Europäisches Patentamt

(19)

European Patent Office Office européen des brevets

*EP001242363B1*
(11)

EP 1 242 363 B1

(12)

EUROPEAN PATENT SPECIFICATION
(51) Int Cl.7:
of the grant of the patent: 02.11.2005 Bulletin 2005/44

(45) Date of publication and mention

(21) Application number: 00985603.0 (22) Date of filing: 18.12.2000

C07C 233/76, C07C 233/33, C07D 307/80, C07D 333/22, A61K 31/165, A61K 31/34, A61K 31/38, A61P 37/06

(86) International application number:
PCT/GB2000/004854

(87) International publication number:
WO 2001/046125 (28.06.2001 Gazette 2001/26)

(54) CD45 INHIBITORS CD45 INHIBITOREN INHIBITEURS DE CD45 (84) Designated Contracting States:
AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR • VEALE, Chris, Allan Wilmington, DE 19850-5437 (US)

(74) Representative: Bryant, Tracey (30) Priority: 21.12.1999 US 172788 P (43) Date of publication of application:
25.09.2002 Bulletin 2002/39 AstraZeneca AB, Global Intellectual Property 151 85 Sodertalje (SE)

(56) References cited: (73) Proprietor: AstraZeneca AB
151 85 Södertälje (SE) US-A- 3 243 444 US-A- 4 746 678 US-A- 4 668 712 US-A- 5 665 774

(72) Inventors:
• CHAPDELAINE, Marc, Jerome Wilmington, DE 19850-5437 (US) • KNAPPENBERGER, Katherine Wilmington, DE 19850-5437 (US) • STEELMAN, Gary Wilmington, DE 19850-5437 (US) • SUCHARD, Suzanne Wilmington, DE 19850-5437 (US) • SYGOWSKI, Linda Wilmington, DE 19850-5437 (US) • URBANEK, Rebecca Wilmington, DE 19850-5437 (US)

• CHEMICAL ABSTRACTS, vol. 51, no. 14, 25 July 1957 (1957-07-25) Columbus, Ohio, US; abstract no. 10466c, SHIMPACHIRO KATO ET AL: "Synthesis of bromophenanthrene quinones" XP002162699 & YUKI GOSEI KAGAKU KYOKAI SHI, vol. 15, 1957, pages 84-7, • CHEMICAL ABSTRACTS, vol. 70, no. 1, 6 January 1969 (1969-01-06) Columbus, Ohio, US; abstract no. 3967b, GORELIK, M V: "Ring opening of 1,2,5-thiazoles and 1,2,5-selenadiazoles under the influence of alkali" page 371; column 2; XP002162700 & ZH. VSES. KHIM. OBSHCHEST., vol. 13, no. 4, 1968, pages 467-8,

EP 1 242 363 B1

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).
Printed by Jouve, 75001 PARIS (FR)

EP 1 242 363 B1
Description Background
5

Field of the Invention [0001] Compounds, compositions and methods for the treatment of immunologically-related diseases and disorders such as autoimmune disorders and organ graft rejection.

10

Related Art [0002] Action of the immune system is known to be involved in immunologically-related diseases and disorders such as autoimmune disorders and in organ graft rejection ("OGR"). Hematopoietic, thymus-derived cells, (so-called "T cells") have an important and pervasive role as regulators and effectors of the functions of the immune system. Hematopoietic cells, and T cells in particular have on their surfaces a major transmembrane glycoprotein designated CD45, characterized by a cluster of antigenic determinants. CD45 is also known as leukocyte common antigen ("LCA"). The cytosolic portion of CD45 has protein tyrosine phosphatase ("PTP") activity and CD45 activity is known to be essential for TCR initiated T cell activation. Studies in CD45-deficient cell lines have shown that CD45 is a positive regulator of the T-Cell Receptor ("TCR") and that CD45 functions in TCR regulation by dephosphorylating the src kinases p56lck and p59fyn, which allows autophosphorylation of the positive regulatory site on these enzymes: these reactions lead to downstream events and ultimately to T cell activation. [0003] Available treatments for autoimmune disorders and OGR have therapeutic disadvantages. For example, Cyclosporin A, the drug most commonly used to treat OGR, has renal and CNS toxicity. Summary of the Invention [0004] Potent inhibitors of CD45 have been discovered. Such inhibitors are useful for the treatment of various autoimmune disorders as well as for treatment of OGR. Inhibition of the phosphatase activity of CD45 by compounds of the present invention has been shown by incubating the cytosolic portion of CD45 with the compounds and p-nitrophenyl phosphate (pNPP), a phosphatase substrate. Spectrophotometric monitoring has shown that the liberation of p-nitrophenol from the substrate by CD45 is inhibited in the presence of the compounds disclosed herein. Inhibition of the phosphatase activity of CD45 by compounds of the present invention has also been shown using a p56lck carboxyterminal phosphorylated peptide as a substrate. Compounds of the present invention have also been shown to inhibit proliferation of T cells in a T-cell proliferation assay. [0005] Compounds of the present invention are substituted phenanthrene-9,10-diones in accord with structural diagram I:

15

20

25

30

35

40

45

50

55

wherein R1 at each occurrence is independently selected from hydrogen, NH-CO-R2, CO-NH-R2, Ar, (CH2)nCH(COOH) R3 COR3, NHCOCH2CH(COOH)NHR4 and N(R5)2; in compounds in accord with structural diagram I, R2 is selected from (C1-C4)alkyl, (CH2)nCOOR6 and phenyl, wherein: n is an integer selected from the range I to 8; phenyl moieties of R2 can be substituted at one, two or three positions with a moiety selected from halogen, NO2 and CF3; alkyl moieties of R2 can be substituted with halogen, and R6 is selected from hydrogen and (C1-C4)alkyl; in compounds in accord with structural diagram I where R1 is Ar, Ar at each occurrence is independently selected from groups in accord with the following structural diagrams:

2

TATEGQ. [0006] Particular compounds of the present invention within the scope of compounds in accord with structural diagram I are substituted phenanthrene-9. GQPQP. GEPEG. R5 at each occurrence is selected from hydrogen and tosyl. QQGQP.EP 1 242 363 B1 5 10 15 20 or from phenyl which can be substituted with a moiety selected from halogen. and FTATEGQ. QEGQP. in compounds in accord with structural diagram I where R1 is N(R5)2. ATEGQ. O-(C1-C4)alkyl and halo (C1-C4)alkyl. GQPEG. EGPEG. QEPQP. RGPEG. EQPQP. GEGQP. (C1-C4)alkyl. REPHG. EGQ. GEPQG. GQGQP. EEPRG. GGPEG. RGPRC GEPRG. GQGEP. in compounds in accord with structural diagram I where R1 is COR3 or (CH2)nCH(COOH)R3. -tripeptide or -oligopeptide selected from Q. GRPEG. RRPEG. R3 at each occurrence is an N-linked oligopeptide selected from GQ-N-iBu. QQPEG. QQPQP. EGPRG. ERPRG and RRPRG. GQPQG. ERPEG. EQGQP.10-diones in accord with structural diagram II: 25 30 35 wherein R5 is selected from hydrogen and tosyl. R4 at each occurrence is a C-linked N-acetyl-amino acid. GRPRG. GEPQP. GGPRG.10-diones in accord with structural diagram III: 40 45 wherein R1 is Ar and Ar is selected from groups in accord with the following structural diagrams: 50 55 3 . [0007] Further particular compounds of the present invention within the scope of compounds in accord with structural diagram I are substituted phenanthrene-9. EEPEG. REPRG. in compounds in accord with structural diagram I where R1 is NHCOCH2CH(COOH)NHR4. QQPQG.

ERPEG. where R4 is a C-linked N-acetyl-oligopeptide selected from Q. and FTATEGQ. [0011] Compounds of the present invention are ligands of CD45 which. GRPRG. GQGEP. ATEGQ. compounds of the invention inhibit the positive regulation of the TCR that leads to downstream events and T cell activation. GQPEG. RGPRG.10-phenanthrenediones are identified with a conventional numbering system. with the proviso that no more than one R1 moiety is other than hydrogen. in accord with the following structural diagram: 55 4 . [0009] Other particular compounds of the present invention within the scope of compounds in accord with structural diagram I are substituted phenanthrene-9. EGPEG. ERPRG and RRPRG. Thus. EGQ.10-diones in accord with structural diagram V: 25 30 35 40 45 50 wherein R1 is NHCOCH2CH(COOH)NHR4. TATEGQ. [0010] Still further particular compounds of the present invention within the scope of compounds in accord with structural diagram I are phenanthrene-9.10-diones which are not substituted at positions 6 and 8 and wherein R1 is selected from hydrogen and NHC(O)(CH2)nCOOCH3 where n is an integer selected from the range 1 to 8. EQPQP. GEPEG. [0012] The present invention also encompasses compositions made with compounds described herein useful for the treatment of immunologically-related diseases and disorders and methods utilizing such compositions for treating such disorders. GRPEG. GGPRG. Binding of a compound of the present invention to CD45 inhibits the activity of CD45 essential for TCR initiated T cell activation. the ring atoms of 9. GEPRG. GQPQG. Detailed Description of the Invention [0013] As described herein. inhibit the activity of the protein tyrosine phosphatase (PTP) activity of the cytosolic portion of CD45.EP 1 242 363 B1 or from phenyl which can be substituted with a moiety selected from halogen. GEPQG. Compounds of the present invention are useful to suppress the action of the immune system in immunologically-related diseases and disorders such as autoimmune disorders and organ graft rejection and to inhibit the action of T cells as functional regulators and effectors of the immune system. QQGQP. GGPEG. RGPEG. EGPRG. REPRG. QEGQP. QQPQG. EEPRG. QQPEG. halo(C1-C4)alkyl and O-(C1-C4)alkyl. [0008] Yet further particular compounds of the present invention within the scope of compounds in accord with structural diagram I are substituted phenanthrene-9. RRPEG. (C1-C4)alkyl. REPEG. EEPEG. (CH2)nCH(COOH)R3 and COR3 where R3 is an N-linked peptide selected from GQ-N-iBu. when bound. QEPQP.10-diones in accord with structural diagram IV: 5 10 15 20 wherein R1 is independently selected at each occurrence from hydrogen. GQPQP. EQGQP. GEGQP. QQPQP. GEPQP. GQGQP.

3 µM particle size. tetrahydrofuran. halo(C1-C4)alkyl has its conventionally-understood meaning and particularly means (C1-C4) alkyl as used herein wherein hydrogen atoms have been replaced by halogen atoms and thus includes monochloromethyl. There was one sample submitted. IC50. 40 Definitions of terms: [0022] DMF. (CH2)n has its conventionally-understood meaning and particularly means linear hydrocarbon chains having from one to n carbon atoms and thus includes methylene. halo. and Threonine/Thr/T. iodine or fluorine. (C1-C4)alkyl has its conventionally-understood meaning and particularly means linear or branched hydrocarbon chains having from one to four carbon atoms and thus includes methyl. with MW 1262 Da. quadropole time of flight. 2. ethyl. ethylene. isobutyl.N'-tetramethyluroniumhexafluorophosphate. [0015] As used herein. while monitoring at 254 and 210 nm.N. The resolution for the instrument was measured at m/∆m = 5100 at 50% peak height for the ion observed at m/z 953. [0018] As used herein. means any integral value in the stated range. Leucine/Leu/L.1 % formic acid). AA. 8 µL of solution was flow-injected into the mass spectrometer with a 35 µL/min flow of 80:20 acetonitrile/water (0. [0019] As used herein. This sample was run scanning the mass range 500-1300 Da using a calibration from the MW range 150 . trifluoromethyl. perfluoro(C1-C4)alkyl. dimethylsulfoxide. 4. N-(9-fluorenylmethoxycarbonyl). DMAP. and the like. ND. n-butylene groups. concentration giving 50% inhibition. TFA. Phenylalanine/Phe/F. 5 or 6. flow rate of 0.1443. EDC. 20%-60% CH3CN in H2O over 7. tert-butyl. or halide have their conventionally-understood meanings and particularly mean chlorine. nuclear magnetic resonance. difluoroethyl. amino acids ("AA") of oligopeptides are identified by conventional abbreviations or oneletter code. [0024] HRMS method used: The sample was solubilized and diluted in MeOH. 45 50 55 5 . [0016] As used herein.5 min. not determined. in this example 1.N-dimethylformamide. the term tosyl has its conventionally-understood meaning and particularly means a group in accord with the following structural diagram: 30 35 [0021] As used herein. 3. perfluoro(C1-C4)alkyl has its conventionally-understood meaning and particularly means (C1-C4)alkyl as used herein wherein each hydrogen atom has been replaced by a fluorine atom and thus includes trifluoromethyl.1300. Compound exact mass 953.1150 Da. propylene. HATU. thin-layer chromatography. amino acid. HRMS. Tyrosine/Tyr/Y. n-butyl. For each sample.5 mL/min. high resolution mass spectroscopy. Arginine/ Arg/R. trifluoropropyl. CC50. holding at 60% CH3CN for 2. DMSO.5 min. trifluoroacetic acid. [0020] As used herein. TLC. NMR. A lock mass reference compound was infused into this flow at a rate of 2 µL/min (Ref. O-(7-Azabenzotriazol-1-yl)-N. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. propyl. 100 Å pore size). FMOC. isopropyl. Glutamine/Gln/Q. concentration giving 50% cytotoxicity. QTOF. with a C18 Dynamax column (5 cm x 4. and the like. the term "from the range 1 to 6" or the like. sec-butyl.6 mm. [0023] HPLC method used: Analytical HPLC using an HP 1100 HPLC. The QTOF mass spectrometer was calibrated using a PEG 400/600/1000 mixture solubilized in 50:50 acetonitrile/water with 50 mM ammonium acetate across a mass range 150 . 4-dimethylaminopyridine. as follows: Glycine/Gly/G. HPLC.N'. the terms halogen. bromine. N.EP 1 242 363 B1 5 10 15 20 25 [0014] As described herein. [0017] As used herein.1443). Glutamic acid/Glu/E. and the like. high performance liquid chromatography. THF. Proline/Pro/P.

