CA2730448A1

CA2730448A1 - Inhibitors of iap

Inhibitors of iap Download PDF

Info

Publication number: CA2730448A1
Authority: CA; Canada
Prior art keywords: alkyl; aryl; compound; cycloalkyl; heterocycle
Prior art date: 2008-08-02
Legal status : Abandoned

Application number

CA2730448A

Other languages

English (en)

French (fr)

Inventor

Danette Dudley

John A. Flygare

Chudi Ndubaku

Current Assignee

Genentech Inc

Original Assignee

Genentech Inc

Priority date

2008-08-02

Filing date

2009-07-23

Publication date

2010-02-11

2009-07-23 Application filed by Genentech Inc filed Critical Genentech Inc

2010-02-11 Publication of CA2730448A1 publication Critical patent/CA2730448A1/en

Status Abandoned legal-status Critical Current

Links

239000003112 inhibitor Substances 0.000 title abstract description 9
150000001875 compounds Chemical class 0.000 claims abstract description 117
230000006907 apoptotic process Effects 0.000 claims abstract description 25
206010028980 Neoplasm Diseases 0.000 claims abstract description 20
108091007065 BIRCs Proteins 0.000 claims abstract description 15
-1 amino, hydroxyl Chemical group 0.000 claims description 217
125000000217 alkyl group Chemical group 0.000 claims description 111
125000003118 aryl group Chemical group 0.000 claims description 106
125000003545 alkoxy group Chemical group 0.000 claims description 68
125000000623 heterocyclic group Chemical group 0.000 claims description 64
229910052736 halogen Inorganic materials 0.000 claims description 60
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 54
150000002367 halogens Chemical class 0.000 claims description 49
125000001072 heteroaryl group Chemical group 0.000 claims description 45
125000000753 cycloalkyl group Chemical group 0.000 claims description 44
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
238000000034 method Methods 0.000 claims description 28
125000003710 aryl alkyl group Chemical group 0.000 claims description 25
102000011727 Caspases Human genes 0.000 claims description 20
108010076667 Caspases Proteins 0.000 claims description 20
125000001188 haloalkyl group Chemical group 0.000 claims description 20
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
125000004104 aryloxy group Chemical group 0.000 claims description 19
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 18
AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 16
125000004442 acylamino group Chemical group 0.000 claims description 16
125000004423 acyloxy group Chemical group 0.000 claims description 16
125000004414 alkyl thio group Chemical group 0.000 claims description 16
230000027455 binding Effects 0.000 claims description 14
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
125000003396 thiol group Chemical group [H]S* 0.000 claims description 12
125000002252 acyl group Chemical group 0.000 claims description 11
201000011510 cancer Diseases 0.000 claims description 11
238000006467 substitution reaction Methods 0.000 claims description 11
229910052717 sulfur Inorganic materials 0.000 claims description 10
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
241000124008 Mammalia Species 0.000 claims description 7
230000001640 apoptogenic effect Effects 0.000 claims description 7
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 7
230000002401 inhibitory effect Effects 0.000 claims description 7
101100439663 Arabidopsis thaliana CHR7 gene Proteins 0.000 claims description 6
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
125000005842 heteroatom Chemical group 0.000 claims description 6
125000004093 cyano group Chemical group *C#N 0.000 claims description 5
229960004679 doxorubicin Drugs 0.000 claims description 5
230000001939 inductive effect Effects 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
230000001235 sensitizing effect Effects 0.000 claims description 5
IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims description 4
NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
125000003282 alkyl amino group Chemical group 0.000 claims description 4
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 4
125000001691 aryl alkyl amino group Chemical group 0.000 claims description 4
125000002102 aryl alkyloxo group Chemical group 0.000 claims description 4
229930012538 Paclitaxel Natural products 0.000 claims description 3
229940009456 adriamycin Drugs 0.000 claims description 3
125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 3
125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 3
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
125000001769 aryl amino group Chemical group 0.000 claims description 3
DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 3
229960004316 cisplatin Drugs 0.000 claims description 3
125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 3
229960001592 paclitaxel Drugs 0.000 claims description 3
RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 3
NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 claims description 2
108010006654 Bleomycin Proteins 0.000 claims description 2
KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 2
CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 2
NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 claims description 2
FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 2
JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 2
229960001561 bleomycin Drugs 0.000 claims description 2
OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 2
VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
229940127093 camptothecin Drugs 0.000 claims description 2
229960001338 colchicine Drugs 0.000 claims description 2
229960004397 cyclophosphamide Drugs 0.000 claims description 2
229960000684 cytarabine Drugs 0.000 claims description 2
VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 2
DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 claims description 2
