-2-苯基环丙基)乙酰胺;
1-(2-甲氧基乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((1,3-二甲基-1H-吡唑-5-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((1-甲基-1H-吡唑-3-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
3-(4-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙氧基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
1-(2-异丙氧基乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
2-(2-氟-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸;
1-(2-(3,5-二氟-4-甲基苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((5-甲基-1,3,4-噻二唑-2-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
2-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)异烟酸;
3-(4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)噁唑烷-2-酮;
1-(2-(4-溴苯氧基)乙基)-4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-2,6-二酮;
N-((1R,2S)-2-苯基环丙基)-1-(2-(吡啶-3-基氧基)乙基)哌啶-4-胺;
7-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮;
6-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯并[d]噁唑-2(3H)-酮;
1-(2-((5-甲基噻唑-2-基)氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
3-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)异烟酸;
2-(3-氯-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸;
2-(3-氟-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸;
2-(3-甲基-4-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙氧基)苯基)乙酸;或者
4-(2-(4-(((1R,2S)-2-(3,4-二氟苯基)环丙基)氨基)哌啶-1-基)乙氧基)苯甲酸;
或其药学上可接受的盐。
19.权利要求1的化合物,其中W为-NR4-和s为1和m为0。
20.权利要求19的化合物,其中R5为芳基,其任选独立地取代有一个或者多个R8。
21.权利要求20的化合物,其中所述芳基为苯基,其任选独立地取代有一个或者多个R8。
22.权利要求21的化合物,其中R8为杂环基,其任选独立地取代有一个或者多个C1-C3烷基。
23.权利要求22的化合物,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、四氢吡喃基、1,3-二氧杂环戊烷基、1,4-二氧杂环己烷基、吗啉基、二甲基-吗啉基、硫吗啉基、1,4-二硫杂环己烷基,或者1,3,5-三硫杂环己烷基。
25.权利要求21的化合物,其中R8为卤素、C1-C6烷基、-(CH2)nCOOR4、-(CH2)pC(O)NR4OC1-C4烷基、-(CH2)pC(O)NR4SO2C1-C4烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-CH=CHC(O)OR4、-CH=CHC(O)NR4SO2C1-C4烷基,或者-CH=CHC(O)NR4SO2芳基。
26.权利要求19的化合物,其中R5为杂芳基,其任选独立地取代有一个或者多个R8。
27.权利要求26的化合物,其中所述杂芳基为吡啶基、6-甲基-吡啶基、4-羧基-吡啶基、二氢喹啉酮、二氢吲哚酮、喹唑啉基、喹啉基、嘧啶基、2-甲基-嘧啶基、哒嗪基、6-甲基-哒嗪基、吡唑基、1-甲基-吡唑基、5-甲基-吡唑基、1,3-二甲基-吡唑基、噻唑基、5-甲基-噻唑基、苯并[d]噁唑-2(3H)-酮基、2H-苯并[b][1,4]噁嗪-3(4H)-酮基、噻二唑基或者5-甲基-噻二唑基。
28.权利要求26的化合物,其中所述杂芳基为吡啶基,其任选独立地取代有一个或者多个R8。
29.权利要求28的化合物,其中R8为杂环基,其任选独立地取代有一个或者多个C1-C3烷基。
30.权利要求29的化合物,其中所述杂环基为氮杂环丁烷基、吡咯烷基、吡唑烷基、哌啶基、哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、四氢吡喃基、1,3-二氧杂环戊烷基、1,4-二氧杂环己烷基、吗啉基、二甲基-吗啉基、硫吗啉基、1,4-二硫杂环己烷基,或者1,3,5-三硫杂环己烷基。
32.权利要求28的化合物,其中R8为卤素、C1-C6烷基、-(CH2)nCOOR4、-(CH2)pC(O)NR4OC1-C4烷基、-(CH2)pC(O)NR4SO2C1-C4烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-CH=CHC(O)OR4、-CH=CHC(O)NR4SO2C1-C4烷基,或者-CH=CHC(O)NR4SO2芳基。
33.权利要求19的式(II)化合物,其中RA为氧代和n为1或者2。
34.权利要求19的式(II)化合物,其中在不同环原子上的两个RA基团一起形成C1-C3桥,其中所述桥碳中的一个任选被-NH-替代。
35.权利要求19的化合物,其中所述化合物为
1-苯氨基-3-[4-[[反式-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇;
1-(N-甲基苯氨基)-3-[4-[[反式-2-苯基环丙基]氨基]-1-哌啶基]丙-2-醇;