10-dione (50 mg.23 (1H. J = 1.47 min.19 (1 H. s). 1. Example 3: N-(9. J = 9 Hz).16 (1H. dd.94 (1H.10-dioxo-9. 7.9. 7. 8. J = 7. s). Example 6: 2. s). s).80-7.3 Hz). 7. dd. m). 7.38 (2H.10-dihydro-phenanthren-2-yl)-2-fluoro-benzamide: [0025] To a solution of 2-amino-phenanthrene-9.1.07 (1H.89 (1H.2 Hz). 7. d.7 Hz). dd. dd. J = 7. CDCl3) δ 10.54 (1H. 7. tq. d. J = 7. dd.31 (1H. m). 1H NMR (300 MHz. J = 1.64 (2H.8 Hz). 8. 4.47 (3H. dd. ~1:3 DMSO-d6:CDCl3) δ 10.70 (1H.01 (2H. 7.2-Trichloro-N-(9.39 (1H. m).09 (1H. 7.1 Hz).2.10-dihydro-phenanthren-2-yl)-2-trifluoromethylbenzamide: 55 [0033] Brown solid. using CH2Cl2-10% EtOAC/ CH2Cl2 as the eluant to yield the pure amide N-(9.7 Hz).6.05 (1H.10-Dioxo-9.5 Hz). d. 4. 1H NMR (300 MHz. 8.5. 7. dd. d. 8. 8. J = 8. HPLC: 6. 7.35 (9H.43 (1H.98 (1H.32 (6H.93 (3H.6 Hz). J = 7.50 (1H. dd.04 (1H. m). 7.24 (1H. s). [0026] The compounds of examples 2 to 8 inclusive were prepared by the method of Example 1. 8. J = 7. J = 7. The mixture was shaken overnight.17 (1H. d.38 (1H.70 (2H. 7. J = 2. 8. 8.9.1443). d. dd. s). dd.76 (1H.2 Hz).07-8. 8.4. 7. 8.10-Dioxo-9. 8 Hz).8 Hz).86 min. 8. J = 7.9. m). 9 Hz).10-dihydro-phenanthren-2-yl)-2-fluoro-benzamide as a red solid.6-Trichloro-N-(9.2. 7. 7. J = 2. J = 8. J = 1. J = 2. 35 Example 5: N-(9. 8.10-dioxo-9. 7.8 Hz). DMSO-d6) δ 11. d.10-dihydro-phenanthren-2-yl)-butyramide: 25 [0028] Red solid. J = 2.2 Hz).51-7.7.20 (1 H. 0.4 Hz). 8.4 Hz). 7. 8. 7. 8. 1H NMR (300 MHz.2 Hz). d. m).02 (1H. 30 Example 4: N-(9. dd. 8. 7. J = 7.2.34 (2H. d. dd. DMSO-d6) δ 10. d.7 Hz). HPLC: 6.EP 1 242 363 B1 Data was acquired from a single 3. 384 µmol).3. 7.1 Hz).6 Hz). br s).84-7.41 (1H. 7.23 (1H. J = 2.43 (1H.47 (1H.23 (1H. 7.4 Hz).10-dihydro-phenanthren-2-yl)-2.6 Hz). dd. HPLC: 7. t.10-Dioxo-9. J = 8.26 (1H. m).10-dioxo-9.35 (1 H. 8. and the signal was averaged from 0. 8. J = 2.2. J = 9 Hz).51 min. d. 7. ddd.25 (1H.75 (4H. J = 2. s). J = 2. 1H NMR (300 MHz. 8. d. 8. 8. 2.4.8 Hz). ddd. J = 8.1 Hz).10-dihydro-phenanthren-2-yl)-2-nitro-benzamide: [0030] Purple solid.6. dd. Example 8: N-(9. J = 8.4 Hz). J = 7.89 (1H.5 Hz). J = 2. dd.97 min. 1.26 (1H.72 (1H.68 min. 7.86-7.8 Hz). 7.99 (2H. then filtered and the solvent evaporated.8 Hz). 8. 8. m). J = 2. m).2-dimethylpropionamide: [0029] Mauve solid. m).10-Dioxo-9.9 Hz). 7. m).45 (1H. 8.61 (1H. Example 7: 2. followed by 2-fluorobenzoylchloride (46 µL. d. s). 7. 8. by utilizing the appropriate acid chloride.75 (1 H. The resulting material was purified on a silica gel column.4 Hz). J = 7. d. J = 2. J = 7.2 Hz).10-dioxo-9.3 Hz). d.10-dihydro-phenanthren-2-yl)-benzamide: [0031] Red solid.05-7. 8. J = 7.78 (1H. 240 µmol) in THF (10 mL) was added an excess of Na2CO3 (1g).9 Hz). 7. HPLC: 6.99 (2H.5. J = 9 Hz). t. 7. 8. DMSO-d6) δ 10. Example 2: 2-Benzyloxy-N-(9. 7.44 (1H. d. dd. J = 1. J = 8 Hz). DMSO-d6) δ 10.5. HPLC: 8. J = 2. Examples 5 Example 1: N-(9.46 (1H. 7. 1H NMR (300 MHz.2 Hz).10 (1H.4.4.19 (1H. 8.3. d. J = 7. 1H NMR (300 MHz.10-8. J = 7. d. br s). J = 1.4. HPLC: 5.80 (1H.47 (1H. 1.5 Hz).9 .1. 7.39 min.10-Dioxo-9.30 (1H.10-dihydro-phenanthren-2-yl)-acetamide: 50 40 45 [0032] Brown solid. dd.37 min. d.98 (2H. ddd.4 Hz).5.75 (1H.65 (2H. d. 7.21 (1H.1 Hz). 7.3 Hz). 8. J = 1. 8. CDCl3) δ 8. 8.7 Hz).5 minute analysis.15 (2H. 8. 8.7 Hz). 6 .50 (1H.10-dihydro-phenanthren-2-yl)-acetamide: 20 10 15 [0027] Mauve solid. J = 1. 8.62 (1H. J =7. 7. 7. s).30 (1H.38 (1H. HPLC: 7. 1H NMR (300 MHz. d. m).3.3.65 (6H.65 min.04-7. 7. 8. J = 7. 7.8 min and then smoothed and centroided using a one-point lock mass correction using the reference compound listed above (m/z = 953. 1H NMR (300 MHz. -1:3 DMSO-d6:CDCl3) δ 10. HPLC: 7.06 (2H.

86 (1H. 7. d. m).61 (1H. 8.02 (3H.7 Hz). t.5.36 (1H. 8.10-Dioxo-9. 7. s). m).10-dihydro-phenanthren-3-yl)-2-fluoro-benzamide: 25 [0038] Yellow solid.8. J = 7. 1. dd. 7. J = 1.29 (9H.5 Hz). ddd.79 mmol) and a catalytic amount of N. J = 8.8.5. m).60 (1H. J = 1. d. Example 14: N-(9.10 (1H. 8 %) which was dried to a yellow solid. J = 8.10-dioxo-9.4. dd. ddd.10-dihydro-phenanthren-2-yl)-4-methyl-N-[(4-methylphenyl)sulfonyl]benzenesulfonamide: [0040] To a solution of 2-amino-phenanthrene-9. 8.1. J = 1. 7.64 (1H.5 g) was added. J = 7. DMSO-d6) δ 8. [0035] The compounds of examples 10 to 13 inclusive were prepared by the method of Example 9. The mixture was shaken overnight.32 (3H. dd.10-dihydro-phenanthren-2-yl)-4-methylbenzenesulfonamide: 50 35 40 45 55 [0041] A second material which eluted from the column was the mono-tosylate of 2-amino-9. 7. J = 1. DMSO-d6) δ 9. followed by butyrylchloride (1 mL). tfa shake-DMSO-d6) δ 8. d.48 (1H. s). J = 8. s). 8. 8. 7. HPLC: 7.1 Hz).8 Hz).5. 7. 7.0 Hz). Example 11: 2.82 (2H.10-dione.56 (1H. by utilizing the appropriate acid chloride.36 (2H.10-dihydro-phenenathren-3-yl)-butyramide: [0034] To a solution of 3-amino-phenanthrene-9. 8. dd.73 (4H.10-dihydro-phenanthren-3-yl)-butyramide as a brown solid. 7.3 Hz).96 (1H. 7.10-phenenthrenedione. then water (1 mL) was added and the mixture was shaken for an additional 30 min. DMSO-d6) δ 10.1 Hz). J = 7. m). 7. 7. N-(9.38 (2H.46 (1H. 8.5 Hz). dd.60 (1H.10-Dioxo-9. J = 1. s). 1H NMR (300 MHz.2.89-7.78-7. 1. the first material eluted from the column was the di-tosylate of 2-amino-phenanthrene9.44 (1H. 8.56 (1H. J = 8. Filtration followed by evaporation under reduced pressure yielded a product which was purified by silica gel chromatography using CH2Cl2 as the eluant.2-dimethylpropionamide: 15 5 10 [0036] Brown solid.4 Hz). 16%) which was dried to an orange solid. N-dimethylaminopyridine.7 Hz).2-Trichloro-N-(9.10-dioxo-9.05-8. 7.15 min.10-dihydro-phenanthren-3-yl)-2-trifluoromethylbenzamide: 30 [0039] Brown solid. d. 140 mmol.99 (3H.3 Hz). dd. s).7 Hz). 7. J = 7.57 (2H. 4.7 Hz). 8.9 Hz).2 Hz). 1H NMR (300 MHz.84 (1H. HPLC: 9. 7. DMSO-d6) δ 10. 7. J = 7. 7.06 (1H. 7. 7.11 (2H.81 (1H.5. HPLC: 7. 7. J = 9 Hz). dd. d.8. s). HPLC: 7. 340 mg.02 (3H. d. dd. DMSO-d6) δ 10. 8. 10-dione (200 mg.75 (6H.10-dione (50 mg. Example 15: N-(9.40 (2H. 2. 8. d. HPLC: 6. 7.50 (6H. HPLC: 7. t.09-8.29 (4H.76 min.10-Dioxo-9.5. 8. s).97 min. J = 1.5.10-dioxo-9.52 (4H. J = 2. s). J = 1.10-Dioxo-9. 7. dd. and the eluate evaporated under reduced pressure to yield a solid. after which time it was diluted with ethyl acetate (25 mL) and washed sequentially with saturated aqueous NH4Cl.31 (1H.5 Hz).36 min. HPLC: 5. J = 1. 7. s). Example 12: N-(9. The resultant solution was stirred overnight. dd.5 Hz). m). 1H NMR (300 MHz. m).5 Hz).10-dioxo-9. 8. J = 1.5 Hz).7 Hz). s). dd.68-7. 8. 7 . J = 7. 7.48 mmol). dd. 7. The solid products were triturated with Et2O. 8. 2. J = 8. 1H NMR (300 MHz.8. s). J = 7. p-toluenesulfonyl chloride (TsCl. m). 7.62 (1H. 900 µmol) in CH2Cl2 (10 mL) under N2 was added Et3N (630 µL. tq. 73 µmol. 8. Example 10: N-(9. and the residual solid material collected by vacuum filtration to yield the pure amide N-(9.89 min.57 (1H. J = 7.5 Hz). 1H NMR (300 MHz. 7.10-dihydro-phenanthren-3-yl)-acetamide: 20 [0037] Brown solid.5.44-7.39 (1H.10-Dioxo-9. water and brine and then dried over Na2SO4. 7. d.85 min. J = 1.02 (3H. 7.17 (1H. 8. s).06-8.EP 1 242 363 B1 Example 9: N-(9.84 (1H.10-dihydro-phenanthren-2-yl)-4-methylbenzenesulfonamide (53 mg.5. 7. 7. d.76 (1 H.91-7.2. J = 8.10-Dioxo-9. s). Example 13: N-(9.14 min.66 (2H.5.10-dihydro-phenenathren-3-yl)-2. m). 1H NMR (300 MHz. 7. 7.91 (1H. 8.5. J = 7.68 (1H.5 Hz). The mixture was filtered through a pad of silica gel using THF as the eluant. J = 8. m).54 (1 H. N-(9.1 Hz). t.5 Hz). 7. 8. 2.09-7.12 (1H.70 (1H.95 (3H.90 (1H. 8.5. m).8 Hz).8 Hz). ddd.31 (1H. 7. 7. DMSO-d6) δ 11.2. 1H NMR (300 MHz. 1. m). 7.77 (1H. 7.5 Hz).10-dihydro-phenanthren-2-yl)-4-methyl-N-[(4-methylphenyl)sulfonyl]-benzenesulfonamide (39 mg.96 (1H. 0. 240 µmol) in THF (10 mL) an excess of Na2CO3 (0.76 (1H.