229960004039 finasteride Drugs 0.000 claims description 2
229960000390 fludarabine Drugs 0.000 claims description 2
GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 2
SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 2
229960005277 gemcitabine Drugs 0.000 claims description 2
229960000485 methotrexate Drugs 0.000 claims description 2
229960004857 mitomycin Drugs 0.000 claims description 2
KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 2
229960001156 mitoxantrone Drugs 0.000 claims description 2
229960001603 tamoxifen Drugs 0.000 claims description 2
229940063683 taxotere Drugs 0.000 claims description 2
UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 2
229960000303 topotecan Drugs 0.000 claims description 2
229960003048 vinblastine Drugs 0.000 claims description 2
JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 2
OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 2
229960004528 vincristine Drugs 0.000 claims description 2
OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 2
239000000203 mixture Substances 0.000 abstract description 31
241000713321 Intracisternal A-particles Species 0.000 abstract description 9
238000011282 treatment Methods 0.000 abstract description 6
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 111
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
229910001868 water Inorganic materials 0.000 description 33
235000019439 ethyl acetate Nutrition 0.000 description 32
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 32
238000006243 chemical reaction Methods 0.000 description 31
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
239000000243 solution Substances 0.000 description 23
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
125000001424 substituent group Chemical group 0.000 description 21
210000004027 cell Anatomy 0.000 description 20
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
108090000623 proteins and genes Proteins 0.000 description 17
102000004169 proteins and genes Human genes 0.000 description 16
238000004587 chromatography analysis Methods 0.000 description 15
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
235000018102 proteins Nutrition 0.000 description 15
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
150000003839 salts Chemical class 0.000 description 14
239000012267 brine Substances 0.000 description 13
229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 12
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 12
125000006239 protecting group Chemical group 0.000 description 12
230000005855 radiation Effects 0.000 description 12
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
230000002829 reductive effect Effects 0.000 description 11
235000017557 sodium bicarbonate Nutrition 0.000 description 11
201000009030 Carcinoma Diseases 0.000 description 10
229910052757 nitrogen Inorganic materials 0.000 description 10
239000012044 organic layer Substances 0.000 description 10
102100033189 Diablo IAP-binding mitochondrial protein Human genes 0.000 description 9
239000002253 acid Substances 0.000 description 9
229910052938 sodium sulfate Inorganic materials 0.000 description 9
235000011152 sodium sulphate Nutrition 0.000 description 9
238000003786 synthesis reaction Methods 0.000 description 9
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
108010049207 Death Domain Receptors Proteins 0.000 description 8
102000009058 Death Domain Receptors Human genes 0.000 description 8
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
239000007832 Na2SO4 Substances 0.000 description 8
150000001412 amines Chemical class 0.000 description 8
229940024606 amino acid Drugs 0.000 description 8
235000001014 amino acid Nutrition 0.000 description 8
150000001413 amino acids Chemical group 0.000 description 8
125000004432 carbon atom Chemical group C* 0.000 description 8
239000000543 intermediate Substances 0.000 description 8
239000010410 layer Substances 0.000 description 8
239000003446 ligand Substances 0.000 description 8
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VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
102100024319 Intestinal-type alkaline phosphatase Human genes 0.000 description 7
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 7
239000005557 antagonist Substances 0.000 description 7
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125000004433 nitrogen atom Chemical group N* 0.000 description 7
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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 7
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
239000003795 chemical substances by application Substances 0.000 description 6
229910052943 magnesium sulfate Inorganic materials 0.000 description 6
125000000714 pyrimidinyl group Chemical group 0.000 description 6
239000011593 sulfur Substances 0.000 description 6
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 5
102000004039 Caspase-9 Human genes 0.000 description 5
108090000566 Caspase-9 Proteins 0.000 description 5
229910052693 Europium Inorganic materials 0.000 description 5
NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
125000003277 amino group Chemical group 0.000 description 5
235000015165 citric acid Nutrition 0.000 description 5
230000008878 coupling Effects 0.000 description 5
238000010168 coupling process Methods 0.000 description 5
238000005859 coupling reaction Methods 0.000 description 5
150000002148 esters Chemical class 0.000 description 5
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 5
125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 5
201000001441 melanoma Diseases 0.000 description 5
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
239000012074 organic phase Substances 0.000 description 5
229940002612 prodrug Drugs 0.000 description 5
239000000651 prodrug Substances 0.000 description 5
239000012453 solvate Substances 0.000 description 5
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