1-(2-(苯基氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-(甲基(苯基)氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((4-溴苯基)氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)哌啶-2-酮;
3-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
4-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)吗啉-3-酮;
N-((1R,2S)-2-苯基环丙基)-1-(2-((4-(哌啶-1-基)苯基)氨基)乙基)哌啶-4-胺;
1-(2-((4-吗啉代苯基)氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
1-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)吡咯烷-2-酮;
3-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)噁唑烷-2-酮;
1-甲基-3-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)咪唑烷-2-酮;
1-(4-(4-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)哌嗪-1-基)乙-1-酮;
3-(4-((2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙基)氨基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
N,6-二甲基-N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)吡啶-3-胺;
1-(2-((4-溴苯基)(甲基)氨基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
3-(4-(甲基(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)苯基)-1,3-氧杂氮杂环己烷-2-酮;
N-甲基-N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)乙酰胺;
N,2-二甲基-N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)吡啶-4-胺;
1-(2-(4-溴-2-氟苯氧基)乙基)-N-((1R,2S)-2-苯基环丙基)哌啶-4-胺;
2-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)异烟酸;或者
3-((2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)氨基)异烟酸;
或其药学上可接受的盐。
36.权利要求1的化合物,其中Y为-C(O)-,s为0,m为0,R2为C1-C4烷基或者芳烷基,R3为氢和R6为杂环基。
37.权利要求36的化合物,其中所述杂环基为哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。
38.权利要求37的化合物,其中R2为甲基。
39.权利要求37的化合物,其中R2为苄基。
41.权利要求1的化合物,其中Y为-C(O)-,s为1,m为0,R2和R3各自独立地为氢,和R6为杂环基。
42.权利要求41的化合物,其中所述杂环基为哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。
44.权利要求1的化合物,其中Y为-C(O)-,s为1,m为1,R2和R3各自为氢,和R6为杂环基。
45.权利要求41的化合物,其中所述杂环基为哌嗪基、4-甲基-哌嗪基、4-酰基-哌嗪基、吗啉基、二甲基-吗啉基,或者硫吗啉基。
47.权利要求1的化合物,其中Y为-C(O)-,s为1,m为1,R2和R3各自为氢,和R6为-NR4R7。
48.权利要求47的化合物,其中R7为烷氧基、-SO2C1-C4烷基、-SO2环烷基,或-SO2芳基,其中各个所述-SO2环烷基和-SO2芳基中的环烷基或者芳基可任选取代有一个或者多个R8。
49.权利要求36、42或者44的化合物,其中所述化合物为
1-吗啉代-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮;
N-甲氧基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙酰胺;
1-吗啉代-3-苯基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮;
1-吗啉代-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮;
N-(甲基磺酰基)-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙酰胺;
3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)-1-(哌嗪-1-基)丙-1-酮;
3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)-N-(苯基磺酰基)丙酰胺;
1-(4-甲基哌嗪-1-基)-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮;
N-(乙基磺酰基)-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙酰胺;
3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)-1-硫吗啉代丙-1-酮;
1-(4-甲基哌嗪-1-基)-4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁-1-酮;
4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)-1-(哌嗪-1-基)丁-1-酮;