8 Hz). d.2. J = 8.21 (2H. m).7 Hz).2 Hz).1 Hz). 7. dd.04 (2H. 7. dd. s).11 (1H.8 Hz). HPLC: 8. J = 8. ddd.8.34 (3H. 1H NMR (300 MHz. J = 7. 8. J = 7.40 (1H.2.6. J = 1. J = 1.1 Hz) 8.5.42-7. s).43 (1H.64 (1H. m).6 Hz). 50 55 8 .5. J = 2. 7. CDCl3) δ 8. dd. q.4. J = 7. J = 1. 7.9.1. s).1 Hz). J = 8. 8.96-7. J = 7.75 (1H. m). 7. HPLC: 8.4 Hz). 7. The soluble material was purified using a Rainin preparative HPLC on a Rainin phenyl column (25 cm x 21.8.51 (2H. HPLC: 8.6.36 (1H. m). CDCl3) δ 8.96 (1H. J = 1. J = 7. d.4 Hz). 7. 1H NMR (300 MHz. CDCl3) δ 8. dd. dd.28-7. dd.5.4 Hz). 7.2 Hz). 7.10-dione: [0048] Violet solid.47 min.09 (2H.73 (1H. 7.56-7. 3. J = 1. J = 1.10-dione (150 mg. CDCl3) δ 8. 7.5 Hz). J = 8. 7.12-6. J = 1.9 Hz).50% for 5 min.51-7.57 (1H.55 min. ddd. s). t.5 Hz). 8.5.EP 1 242 363 B1 Example 16: 2-Benzofuran-2-yl-phenanthrene-9. 1. 7.02 (1 H.10 (2H. J = 1.3 Hz).80% dioxane/H2O for 40 min.4 Hz).9 Hz).21-7. 1H NMR (300 MHz. dd. tri-otolylphosphine (32 mg.03 (1H. m).23 (1H.02 (1 H.10-dione: [0042] To a mixture of 2-bromo-phenanthrene-9. 8. d. ddd. 7. 7.04 (1H. 7. 7. 8.8 Hz).2 Hz).4 Hz). 6. d. J = 1.21 (1H. 8. J = 6. d.5 Hz).10-dione: 30 5 10 15 20 25 [0046] Orange solid.10-dione: [0045] Orange solid. d.77 (1H. 8. 52 µmol). 8.8 Hz).93 (1H. d. dd.4 Hz). J = 8. J = 1. J= 2. 7. J = 8. The resultant mixture was heated at 80 °C for 18 h and the solid material was removed by filtration.35 (1H.5.16 (1 H. 7. J = 7.2. d.10-dione: [0044] Orange solid. J = 8.8 Hz).8 Hz). 7.06 (1 H.1 Hz). J= 2. Purple solid.10 (1H. Example 20: 2-(2-Methoxy-phenyl)-phenanthrene-9.4 mmol).73 (1H. HPLC: 8.76 min.04 (1H. Example 17: 2-Thiophen-3-yl-phenanthrene-9. 520 µmol) in dioxane (5 mL) and H2O (0. m).45 (3H. 7. m). 8. the material was then chromatographed on a silica gel column using CH2Cl2 as the eluant. d. Example 18: 2-(2-Fluoro-phenyl)-phenanthrene-9.73 (1H.95 (1H.1 Hz). J = 7. d.86 (1H.6.2. 7. 8.2 Hz).20 (1 H.33 (1H.25 (1H.5 mL). d.8. 8.8.10 (1H.8 Hz). m). 7. ddd.99 (2H. m). HPLC: 9.52-7. s). tris(dibenzylideneacetone)-dipalladium(0) (48 mg. m).7 Hz). d. 7.31 min. 7.2 Hz). 8. J = 0.50 (1H. 7.05 (1H.8 Hz).71 min.8 Hz).71 min.20 (1H.1 Hz). 8 µM particle size. d. m). 7. [0043] The compounds of examples 17 to 22 inclusive were prepared by the method of Example 16. dd.7. 7. J = 7.86 (3H.97 min. J = 8.41-7. 7.49-7. 4. 7. 45 Example 22: 2-(2-Ethoxy-phenyl)-phenanthrene-9. d.4 mm.47 (1H. 8.57 mmol) were added. d.28 (2H.4.8. J = 7. ddd.39 (3H. 7. m). 60 Å). 7. dd.47 (1H.91 (1H.9. 7.10-dione: 35 [0047] Orange solid. Example 19: 1-Naphthalen-2-yl-phenanthrene-9. dd. d. 7. J = 7.1 Hz). 8. 7. 7. 8. CDCl3) δ 8. J = 1.38 (1H.31-7. 7. 7.64 (1H. 6.47 (5H.14 (2H. J = 2. d. If the purity at this stage was not sufficient. 7.3]dioxol-5-yl-phenanthrene-9. by utilizing the appropriate boronic acid. d. 8.8 Hz). HPLC: 10. 7. d. 8. 7. CDCl3) δ 8.4. 8. ddd. 7. 1. J = 7. 1H NMR (300 MHz. d. 1H NMR (300 MHz. m).75 (1H.6 Hz).94 (1H. 7. s). 1. 7. 1H NMR (300 MHz.1 Hz). 1.35 (1H.84 (4H. J = 7.20 (2H.36 (2H.20 (1H. J = 1.10 (2H. 7. 8. 7. HPLC: 10. J = 7. benzo[b]furan-2-boronic acid (169 mg. ddd. 8. m). 8. J = 7. CDCl3) δ 8. 6. 40 mL/min.64 (1H. m). 7.1 Hz). 8. with 50% .8 Hz). 7.73 (1H. 6.5. J = 0. 7. d.10-dione: [0049] Orange solid. 7.4 mmol) and K2CO3 (220 mg. 7. followed by 80% . 40 Example 21: 2-Benzo[1.8 Hz). d.07 (1H.38 (1H. 1H NMR (300 MHz. J = 8.

and diisopropylethylamine (1.14 g. 3. N. then treated with TFA containing 2% water and 2% thioanisole (10 mL) for 2 h.5 g.1 mL. Fractions containing pure product were combined and lyophilized to give the compound in accord with structural diagram VII (170 mg) as an orange solid. CH2Cl2 (5 x 300 ml) and methanol (5 x 300 ml).40.EP 1 242 363 B1 Example 23: A compound in accord with structural diagram VII: [0050] 5 10 15 20 25 30 35 40 45 [0051] Polystyrene resin with the Ellman's aldehyde linker (50 mmol. 60 A) using a gradient of 10% to 40% acetonitrile in water with 0.5 mmol).06. 5. 3 x 300 mL). at which time isobutylamine (32 mL. The resin was dried for 16 h in vacuo. HPLC: 3. 5. The resin was dried in vacuo at 40 °C for 16 h. Found: C. A solution of FMOCGln (Trt)OH (2. then again treated with 20% piperidine in DMF (10 mL) for 7 min and drained. 3 mmol). for C26H28N4O6-0.5 mmol). The liquid was drained and the resin was washed with DMF (10 x 10 mL). Anal. Orange solid.14 g. 3.2 g.03. 10. A mixture of 9. p. 325 mmol) and sodium triacetoxyborohydride (69. 57. A mixture of FMOCGlyOH (1. H.10-dioxo9. then washed three times with DMF. N. see J. This product was purified by preparative HPLC on a C18 Dynamax column (21. HATU (1. 5. H. and diisopropylethylamine (1.95 min. washed with H2O (3 x 25 mL) and dried in vacuo for 2 h. The resulting solid was collected by vacuum filtration. then treated with another 20% piperidine in DMF (10 mL) for 7 min and drained. then transferred to a fritted glass funnel and was washed with MeOH and DMF (1:1 mixture.31. 6 mmol) in DMF (10 mL) was added to the resin and allowed to react for one hour. 3 mmol). DMF (3 x 300 mL). 58. The above resin (1. 9.88. 3.1 mL.4 mm X 25 cm.1 mL. The liquid was drained and the resin was washed with DMF (10 x 10 mL).5H2O-0.88.5CF3CO2H C. and Et2O (5 x 10 mL). 6 mmol) was added to the resin and allowed to react for 1 h.1% TFA. 50 55 9 . The solids were removed by filtration and washed with CH2Cl2 (10 mL). CH2Cl2 (5 x 10 mL). Org. The resin was washed with DMF (10 x 10 mL). Calcd. The resin was washed with DMF (10 x 10 mL). The resin was treated with 20% piperidine in DMF (10 mL) for 3 min. The resin was treated with 20% piperidine in DMF (10 mL) for 3 min.10-dihydro-phenanthrene-3-carboxylic acid (880 mg.32. 9. HATU (1. drained. 58. HATU (1. 1 mmol) was swelled in DMF for 15 min.98. 62.14 g. drained. The volume of combined filtrate was reduced to about 1 mL by rotary evaporation and precipitation was induced by addition of Et2O (25 mL).5 mmol).14 g. 1997.04 g. 3 mmol). The mixture was stirred with an overhead stirrer for two hours. 328 mmol) were added. 6 mmol) in DMF (10 mL) was added to the resin and allowed to react for1 h. Chem. and diisopropylethylamine (1. 1240) was swelled in DMF (1 L) and acetic acid (10 mL) for 10 minutes.48. The liquid was drained and the resin washed with DMF (10 x 10 mL).

A solution of 9. A solution of FMOCglutamine(Trt)OH (610 mg. HPLC: 2. The material was purified by preparative HPLC on a C18 Dynamax column (21. drained. A solution of FMOCglutamateOH(OtBu) (830 mg. having 3-carboxy-linked peptides. using either 9. 5. The solution was drained and the resin was washed with DMF (10 x 5 mL). Addition of Et2O (10 mL) induced precipitation. CH2Cl2 (5 x 5 mL). After 15 min. 5. 10. The resin was treated with 20% piperidine in DMF (5 mL) for 3 min. The solution was drained and the resin was washed with DMF (10 x 5 mL).01. and diisopropylethylamine (350 µL) in DMF (5 mL) was added to the resin and mixed with a gentle nitrogen bubbling for 2.55 min.5 h.10-dioxo-9.10-dioxo-9. The resin was washed with DMF (10 x 5 mL). and Et2O (2 x 50 mL).5 mmol) and diisopropylethylamine (1.10.10-dihydro-phenanthrene-3-carboxylic acid (250 mg. 54. then another portion of 20% piperidine in DMF (5 mL) for 7 min and drained. The resin was washed with DMF (10 x 5 mL). Calcd. the resin was transferred to a fritted glass funnel and washed with DMF (2 x 50 mL). then with another 20% piperidine in DMF (5 mL) for 7 min and drained. The solution was drained and the resin washed with DMF (10 x 5 mL).19. and diisopropylethylaminc (350 µL) in DMF (5 mL) was added to the resin and mixed with a gentle nitrogen bubbling for 2 h. The reaction was gently mixed under a nitrogen atmosphere for 30 min. 3. The resin was treated with TFA containing 2% thioanisole and 2% water (5 mL) for 3 h.81. for C40H45N7O13-1. then MeOH (3 mL) was added to cap the unreacted sites. The resin was washed with DMF (10 x 5 mL).5CF3CO2H C. Fractions containing pure product were combined and lyophilized to give M374187 (100 mg) as a yellow solid.1% TFA.0H2O-0. The resin was washed with DMF (10 x 5 mL).10-dioxo-9. I mmol). 1 mmol).04. 1 mmol). I mmol). 54. HATU (380 mg. 1 mmol). 7 mmol) was swelled in dry CH2Cl2 (30 mL) and a solution of FMOCprolineOH (1.30. below. drained. The resin was treated with 20% piperidine in DMF (5 mL) for 3 min. N. 10 . Anal. MeOH (2 x 50 mL). and diisopropylethylamine (350 µL) in DMF (5 mL) was added to the resin and mixed with a gentle nitrogen bubbling for 2 h. A solution of FMOCglutamineOH (370 mg.18 g. and this solid was collected by vacuum filtration to give the product (300 mg) as a pink solid. HATU (380 mg.23. N. 1 mmol). 1 mmol). were synthesized by the method of Example 24. A solution of FMOCprolineOH (340 mg.8 mL.5 g. 10.99. The resin was dried in vacuo at 50 °C to constant weight. The solution was drained and the resin was washed with DMF (10 x 5 mL). The resin was treated with 20% piperidine in DMF (5 mL) for 3 min. 1 mmol). A portion of this material (1. 5. 10. HATU (380 mg. HATU (380 mg. [0054] The compounds shown in tables I and 2. The resin was treated with 20% piperidine in DMF (5 mL) for 3 min. 1 mmol). The solution was drained and the resin was washed with DMF (10 x 5 mL).EP 1 242 363 B1 Example 24: A compound in accord with structural diagram VIII: [0052] 5 10 15 20 25 30 35 40 45 50 55 [0053] 6-Chlorochlortrityl resin (6.10-dihydro-phenanthrene-2-carboxylic acid as the starting material and a suitable peptide fragment: [0055] Table 1 shows compounds of the invention in accord with structural diagram VIII.4 mm X 25 cm. The solids were filtered off and the filtrate was evaporated to a red oil. The resin was washed with DMF (10 x 5 mL). The resin was treated with 20% piperidine in DMF (5 mL) for 3 min. H.25 mmol) was swelled in DMF (5 mL) for 15 min then washed with DMF (3 x 5 mL). Found C. and diisopropylethylamine (350 µL) in DMF (5 mL) was added to the resin and mixed with a gentle nitrogen bubbling for 16 h.10-dihydro-phenanthrene-3-carboxylic acid or 9. then dried under a stream of N2. drained. drained. Et2O (5 x 5mL). and diisopropylethylamine (350 µL) in DMF (5 mL) was added to the resin and mixed with a gentle nitrogen bubbling for 16 h. HATU (380 mg.19 g. 54. then with another 20% piperidine in DMF (5 mL) for 7 min and drained. 60 Å) using a gradient of 10% to 26% acetonitrile in water with 0.5 mmol) in dry CH2Cl2 (10 mL) was added. then another portion of 20% piperidine in DMF (5 mL) was added and mixed for 7 min then drained. then treated with another 20 % piperidine in DMF (5 mL) for 7 min and drained. 1 mmol).28. 0. H. 11. drained. CH2Cl2 (2 x 50 mL).

H. 5. 4. Found C. 53. 53. 5.81.0H2O-0.67 min. HPLC: 2. H.42. 52. 53.5H2O-0.17. N.5CF3CO2H C. N.34 min.68.31. Found C.59. 54. 5. Calcd. 54. HPLC: 2.80. Found C. 5.69. 10. [0068] Example 37: Yellow solid.83.31. HPLC: 2.5H2O-0. Anal. 10. 52.88 min. H. 51. HPLC: 2. 11.57. N.6CF3CO2H C. 10.5CF3CO2H C.13 min.54. Anal.17. 5. 12. 53.41 min.75. 12. 12. 51. 10. 10. HPLC: 2. 53. Anal.93. for C34H36N6O12-1.52 min.07 min. Anal. 52.25. H. H.4.48. 5.42. Anal. N. Anal. [0064] Example 33: Yellow solid.46. Found: C.37.90.44. N.5CF3CO2H C. N. HPLC: 2.82.20. [0067] Example 36: Yellow solid. Anal. 11. H. HPLC: 2. N.31.0H2O-0.24.98. 10.25.0H2O-0. 5. 12.50 min. N. 52. 10.52.02 min.77. Calcd.5CF3CO2H C.06. 4. 12. 52. HPLC: 2.42. having 2-carboxy-linked 11 . 11. H.80. Anal. H. H. N. for C34H36N6O12-1. 12. 11. Found C. 13. 5.94.84.82. 4.05.14. H. 11.4CF3CO2H C.24. 53. N. 51. N. 10. Anal.91. for C37H41N7O13-1. Anal. 53. [0070] Example 39: Yellow solid. 5.7H2O-0.52. 4. H. 54. for C37H41N7O13-1.37. Calcd. 11. 52. N.47 min: Anal. for C34H36N6O12-0.60.56.30. 52. N. 52.80.43. HPLC: 2. 11.5H2O-0. Found C. 10. 51. for C37H42N8O12-1. Found C. 4. Anal. 10. 54.EP 1 242 363 B1 Table 1: Example No. 5. [0061] Example 30: Yellow solid. 12.0H2O-0. Calcd.74. [0062] Example 31: Yellow solid.87. 52.5H2O-0. 52. Found C.66. 5.61.53. 4.5CF3CO2H C. 11.0H2O-0. for C34H37N7O11-0.51. 51. [0058] Example 27: Yellow solid. 4.57. for C37H41N7O13-1.78.72. for C34H37N7O11-1.21.12. 5. HPLC: 2. 10. 5. 11. N.5CF3CO2H C. 4.39.32.97.98. H.24. 5. 4. 10.28. 5. 4. 4. H. for C40H45N7O13-1. 5. [0063] Example 32: Yellow solid. 10.35. 13.78. Found 53.5CF3CO2H C.66.91. 10. H. for C37H42N8O12-2. Calcd.49.79.95. 51. Calcd. H. HPLC: 2.80.83.92. H. 52. 4. Found C. 12.01. Found C. Calcd.31.57. N.12.00.15. HPLC: 2.15.44.88. 52. for C37H40N6O12-1. H. [0057] Example 26: Yellow solid. H. H.85.80. N. for C34H36N6O12-0. [0071] Table 2 shows compounds of the invention in accord with structural diagram VIII.13.61. N. [0059] Example 28: Yellow solid. 4.48. N.18.47 min: Anal. 53. 54.08. 4. N. 5. 4. Calcd.86. 11. 11. [0069] Example 38: Yellow solid. 4.85. 10. H. Anal. H. [0065] Example 34: Yellow solid.84.01. 4.05. 52. 54. N. 51. Calcd. 10.5H2O-0. 12. Found C. 5. 53.20. Calc. Calcd. 52. 11. N. H.56.11. 4.29.49 min. For C37H41N7O11-1.99.96. 52. [0066] Example 35: Yellow solid. 5. N. 10.52.26 min. 4. N. H. [0060] Example 29: Yellow solid.28. 52. N.30.93.79. Found C.06. 52. N.81. Calcd. HPLC: 2. 10.6CF3CO2H C.97.66.25 min. 5 AA1 Glu Gly Gln Gly Gln Gly Gln Glu Gly Gln Gln Gly Gly Gln Gly Gly AA2 Gln Gln Gln Glu Glu Gin Gln Gln Glu Glu Gin Gln Gln Gin Glu Gln AA3 Pro Pro Pro Pro Pro Gly Gly Gly Gly Gly Pro Gly Pro Pro Pro Pro AA4 Gln Gln Gln Gln Gln Gln Gln Gln Gin Gin Glu Glu Gln Gln Gln Glu AA5 Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Gly Pro Gly Gly Gly Gly 24 25 26 27 10 28 29 30 15 31 32 33 34 20 35 36 37 25 38 39 30 35 40 45 50 55 [0056] Example 25: Yellow solid. H.60 min.73.5CF3CO2H C.80. N. H.40. H.31. 5.5H2O-0.01.38. 53.93. Calcd.0H2O-0. 5.5CF3CO2H C. N.6CF3CO2H C. HPLC: 2. 5.59.6CF3CO2H C. Calcd.87.92. HPLC: 2.87.0H2O-0.08. H.

52.46. For C32H36N8O9-0.14. 4.66. 12. H. 49. For C36H45N11O9-1.EP 1 242 363 B1 peptides. 4. Calc. H. For C31H31N5O11-1.83 min. Calc. HPLC: 2. 4. 4. 8. 4.62.90.72. Anal.0H2O-0.74. Table 2: Example No.75.84. [0074] Example 42: Yellow solid. 4. 49.90. H. For C34H35N5O13-0. H. Found: C. 48. 4. N. 48. N.04. Calc. 9. N.23.15. 4.33. 13. 13. 4.84 min. 4. [0076] Example 44: Yellow solid. N. N.85.06.67. H. 4. N.16. 12 .76.08. N.5CF3CO2H C.81 min.69.96. [0079] Example 47: Yellow solid. 5 AA1 Gly Glu Arg Gly Glu Arg Gly Glu Arg Gly Glu Arg Gly Glu Arg Gly Glu Are AA2 Gly Gly Gly Glu Glu Glu Arg Arg Arg Gly Gly Gly Glu Glu Glu Arg Arg Arg AA3 Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro Pro AA4 Glu Glu Glu Glu Glu Glu Glu Glu Glu Arg Arg Arg Arg Arg Arg Arg Arg Arg AA5 Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 40 41 42 10 43 44 45 46 15 47 48 49 20 50 51 52 25 53 54 55 56 30 57 35 40 45 50 55 [0072] Example 40: Yellow solid: HPLC: 2.75.25H2O-1. H.68. 12. For C39H49N11O11-2. Anal. N.61.5CF3CO2H C. Anal. For C37H39N5O15-0. Found: C.94. 11.22. H.75.79.97. Anal. 53.83 min.75.5H2O-1. N. Found: C. 49.53. Found: C. 9. 45. 13. HPLC: 2. 11.76. 48. N. Calc. 4.94. [0082] Example 50: Yellow solid. Anal. HPLC: 2.79. Anal.68.46. H. [0078] Example 46: Yellow solid. 48. H.68.35. For C38H44N8O13-1.08. H.83 min. [0083] Example 51: Yellow solid. 13.07. 8. For C38H44N8O13-1.14. For C35H40N8O11-1. 13.23.94.4CF3CO2H C. [0075] Example 43: Yellow solid.55.27.64. C. 48. 4.29.74 min. 4.5CF3CO2H C. For C35H40N8O11-0.5CF3CO2H C.60. 45. H. Found: C. N.92. HPLC: 2. 13. 12. Anal. N. 14.61.34. 53.14. [0073] Example 41: Yellow solid. 52. Anal. Found: C. 48.00.58.75. 4.28.80. N. 53. 48.5CF3CO2H C.09. 14. Anal. Calc. 45. N.5CF3CO2H C. Found: C.64. N. 9. N. HPLC: 2. 49. 4.06.28. 49. H.4CF3CO2H C. Anal.27. 4. 45. H.0H2O-2. 45. [0081] Example 49: Yellow solid.76.06.90.53. 11.70.0H2O-1. 52.61. HPLC: 2. Calc. 8. 49. 45. 13. Calc.61.5H2O-1.5H2O-0.04. 48.12. H. 4.10.06.49 min. 9. 49.79. N. 13. N. 12. 12.14.75. Found: C. H. Calc. [0077] Example 45: Yellow solid. H. 53.48 min.5CF3CO2H C. 12. 53. 4. N.00. 12. HPLC: 2.67.24. Calc.5CF3CO2H C.67.53.5H2O-2. 4. N. [0080] Example 48: Yellow solid.74.5H2O-1. Anal. N.89 min. 4.12.37. 12.5H2O-1. N.86. N. 14.5H2O-0. Found: C.36. H. HPLC: 2. Calc.83. HPLC: 2.62. [0084] Example 52: Yellow solid.74 min.89.07. H. 4.2CF3CO2H C. HPLC: 2.74 min. 4. 13. For C35H40N8O11-0. 45.87. 4.06. 11. 53. 8. 12.78 min. H.49 min. N. For C34H35N5O13-0. 49. Calc.5CF3CO2H C. 4. HPLC: 2. Found: C. 4. 11.22. Found: C.75H2O-0.61. Anal. H. 4. H. 45. 11.71. HPLC: 2.10. Calc.44. 8.63. 4.06.54. 49. Found: C.77 min. 49. 4. H. 4.5CF3CO2H C. H. N. 4.61. H. Anal.5H2O-1. H.29. N.10. 4. 53. 4.72. H. 4.99. 45. 4. 53.58.93.88. 9.66.68. H.64. 8. 4. 4. 53. Calc.14. 4. 8. For C35H40N8O11-0. 4.10.87.30. 48.90. Found: C.

5H2O-2.66. 10 mol).60.73. drained. HPLC: 2. then was treated with more 20% piperidine in DMF (10 mL) for 7 min and drained. maintaining reaction temperature below -7 °C.13. aq. Calc. CH2Cl2 (2 x 10 mL) and MeOH (3 x 10 mL).76.10-dione) was calculated based on the increase of mass to 5. HPLC: 2. After 3 h. 10 mmol).12 g. [0088] Example 56: Yellow solid. and reaction was complete after 7 d. DMF (2 x 10 mL). drained. then another portion of 20% piperidine in DMF (10 mL) was added for 7 min and drained.2CF3CO2H C. 8 mmol) were dissolved in dry THF (20 mL) and chilled to -10 °C. 10%) was removed for other reactions and the remaining resin was treated with a solution of FMOCGlyOH (1. EtOAC:CH2Cl2. 12. 45.10-dione (1. N. drained. 13. diisopropylethylamine (5 mL) and dry DMF (10 mL) were added under N2. 4. 14.50. 4.36.52. 25:75 EtOAc:CH2Cl2. then treated with additional 20% piperidine in DMF (10 mL) for 7 min and drained. H. The reaction was drained and washed with DMF (10 x 10 mL). Anal. 4. Found: C. 43.74.81. 13.10-dione was monitored by TLC (Rf = 0. The resin was collected by vacuum filtration and washed with CH2Cl2 (5 x 10 mL).40.2 mmol/ g.68. 11.8 g. then washed with DMF (5 x 25 mL).86. N. 8 mmol) and N-methylmorpholine (900 µL. H. [0086] Example 54: Yellow solid. 4.5 mmol) was added to the mixture and mixed by shaking. v/v.74. 43. 4. The solvent was removed by rotary evaporation and the residue was partitioned between EtOAc and sat'd. The resin was washed with DMF (10 x 10 mL). H. For C39H49N11O11-1. N.57. H. HATU (3.72 g.5H2O-2. [0090] Example 58: A compound in accord with structural diagram IX: 5 10 15 20 25 30 35 40 45 50 55 [0091] A compound in accord with structural diagram IX having the N-Ac-amino acid sequence N-Ac-Glu-Gly-Gln was synthesized as follows: FMOCAsp(OH)OtBu (3.92 min.8 g.55. The resin was dried for 64 h in vacuo. Found: C. Found: C. Anal.8 g. 48. 15. HPLC: 2. 46. Found: C. The resin was treated with 10 ml 20% piperidine in DMF (10 mL) for 3 min. HPLC: 2. 4.38. [0089] Example 57: Yellow solid.3 g. N.5H2O-3. v/v on a silica gel plate). The resin was washed with DMF (10 x 10 mL).5 mL) in DMF (15 mL) for 16 h. H. 13.2CF3CO2H C.10. The resin was treated with 20% piperidine in DMF (10 mL) for 3 min. Anal. 4. H. 45.EP 1 242 363 B1 4.63. A solution of FMOCGIn(trt)OH (6. 43. A portion of the resin (ca.57. 2-chlorochlortrityl resin (4.68 g. 45. A portion of the resin (about 10%) was removed for other reactions and the remaining resin was treated with a solution of FMOCGlu(tBu)OH (4.5 mL) in DMF (15 mL) for 1 h. N.5 g of 1.57.5CF3CO2H C. 48.63.79. 4.10. 11 mmol). The resin was swelled in DMF (25 mL) for 1 h. An incorporation of 2. 12. 11 mmol). 15. aq. then dried over anhydrous MgSO4. 63%) as a red solid.05. 5 mmol) in dry THF (40 mL).57 min. 7 mmol) was added dropwise.83.62. 46. The resin was treated 13 . 48.05.03. Residual TFA was removed by dissolving the material in CH2Cl2 and concentration on the rotary evaporator twice. The solution was drained and the resin was washed with DMF (10 x 10 mL). N.83.71 min.0H2O-1.28. 4. 46. N.69. HPLC: 2. The resin was treated with 20% piperidine in DMF (10 mL) for 3 min.81.93 g. HATU (3. 13. H. Calc. 48.40.58. H. HATU (3. 10 mmol). Calc.3CF3CO2H C.28. N. This was dissolved in dry CH2Cl2 (100 mL). 45.3CF3CO2H C. 4.72.09 min. Calc.90. NaHCO3 and brine. N. Anal. This intermediate was dissolved in CH2Cl2 (100 mL) and TFA (30 mL) was added. This mixture was filtered and the filtrate was concentrated to a red-brown solid and chromatographed on silica gel with 15:85. 11 mmol).52. N. and diisopropylethylamine (3.34. 4. 48. For C38H44N8O13-1. 11.67.20.89. 15.92 g. 3. N. 4.61. and diisopropylethylamine (3.56 min. N. 4. 14. 11. For C39H49N11O11-1. diisopropylethylamine (3. The resin was washed with DMF (10 x 10 mL). 14. after 1h the volatiles were removed by rotary evaporation. For C40H54N14O9-2. 11. 13. and the reaction was allowed to warm to ambient temperature. Found: C.58.5 mL) in DMF (15 mL) was added to the resin and mixed with gentle nitrogen bubbling for 2 h.26.3 mmol of FMOCAsp(3-aminophenanthrene-9. H. Isobutylchloroformate (910 µL.55. 4. 13.65. This gave FMOCAsp-2-aminophenanthrene9. The solution was drained and the resin was washed with DMF (10 x 10 mL). The organic phase was washed with sat'd.1 mmol.89.71. 4.37. 4. N. MeOH (10 mL) was added and the shaking was continued for an additional 10 min. To this mixture was added a suspension of 2-amino-phenanthrene9. Anal. NH4Cl.26. 45. [0085] Example 53: Yellow solid. The disappearance of 2-aminophenanthrene-9. Calc. For C36H45N11O9-2. [0087] Example 55: Yellow solid.10-dione (1. H. 4.0H2O-2. Found: C.46. 5. 45.42.8 g.