1-吗啉代-4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁-1-酮;
4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)-N-(苯基磺酰基)丁酰胺;
N-(环丙基磺酰基)-4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁酰胺;
N-(乙基磺酰基)-4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁酰胺;
N-(甲基磺酰基)-4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁酰胺;或者
1-(顺式-2,6-二甲基吗啉代)-3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙-1-酮;
或其药学上可接受的盐。
50.权利要求1的化合物,其中Y为-NR4SO2-,m为1,R2和R3各自为氢,和R6为C1-C6烷基或者芳基,其中所述芳基可任选独立地取代有一个或者多个C1-C3烷基、卤素、卤代烷基或者氰基。
51.权利要求50的化合物,其中所述化合物为
N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)甲烷磺酰胺;
N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)苯磺酰胺;
N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)丙烷-2-磺酰胺;
N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙基)甲烷磺酰胺;
N-甲基-N-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙基)甲烷磺酰胺;
N-(2-(3-((((1R,2S)-2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-基)乙基)甲烷磺酰胺;
N-甲基-N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)甲烷磺酰胺;
N-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)环丙烷磺酰胺;
或其药学上可接受的盐。
52.权利要求1的化合物,其中Y为-SO2NR4-,s为1,m为1,R2和R3各自独立地为氢和R6为C1-C6烷基或者芳基,其中所述芳基可任选独立地取代有一个或者多个C1-C3烷基、卤素、卤代烷基或者氰基。
53.权利要求46的化合物,其中所述化合物为
N-苯基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙烷-1-磺酰胺;或者
N-甲基-2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙烷-1-磺酰胺;
或其药学上可接受的盐。
54.权利要求1的化合物,其中Y为-NR4C(O)-,s为1,m为1,R2和R3各自为氢和各个R4独立地为氢或者C1-C3烷基。
55.权利要求54的化合物,其中R4为C1-C3烷基。
56.化合物,其中所述化合物为1,1-二甲基-3-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)脲或1-甲基-3-(2-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)乙基)脲。
57.化合物,其为:
3-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丙酸;或者
4-(4-(((1R,2S)-2-苯基环丙基)氨基)哌啶-1-基)丁酸;
或其药学上可接受的盐。
58.药物组合物,其包含有效LSD-1抑制量的权利要求1-57中的任一项的化合物,和药学上可接受的赋形剂。
59.药物组合物,其包含治疗有效量的权利要求1-57中的任一项的化合物,和药学上可接受的赋形剂。
60.权利要求1的式(I)或者式(II)的化合物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途。
61.权利要求60的用途,其中所述化合物的治疗有效量为每天约0.01至300mg/kg。
62.权利要求61的用途,其中所述化合物的治疗有效量为每天约0.1至100mg/kg。
63.权利要求62的用途,其中所述癌症选自心脏:肉瘤、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤;肺:支气管原癌、肺泡癌、支气管腺瘤、肉瘤、淋巴瘤、软骨错构瘤、间皮瘤;胃肠道:食道、胃、胰腺、小肠、大肠;泌尿生殖道:肾、膀胱和尿道、前列腺、睾丸;肝:肝癌、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞性腺瘤、血管瘤;胆道:胆囊癌、壶腹癌、胆管癌;骨:成骨性肉瘤、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因肉瘤、恶性淋巴瘤、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤、良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤;神经系统:头骨、脑膜、脑、脊髓;妇科:子宫、宫颈、卵巢、阴道、输卵管;血液方面:血液、霍奇金病、非霍奇金淋巴瘤;皮肤:恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、牛皮癣;和肾上腺:神经母细胞瘤。
64.权利要求60的用途,其中所述癌症为非小细胞肺癌。
65.式(I)或者式(II)的化合物:
或其药学上可接受的盐:
其中:
R1为氢、C1-C4烷基或者C1-C4酰基;
L为-(CH2)s-CR2R3-(CH2)m-;
R2和R3各自独立地为氢、C1-C4烷基、-OR4或者芳烷基;
各个R4独立地为氢或者C1-C4烷基;
X为-W-R5或者Y-R6;
W为-O-;
Y为-C(O)-、-S-、-SO-、-SO2-、-NR4SO2-、-SO2NR4-或者-NR4C(O)-;
R5为芳基,其任选独立地取代有一个或者多个R8且所述芳基为苯基,其任选独立地取代有一个或者多个R8;