1. s).5. Example 67: 4-(9. dd. t.2307 amu.53 (1H.75 (1H. 7. s). 7.50 (1H.6 Hz).0 Hz).5. HRMS theor. [0094] Example 60: Red solid.4322 amu. using CH2Cl2-5% EtOAC/CH2Cl2-10% EtOAC/CH2Cl2-20% EtOAC/CH2Cl2 as the eluant. [M+H]: 509. J= 7. 60 Å) using a gradient of 10% to 26% acetonitrile in H2O with 0. 7. 15%) was removed and treated with a solution of Ac2O (1 mL) and diisopropylethylamine (2 mL) in DMF (5 mL) for 2 h. 7.69 min .3161 amu. HPLC: 2. 7. 2. t. m).8 Hz).58 (4H. 8. HPLC: 2. 7. [M+H]: 1115. followed by 3-carbomethoxypropionyl chloride (381 µmol.31 (2H. Addition of Et2O (10 mL) induced precipitation of a red solid. 1% TFA. 323 µL).10-Dioxo-9. J = 1. 2. [0097] Example 63: N-(9. HPLC: 3.85 min. HRMS theor. [M+H] 695. m).75-7.92 (1H. d). 1H NMR (300 MHz.69 min. d. HPLC: 3.8 Hz). dd. J = 1.01 (1H. 7. 7. 8.4 Hz). DMSO-d6) δ 10. 1. Example 68: 7-(9. 58 59 amino acid sequence N-Ac-Glu-Gly Gln N-Ac-Gln N-Ac-Ala-Thr-Glu-Gly-Gln N-Ac-Thr-Ala-Thr-Glu-Gly-Gln N-Ac-Phe-Thr-Ala-Thr-Glu-Gly-Gln 20 60 61 62 25 30 35 40 [0093] Example 59: Red solid. s).81 min. s).44-2.92 (1H.8 Hz). deviation of -1.10-dihydro-phenanthren-4-ylcarbamoyl)-heptanoic acid methyl ester: [0101] Orange solid. 2. The resin was treated with a solution of TFA containing 2% H2O and 2% thioanisole (5 mL) for 2 h. deviation of -3 ppm.3619. J = 6 Hz).43 (1H. obs.2 ppm. J = 7. d.69 min. [M+H] 867. d.1657 amu. 1H NMR (300 MHz. J = 1.9 ppm. 8.33 (4H. s). The solids were removed and the solution was concentrated to a red oil. [0095] Example 61: Red solid.53 (1H.10-dihydro-phenanthren-4-ylcarbamoyl)-butyric acid methyl ester: [0100] Orange solid.82 (2H. d. [M+H] 1115.62 (3H.35 (1H.2 Hz). J = 9 Hz). dd. [M+H] 509.4. obs. [0092] Table 3 shows compounds of the invention in accord with structural diagram IX. [0099] The compounds of examples 67 to 79 inclusive were prepared by the method of Example 63. 238 µmol) in THF (10 mL) an excess of Na2CO3 (1g) was added.4.2313 amu. d. 7. 2.26 (1H. J = 7. The reaction mixture was then purified on a 10 g silica gel column. m).8.93 (1H. then additional 20% piperidine in DMF (10 mL) was added for 7 min and drained.8 Hz).10-Dioxo-9. and this was followed by filtering and evaporating the solvent. 7. [M+H]: 867. J = 6 Hz). 7.50 (1H. J = 9 Hz).4286 amu.37 (4H. ddd.10-Dioxo-9. d. 7. obs. d.89 min.1672 amu. deviation of -0. which consisted of vortexing the mixture twice for 10 s. was repeated 10 times. d. The reaction cycle. J = 7. 7. to yield the pure N-(9.8 Hz).99 (1H.37 (2H. HPLC: 3. m). deviation of -3. HPLC: 2. J = 7.67 (2H. HRMS theor. J = 7.59 (3H. [M+H]:695.66 (2H. The resin was washed with DMF (10 x 10 mL). which was collected by vacuum filtration. DMSO-d6) δ 10.3638 amu. HRMS theor.14 (1H.99 (1H.91-1.67 (4H. drained. made by the method of Example 58.68 (1H.10-dihydro-phenanthren-4-yl)-succinamic acid methyl ester as a brown solid. 7.10-Dioxo-9. J = 1.6 Hz). 8. d. HPLC: 2. Fractions containing pure product were combined and lyophilized to give the product (40 mg) as a red solid. 45 50 55 14 . 1.8 ppm. m). [M+H] 968. Table 3: 15 5 10 Example No.10-dihydro-phenanthren-4-yl)-succinamic acid methyl ester: [0098] Using a BOHDAN Automated RAM Synthesizer. obs.18 (1H. The material was purified by preparative HPLC on a C18 Dynamax column (21. 3. DMSO-d6) δ 10. [M+H]: 968.81 min.75-7. deviation of -1. [0096] Example 62: Red solid. 7. m). utilizing the appropriate acid chloride. CH2Cl2 (5 x 5 mL). d. 3. 7.7 Hz).3145 amu. HRMS theor.4 mm X 25 cm. J = 9 Hz). s). A portion of this material (ca. HPLC: 5.5 Hz).51 (2H. utilizing the appropriate peptide fragments. d. J= 8. 3. 7. 7.62 (3H. m). obs. 1H NMR (300 MHz. J= 7. to a solution 4-amino-phenanthrene-9.35 (1H. The solution was drained and washed withDMF (10 x 5 mL). 7.9 ppm.10-dione (50 mg.EP 1 242 363 B1 with 20% piperidine in DMF (10 mL) for 3 min. Et2O (5 x 5 mL) and dried under a N2 stream.57 min.

8. m). tt. 7. Example 74: 4-[5-(4-Methoxycarbonyl-butyrylamino)-9.63 (1H. 1. 7.7 Hz).9 Hz). s). 3. 8.38-2.98 (3H. s). s).58 (3H. DMSO-d6) δ 10.23 (1H. d.63 (3H. s). d.7.22 (1H.62-1. m).9 Hz).29 (8H. J = 1.J= 7. 7.1 Hz).64 (1H. d. m). 7.22 (1H.62 (3H. m). 3.2 Hz). 7. 1H NMR (300 MHz. m).2 Hz).70 (2H. HPLC: 3.28 (1H.47 (1H. 7.99 (1H.90 (2H. HPLC: 8. m).5 Hz). J = 7. J = 2.10-dihydro-phenanthren-2-ylcarbamoyl)-butyric acid methyl ester: [0103] Brown solid. J = 7. s). DMSO-d6) δ 10. 8. J = 8. HPLC: 7.50 (8H. 2. 7. 7.10-Dioxo-9. DMSO-d6) δ 10.10-dihydro-phenanthren-4-ylcarbamoyl)-nonanoic acid methyl ester: [0102] Brown solid.75 (1H.56 (8H.26 min.28 (4H. J = 7.98 (2H. 1H NMR (300 MHz. DMSO-d6) δ 10. 3. dd. 2. 8.5 Hz).10-dioxo-9. d.5 Hz).57 (3H. m). d. 1H NMR (300 MHz.31 (8H.34 (2H. 2. 10. s).53 (1H. d. 7. 3. 2.4.0. 7. dd.57 min. J = 7.52 (4H. 2.58 (6H. 7.7 Hz). s). d.0 Hz). HPLC: 5.7 Hz). 3. s).45 (1 H.29 (1H. 8.12 (1H.03 (1H.98 (2H.10-dihydrophenanthren-2-ylcarbamoyl]nonanoic acid methyl ester: [0109] Brown solid.10-Dioxo-9.21 min. 40 45 Example 76: 9-[5-(9-Methoxycarbonyl-nonanoylamino)-9. J = 7. Example 75: 7-[5-(7-Methoxycarbonyl-heptanoylamino)-9. DMSO-d6) δ 10.10-Dioxo-9. 7. J = 2. d.09 min. J = 7.61 (3H. 25 Example 73: N-[5-(3-Methoxycarbonyl-propionylamino)-9.57 (6H.83 (1H. J = 7. 1. d.7.5.3 Hz). 2.47 (1 H. 7.47 (1 H. 1. J = 8.30 (3H. dd. m). 7.3 Hz). tt. 3.56 (1H.11 (1H. m).2. 3. DMSO-d6) δ 10.7 Hz). 8.44 (1H. DMSO-d6) δ 10. 10. m).7 Hz).39 (1H. dd. 1H NMR (300 MHz.3 Hz). J = 7.7 Hz).63 (1H. m).3 Hz). 1. m). dd. 7.22 (1H. 2. dd.10-dihydrophenanthren-2-ylcarbamoyl]heptanoic acid methyl ester: [0108] Brown solid.22 (1H. HPLC: 7. d. 1H NMR (300 MHz. 1H NMR (300 MHz. 8. dd. d. s).60 (3H. s). t.60 (3H.10-dioxo-9.67 (1H.7. HPLC: 5. d.29 (1H.10-Dioxo-9. 2. 7. 8. 8. m). J= 7.10-dihydrophenanthren-2-ylcarbamoyl]-butyric acid methyl ester: 30 35 [0107] Brown solid. s). 1.19 (1H.40 (1H.37 (2H. Example 77: 4-(9.92 (1H. 7. J = 7.61 (2H.23 (1H. dd.3. 7. 8. J = 7. J = 8.63-1. m). 1. 7. J = 7. 7. 1. 7. 1. s). 7.20 (1H.19 (1H.52 (2H.7.20 (1H.46 (1H. s).28 (1H.7 Hz).89 (2H. J = 2. J = 7.29 (1H.2 Hz). s). J = 2. 8. Example 71: 7-(9. J = 2.27 (1H. 7. 7. 8. 7.4 Hz).31 (1H. s).1 Hz).31 min. 1H NMR (300 MHz. 8. 7. d.29 (2H.8 Hz).52 (1H. m). 7.89 (1H.3. DMSO-d6) δ 10.10-dihydro-phenanthren-2-ylcarbamoyl)-nonanoic acid methyl ester: 20 [0105] Brown solid. m). s).3 Hz). 8. 3. 7.61 (2H.90 (2H. d. J = 7.75 (1 H. 3. 7. 7. 2. J = 8.62 (1H.0 Hz). 7. d.58 min.99 (1H.9 Hz).40 (8H. 8.23 (1H. 2. dd.40 (4H.5 Hz).8 Hz). dd.47 (1H. d. J = 8.75 (1H.50 (1 H. 1. 7. dd. J = 7.28 (16H. d.EP 1 242 363 B1 Example 69: 9-(9. J = 2. s). 8. 8. d. 15 .44 (1H.91 (2H. 1H NMR (300 MHz.10-dioxo-9.30 (8H. dd. DMSO-d6) δ 10. 1. 1H NMR (300 MHz. HPLC: 7. 7.28 (2H.10-dioxo-9. 7.45 (4H. J = 7.10-dihydrophenanthren-2-yl]-succinamic acid methyl ester: [0106] Pink solid. J = 7. 7. 8. J = 7. J = 7. 7.0 Hz).64 min. 8. J = 7. s).2 Hz).3.9 Hz). s). m). 1. m). m). m). d.24 min. J = 8.10-dihydro-phenanthren-3-ylcarbamoyl)-butyric acid methyl ester: 55 50 [0110] Orange solid. J = 7. J = 8. d. J = 8.10-dihydro-phenanthren-2-ylcarbamoyl)-heptanoic acid methyl ester: 15 5 10 [0104] Brown solid. m).52 (2H. s). 10. s).87 (4H. 10. s).10-Dioxo-9. 8.6 Hz). 3.93 (1H. 1.7 Hz). J = 7.4 Hz). J = 1.65 (8H.7 Hz). J = 8. m).5. t.7.7 Hz).20 (2H.94 (1H. 7.68 min. dd.18 (1H. t. s). 3. dd. s). t. m). 7. 1.7 Hz).87 (2H. s). d.7 Hz).26 (8H. m): HPLC: 4. m).9 Hz). 7. d. 7. d.6 Hz). 7.35 (1H. J = 8. m). J = 7.7.04-7. 7. 2.37-2.6 Hz). J= 7. 1. 7. d. s). 7. Example 70: 4-(9.6 Hz). 7.6 Hz).61 (3H.31 (4H.28 (1H.7.7. J = 7. HPLC: 9. J = 7. m). Example 72: 9-(9. d.0 Hz).03 (1H.