R6为C1-C6烷基、芳基、-NR4R7或者杂环基,其在一个或者多个碳原子上任选独立地取代有C1-C6烷基、卤素、氰基、卤代烷基或者在一个或者多个氮原子上任选独立地取代有-C(O)C1-C6烷基、-C(O)OC1-C6烷基、-C(O)NR4C1-C6烷基,或者-S(O)2NR4C1-C6烷基;
R7为羟基、烷氧基、-SO2C1-C6烷基、-SO2环烷基,或者-SO2芳基,其中各个所述-SO2环烷基和-SO2芳基中的环烷基或者芳基任选独立地取代有一个或者多个R8;
R8为杂环基,其任选独立地取代有一个或者多个C1-C3烷基或C1-C4酰基;
m为0;
s为1;
各个n为0、1,或者2;
各个p为0、1或者2;
各个RA基团独立地为氧代或者C1-C3烷基,或者在不同环原子上的两个RA基团一起形成C1-C3桥,其中所述桥碳中的一个任选被-NH-替代;和
各个Q1、Q2和Q3独立地为氢、卤素、卤代烷基、C1-C4-烷基,或者C1-C4-烷氧基。
66.式(I)或者式(II)的化合物:
或其药学上可接受的盐:
其中:
R1为氢、C1-C4烷基或者C1-C4酰基;
L为-(CH2)s-CR2R3-(CH2)m-;
R2和R3各自独立地为氢;
各个R4独立地为氢或者C1-C4烷基;
X为-W-R5或者Y-R6;
W为–NR4-或者-O-;
Y为-SO2NR4;
R5为酰基、C1-C4烷基、环烷基、杂环基、芳基或者杂芳基,其中所述环烷基、杂环基、芳基或者杂芳基中的每个任选独立地取代有一个或者多个R8;
R6为环烷基,其中所述环烷基可任选独立地取代有一个或者多个C1-C3烷基、卤素、卤代烷基、氨基或者氰基;
R7为羟基、烷氧基、-SO2C1-C6烷基、-SO2环烷基,或者-SO2芳基,其中各个所述-SO2环烷基和-SO2芳基中的环烷基或者芳基任选独立地取代有一个或者多个R8;
各个R8为卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代烷基、烷氧基、烷基氨基、二烷基氨基、环烷基、芳基、杂芳基、杂环基、芳烷基、杂芳基烷基、-(CH2)nCOOR4、-(CH2)nC(O)NR4OC1-C6烷基、-(CH2)nC(O)NR4SO2C1-C6烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-C2-C6烯基C(O)OR4、-C2-C6烯基C(O)NR4SO2 C1-C4烷基,或者-C2-C6烯基C(O)NR4SO2芳基,其中所述环烷基、芳基、杂芳基、杂环基中的每个任选独立地取代有一个或者多个C1-C3烷基或者-CH2NR4SO2芳基;
m为1;
s为0或者1;
各个n为0、1,或者2;
各个p为0、1或者2;
各个RA基团独立地为氧代或者C1-C3烷基,或者在不同环原子上的两个RA基团一起形成C1-C3桥,其中所述桥碳中的一个任选被-NH-替代;和
各个Q1、Q2和Q3独立地为氢、卤素、卤代烷基、C1-C4-烷基,或者C1-C4-烷氧基。
67.式(I)或者式(II)的化合物:
或其药学上可接受的盐:
其中:
R1为氢、C1-C4烷基或者C1-C4酰基;
L为-(CH2)s-CR2R3-(CH2)m-;
R2和R3各自独立地为氢;
各个R4独立地为氢或者C1-C4烷基;
X为-W-R5或者Y-R6;
W为-NR4-或者-O-;
Y为-SO2NR4;
R5为酰基、C1-C4烷基、环烷基、杂环基、芳基或者杂芳基,其中所述环烷基、杂环基、芳基或者杂芳基中的每个任选独立地取代有一个或者多个R8;
R6为C1-C6烷基或者芳基,其中所述芳基可任选独立地取代有一个或者多个氨基;
R7为羟基、烷氧基、-SO2C1-C6烷基、-SO2环烷基,或者-SO2芳基,其中各个所述-SO2环烷基和-SO2芳基中的环烷基或者芳基任选独立地取代有一个或者多个R8;
各个R8为卤素、羟基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代烷基、烷氧基、烷基氨基、二烷基氨基、环烷基、芳基、杂芳基、杂环基、芳烷基、杂芳基烷基、-(CH2)nCOOR4、-(CH2)nC(O)NR4OC1-C6烷基、-(CH2)nC(O)NR4SO2C1-C6烷基、-(CH2)nC(O)NR4SO2环烷基、-(CH2)nC(O)NR4SO2芳基、-C2-C6烯基C(O)OR4、-C2-C6烯基C(O)NR4SO2 C1-C4烷基,或者-C2-C6烯基C(O)NR4SO2芳基,其中所述环烷基、芳基、杂芳基、杂环基中的每个任选独立地取代有一个或者多个C1-C3烷基或者-CH2NR4SO2芳基;
m为1;
s为1;
各个n为0、1,或者2;
各个p为0、1或者2;
各个RA基团独立地为氧代或者C1-C3烷基,或者在不同环原子上的两个RA基团一起形成C1-C3桥,其中所述桥碳中的一个任选被-NH-替代;和
各个Q1、Q2和Q3独立地为氢、卤素、卤代烷基、C1-C4-烷基,或者C1-C4-烷氧基。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562272082P | 2015-12-29 | 2015-12-29 | |
US62/272,082 | 2015-12-29 | ||
US201662295369P | 2016-02-15 | 2016-02-15 | |
US62/295,369 | 2016-02-15 | ||
PCT/US2016/060379 WO2017116558A1 (en) | 2015-12-29 | 2016-11-03 | Lsd1 inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108884029A CN108884029A (zh) | 2018-11-23 |
CN108884029B true CN108884029B (zh) | 2021-10-26 |
Family
ID=57472003
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680077382.5A Active CN108884029B (zh) | 2015-12-29 | 2016-11-03 | Lsd1抑制剂 |
Country Status (11)
Country | Link |
---|---|
US (2) | US9809541B2 (zh) |
EP (1) | EP3397616B1 (zh) |
JP (1) | JP6916795B2 (zh) |
KR (1) | KR20180117602A (zh) |
CN (1) | CN108884029B (zh) |
AU (1) | AU2016382463B2 (zh) |
CA (1) | CA3009805C (zh) |
IL (1) | IL260217B (zh) |
MX (1) | MX2018008052A (zh) |
SG (1) | SG11201805645QA (zh) |
WO (1) | WO2017116558A1 (zh) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2734209T3 (es) | 2013-08-06 | 2019-12-04 | Imago Biosciences Inc | Inhibidores de KDM1A para el tratamiento de enfermedades |
PL3105218T3 (pl) | 2014-02-13 | 2020-03-31 | Incyte Corporation | Cyklopropyloaminy jako inhibitory lsd1 |
LT3105226T (lt) | 2014-02-13 | 2019-11-11 | Incyte Corp | Ciklopropilaminai, kaip lsd1 inhibitoriai |
WO2016007722A1 (en) | 2014-07-10 | 2016-01-14 | Incyte Corporation | Triazolopyridines and triazolopyrazines as lsd1 inhibitors |
CN107427699B (zh) | 2015-02-12 | 2021-10-19 | 伊美格生物科学公司 | 用于治疗疾病的kdm1a抑制剂 |
EP3277689B1 (en) | 2015-04-03 | 2019-09-04 | Incyte Corporation | Heterocyclic compounds as lsd1 inhibitors |
SG10202001219UA (en) | 2015-08-12 | 2020-03-30 | Incyte Corp | Salts of an lsd1 inhibitor |
US10059668B2 (en) * | 2015-11-05 | 2018-08-28 | Mirati Therapeutics, Inc. | LSD1 inhibitors |
AU2017263361B2 (en) * | 2016-05-09 | 2021-08-05 | Jubilant Epicore LLC | Cyclopropyl-amide compounds as dual LSD1/HDAC inhibitors |
WO2018035259A1 (en) | 2016-08-16 | 2018-02-22 | Imago Biosciences, Inc. | Methods and processes for the preparation of kdm1a inhibitors |
WO2018083189A1 (en) | 2016-11-03 | 2018-05-11 | Oryzon Genomics, S.A. | Biomarkers for determining responsiveness to lsd1 inhibitors |
JP7082806B2 (ja) * | 2017-07-07 | 2022-06-09 | 学校法人自治医科大学 | 多能性幹細胞からのテラトーマ形成抑制剤及びその用途 |
WO2019025588A1 (en) | 2017-08-03 | 2019-02-07 | Oryzon Genomics, S.A. | METHODS OF TREATING ALTERATIONS IN BEHAVIOR |
WO2019083971A1 (en) | 2017-10-23 | 2019-05-02 | Children's Medical Center Corporation | METHODS OF TREATING CANCER USING LSD1 INHIBITORS IN COMBINATION WITH IMMUNOTHERAPY |
EP3790867B1 (en) * | 2018-05-11 | 2024-03-27 | Imago Biosciences Inc. | Kdm1a inhibitors for the treatment of disease |
WO2020047198A1 (en) | 2018-08-31 | 2020-03-05 | Incyte Corporation | Salts of an lsd1 inhibitor and processes for preparing the same |
EP3941465A1 (en) | 2019-03-20 | 2022-01-26 | Oryzon Genomics, S.A. | Methods of treating attention deficit hyperactivity disorder using kdm1a inhibitors such as the compound vafidemstat |
AU2020242302A1 (en) | 2019-03-20 | 2021-09-16 | Oryzon Genomics, S.A. | Methods of treating borderline personality disorder |
CN114341366A (zh) | 2019-07-05 | 2022-04-12 | 奥莱松基因组股份有限公司 | 用于使用kdm1a抑制剂个体化治疗小细胞肺癌的生物标志物和方法 |
AU2022254484A1 (en) | 2021-04-08 | 2023-11-09 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors for treating myeloid cancers |
WO2023067058A1 (en) | 2021-10-20 | 2023-04-27 | Queen Mary University Of London | Sequential treatments and biomarkers to reverse resistance to kinase inhibitors |