4.4. 1H NMR (300 MHz. and chromatographed on silica gel with ethyl acetate as the eluant to yield N-(9.84 (1H. DMSO-d6) δ 10. 1H NMR (300 MH2. 8.61 (6H.10-Dioxo-9. ddd. 1. DMSO-d6) δ 10.6. Example 90: N-(9. J= 2.10-Dioxo-9. 7.7-diamino-phenauthrene-9. 8. HPLC: 8. 30 Example 82: N-[7-(3-Methoxycarbonyl-propionylamino)-9. brine. 1. 1H NMR (300 MHz. d. m). [0113] Compounds of examples 80 and 81 were made as follows: To a solution of 2-amino-phenanthrene-9. dd.61 min.7. d.34 (2H.0 mmol) was added. 7. 8.42 min.10-dihydro-phenanthren1-yl)-succinamic acid methyl ester as an orange solid.9 Hz). J = 1.10-dihydro-phenanthren-2-yl)-acetamide (284 µL. 2. 2.23 (1H. 8. 6.1.7.54 (1H.40 (2H.44 min. d.82 min.5 Hz). Example 80: N-(9. N-(9.84 (1H. 8. DMSO-d6) δ 12.6 Hz).56 (1H.10-dihydro-phenanthren-3-yl)succinamic acid methyl ester as an orange solid.0 mmol). 8.8 Hz).3. d.79 (2H.83 (1H. 3.6 Hz). J = 7.0.61 (3H.4.7 Hz).54 (2H.62 (3H. 1H NMR (300 MHz. filtered. 8. Anal.32 (4H. 7.03 (2H.7. 8.75 (1H.0 Hz). 7.74 (1H. s).02 (3H.30 (2H. 7. dd.47 (1H. 2.54 (1H. J = 8.10-Dioxo-9.91 (1H. J = 7. 7. 2. 2. 7. J= 1. ddd. Example 91: N-(9. 8.23 (1H. J = 7.1 Hz). J = 7. 2. 8.8 Hz). d.2 mmol). J = 2. m).10-dihydro-phenanthren-2-yl)-acetamide: [0115] Purple solid.42 (1H. 7.3 Hz). 7. s).10 (3H.10-Dioxo-9. J = 1. 2.29 (8H. J = 1. HPLC: 4. 7. 2.10-dione (670 mg.28 (2H. 7.2.10-dione.67 (2H. J = 7. Each reaction was stirred for 2.10-dihydro-phenanthren-3-yl)-succinamic acid methyl ester: [0117] To a solution of 3-amino-phenanthrene-9. 8. J = 8. s).65 (1H. m). J= 1. 8. J = 7. 3. 240 µmol) in THF (50 mL) was added Na2CO3 (210 mg. dd. m). 7.56 (1H.7 Hz). 2.65 (4H. s). J = 7. The mixture was stirred overnight. The material was chromatographed on silica gel with 20% EtOAc in CH2Cl2 as eluant and dried to give N-(9. ddd. 2. J= 9.4. 8. was used and 2. Purple solid.52 (2H. 7.10-dihydro-phenanthren-2-yl)-succinamic acid methyl ester (490 µL. dd.2 Hz).6 Hz).1. J = 9. Calcd for 35 40 45 50 55 16 . s). J= 1. 7.2 Hz).EP 1 242 363 B1 Example 78: 8-(9. J= 7. dried over Mg2SO4. m). 8. J = 7.40 (2H. HPLC: 6. 1.4 Hz).04 (1H. 7. J = 2.1 Hz).7.7 Hz).5 h.99 (1H.78 min.29 (1H.04-7.10-dioxo-9. 8.0 mmol). 1H NMR (300 MHz.63 (2H.7 Hz).10-dioxo-9.0 Hz). 25 Example 81: N-(9. The organic layer was washed with water. 7. d.58 (3H.19 (1H.56 (1H. t. 2.10-dione (50 mg. m). d.7 Hz).39 (1H.47 (1H. d.30 min.55 (1H. HPLC: 7. J = 8.25 (2H.99 (1H. m).0 mmol) in THF (70 mL) diisopropylethylamine (1.6 Hz). HPLC: 5. m). dd. 8. filtered. dd.10-dione (400 mg. HPLC: 4. s).98 (3H. 8. J= 1. s). J = 1. 1.9 Hz). dd.6. m). 7.9. m). DMSO-d6) δ 10. 7.0 Hz).5 Hz). 8.4 Hz). d.1.2 Hz). and diluted with ethyl acetate. 7.2. 1H NMR (300 MHz. J = 2.10 (2H.50 (8H. 7.7 Hz).98 (3H.19 (1H. s). 8. J = 7.81 (2H. 2.60 (1H. 2. m). J = 7.10-dihydro-phenanthren-2-yl)-succinamic acid methyl ester: 20 5 10 15 [0114] Brown solid. s). 3.7 Hz). 8. 1. 8. 7.10-dihydrophenanthren-2-yl]-suceinamic acid methyl ester: [0116] The compound of example 82 was synthesized by a method that differed from that of example 80 only in that double the amount of acid chloride. CH2Cl2: MeOH. dd. J= 2.6. s).87 (2H. 3. d.3 Hz).63 (2H. 5. 1H NMR (300 MHz. then the THF was removed by rotary evaporation.61 (1H. d. 1.69 (1H. 7.0 mmol) or acetyl chloride for Example 82. DMSO-d6) δ 10. 7.3 Hz). J= 1. J = 1.10-Dioxo-9. Example 79: 9-(9.7 Hz). t. 8. J = 1. 7.7 Hz).10-dioxo-9.1 Hz). 7. followed by methyl 4-chloro4-oxobutyrate for Example 81 N-(9. d. 7. m).42 (1H.32 (1H. 1.10-Dioxo-9. m). methyl 4-chloro-4-oxobutyrate. m).3 Hz). s). v/v) and the product eluted.3 Hz).1 mL. dd. dd. DMSO-d6) δ 10. 6.10-dihydro-phenanthren-1-yl)-succinamic acid methyl ester: [0118] To a solution of 1-amino-phenanthrene-9. 8.68 (1H. 7. 7. 7. then filtered and the solvent was removed under reduced pressure.04-7. J = 7.33 (1H. dd.2. J = 9. s). 3.7. HPLC: 4.72 (2H. dd.8 mmol) in dioxane (100 mL) was added a large excess of Na2CO3 followed by methyl 4-chloro-4-oxobutyrate (240 µL.89 (2H. J = 7. t.5 Hz).5. dd. 3. t. s). and the reaction mixture was chromarographed on silica gel (9:1.0 Hz).69 (2H.60 (1H. 7.10-dione was used in place of 2-amino-phenanthrene-9. 3.10-Dioxo-9. 2. 7. m). J = 2. s).95 (1H.6. m). followed by methyl 4-chloro-4-oxobutyrate (60 µL. 7. 8. 7.10-dihydro-phenanthren-3-ylcarbamoyl)-nonanoic acid methyl ester: [0112] Brown solid. 8.49 min.26 (1H. dd. The reaction was stirred for several hours.92 (1H.10-dihydro-phenanthren-3-ylcarbamoyl)-heptanoic acid methyl ester: [0111] Orange solid. 7.10-dioxo-9.56 (1H. dd. J = 7. DMSO-d6) δ 10. 4. ddd. 500 µmol).7.57 (3H.7 Hz). m). s). dd.0. d.

3.5 Hz). For C14H9O2N0. H. 7.1 Hz). dd.12. J = 0. 1H NMR (300 MHz.26. 2. and chromatographed on silica gel with ethyl acetate as the eluant to yield N-(9. filtered.0.14. J = 8.. HPLC: 6. 52-59.21. 3726-3730. 1. H.32 (1H.53.10-dione: 55 [0126] Yellow solid. 9.6 Hz). J = 1. 7. 74. dd. 7. m).39.22 Found: C.78 (1H. 4. 65. DMSO-d6) δ 12. 1H NMR (300 MHz. m). s). J = 8. J = 8. J = 7. 7. 66. 8. 1903.10-dihydro-phenanthren-3-yl)-succinamic acid methyl ester: [0121] To a solution of 3-amino-phenanthrene-9.79. 7. DMSO-d6) δ 7. m). filtered. DMSO-d6) δ 8. J = 7.83.94 (1H.2.70. DMSO-d6) δ 10.1 Hz).9 Hz). 56. 66. Example 91: N-(9.22. tfashake-DMSO-d6) δ 8. N. 2. s). 4. 8. 56.9 Hz).08.0. d.30 min. 8. 2.10 (1H. The reaction was stirred for several hours.10-dihydro-phenanthren1-yl)-succinamic acid methyl ester as an orange solid.72. 6.10-Dioxo-9.43. 8.95. 6.7 Hz).9 Hz).0 Hz).8. d. 7. N. J = 2. 65.19. 6. J = 1.10-dione: 5 [0119] Brown solid.69 (2H.22 (1H. 6. Chem. 4. J = 1. 7.64 (1H. 5. N.94. 8. m).8 Hz).2 Hz). m). d.44. d. 7.51 (1H. 73. dd. then filtered and the solvent was removed under reduced pressure.56 (1H. 8.3 Hz). Examples 92 to 95: [0123] Compounds of examples 92 to 95 inclusive were prepared substantially in accordance with the procedures disclosed in Schmidt. 7.20 (2H. N. d. 1943. 7. 6. Example 89: 4-Amino-phenanthrene-9. 2.4. which procedures and results are incorporated herein by reference.56 (1H. 8. Anal. 8.17 (1H. 75. 1H NMR (300 MHz.55 (1H. 8. J = 7.30 (1H. dd.36 (1H. d.12. 7. J = 8. 7. 7.71 (2H.9. J = 1.28. brine.4 Hz). 6. N.99 (2H.41. Example 94: 2. 7.20.10. 6.39 Found: C. J = 1.69 (1H.5.62 (2H. 7. d.7 Hz).81 (2H. C. 8.7 Hz).27 (1H.6.44.0 mmol). DMSO-d6) δ 8. 7.28. J = 1. 2. Anal. 8. 23.10-dione (50 mg.9 Hz). N.2 mmol). For C14H9NO2 C.30. J = 1. 8.33. 75.33 H2O C. J = 2. ddd. 500 µmol).10-Dioxo-9. s). 1H NMR (300 MHz.04-7.7-Dinitro-phenanthrene-9. dd.60 (1H.76 (2H. taking into account the results disclosed by Ray. 7.60 (1H. 75. 8. 2. Calcd. 5. 5.5.83 (1H. 15 Example 90: N-(9.21. 7. 2.7. Calcd. dd.71.10-dioxo-9. s).39. 4. 2.83. Calcd. dd. The organic layer was washed with water. Anal. 7. 1H NMR (300 MHz. H.57. followed by methyl 4-chloro-4-oxobutyrate (60 µL. d. Chem.2 Hz). 9.0 Hz). 74. 7. N. 3. H. W.10-dione: [0124] Orange solid.3.EP 1 242 363 B1 C14H9NO2-0.10 H2O C. 7. J = 3.84 (2H. J = 2. ddd.74. 7.24. Example 88: 3-Amino-phenanthrene-9. for C14H6N2O6 C.10-Dioxo-9.65 (1H. 8. 4.27 Found: C. Example 93: 4-Nitro-phenanthrene-9.63 (1H.5 Hz).8 Hz). 4. m).7 Hz). 7. J = 7. H. 7.4. J = 7.6 Hz). H. 7. 66.8 mmol) in dioxane (100 mL) was added a large excess of Na2CO3 followed by methyl 4-chloro-4-oxobutyrate (240 µL.6.2. d. J = 2.11. 5.7 Hz).04 (1H. 74. 2. 8.63.06. Calcd. 8. 2. 6.7 Hz).79 (2H.98 (3H. 65. 7.26. Org.17. 5.5 Hz).2.02. J = 7.84. 8. J = 1. N.5.1. dd.41 (1H. 6. H.7. H. 2. 4. 1H NMR (300 MHz. d.46 (1 H. dd. 7.80 (1H. dd.2 Hz). Anal.61 (1H. J = 8. 7. The mixture was stirred overnight. 4.89. d. dd.5.20.67 (2H. ddd. and diluted with ethyl acetate. m). s). 2.10-dihydro-phenanthren-1-yl)-succinamic acid methyl ester: [0122] To a solution of 1-amino-phenanthrene-9.73 (1H. 73.1 Hz). The material was chromatographed on silica gel with 20% EtOAc in CH2Cl2 as eluant and dried to give N-(9. ddd. 7. 73.62 (3H.9.12. 7.6.29. Ber. Found: C. J. 6. dd. 1H NMR (300 MHz.8 Hz). H. dd. N. 7. 8. Calcd.9. J. For C14H7NO4-0.6. 7. 7.79-7.93 (1H. m). HPLC: 5. dried over Mg2SO4. s).49 min. ddd. DMSO-d6) δ 8. Found: C.10-dihydro-phenanthren-3-yl)succinamic acid methyl ester as an orange solid. m). 17 . N. 20 25 30 35 40 Example 92: 2-Nitro-phenanthrene-9. Francis. 2. 7.60 (1H. 2.8 Hz). J = 7.7 Hz). 7.25 H2O C. F. J = 1. 5. J = 1.89 (2H.84 (1H.93. H. 240 µmol) in THF (50 mL) was added Na2CO3 (210 mg. 8.9 Hz). J = 7. 5.56 (1H. 56. dd.25 N.4. 7. 8.33.10-dione: 50 45 [0125] Orange solid.10-dione: 10 [0120] Black solid.2 Hz).73 (1H. 2. 6.29.03 (2H. Anal. d. J = 9. 8. m). J = 2. N.53 (1 H.77 (2H. 5. J = 1.43.10-dione (400 mg.35 4. Found: C.72 (2H. dd. H. E. For C14H7NO4: C.82.

8.04 (1H.2. v/v) to afford a yellow solid (500 mg).10-dione: [0128] This compound was prepared substantially in accordance with the procedures disclosed in Bhatt. J = 8. and chromatographed on silica gel (3:1 EtOAc:CH2Cl2.8 Hz).4. J= 2. 8. 7.02 (1H. 8. 8. 7. 9. J = 7.27 min. Examples 100 and 101: [0132] The compounds of examples 100 and 101 were prepared substantially in accordance with the procedures disclosed in Mosettig.76. J = 8.3. 7. For C15H8O4-0. 8. Examples 97 and 98: 15 10 [0129] The compounds of examples 97 and 98 were prepared substantially in accordance with the procedures disclosed in Langenbeck.82 (1H. J = 1. Am.81 (1H. ddd. 4.8 Hz).4 Hz). d. 8. 803-821. H. 7. d.10-dione: 40 30 35 [0133] Orange solid. ddd.1 Hz).61 (1H. J = 7. J = 7. 7.71 (1H. d.. dd. H. 7. J= 0.6 Hz).07 (1H. DMSO-d6) δ 13.10-Dioxo-9. K.41. 7. J = 1. V.2.8.5 Hz).27 (1H. filtered. 7. dd. 7. 7. J = 7.70 (1H.9 Hz). d. 2. 7.39 (1H.9 Hz).8 Hz). dd.07 (1H.5 Hz). Example 101: 2-Acetyl-phenanthrene-9. 8.5.26 (1H. 58. 1483-1488. 70.08 (1H. 8. d. J= 1.EP 1 242 363 B1 Example 95: 2. m).36 (1H. 7. 8.4 H2O C.02 (2H. Yellow solid. 6.79 (1H. 7.5 Hz).67 (1H. Soc.49-8.5 Hz).42.0 mmol). 7. R. J = 2. J= 8. 2. DMSO-d6) δ 8. d. dd.45 (2H.5. J = 1. sat'd aq. 8. J = 8. dd. dd.4 Hz). 8. 8. 7.0 Hz). 75. 7. Calcd.45 (1H. 1942.5.2 Hz).1. DMSO-d6) δ 8.6 Hz).2 Hz).58 (1H. 20. 7. dd. 8.44. 7.24 (1H. 8.46 (1H. Chem. J = 8. which procedures are incorporated herein by reference. H 3. which procedures are incorporated herein by reference. 8. EDC (1. dd. J = 2. 20 Example 97: 9. For C14H7O2 C. Anal.10-dihydrophenanthrene-3-carbonyl)-amino]-acetic acid tert-butyl ester (310 mg. 69. J = 1.13 (1H. 1H NMR (300 MHz.1 Hz).35 (1H. d. 3. E. 8.45. Found: C. 1H NMR (300 MHz. J = 7.5. 2.87 (1H.1 g. 7.08 (1H.7. dd.54 (1H.6 Hz).5 mmol) in anhydrous DMF (10 mL) under N2 was added t-butyl glycine hydrochloride (760 mg. DMSO-d6) δ 13.6 Hz). 8.6.2 Hz).16.5. 31 %). Van de Kamp. 8. This solid was subsequently recrystallized from refluxing EtOAc to afford pure [(9.75 (3H. J. J = 1. J = 8.6 Hz). 3. Arneberg. concentrated.1 Hz).0 Hz). d.61. 4. 8. d. J = 7. DMAP (60 mg.8 Hz). 8. ddd. 2.6 mmol).2.17. 8. d. 8.68 (3H. 500 µmol) and diisopropylethylamine (2. 1H NMR (300 MHz.66 (1H. 1930. 7. d. 8.1 hz). Anal.10-dihydro-phenanthrene-3-carboxylic acid: [0131] Orange solid. J= 2.10-dione: 45 [0134] Yellow solid. 7.5. H. dd. 7.5. J = 8. 69.1 mL. M. s). d.0 Hz). 25 Example 98: 9. dd.10-dione: [0127] Yellow solid. dd. NaHCO3 and brine. Orange solid. dd. 3704-3710. 5 Example 96: 2-Bromo-phenanthrene-9. water. 3.1 g.1 Hz). J = 1. s). 8.56 (1H. d.5. J= 1. dd. Example 100: 3-Acetyl-phenanthrene-9. 3.08-8. J = 2.75.42 Found: C. For C15H8O4-0.5-Dinitro-phenanthrene-9.0. d.10-dihydro-phenanthrene-2-carboxylic acid: [0130] Yellow solid.31 Found: C. 58. J = 2. H.5 Hz) Anal calcd.48 min. 1H NMR (300 MHz. 8.4.65.10-dihydro-phenanthrene-3-carboxylic acid (1.45 (1H.9 Hz). ddd. DMSO- 55 18 .4 Hz). 52. 1H NMR (300 MHz. 58. The organic layer was dried over MgSO4.83 (1H. J= 2.6. J = 1. J = 7.10-Dioxo-9. H.73 (1H.58 (1H.30 (1H.10-dioxo-9. dd. DMSO-d6) δ 8. HPLC: 5. Tetrahedron 1964. J = 8. 7. 2. 8.1 Hz).59.5 Hz). 7. Chem. Schaller.57. 70.7. 7. W. 8. 70..8 Hz). HPLC: 5.27 (1H. 8. 50 Example 102: [0135] To a solution of 9.96 (1H. The reaction was diluted with EtOAc and washed with 1 M HCl. s). 69.2 Hz). J = 2.2. m). J = 7.83 (1H. 7. dd.46. 12 mmol) and the resultant solution was stirred for 16 h. which procedures are incorporated herein by reference.61 (1H.63. 7. 7.4.37 (1H. br s).0.51 (1H. 1H NMR (300 MHz.22. 8. J = 2. Calcd.10-dioxo-9. 7.. J = 8.29.12 (1H. d. DMSO-d6) δ 8. 7.. dd. Ber.66. s).4 Hz). J. 1H NMR (300 MHz. 3.2 H2O C.

For C21H19NO5-0. dd.13 (1H.10-Phenanthrenedione was purchased from Aldrich Chemical Company. 8. 68. J = 5. ddd. J = 1. 7. N. 3. Freeman and Co.1. 1H NMR (300 MHz.82 (1H. J = 7. 7. For C17H11NO5: C.46 (1H.82 (1H. 9.54 (1H.71.2H2O: C.46.61.97 (1H.71 (1H. to preferentially expand the T-cell population. 7.9 Hz). (Bradley.00. PA).29 (1H.5. 7. Milwaukee. 50 mM NaCl. 4. H. J = 1. s). 62.2 Hz). N. 5.98 (1H. 7.47. Anal. Example 103: [(9. dd. This mixture was stirred for 2 h and concentrated under reduced pressure. 8. d.58.10-dihydro-phenanthrene-3-carbonyl)-amino]-acetic acid tert-butyl ester (200 mg.5. dd. 68. J = 6. J = 8. 62. 66. 3. d. Mishell. 4.39 (1 H.59. J = 1. 68. 7. 3. 8. DMSO-d6) δ 9. 8. dd. dd.5. 8. d. 68. 8.63. dd. J = 2. 8. by utilizing [(9.7 Hz).67.7 Hz). 66.. H. H. s).58. J = 8. J = 6.5. 8. d.00 (2H. Calcd.10-dioxo-9. J = 8. B. d. J = 1.7. s). N. The material was recrystallized from refluxing EtOAc to afford [(9. d. OR) uptake. Eds.3 Hz). Example 105: [(9.6.22. Method B: Cytotoxicity Assay: 45 50 55 [0142] Calcein-AM (Molecular Probes. dd.9 Hz). 8. s). 1H NMR (300 MHz. d. 62.3 Hz). 4.1H2O: C.8.77. 1. J = 8. J = 1.5 Hz).59 (1H.0 Hz).6 Hz). Orange solid. 4. 6. 8.4.44 (9H.0. ddd.46 (1 H.59. H. 9. d. Calcd. J = 1. 7. Calcd.5. Example 104: [0138] To a solution of [(9.1 Hz).10-dioxo-9. 8. J = 8. J = 5.7 (1H.07 (1H. 3. Cell Poliferation in Selected Methods in Cellular Immunology.78. 47 %). dd.EP 1 242 363 B1 d6) δ 9. J = 7.59 (1H.01 µM. 7.48. Assays for Biological Activity 35 40 Method A: Phosphatase assay using pNPP as substrate: [0141] CD45 enzyme was obtained from BIOMOL (Plymouth Meeting.10-dioxo-9. dd.7.2 Hz). [0136] The compound of example 103 was prepared by the method of Example 102. J = 8. 7. San Francisco. 7. ddd. 7. Calcd. PBMC were treated for 3-7 days with 3-10 µg/ml PHA. N. Eugene.0 Hz). 3. Activity was measured by following the increase in absorbance at 405 nm using a SpectraMax Plus spectrophotometric plate reader (Molecular Devices. 8. J = 7.7. d. 5.10-dihydro-phenanthrene-2-carbonyl)-amino]-acetic acid tert-butyl ester: 10 5 [0137] Yellow solid. For C17H11NO5-1. DMSO-d6) δ 12.9 Hz).53.9 Hz).84. J= 7. 550 µmol) in CH2Cl2 (10 mL) under N2 was added TFA (10 mL).5 mM ethylenediaminetetraacetic acid ("EDTA"). 8. 1980. 5. a potent T-cell mitogen. dd. J= 1.89. 4. Example 106: 9.39. 8. 68. 3.1 Hz). 4.7 Hz). J = 8. 3.4 Hz).10-dihydro-phenanthrene-3-carbonyl)-amino]acetic acid (70 mg.10-dihydro-phenanthrene-2-carboxylic acid as the starting material. Phosphatase activity was assayed in a buffer containing final concentrations of 25 mM imidazole at pH 7. 7.22 (1H.M. Anal. J = 1. was used to evaluate the toxic effect of compounds on T cells. J = 5.1. 7.69.38.28. H. Found: C. 5.0.9. 8. H. 5 mM dithiothreitol ("DTT") and 10 µg/mL bovine serum albumin ("BSA") using pNPP as a substrate. J = 5. 4. with a final concentration of I or 5% dimethylsulfoxide ("DMSO").0H2O: C.94 (2H.69 (1H.3 Hz). 8.7 Hz).9 Hz). Linda M.5 Hz). 5.9 Hz). 8.3.36. d.27.7 Hz).08 (1H.4 Hz). 66.10-dihydro-phenanthrene-2-carbonyl)-amino]-acetic acid tert-butyl ester as the starting material.3 Hz). N.09. 5. 1. Found: C. 8.2. J = 1. dd.7 Hz). 68. 8.B.0 Hz). s).23 (1H. H. 8.87. ddd. 7.10-Dioxo-9.38 (1H.59 (1 H. Briefly.36. 8.45 (9H.03 (2H.28. CA).0. N. depending on the compound solubility. 7. s). J = 6.07 (1H.6. Found: C. d.5 Hz). 3. Anal. The residue was dissolved in CH2Cl2 and evaporated once again to rid residual TFA. 7.81. N.0 Hz).8 Hz).8 Hz). WI and used as received. 8. as a quantitative measure of cell viability. and Shiigi. 3. 8.2 Hz). J = 1. 7. 5. W. 3.85 (1 H.13 (1H. dd. 7.0.10-dioxo-9. 3.07 (1H. 3.10-dihydro-phenanthrene-2-carbonyl)-amino]-acetic acid: 15 20 25 30 [0140] Orange solid. dd.85 (1 H. 3.10-Dioxo-9. 2. S. dd.22 (1H.2. d. J = 6. Sunnyvale.80..39 (1H. 4.54 (1H.3.71 (1H. For C21H19NO5-0. d.H. 4.9. 7. N.30.0 Hz). H. J = 1. 8. 7. Anal.23 (1 H.) 19 . J = 1.39 (1 H.69.20.41. J = 1.02. 6. J = 7. 8. 5.97 (2H. Found: C. dd. Compounds were tested in a range from 30 to 0. [0139] The compound of example 105 was prepared by the method of example 104. 8. 8. 7. utilizing 9.5.17.29 (1H. DMSO-d6) δ 12. ddd.58 (1H. d. 1H NMR (300 MHz.

Table 4: Example.5 0.1 mg/mL gentamycin and 10% heat inactivated human serum. San Diego. at room temperature for 1. the plates incubated at room temperature for 30 min and absorbance read at 620 nm.9 T cell prolif. Bannwarth. At the end of the incubation period.. PA) was added to each well. washed. cells were washed with Dulbecco's phosphate. using the lck carboxy-terminal peptide TEGQpYQPQP as the substrate (Cho. CT). After the incubation period. Norway).3 lck IC50 (µM) 11 11 17 3. H.2 0. OKT3 (30 ng/mL).. R.2 12 9 12 9.5 8..7 CC50 (µM) 20 14 8.5 0. and CD45) toward the phosphotyrosylpeptide substrates and thiophosphotyrosylated peptides as inhibitors. the bottom of the plate sealed. W. Inhibition in the T cell proliferation assay.3%. Oslo. BIOMOL "Green Reagent" (BIOMOL.4 0.8 0.0 1. Itoh.1 1. [0146] Table 4 shows the inhibition of CD45 activity in the pNPP asssay and the lck assay certain compounds of the present invention.8 12 16 13 15 5. 1993. The filter plate was dried. Percent viability was assessed on a fluorescent plate reader (excitation filter 485/20 nm.5 0. 0. E. M. Method C: 10 5 Phosphatase assay using lck 10-mer as substrate: [0144] Phosphatase activity was assayed in 96 well plates in a buffer containing final concentrations of 25 mM HEPES at pH 7..1 1.. with or without compound.6 0.2.5 1.. 25 µL of Microscint 20 scintillation fluid added to each well.01 µM in a final concentration of 5% DMSO.EP 1 242 363 B1 [0143] The T-cell lymphoblasts were purified by separation over Lymphoprep. The dilution scheme and culture media were the same as those used in the T-cell proliferation assay. with the final concentration of DMSO not to exceed 0. Walsh.1 10 30 35 40 45 1 2 3 4 50 5 6 7 55 8 9 10 20 .2 4. emission filter 530/25 nm) where the 100% control value is the fluorescence intensity observed in the absence of test compound. Peripheral blood mononuclear cells ("PBMC") were isolated using Lymphoprep density-gradient centrifugation (Nycomed Amersham. Krishnaraj. Method D: 25 15 20 Cell isolmion and T cell proliferation assay: [0145] Whole blood was obtained from healthy human blood donors. H. Compounds were tested in a range from 30 to 0.T.1 0. LAR. After 24 hours in culture. The data from the TopCount is transferred into Excel 5 (Microsoft. C. the cells were pulsed with [3H]thymidine (1 µCi/well) overnight and harvested the next day onto 96-well Packard GF/C filter plates using a Packard Cell Harvester (Packard Instruments. Enzyme was incubated with substrate.4 0. as well as results from T cell cytotoxicity assay are shown.buffered saline (D-PBS) and incubated with 1µM Calcein-AM for 30-45 min in D-PBS as described in the technical sheet provided with The LIVE/DEAD Viability/Cytotoxicity Kit from Molecular Probes. WA) and formatted for EC50 determination using Prism software (GraphPad Software. 5 mM DTT and 10 µg/mL BSA. plated at 2 x 105/well in a round bottom 96-well plate containing RPMI with compound and incubated overnight at 37 °C in an incubator containing 5% CO2. IC50 (µM) 3. counted and resuspended at 2 X 106 cells/mL in RPMI 1640 medium containing glutamine. Plymouth Meeting. and the plate counted on a Packard TopCount.5 0.7 0.2 3. and incubated for 1 hour before addition of the activating anti-CD3 antibody.5 h.3 0. Kitas. Meriden. PBMC were transferred to 96-well plates (2 X 105 cells/well) containing compound or vehicle control. CA). Substrate specificities of catalytic fragments of protein tyrosine phosphatases (HPTPb.0 1. Protein Science 2:977-984). pNPP IC50 (µM) 0. Redmond. the top of the plate sealed with TopSeal-A. Saito. No.8 1.

7 1.5 1.9 0.1 0.1 1.4 1.75 4.5 2.1 0.2 0.0 2.9 3.3 8.8 3.7 3.9 1.9 >30 >30 >30 >30 >30 >30 >30 >30 >30 >30 >30 >30 ND >30 >30 >30 ND >30 >30 >30 >30 >30 >30 >30 >30 >30 11 12 13 14 10 15 16 17 15 18 19 20 20 21 22 23 24 25 25 26 27 30 28 29 30 31 35 32 33 34 40 35 36 37 38 45 39 40 41 50 42 43 44 45 55 46 47 21 .1 2.3 3.9 1.2 T cell prolif.7 0.3 1.6 1.7 0.3 >30 3.0 5.5 7 10. No.9 0.0 0.99 0.0 5.6 7.6 1. 5 pNPP IC50 (µM) 2.8 >30 15 >30 >30 >30 >30 >30 >30 9.1 0.5 3.7 2.8 0.2 2.5 3.9 1.3 1.5 3.5 2.0 1.99 3.6 1.2 2.1 2.0 14.0 1.3 9.8 1.8 3.2 5.6 6.4 8.1 1.6 2.3 2.8 0.0 CC50 (µM) >30 15 14 5.7 0.9 1.5 16 >30 >30 >30 >30 >30 >30 19.9 4.8 1.6 0.49 0.EP 1 242 363 B1 Table 4: (continued) Example.7 lck IC50 (µM) 11.8 4.4 2.0 3.1 12. IC50 (µM) 6.5 3.8 3.5 0.4 4.7 20 >30 >30 >30 >30 5 20 14.4 2.8 1.3 3.8 6.9 3.9 1.3 8.7 1.5 1.1 0.2 2.4 0.1 1.4 0.7 0.

5 0.5 48 49 50 51 10 52 53 54 15 55 56 57 20 58 59 60 61 25 62 63 67 30 68 69 70 71 35 72 73 74 40 75 76 77 78 45 79 80 81 50 82 90 91 97 55 98 100 22 .3 10.7 6.8 1.5 14 3 14 ND 11 19 13 >30 9 28 >30 6.4 0.3 0.3 3.5 1.6 0.6 1.7 0.8 4.8 lck IC50 (µM) 5.2 4.3 0.0 1.2 4.5 0.9 0.2 0.5 >30 0.7 3.0 1.6 5.8 1.7 1.0 0.6 2.9 3.7 3.8 5.9 8.0 3.6 0.1 0.4 4.1 2.5 >30 >30 0.3 2.6 0.9 4.0 1.0 0.8 4.4 1.8 7.8 0.9 2.9 7 18 9 >30 ND 3.3 1.4 23 >30 1.5 15.8 4.9 1.0 >30 2.2 17.9 6.7 1.0 0. 5 pNPP IC50 (µM) 0.7 ND 3.7 1.6 2.0 2.5 2.4 0.0 1.1 2.9 1. IC50 (µM) 11 16 23 14 20 16 20 >30 19 21 >30 >30 21.7 3.8 CC50 (µM) >30 >30 >30 >30 >30 >30 >30 >30 >30 >30 ND ND ND ND ND 8 4 7.9 >30 4.8 1.8 1.6 7.5 0.0 3.5 1.4 0.2 T cell prolif.7 2.5 0.8 3.3 2.8 9.8 0.2 0. No.0 0.3 ND 5.4 0.2 1.2 3.EP 1 242 363 B1 Table 4: (continued) Example.1 1.