GB202115017D0 (en) | 2021-10-20 | 2021-12-01 | Univ London Queen Mary | Sequential treatments and biomarkers to reverse resistance to kinase inhibitors |
WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
WO2024110649A1 (en) | 2022-11-24 | 2024-05-30 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors and menin inhibitors for treating cancer |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010043721A1 (en) * | 2008-10-17 | 2010-04-22 | Oryzon Genomics, S.A. | Oxidase inhibitors and their use |
CN103857393A (zh) * | 2011-03-25 | 2014-06-11 | 葛兰素史密斯克莱知识产权(第2号)有限公司 | 环丙基胺作为lsd1抑制剂 |
CN104203914A (zh) * | 2011-10-20 | 2014-12-10 | 奥瑞泽恩基因组学股份有限公司 | 作为lsd1抑制剂的(杂)芳基环丙胺化合物 |
WO2015123408A1 (en) * | 2014-02-13 | 2015-08-20 | Incyte Corporation | Cyclopropylamines as lsd1 inhibitors |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7244751B2 (en) | 2003-02-14 | 2007-07-17 | Shenzhen Chipscreen Biosciences Ltd. | Histone deacetylase inhibitors of novel benzamide derivatives with potent differentiation and anti-proliferation activity |
EP2061772A4 (en) | 2006-09-11 | 2011-06-29 | Curis Inc | MULTIFUNCTIONAL SMALL MOLECULES AS PROLIFERATION-ACTIVE ACTIVE SUBSTANCES |
WO2010084160A1 (en) * | 2009-01-21 | 2010-07-29 | Oryzon Genomics S.A. | Phenylcyclopropylamine derivatives and their medical use |
MX338041B (es) | 2009-09-25 | 2016-03-30 | Oryzon Genomics Sa | Inhibidores de demetilasa-1 especificos de lisina y su uso. |
EP2486002B1 (en) | 2009-10-09 | 2019-03-27 | Oryzon Genomics, S.A. | Substituted heteroaryl- and aryl- cyclopropylamine acetamides and their use |
MX2012012111A (es) | 2010-04-19 | 2013-05-30 | Oryzon Genomics Sa | Inhibidores de demetilasa-1 especifica de lisina y su uso. |
RS57331B1 (sr) | 2010-07-29 | 2018-08-31 | Oryzon Genomics Sa | Inhibitori demetilaze za lsd1 zasnovani na arilciklopropilaminu i njihova medicinska upotreba |
US20130303545A1 (en) | 2010-09-30 | 2013-11-14 | Tamara Maes | Cyclopropylamine derivatives useful as lsd1 inhibitors |
US9061966B2 (en) | 2010-10-08 | 2015-06-23 | Oryzon Genomics S.A. | Cyclopropylamine inhibitors of oxidases |
EP2712316A1 (en) | 2011-02-08 | 2014-04-02 | Oryzon Genomics, S.A. | Lysine demethylase inhibitors for myeloproliferative or lymphoproliferative diseases or disorders |
EP2693882B1 (en) | 2011-04-08 | 2017-06-28 | Merck Sharp & Dohme Corp. | Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment |
EP2743256B1 (en) | 2011-08-09 | 2018-06-27 | Takeda Pharmaceutical Company Limited | Cyclopropaneamine compound |
PE20141692A1 (es) | 2011-10-20 | 2014-11-08 | Oryzon Genomics Sa | Compuestos de (hetero) aril ciclopropilamina como inhibidores de lsd1 |
EP2877444B1 (en) | 2012-07-27 | 2020-09-02 | The Broad Institute, Inc. | Inhibitors of histone deacetylase |
WO2014058071A1 (ja) | 2012-10-12 | 2014-04-17 | 武田薬品工業株式会社 | シクロプロパンアミン化合物およびその用途 |
US9388123B2 (en) | 2012-11-28 | 2016-07-12 | Kyoto University | LSD1-selective inhibitor having lysine structure |
EP2740474A1 (en) | 2012-12-05 | 2014-06-11 | Instituto Europeo di Oncologia S.r.l. | Cyclopropylamine derivatives useful as inhibitors of histone demethylases kdm1a |
WO2014164867A1 (en) | 2013-03-11 | 2014-10-09 | Imago Biosciences | Kdm1a inhibitors for the treatment of disease |
EP3003301B1 (en) | 2013-05-30 | 2021-02-24 | Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Las Vegas | Novel suicidal lsd1 inhibitors targeting sox2-expressing cancer cells |
ES2935746T3 (es) | 2013-12-11 | 2023-03-09 | Celgene Quanticel Res Inc | Inhibidores de desmetilasa-1 específica de lisina |
WO2015123437A1 (en) | 2014-02-13 | 2015-08-20 | Incyte Corporation | Cyclopropylamines as lsd1 inhibitors |
PL3105218T3 (pl) * | 2014-02-13 | 2020-03-31 | Incyte Corporation | Cyklopropyloaminy jako inhibitory lsd1 |
LT3105226T (lt) | 2014-02-13 | 2019-11-11 | Incyte Corp | Ciklopropilaminai, kaip lsd1 inhibitoriai |
MY180575A (en) | 2014-04-11 | 2020-12-02 | Takeda Pharmaceuticals Co | Cyclopropanamine compound and use thereof |
DK3137169T3 (da) | 2014-05-01 | 2022-02-14 | Celgene Quanticel Res Inc | Hæmmere af lysin-specifik demethylase-1 |
ES2935114T3 (es) | 2014-09-05 | 2023-03-01 | Celgene Quanticel Res Inc | Inhibidores de la desmetilasa 1 específica de lisina |
JP6636031B2 (ja) | 2015-01-30 | 2020-01-29 | ジェネンテック, インコーポレイテッド | 治療用化合物およびその使用 |
CN107427699B (zh) | 2015-02-12 | 2021-10-19 | 伊美格生物科学公司 | 用于治疗疾病的kdm1a抑制剂 |
EP3277689B1 (en) | 2015-04-03 | 2019-09-04 | Incyte Corporation | Heterocyclic compounds as lsd1 inhibitors |
WO2017109061A1 (en) | 2015-12-23 | 2017-06-29 | Ieo - Istituto Europeo Di Oncologia S.R.L. | Spirocyclopropylamine derivatives useful as inhibitors of histone demethylases kdm1a |
-
2016
- 2016-11-03 CA CA3009805A patent/CA3009805C/en active Active
- 2016-11-03 WO PCT/US2016/060379 patent/WO2017116558A1/en active Application Filing
- 2016-11-03 MX MX2018008052A patent/MX2018008052A/es unknown
- 2016-11-03 KR KR1020187021819A patent/KR20180117602A/ko not_active Application Discontinuation
- 2016-11-03 SG SG11201805645QA patent/SG11201805645QA/en unknown
- 2016-11-03 EP EP16805585.3A patent/EP3397616B1/en active Active
- 2016-11-03 JP JP2018534842A patent/JP6916795B2/ja active Active
- 2016-11-03 US US15/343,008 patent/US9809541B2/en active Active
- 2016-11-03 CN CN201680077382.5A patent/CN108884029B/zh active Active
- 2016-11-03 AU AU2016382463A patent/AU2016382463B2/en active Active
-
2017
- 2017-10-05 US US15/725,949 patent/US10233152B2/en active Active
-
2018
- 2018-06-22 IL IL260217A patent/IL260217B/en active IP Right Grant
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010043721A1 (en) * | 2008-10-17 | 2010-04-22 | Oryzon Genomics, S.A. | Oxidase inhibitors and their use |