EQPQP. alkyl moieties of R2 can be substituted with halogen. RGPEG.4 0. No. QEPQP.7 lck IC50 (µM) 2. Ar at each occurrence is independently selected from groups in accord with the following structural diagrams. 5 pNPP IC50 (µM) 0. (C1-C8)alkylCOOR6 and phenyl. (C1-C4)alkyl.2 3.8 0. RRPEG. Ar.5 10 >30 >30 1. EQGQP. EEPRG. wherein phenyl moieties of R2 can be substituted at one. GGPEG. GRPEG. wherein: R2 is selected from (C1-C4)alkyl. 35 40 45 50 55 or from phenyl which can be substituted with a moiety selected from halogen.4 6. NHCOCH2CH(COOH)NHR4 and N(R5)2. IC50 (µM) 1. GGPRG. GEPEG.3 101 102 103 104 10 105 106 15 Claims 1.6 0. GQPQG.5 0. EEPEG. GEPQP. GQPQP. GQPEG.3 0. QQPEG. QEGQP. NO2 and CF3. GEGQP.9 3. GRPRG.3 CC50 (µM) 4. O-(C1-C4)alkyl and halo(C1-C4)alkyl. GEPRG.8 0. GQGQP. wherein: R1 at each occurrence is independently selected from hydrogen. R3 at each occurrence is an N-linked oligopeptide selected from GQ-N-iBu. NH-CO-R2. ERPRG and RRPRG. RGPRG. QQGQP. A compound in accord with structural diagram I.4 4. EGPEG.6 0. REPEG. ERPEG.5 2.5 4. GEPQG. (CH2)nCH(COOH) R3 COR3. GQGEP. REPRG. CO-NH-R2. QQPQP. EGPRG. QQPQG.EP 1 242 363 B1 Table 4: (continued) Example.9 3. and R6 is selected from hydrogen and (C1-C4)alkyl.1 0. 23 .1 T cell prolif. two or three positions with a moiety selected from halogen.4 2. 20 25 30 or tautomers thereof or pharmaceutically-acceptable salts thereof.

EP 1 242 363 B1 R4 at each occurrence is a C-linked N-acetyl-oligopeptide selected from Q. 4. A compound according to Claim 1. 9. O-(C1-C4)alkyl and halo(C1-C4)alkyl. and FTATEGQ. in accord with structural diagram III. 24 . 25 3. 10 15 20 wherein: R1 is N(R5)2. 2-acetyl-phenanthrene9. in accord with structural diagram II. 3-acetyl-phenanthrene-9.10-dihydro-phenanthrene-3-carboxylic acid.10-dione. in accord with structural diagram IV 55 5. A compound according to Claim 3.10-dioxo-9. wherein Ar is phenyl substituted with perfluoromethyl. (C1-C4)alkyl.10-dioxo-9. A compound according to Claim 1. TATEGQ.10-dione. 5 with the proviso that said compound is not 9. A compound according to Claim 1. where R5 is selected from hydrogen and tosyl with the proviso that at least one R5 moiety is tosyl. EGQ. 2.10-phenanthrenedione. and R5 at each occurrence is selected from hydrogen and tosyl. 30 35 wherein: 40 R1 is Ar and Ar is selected from groups in accord with the following structural diagrams: 45 50 or from phenyl which can be substituted with a moiety selected from halogen. ATEGQ. or 9.10-dihydrophenanthrene-2-carboxylic acid.

20 7. and a pharmaceutically-acceptable excipient or diluent. GQGQP. QEPQP. wobei die Phenylgruppierungen von R2 an einer. 50 wobei: R2 ausgewählt ist aus (C1-C4)-Alkyl. 55 25 . 35 40 45 oder Tautomere davon oder pharmazeutisch annehmbare Salze davon. CO-NH-R2. zwei oder drei Positionen mit einer Gruppierung. GEPRG. Ar. wherein R1 is selected from hydrogen and NHC(O)(CH2)nCOOCH3 where n is an integer selected from the range 1 to 8. QQPEG. GQPEG. REPRG. RGPEG. QQPQG. ERPRG and RRPRG. GGPRG. (CH2)nCH(COOH)R3 COR. GQPQP. GQPQG.EP 1 242 363 B1 5 10 wherein: 15 R1 is selected from hydrogen. 6. GEPQP. GEPQG. A pharmaceutical composition comprising an effective amount of a compound according to any one of Claims 1 to 6. RGPRG. GRPEG. ERPEG. QQPQP. EEPRG. GEPEG. GRPRG. (CH2)nCH(COOH)R3 and COR3 where R3 is an N-linked peptide selected from GQ-N-iBu. EGPEG. GGPEG. EEPEG. NH-CO-R2. EGPRG. QEGQP. REPEG. die Alkylgruppierungen von R2 mit Halogen substituiert sein können und R6 ausgewählt ist aus Wasserstoff und (C1-C4)-Alkyl. Ar jeweils unabhängig ausgewählt ist aus Gruppen gemäß den folgenden Strukturdiagrammen. with the proviso that no more than one R1 moiety is other than hydrogen. ausgewählt aus Halogen. GQGEP. GEGQP. NO2 und CF3. Verbindungen gemäß dem Strukturdiagramm I. EQPQP. (C1-C8)-AlkylCOOR6 und Phenyl. NHCOCH2CH(COOH)NHR4 und N (R5)2. 25 Patentansprüche 30 1. QQGQP. substituiert sein können. A compound according to Claim 1. wobei: R1 jeweils unabhängig ausgewählt ist aus Wasserstoff. RRPEG. EQGQP.

REPRG. RGPEG. EQGQP. GEPEG. GRPRG. ATEGQ. EEPEG. ausgewählt aus Halogen. GQGQP. worin R5 ausgewählt ist aus Wasserstoff und Tosyl. steht. GQPQP.10-dion. QQPQP. Verbindungen nach Anspruch 1. QQGQP. 25 2. GGPEG.10-dihydro-phenanthren-2-carbonsäure.10-Phenanthrendion handelt. ausgewählt aus Q. 45 50 55 wobei: R1 für Ar steht und Ar ausgewählt ist aus Gruppen gemäß den folgenden Strukturdiagrammen: 26 . gemäß dem Strukturdiagramm II. ERPRG und RRPRG. EEPRG. GEGQP. 9. 3. RRPEG. GQGEP. das mit einer Gruppierung.10-dihydro-phenanthren-3-carbonsäure.10-Dioxo-9. 2-Acetyl-phenanthren9. EGPEG. RGPRG. TATEGQ und FTATEGQ. mit der Maßgabe. EQPQP. Verbindungen nach Anspruch 1. REPEG. EGPRG. GQPQG. O-(C1-C4)-Alkyl und Halogen(C1-C4)-Alkyl substituiert sein kann. 3-Acetyl-phenanthren-9. EGQ. daß es sich bei wenigstens einer R5-Gruppierung um Tosyl handelt. QQPQG.10-dion. 30 35 wobei: 40 R1 für N(R5)2 steht. R4 jeweils für ein C-verknüpftes N-Acetyl-Oligopeptid. QEPQP. (C1-C4)-Alkyl. gemäß dem Strukturdiagramm III. mit der Maßgabe. steht und 15 20 R5 jeweils ausgewählt ist aus Wasserstoff und Tosyl. GEPRG. GQPEG.10-Dioxo-9. ERPEG. GEPQG. daß es sich bei der Verbindung nicht um 9. GEPQP.EP 1 242 363 B1 5 10 oder aus Phenyl. GGPRG. QEGQP. ausgewählt aus GQ-N-iBu. oder 9. GRPEG. R3 jeweils für ein N-verknüpftes Oligopeptid. QQPEG.

worin n für eine ganze Zahl. sowie ein pharmazeutisch annehmbares Hilfsmittel oder Verdünnungsmittel. wobei R1 ausgewählt ist aus Wasserstoff und NHC(O)(CH2)nCOOCH3. GGPRG. 15 20 25 wobei: R1 ausgewählt ist aus Wasserstoff. GRPEG. GQGQP. ERPEG. umfassend eine wirksame Menge einer Verbindung nach einem der Ansprüche 1 bis 6. QQGQP. ausgewählt aus GQ-N-iBu. RRPEG. QEPQP. 40 Revendications 45 1. EQPQP. GQPQG. mit der Maßgabe. QQPQP. gemäß dem Strukturdiagramm IV. handelt. GQGEP. REPEG. RGPRG. daß es sich bei höchstens einer R1-Gruppierung nicht um Wasserstoff handelt. GGPEG. 4. worin R3 für N-verknüpftes Peptid. GEPQP. (CH2)nCH(COOH)R3 und COR3.EP 1 242 363 B1 5 10 oder aus Phenyl. O-(C1-C4)-Alkyl und Halogen(C1-C4)-Alkyl substituiert sein kann. ausgewählt aus dem Bereich 1 bis 8. EEPEG. QQPQG. wobei es sich bei Ar um mit Perfluormethyl substituiertes Phenyl handelt. GEPEG. EGPRG. Pharmazeutische Zusammensetzung. 30 35 7. EQGQP. ERPRG und RRPRG. ausgewählt aus Halogen. (C1-C4)-Alkyl. GEPQG. Verbindungen nach Anspruch 1. RGPEG. 6. GQPQP. GEGQP. Composé conforme au diagramme structural I 50 55 27 . QQPEG. GQPEG. EGPEG. Verbindungen nach Anspruch 1. 5. REPRG. das mit einer Gruppierung. steht. GRPRG. GEPRG. QEGQP. Verbindungen nach Anspruch 3. EEPRG.

QEPQP. ou la 9.10-dioxo-9. ATEGQ. EQGQP. COR3. (CH2)nCH (COOH)-R3. ERPEG. RGPEG.EP 1 242 363 B1 ou des tautomères de celui-ci ou des sels pharmaceutiquement acceptables de celui-ci. EQPQP. la 3-acétylphénanthrène-9. GQPQP. GGPRG. QQPQP. RRPEG. ERPRG et RRPRG. alkyl(C1-C8)COOR6 et phényle. GEGQP. conforme au diagramme structural II 35 40 45 dans lequel : 50 R1 est N(R5)2. RGPRG. NO2 et CF3. R4 à chaque occurrence est un N-acétyloligopeptide C-lié choisi parmi Q. GQGEP. dans lequel : R1 à chaque occurrence est choisi indépendamment parmi hydrogène. QQGQP. GEPEG. GEPQG.10-dione . GEPRG. GQGQP. GQPEG. conforme au diagramme structural III 55 28 . GQPQG. et R6 est choisi parmi hydrogène et alkyl(C1-C4) . EGQ. deux ou trois positions par un motif choisi parmi halogène. à condition qu'au moins un motif R5 soit tosyle. GRPEG.10-dioxo-9. alkyl(C1-C4). O-alkyl(C1-C4) et halogénoalkyl(C1-C4) . QQPQG. EGPRG.10-dihydrophénanthrène-2-carboxylique . REPEG. 3. TATEGQ et FTATEGQ. et R5 à chaque occurrence est choisi parmi hydrogène et tosyle . REPRG. Ar. R3 à chaque occurrence est un oligopeptide N-lié choisi parmi GQ-N-iBu. EEPEG. GEPQP. 2. l'acide 9.10-dione .10-dihydrophénanthrène-3-carboxylique . où R2 est choisi parmi alkyl(C1-C4). QQPEG. Composé selon la revendication 1. Ar à chaque occurrence est choisi indépendamment parmi des groupements conformes aux diagrammes structuraux suivants 5 10 15 20 25 30 ou parmi phényle qui peut être substitué par un motif choisi parmi halogène. où les motifs phényle de R2 peuvent être substitués au niveau d'une. EEPRG. la 2-acétylphénanthrène-9. NHCOCH2CH(COOH)NHR4 et N(R5)2. Composé selon la revendication 1. NH-CO-R2. QEGQP. à condition que ledit composé ne soit pas l'acide 9. CO-NH-R2. où R5 est choisi parmi hydrogène et tosyle. GRPRG.10-phénanthrènedione. GGPEG. EGPEG. les motifs alkyle de R2 peuvent être substitués par halogène.

REPRG. 29 . GEPQP. QQPQG. ERPEG. RGPEG. conforme au diagramme structural IV 30 35 40 dans lequel : 45 50 R1 est choisi parmi hydrogène. EGPEG. 4. (CH2)nCH(COOH)R3 et COR3. GEPQG. GEPRG. GEGQP. EEPRG. dans lequel Ar est phényle substitué par perfluorométhyle. Composé selon la revendication 1. 5. QEPQP. O-alkyl(C1-C4) et halogénoalkyl(C1-C4). 55 7. REPEG. GGPEG. GRPRG. dans lequel R1 est choisi parmi hydrogène et NHC(O)(CH2)nCOOCH3. RRPEG. où n est un nombre entier choisi dans la plage de 1 à 8. Composé selon la revendication 3. GQPEG. GQGQP. Composition pharmaceutique comprenant une quantité efficace d'un composé selon l'une quelconque des revendications 1 à 6. GQGEP. à condition qu'un motif R1 au plus soit autre qu'hydrogène. GGPRG. EGPRG. Composé selon la revendication 1. EQGQP. 6. QQPQP. ERPRG et RRPRG. QEGQP. QQPEG. alkyl(C1-C4). EEPEG. GQPQP. GQPQG. GEPEG. et un excipient ou diluant pharmaceutiquement acceptable.EP 1 242 363 B1 5 10 dans lequel : R1 est Ar et Ar est choisi parmi des groupements conformes aux diagrammes structuraux suivants 15 20 25 ou parmi phényle qui peut être substitué par un motif choisi parmi halogène. QQGQP. où R3 est un peptide N-lié choisi parmi GQ-NiBu. RGPRG. GRPEG. EQPQP.