CN103857393A (zh) * | 2011-03-25 | 2014-06-11 | 葛兰素史密斯克莱知识产权(第2号)有限公司 | 环丙基胺作为lsd1抑制剂 |
CN104203914A (zh) * | 2011-10-20 | 2014-12-10 | 奥瑞泽恩基因组学股份有限公司 | 作为lsd1抑制剂的(杂)芳基环丙胺化合物 |
WO2015123408A1 (en) * | 2014-02-13 | 2015-08-20 | Incyte Corporation | Cyclopropylamines as lsd1 inhibitors |
Non-Patent Citations (2)
Title |
---|
Lysine Demethylases Inhibitors;Takayoshi Suzuki等;《Journal of Medicinal Chemistry》;20110928;第54卷(第24期);8236-8250 * |
抗肿瘤药物新靶点:表观遗传组蛋白赖氨酸特异性去甲基化酶1;郑一超等;《国际药学研究杂志》;20140228;第41卷(第1期);30-36 * |
Also Published As
Publication number | Publication date |
---|---|
WO2017116558A1 (en) | 2017-07-06 |
CA3009805C (en) | 2023-10-17 |
CA3009805A1 (en) | 2017-07-06 |
AU2016382463A1 (en) | 2018-07-12 |
EP3397616B1 (en) | 2020-06-10 |
CN108884029A (zh) | 2018-11-23 |
IL260217B (en) | 2020-09-30 |
JP6916795B2 (ja) | 2021-08-11 |
US20180127369A1 (en) | 2018-05-10 |
US10233152B2 (en) | 2019-03-19 |
SG11201805645QA (en) | 2018-07-30 |
JP2019504059A (ja) | 2019-02-14 |
MX2018008052A (es) | 2019-03-14 |
KR20180117602A (ko) | 2018-10-29 |
EP3397616A1 (en) | 2018-11-07 |
US20170183308A1 (en) | 2017-06-29 |
US9809541B2 (en) | 2017-11-07 |
AU2016382463B2 (en) | 2021-05-27 |
IL260217A (en) | 2018-07-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108884029B (zh) | Lsd1抑制剂 | |
CN109153636B (zh) | 作为双重lsd1/hdac抑制剂的环丙基-酰胺化合物 | |
CN103524392B (zh) | 作为用于治疗增生性疾病的mek 抑制剂的吖丁啶 | |
CN110612297A (zh) | 雌激素受体蛋白水解调节剂及相关使用方法 | |
CN108137541B (zh) | 用于用作溴结构域抑制剂的吡啶酮二甲酰胺 | |
KR20180035828A (ko) | 단백질 분해의 mdm2계 조절인자 및 관련된 이용 방법 | |
CN108137542B (zh) | 用作溴结构域抑制剂的吡啶酮二甲酰胺 | |
CN112236423B (zh) | 哌啶基-3-(芳氧基)丙酰胺和丙酸酯 | |
WO2001007411A1 (fr) | Derives de biaryluree | |
EA039808B1 (ru) | Аминотриазолопиридины в качестве ингибиторов киназ | |
BR112016011755B1 (pt) | Derivado de ureia ou sal farmacologicamente aceitável do mesmo, seu uso e composição farmacêutica que os compreende | |
TW200815412A (en) | A pharmaceutical combination comprising 3-or 4-monosubstituted phenol and thiophenol derivatives | |
AU2016297886A1 (en) | Compounds, compositions and methods of increasing CFTR activity | |
CA2871237A1 (en) | Benzamide derivative | |
CA2822787C (en) | Substituted isoquinoline derivative | |
CN114269748A (zh) | 作为用于治疗癌症的PRC2抑制剂的咪唑并[1,2-c]嘧啶衍生物 | |
TW202222770A (zh) | 苄胺或苄醇衍生物及其用途 | |
KR20240062147A (ko) | P53의 돌연변이체를 표적으로 하는 화합물 | |
KR20210118884A (ko) | 헤테로시클릭 유도체 | |
CA3081558A1 (en) | Anti-infective heterocyclic compounds and uses thereof | |
US20190055212A1 (en) | Histone demethylase inhibitors | |
US11274092B2 (en) | Potassium channel inhibitors | |
TW202204341A (zh) | N-雜芳基烷基-2-(雜環基及雜環基甲基)乙醯胺衍生物 | |
WO2023187677A1 (en) | N-(pyrrolidin-3-yl or piperidin-4-yl)acetamide derivatives | |
JP2023506368A (ja) | イソキノリノン誘導体、その製造方法及びそれを有効成分として含有するポリ(adp-リボース)ポリメラーゼ-1(parp-1)関連疾患の予防又は治療用薬学的組成物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |