MXPA01001465A - Antiviral indoleoxoacetyl piperazine derivatives - Google Patents

Antiviral indoleoxoacetyl piperazine derivatives

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Publication number
MXPA01001465A
MXPA01001465A MXPA/A/2001/001465A MXPA01001465A MXPA01001465A MX PA01001465 A MXPA01001465 A MX PA01001465A MX PA01001465 A MXPA01001465 A MX PA01001465A MX PA01001465 A MXPA01001465 A MX PA01001465A
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Mexico
Prior art keywords
alkyl
cycloalkyl
independently
alkynyl
halogen
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MXPA/A/2001/001465A
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Spanish (es)
Inventor
S Blair Wade
Deshpande Milind
Fang Haiquan
Lin Pinfang
P Spicer Timothy
B Wallace Owen
Wang Hui
Wang Tao
Zhang Zhongxing
Yeung Kapsun
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Bristolmyers Squibb Company
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Publication of MXPA01001465A publication Critical patent/MXPA01001465A/en

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Abstract

This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with indoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.

Description

ANTIVIRAL DERIVATIVES OF INDOLOXOACETIL PIPERACIN BACKGROUND OF THE INVENTION Field of the invention This invention provides compounds having pharmacological and bio-affective properties, their pharmaceutical compositions and the method of use. In particular, the invention relates to indoloxoacet yl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, anti-infectives, immunomodulators or inhibitors of HIV entry. More particularly, the present invention relates to the treatment of HIV and AIDS.
Background Art HIV-1 infection (human immunodeficiency virus-1) remains a major medical problem, with an infected population estimated at 33.4 million worldwide.
REF. DO NOT. 127147 Drugs currently available for HIV include six nucleoside reverse transcriptase (RT) inhibitors (zidovudine, didanosine, stavudine, lamivudine, zalcitabine, and abacavir), three non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine, and efavirenz), as well as five inhibitors of proteomics peptide mimics (saquinavir, indinavir, ritonavir, nelfinavir and amprenavir). Each of these drugs can only temporarily restrict viral replication if isolates are used. However, when used in combination, these drugs have a profound effect on the progression of the disease. In fact, significant reductions in mortality rates among AIDS patients have recently been documented. Despite these results, 30 to 50% of patients fail combined pharmacological therapies. Insufficient pharmacological potency, non-attachment, restricted tissue penetration, and drug-specific limitations within certain cell types (e.g., many nucleoside analogues can not be phosphorylated in resting cells) may account for the incomplete suppression of sensitive viruses. In addition, the high speed of replication and the rapid The production of HIV-1 combined with the frequent incorporation of mutations, leads to the appearance of variants in drug resistance and therapeutic failures when suboptimal drug concentrations are present (Larder and Kemp, Gulick, Morris-Jones, et al, Kuritzkes , Vacca and Condra, Schinazi, et al and Flexner, Ref. 6-12). Therefore, new anti-HIV agents that exhibit different resistance patterns, and favorable pharmacokinetics as well as safety profiles are needed to provide more therapeutic options.
Currently commercialized HIV-l drugs are dominated by nucleoside reverse transcriptase inhibitors or peptide protease inhibitors. Inhibitors of non-nucleoside reverse transcriptase have recently become increasingly important in the therapy of HIV infections. At least 30 different classes of NNRTIs have been published in the literature (DeClercq, Ref. 13). Dipir idodia zepinone (nevirapine), Benzoxazinone (efavirenz) and bis (heteroaryl) piperazine derivatives (delavirdine) are already approved for use clinical. In addition, various indole derivatives that include indole-3-sulfones, piperazino-indoles, pyrazine, and 5H-indole [3, 2-b] benzothiazepines derivatives have been reported as inhibitors of HIV-1 reverse transcriptase (Greenlee et al. , Ref. 1, Williams et al, Ref.2, Romero et al, Ref.3, Font et al, Ref 14, Romero et al, Ref-15, Young et al, Ref.16, Genin et al, Ref. 17 and Silvestri et al, Ref. 18). Indole 2 -carboxamides have also been described as inhibitors of cell adhesion and HIV infection (Boschelli et al., In US 5,424,329, Ref.4). Finally the natural products indole 3-their ti tuidos (Semicochliodinol A and B, didemet ilas t err iquinone and isococliodinol) were described as inhibitors of HIV-1 proteases (Fredenhagen et al, Ref. 19). However, none of these references can be made to describe or suggest the new compounds of this invention and their use to inhibit viral infection, including HIV infection.
Structurally related compounds have been previously described (Brewster et al, Ref. 20, Archibald et al, Ref. 21, American Home Products in GB 1126245, Ref.5). However, the structures they differ from those claimed herein, in that they are symmetrical bis (3-indolylglyoxamides) in place of aroyl indoloxoacet yl piperazine derivatives, and use to treat viral infections is not mentioned. Interestingly, the indole radical present in the compounds described herein is the common feature of many non-nucleoside inhibitors of HIV-1 reverse transcriptase including Delavirdine from Upjohn (Dueweke et al., 1992, 1993, Ref.22 and 23) .
Additionally, the following compounds are commercially available, but have not been reported to be useful as pharmaceuticals, and more specifically for antiviral use in mammals.
Compound LJ952 (available from Menai Organics Ltd., Gwynedd, North Wales): Compound TRI-29586 (available in Tripos) REFERENCES CITED Patent Documents 1. Greenlee,. J.; Srinivasan, P.C., nature reverse transcript ase inhibitors. U.S. Patents 5,124,327. 2. Williams, T.M .; Ciccarone, T.M .; Ciccarone, T.M .; Saari, W.S .; Wai, J.S .; Greenlee, W.J .; Balani, S. K; Goldman, M. E.; Theohrides, A.D., as inhibitors of HIV reverse Transcript ase. European Patent 530907. 3. Romero, D L.; Thomas, R.C., Preparation of substitute Índoles as anti AIDS pharmaceuticals. PCT WO 93/01181. 4. Boschelli, D.H., Connor, D.T .; Unangst, P.C., Indole-2-carboxamides as inhibitors of cell adhesion. U.S. Patent 5,424, 329.
. Therapeutic bis (indolyl) compounds. British Patent 1126245 (American Home Products Corp.).
OTHER PUBLICATIONS 6. Larder B.A. & Kemp S.D., Multiple mutations in the HIV-1 reverse transferase confer high-level resistance to zidovudine (AZT), Science, 246: 1155-1158, 1989. 7. Gulick R.M., Current antirete roviral therapy: an overview., Quality of Life Reseach, 6: 471-474, 1997. 8. Kuritzkes D.R., HIV resistance to current therapies, Antiviral Therapy, 2 (supplement 3): 61-67, 1997. 9. Morris-Jones S, Moyle G & Easterbrook P.J., Ant ire t rovi ral therapies in HIV-1 infection, Exper op Op e n on on t i ga t i on a 1 Dru gs, 6 (8): 1049-1061, . Schinazi R.F., Larder B.A. & Mellors J.W., Mutations in Retroviral Genes Associated with Drug Resistance, In t ern a t i ona l An t i vi ra l News, 5: 129-142, 1997. 11. Vacca, J.P & Condra J.H., Clinically effective HIV-1 protease inhibitors. Drug Di s covery Today, 2: 261-272, 1997. 12. Flexner D., HlV-protease inhibitors, Drug Th erapy, 338: 1281-1292, 1998. 13. De Clercq E., The role of non-nucleos ide reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection, Antiviral Research Vol.38 pp.153-179, 1998. ' 14. Font, M .; Monge, A .; Cuartero, A .; Elorriaga, A .; Martinez-Irujo, J.J .; Alberdi, E .; Prieto, I .; Lasarte, J. J.; Sarobe, P. And Borras, F., índoles and pyrazino [4, 5-b] Índles as nonnucleos ide analog inhibitors of HIV-1 reverse transcriptase, Eur.J. Med. Chem., 30, 963-971, 1995.
. Romero, D. L.; Morge, R. TO .; Genin, M.J .; Biles, C; Busso, M .; Resnick, L.; Althaus, I. W.; Reusser, F .; Thomas, RC and Tarpley, WG, Bis (heteroaryl) piperazine (BHAP) reverse transcriptase inhibitors: structure activity relationships of novel substituted nature analogues and the identification of l - [(5-methanesulfonamido-lH-indol-2-yl) -carbonyl ] -4- [3- [1-methylethyl) amino] -pyridinyl] piperazine momomethasunfonate (U-90152S), to second generation clinical candidate, J. Med. Chem., 36, 1505-1508, 1993. 16. Young, S.D .; Amblard, M.C .; Britcher, S.F .; Gray, V.E .; Tran, L O; Lumma,. C.; Huff, J.R .; Schleif, W.A .; Emini, E.E .; O'Brien, J.A .; Pettibone, D.J. 2- Heterocyclic indole-3 -sulphones as inhibitors of HlV-reverse transcriptase, Bioorg. Med. Chem. Lett, 5, 491-496, 1995. 17. Genin, M.J .; Poel, T.J .; Yagi.Y .; Biles, C; Althaus, I .; Keizer, B. J.; Kopta, L.A .; Friis, J.M .; Reusser, F .; Adams, W. J.; Olmsted, R.A .; Voorman, R.L .; Thomas, R.C. and Romero, D. L.; Synthesis and bioactivity of novel bi s (het eroaryl) piperazine (BHAP) reverse transcriptase inhibitors: structure- activity and increased metabolic stability of novel substituted pyridine analogs, J. Med. Chem., 39, 5267-5275, 1996. 18. Silvestri, R.; Arctic, M .; Bruno, B .; Massa, S .; Novellino, E.; Greco, G.; Marongiu, M.E .; Pañi, A .; De Montis, A and La Colla, P., Synthesis and biological evaluation of 5H-indolo [3, 2-b] [1, 5) benzothiazepine derivatives, designed as conformationally constrained analogues of the human immunodeffection virus type 1 reverse transcriptase inhibitor L-737, 126. Antiviral Chem. Chemother., 139-148, 1998. 19. Frederhagen, A .; Peterson, F .; Tintelnot-Blomley, M .; Rosel, J.; Mett, H and Hug, PJ, Semicochliodinol A and B: inhibitors of HIV-1 protease and EGF-R protein Tyrosine Kinase related to As t errioquinones produced by the fungus Ch rys ospori um n erda ri um, Antibiotics, 50,395-401, 1997 . Brewster, K .; Green, D.M .; Pinder, R.M .; Thompson, P.B.J., Ant ihypertens ive 1, -bis (2-indol-3-ylethyl) piperazines, Ch im. Th er. , 8, 169-72, 1973. 21. Archibald, John L.; Freed, Meier E., 1,4-Bis (2-indol-3-ylethyl) piperazines, J, Med. Chem, 17.745-7, 1974. 22. Dueweke T.J. et al, The binding of a novel bisheteroaryliperazine mediates inhibition of human immunodeficiency virus type 1 reverse transcriptase, J Biol. Chem. Vol. 267 pp 27-30, 1992. 23. Dueweke T.J. et al, U-90152, a potent inhibitor of human immunodeficiency virus replication, Antimicrob. Agent Chemother. Vol. 37 pp 1127-1131, 1993. 24. Gribóle, G. .; Recent developments in Nature ring synt hes i -methodlogy and applications, Contemp. Org: Synth. , 1, 145-72, 1994.
. Lingens, F.; Lange, J. , Synthesis of 3-indol-3-ylglycerol and of 3- (N-methylindol -3-yl) glycerol., Justus Liebigs Ann. Chem., 738. 46-53, 1970. 26. Desai, M .; Watthey, J. W. H.; Zuckerman, M., A convenient preparation of 1-aroylpiperazines, Org, Prep. Procedure Int., 8, 85-6, 1976. 27. Potts, B.J., Mini Reverse transcriptase (RT) assay, In Aldovini A., B.D. Waiker (ed), Techniques in HIV Reseach, Stockton Press, NY, p. 103-106, 1990. 28. Weislow, O.S., R. Kiser, D.L. Fine, J, Bader, R.H. Shoemaker, and Boyd, MR, New soluble-form zan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural produets for AI DS-ant iviral activity, Journal of National Cancer Institute 81: 577-586, 1989 29. Johnson, V.A. and R.E. Byrington, Infectivity assay, p. 71-76 in A. Aldovini and B.D. Waiker (ed), techniques in HIV Research, Stockton Press, New York, 1990.
. Harada, S., Koyanagi, Y., and N. Yamamoto, Infection of HTLV-III / LAV in HTLV-I carrying cells MT-2 and MT-4 and application in a plaque assay, Science 229: 563-566, 1985 . 31. (a) Behun, J.D .; Levine, R. J. Org. Chem, 1961, 26, 3379. (b) Rossen, K .; Weissman, S.A .; Sager, J .; Reamer, R.A .; Askin, D .; Volante, R.P .; Reider, P.J. Asymmetric Hydrogenation of t and rahydropyra zines: Synthesis of (S) -pipera zine 2-tert-butylcarboxamide, an intermediate in the preparation of the HIV protease inhibitor Indinavir. Tetrahedron Lett. , 1995, 36, 6419-6422. (c) Jenneskens, L.W .; Mahy, J .; den Berg, E. M. M. de B.-v .; Van der Hoef, I.; Lugtenburg, J. Red. Trav. Chim. Pays-Bas 1995, 114, 97. 32. Wang, T .; Zhang, Z .; Meanwell, N.A. Benzoylation of Dianions: Preparation of mono-Benzoylat ed Symmetric Secondary Diamines. J. Org. Chem., 1999, 64, 7661-7662. 33. (a) Adamczyk, M.; Fine; J.R. Synthesis of procainamide metabolites. N-acetyl deethylprocainamide and deethylprocainamide. Org. prep .. Procedure. Int. 1996, 28, 470-474. (b) Wang, T .; Zhang, Z .; Meanwell, N.A. Regioselect ive mono-Benzoylation of Unsymmet rical Piperazines. J. Org. Chem. , in press. 34. Masuzawa, K .; Kitagawa, M .; Uchida, H. Bull Chem. Soc. Jpn.1961, 40, 244-245.
. Furber; M., Cooper, M.E .; Donald, D.K. Tetrahedron Lett. 1993, 34, 1351-1354. 36. Bartoli et al. a) Tetrahedron Lett. 1989, 30, 2129. b) J. Chem. Soc. Perkin Trans. 1 1991, 2757. c) J. Chem. Soc. Perkin Trans. II 1991, 657. 37. Chen, B.K., Saksela, K., Andino, R., and D. Baltimore. 1994. Distinct modes of human immunodeficiency type 1 proviral latency revealed by superinfect ion of nonproduct ively infected cell lines with recombinant luci ferase-encoding viruses. J. Virol. 68: 654-660.
BRIEF DESCRIPTION OF THE INVENTION It has now been surprisingly found that the compounds of the formula I, or the pharmaceutically acceptable salts thereof, are effective antiviral agents, particularly for treating HIV, if isolates are used or in combination with other antiviral, antiviral, and infectious agents, immunomodulators or inhibitors of the entry of HIV The present invention comprises compounds of formula I, or pharmaceutically acceptable salts thereof, where R1 R2 / R3? 4 and R5 are each independently H, C?-C6 alkyl, C3-C6 cycloalkyl, C2-C al alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, halogen, CN, nitro, COOR6 or XR7, each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different halogen, amino, OH, CN or N02; R6 is H, C? -C6 alkyl, or C3-C6 cycloalkyl, benzyl, each alkyl, cycloalkyl and benzyl is optionally substituted with one to three of the same or different halogen, amino, OH, CN, or N02; X is 0, S or NR6R7; R 7 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkynyl or C (0) R 8 each of alkyl and cycloalkyl is optionally substituted with one to three thereof or different halogen, amino, OH, CN, or N02; R8 is H, C? -C6 alkyl or C3-C6 cycloalkyl; -W- is R? , RlO, Rll, Rl2, Rl3 # Rl4, Rl5 Rl6 - Rl7 • Rl8 Rl9 f 2or R2if R22 are each independently H, C?-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, CR23R24OR25, COR26, COOR27 or C (0) NR2sR29 each of alkyl and cycloalkyl is optionally substituted with each other. three of the same or different halogen, amino, OH, CN, or N02; R 23 R 24, R 25, R 26, R 27, R 28, R 29 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkenyl, or alkynyl C 2 -C 6; Ar is a 4-7 membered aromatic ring that could contain one to five heteroatoms independently selected from the group consisting of O, S, N or NR6, wherein the aromatic ring is optionally fused to group B; B is an aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; or a heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1, 3, 5- tritanoynyl, indolyl zinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, lH-indazolyl, benzimidazolyl, benz thiazolyl, purinyl, 4H-quinol and zinyl, quinolinyl, isoquinolinyl, cinnolinyl , phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphidinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazine and phenoxazinyl; B and the aromatic ring of 4-7 members could each independently contain one to five substituents each independently selected from R30 R3 ?, R32, R33 or R3; Ra and b are each independently H, C 1-6 alkyl or phenyl; Z is -methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimet and 1 isoxa zoi lo, isoxazoyl, 2-met ilt-iazoyl, thiazoyl, 2-thienyl, 3-thienyl or pyrimidyl; and p is 0-2; R30 R3 ?, 32, R33 and R34 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C3 cycloalkenyl, C2-C6 alkynyl, halogen, CN, nitro, C (0) R35, COXR36, hydroxyl, COORd, hydroxymethyl, trifluoromethyl, trifluoromethoxy, 0- [straight or branched chain (C? -C) alkyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, OC (0) alkyl C? -6, SC (0) C 1-6 alkyl, S (0) malcyl C? -6, S (0) 2 NRaRb > amino, carboxyl, OZ, CH2 ~ (CH2) PZ, 0- (CH2) pZ, (CH2) p-0-Z, CH = CH-Z or XR37, each of alkyl and cycloalkyl is optionally substituted with one to three the same or different from halogen, amino, OH, CN or N02; m is 0-2; R 35 and R 36 are each independently H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; R37 is H, C? -C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, C (0) R38 or C (0) OR39, each of alkynyl and cycloalkyl is substituted optionally with one to three of the same or different from halogen, amino, OH, CN or N02; R38, R39 are each independently H, C? -C6 alkyl or C3-C6 cycloalkyl, each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different from halogen, amino, OH, CN or N02; with the proviso that R39 is not H; R40 is (CH2) n-Y, where n is 0-6; And it is selected from (1) H, C? -C6 alkyl, C3-C6 cycloalkyl C2-6 alkenyl, C3_6 cycloalkenyl, C2-6 alkynyl, halogen, CN, nitro, Ar, COOR6, COOAr, -CONRaRb, TR6, NRaRb, -NC ( 0) NRaRb, -OC (0) R6, -C [N (Ra) 2] = NT-Rb, XR6, -C (0) R6, -C (0) Ar, -S (0) Ra or -S (0) 2Ra, with the proviso that when Y is -S (0) Ra or -S (0) 2Ra then Ra is not H; Y (2) a 4-7 membered heterocyclic ring, optionally substituted with R6, which could contain 1-3 heteroatoms selected from the group consists of 0, S, SO, S02, N and NR4 ?, where R4? is selected from the group consisting of straight or branched chain (C? -C4) alkyl, straight or branched alkyl, alkenyl or (C2-C4) alkynyl of straight or branched chain; T is S u 0; with the proviso that R? -R5, R9-R? 6 and R3o "R3 are not all H at the same time and Ar is phenyl; with the proviso that R1-R5, R9-R6 and R3 or R34 are not all H at the same time and Ar is 2-furyl.
Another embodiment of the invention is a pharmaceutical formulation comprising an effective antiviral amount of a compound of formula I.
Another embodiment of the invention is a pharmaceutical formulation useful for treating HIV infection which additionally comprises an effective antiviral amount of an AIDS treatment agent selected from the group consisting of: a) an AIDS antiviral agent; (b) an anti-infective agent; (c) an immunomodulator; Y (d) inhibitors of HIV entry Another embodiment of the invention is a method for treating mammals infected with a virus (e.g. HIV), which comprises administering to the mammal an effective antiviral amount of a compound of formula II or pharmaceutically acceptable salts thereof; where : Ri, R 2, R 3, R 4 and R 5 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkynyl, halogen, CN, nitro, COOR 6 or XR 7 , each of alkyl and cycloalkyl are optionally substituted with one to three of the same or different from halogen, amino, OH, CN or N02; R6 is H, C? -C6 alkyl or C3-C6 cycloalkyl, benzyl, each alkyl, cycloalkyl and benzyl are optionally substituted with one to three of the same or different from halogen, amino, OH, CN or N02; X is O, S or NR6R7; R7 is H, C? -C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C-C6 cycloalkenyl, C2-C6 alkynyl or C (0) Rs each of alkyl and cycloalkyl are optionally substituted with one to three thereof or different from halogen, OH, amino, CN or N02; R8 is H, Ci-C6 alkyl or C3-C6 cycloalkyl; -W- is Rg, RlO / ll, Rl2, Rl3, Rl4, Rl5, Rl6 / Rl7, Rl8, l9 / R20, R21, R22 are each independently H, C? -C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C3 cycloalkenyl, C2-C6 alkynyl, CR23R24OR25, COR26, COOR27 or C (0) NR28R29, each one of alkyl and cycloalkyl are optionally substituted with one to three of the same or different from halogen, amino, OH, CN or N02; R 23, R 24, R 25, R 26, R 27, R 2, R 29 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkenyl or C 2 -C 6 alkynyl; Ar is a 4-7 membered aromatic ring that could contain one to five heteroatoms independently selected from the group consisting of O, S, N or NR6, wherein the aromatic ring is optionally fused to group B; B is an aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; or a heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1, 2, 3-triazolyl, 1, 3, 4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5- triazinyl, 1, 3, 5- t ri t ianilo, indoli zinilo, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, lH-indazolyl, benzimidazolyl, benz t ia zolilo, purinyl , 4H-quinoli zini it, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphth iridinilo, pteridinyl, carbazolyl, acridinyl, phenazinyl, FENOT ia zini it and phenoxazinyl; B and the 4-7 membered aromatic ring could each independently contain one to five substituents which are each independently selected from R30 R3 ?, 32, R33 or R3; R a and R b are each independently H, C 1-6 alkyl or phenyl; Z is -methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylathiazoyl, thiazoyl, 2-thienyl, 3-thienyl or pyrimidyl; and p is 0-2; R3O R31, R32, R33 and R3 are each independently H, C? C6 alkyl, C3- C6 cycloalkyl, C2-C6 alkenyl, C3-Ce cycloalkenyl, C2-C6 alkynyl, halogen, CN, nitro, C (0) R35, COXR36, hydroxyl, COOR6, hydroxymethyl, trifluoromethyl, trifluoromethoxy, O- [(C- -C alkyl) straight or branched chain], O-benzyl, O-phenyl, 1,2-methylenedioxy, OC (0) alkyl C? _6, SC (0) C 1-6 alkyl, S (0) m C? -6 alkyl, S (0) 2 NRaRb, amino, carboxyl, OZ, CH2- (CH2) PZ, 0- (CH2) pZ, (CH2) p-0-Z. CH = CH-Z or XR37, each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different halogen, amino, OH, CN or N02; is 0 -2; R35 and R36 are each independently H, C6-C6 alkylated or C3-C6 cycloalkyl; R37 is H, C? -C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, C (0) R38 or C (0) OR39, each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different halogen, amino, OH, CN or N02; R38, R39 are each independently H, Ci-Cß alkyl or C3-C6 cycloalkyl, each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different halogen, amino, OH, CN or N02; with the proviso that R39 is not H; R40 is (CH2) n-Y, where n is 0-6; And it is selected from (1) H, Ci-Ce alkyl, C3-Cd, C2_6 alkenyl, C3_6 cycloalkenyl, C2-6 alkynyl, halogen, CN, nitro, Ar, COOR6, COOAr, -CONRaRb, TR6, NRaRb, -NC (0) NRaRb, -OC (0) R6, -C [N (Ra) 2] = NT-Rb, XR6, -C (0) R6, -C (0) Ar, -S (0) Ra or -S (0 ) 2Ra, with the proviso that when Y is -S (0) Ra or -S (0) 2Ra then Ra is not H; Y (2) a 4-7 membered heterocyclic ring, optionally substituted with R6, which could contain 1-3 heteroatoms selected from the group consisting of 0, S, SO, S02, N and NR4 ?, where R4? is selected from the group consisting of straight or branched chain (C? -C4) alkyl, straight or branched alkyl, alkenyl or (C2-C4) alkynyl of straight or branched chain; Y T is S u 0; In a preferred embodiment, the compounds of formula I and II include 'those wherein Ar is phenyl, furyl, isoxazolyl, thiophenyl, pyrazolyl, pyridyl, benzofuryl, iofeni benzot I, indolyl, pyrazinyl, thiazolyl, imidazolyl, thiadiazolyl.
Also preferred are the compounds of the formulas I and II wherein W e s < 16 < 13 < fifteen " * R9, Ri or, Rn, R 12, R 13, 14 and 15 s on ca gives one H; Y R16 is methyl.
Also preferred are the compounds of the formulas I and II wherein R2 is H, fluoro or methoxy.
Also preferred are the compounds of the formulas I and II wherein Ri, R3 and R4 are each H.
DETAILED DESCRIPTION OF THE INVENTION The synthesis procedures and anti-HIV-1 activities of the new indoloxoacet i 1 piperazine analogs of the formula are summarized below.
I: Chemistry The present invention comprises compounds of formula I, their pharmaceutical formulations and their use in patients suffering from or susceptible to HIV. The compounds of the formula I which include the pharmaceutically acceptable salts thereof, The term "Ci-β alkyl" as used herein and in the claims (unless the context indicates otherwise) means branched or straight chain alkyl groups, such as methyl, ethyl propyl, isopropyl, butyl, isobutyl, t- butyl, amyl, hexyl, and the like. Similarly, "C2-6 alkenyl" and "C2-6 alkynyl" include straight or branched chain groups.
The term "pharmaceutically acceptable salt" as used herein and in the claims is intended to include non-toxic basic addition salts. Suitable salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, acid aconitic, salicylic acid, phthalic acid and the like.
Halogen refers to chlorine, bromine, iodine or fluorine.
In the method of the present invention, the term "effective antiviral amount" means the total amount of each active component of the method that is sufficient to show a significant benefit to the patient, ie, cure of acute conditions characterized by inhibition of infection. viral, including HIV infection. When the active ingredient, administered alone, is applied to an individual, the term refers to the ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the desired antiviral effect, if administered in combination, serially or simultaneously. The terms "treating, treating, treating" as used herein and in the claims means preventing or decreasing the viral infection associated with diseases, including HIV infection.
The present invention also relates to combinations of compounds with one or more agents useful in the treatment of AIDS. For example, the compound of this invention can be effectively administered either in pre-exposure and / or post-exposure periods, in combination with effective amounts of antivirals for AIDS, immunomodulators, anti-infectives or vaccines, such as those of the following table.
ANTIVIRALS Name of the drug Manufacturer Indication 097. Hoechst / Bayer HIV Infection, AIDS, ARC, Non-nucleoside Reverse Transcriptase (RT) Inhibitor Amprenavir Glaxo Wellcome Infection By 141W94 HIV, AIDS, ARC, GW141 8 Protease inhibitor) Abacavir (1592U89) Glaxo Wellcome Infection by GW1592 HIV, AIDS, ARC, (RT Inhibitor) Acemannan Carrington ARC Labs (Irving TX) Acyclovir Burroughs Wellcome infection HIV, AIDS, ARC, in combination with AZT AD-439 Tanox Biosystems infection HIV, AIDS, ARC AD-519 Tanox Infection by Biosystems HIV, AIDS, ARC Adenofovir Gilead HIV infection dipi voxi 1 Sciences AL-721 Ethigen (ARC, PGL, HIV Angeles, CA) positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination w / Retrovir Ansamycin LM 427 Adria 'ARC Laboratories (Dublin, OH) Erbamont (Stamford, CT) Antibody that Advanced AIDS, ARC neutralizes aberrant Biomedicine interferon alfa-Concepts at pH (Rockville, MD labile) AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-f luoro-ddA Nat'l Cancer Diseases Institute related to AIDS BMS-232623 (CGP- Bristol-Myers Infection by 73547) Squibb / Novartis HIV, ARC (protease inhibitor) BMS234475 Bristol-Myers Infection by (CGP-61755) Squibb / Novartis HIV, AIDS, ARC (Protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Retinitis by Sciences CMV, Herpes, papillomavirus.
Curdlan sulfate AJÍ Pharma USA HIV infection Medial Immunoglobulin CMV retinitis Cytomegalovirus Ganciclovir Syntex CMV ocular, cytoven CMV peripheral retinitis. Delavirdine Pharmacia- Upj ohn HIV infection, AIDS (RT Inhibitor) Dextran Sulfate Ueno Fine AIDS ARC HIV Chem, positive Ind asymptomatic Ltd. (Osaka Japan) ddC Hoffman- Infection with Idioxicit idina LaRoche HIV, AIDS, ARC. ddl Didesoxinosin Bristol-Myers Squibb infection HIV, AIDS, ARC, Combined with AZT / d4T DMP-450 AVID (Camden, NJ infection) HIV, AIDS. ARC (Protease inhibitor) Efavirenz (DMP266) Dupont Merck Infection with (-) 6-Chloro-4- (S) - HIV, AIDS, cyclopropylethynyl-ARC (RT 4 (S) -trifluorono-nucleoside) methyl-1 inhibitor, 4-dihydro-2H-3, 1-benzoxazin-2-one, STOCRINE EL10 Elan Corp, PLC Infection by Gainesville, HIV. GA) Famciclovir Smith Kline Herpes zoster Herpes simple FTC Emory University infection HIV, AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIV infection, AIDS, ARC, (Reverse transcriptase inhibitor) HBY097 Hoechst Marion Roussel infection HIV, AIDS, ARC (Reverse reverse transcriptase inhibitor no - nucleoside). Hypericin VIMRx Pharm, HIV infection, AIDS, ARC.
Infected Beta Triton AIDS, Sarcoma de Recombinant Biosciences Kaposi, Human ARC (Almeda, CA 'Inferieron alfa-n3 Inferido ARD, SIDA Sciences Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT / ddI / ddC. ISIS 2922 ISIS Retinitis by Pharmaceuticals CMV. KNI-272 Nat'l Cancer Diseases Institute Associated with HIV.
Lamivudine, 3TC Glaxo Wellcome Infection with HIV, AIDS, ARC, (Reverse Transcriptase Inhibitor) also with AZT. Lobucavir Bristol-Myers CMV infection Squibb Nelfinavir Agouron Pharmaceuticals infection HIV, AIDS, ARC (Protease inhibitor) Nevirapina Boeheringer Infection by Ingleheim HIV, AIDS, ARC, (RT Inhibitor) Novapren Novaferon HIV Labs Inhibitor, Inc. 'Akron, OH) Peptide T Peninsula Labs AIDS Sequence from (Belmont, CA) Octapeptide gone Phosphonoformate from Astra Pharm, Trisodium retinitis Products, Inc CMV, HIV infection, Other CMV infections PNU-140690 Pharmacia Upj infection ohn HIV, AIDS, ARC (Protease inhibitor) Probucol Vyrex HIV infection, RBC-CD4 AIDS Sheffield Med. Tech infection (Houston, HIV, AIDS, ARC. TX) Ritonavir Abbott HIV infection, AIDS, ARC, (Protease inhibitor) Saquinavir Hoffman- LaRoche infection HIV, AIDS, ARC (Protease inhibitor) Stavudine; D4T Bristol-Myers Infection by Dideshidro- Squibb HIV, AIDS, ARC.
Deoxitimidine Valaciclovir Glaxo Wellcome Genital infections by HSV and CMV. Rivabir ina Viratek / ICN HIV positive Virazole (Costa Mesa, asymptomatic, CA) LAS, ARC. Vx-478 Vértex Infection with HIV, AIDS, ARC.
Zalcitabine Hoffman- Infection by LaRoche HIV, AIDS, ARC, with AZT.
Zidovudine; AZT Glaxo Wellcome Infection with HIV, AIDS, ARC, Kaposi's sarcoma, In combination with other therapies IMMUNOMODULATORS Manufacturer Name Indication Drug AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn Advanced AIDS. Acemannan Carrington Labs, AIDS, ARC. Inc, (Irving, TX) CL246, 738 American Labs AIDS, Cyanamid Sarcoma Lederle Kaposi. EL10 Elan Corp, PLC HIV infection. (Gainesville, GA) FP-21399 Fuki ImmunoPharm Blockers of HIV fusion with CD4 cells.
Genentech ARC injected in combination Gamma with TNF (tumor necrosis factor) Factor Genetics AIDS, Stimulant Institute Sandoz Colonies of Granulocytes- Macrophages Factor Hoechst-Roussel AIDS. Stimulant of Immunex Colonies of Granulocytes - Macrophages. Schering-Plow Factor AIDS in Stimulant of combination with the Colonies AZT. of Granulocytes' Macrophages Immunostimulation - HIV Seropositivity. of HIV core particles IL-2 Cetus AIDS, in Interleukin- combination with 2 AZT. IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combination with AZT. IL-2 Chiron AIDS, Increase in Interleukin-2 cell count (Aldeslukin) CD4 Immunoglobulin Cutter Pediatric AIDS in Intravenous Biological combination with (human) (Berkeley, CA) AZT. IMREG-1 Imreg AIDS, Sarcoma (New Orleans, Kaposi, ARC, PGL LA) IMREG-2 Imreg AIDS, Sarcoma (New Orleans, Kaposi, ARC, PGL LA) Carbamate Institute AIDS, ARC dithioimuthiol- Merieux Diethyl Inferred Schering-Plow Kaposi sarcoma ally-2 with AZT, AIDS. Met ionin- TNI AIDS, ARC. Enceíaliña Pharmaceuticals (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma.
Murami 1-tripeptide Factor Amgen AIDS, in Stimulant of combination with Colonies of AZT. Granulocytes Remune Immune Response Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC. Human CD4 soluble Recombinant. RCD4-IgG AIDS, ARC Hybrids Human CD4 Biogen AIDS, ARC. Soluble Recombinant Inferished Hoffman-LaRoche Kaposi's Sarcoma, Alpha-2A AIDS, ARC, in combination with AZT SK &F106528 Smith Kline HIV Infection. T4 Soluble Timopentine Immunobiology HIV infection. Research Inst itute (Annandale, NJ) Genentech ARC factor in combination Necrosis with Tumor Inferior; TNF gamma.
ANTI-INFECTIOUS Name of the Drug Manufacturer Indication Clindamycin with Pharmacia PCP Pr imaquina Upj ohn Fluconazole Pfizer Meningitis Cryptococcus, candidiasis Nystatin Tablets Squibb Corp. Prevention of oral candidiasis Efornitin Ornidil Merrell Dow PCP LyphoMed isotionate Pentamidine treatment (IM &Rosemont, IL) PCP) IV) Trimet roprim Antibacterial Trimetroprim / sulfa Antibacterial Pir i t rexim Burroughs Treatment of Wellcome PCP I set ionat or of Fisons Prophylaxis of PCP Pentamidine for Corporat ion inhalation Spiramycin Rhone-Poulenc Diarrhea due to cryptosporidiosis Itraconazole Jannsen- Histoplasmosis, R51211 Pharm. Cryptococcal meningitis.
Trimet rexato Warner- PCP Lambert Daunorubicina NeXstar, Sarcoma of Sequus Kaposi. Erit ropoyetina Ortho Pharm. Severe human recombinant anemia associated with AZT therapy. Serono hormone loss of weight and growth of human recombinant cachexia related to AIDS. Bristol-Myers Acetate Treatment of the Megestrol Squibb anorexia associated with AIDS. Testosterone Boost, Smith Kline weight loss related to AIDS. Enteral Nutrition Norwich Eaton Diarrea and Total Pharmaceuticals malabsorption related to AIDS.
Additionally, the compounds of the invention could be used here in combination with other classes of agents for treating AIDS which are called HIV entry inhibitors. Examples of such HIV entry inhibitors are discussed in DRUGS OF THE FUTURE 1999, 24 (12), pp. 1355-1362; CELL, Vol.9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol .5, No.5, May 2000, pp. 183-194.
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives, HIV entry inhibitors or vaccines is not limited to the list in the following Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternative treatments with a compound of the present invention and an HIV protease inhibitor and / or a reverse transcriptase inhibitor of non-nucleoside HIV. A fourth optional component in the combination is a reverse transcriptase inhibitor of HIV such as AZT, 3TC, ddC or ddl. A preferred inhibitor of HIV protease is indinavir, which is the sulfated salt of ethanolate of N- (2 (R) -hydroxy-1- (S) -indanyl) -2 (R) -phenylmet i 1-4 - ( S) -hydroxy-5- (1- (4- (3-pyridyl-methyl) -2 (S) -N '- (t-but i 1 -carboxamido) - piperazinyl)) of pentanamide, and is synthesized according to U.S. 5,413,999. Indinavir, in general, is administered in a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg total dose per day. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz. The preparation of ddC, ddl and AZT are also described in EPO 0,484,071. These combinations could have unexpected effects on the limitation of progression and the degree of HIV infection. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and / or 3TC and / or ddl and / or ddC; (2) indinavir, and either AZT and / or ddl and / or ddC and / or 3TC, in particular, indinavir and AZT and 3TC; (3) Stavudine and 3TC and / or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.
In such combinations the compound of the present invention and other active agents could be administered separately or in combination. Further, the administration of an element could be before, simultaneous or subsequent to the administration of another agent (s).
The procedures for making the compounds of the formula I are shown in Schemes 1-13, and are further exemplified in Tables 5-8.
Scheme 1 The initiating characters 1 (Scheme 1) are known or easily prepared according to the procedures of the literature, such as those described in Gribble, G. (Ref.24) or Bartoli et al (Ref. 36). The indoles 1 are treated with chloride of oxalyl either in THF (tetrahydrofuran) or ether to provide the desired glyoxyl chlorides 2 according to the procedures of the literature (Lingens, F. et al, Ref. 25). The intermediate glyoxyl chlorides 2 are then coupled with benzoyl piperazine 3 (Desai, M. et al, Ref. 26) under basic conditions to provide 4.
Scheme 2 Treatment of indole-3-glyoxyl chloride 2 (Scheme 2) with 1-piperazincarboxylate or tert-butyl provides the coupled product 6. The deprotection of the Boc group of 6 is carried out with 20% of TFA (trifluoroacetic acid) / CH2C12 to produce 7. This product is then coupled with carboxylic acid in the presence of the supported polymer 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (P-EDC) to provide the products 8.
Scheme 3 For Examples 58-81, piperazine 7 (Scheme 3) was treated with protected Boc aminobenzoic acid in the presence of EDC to provide 8a. A portion of the resulting product was separated and subjected to TFA to remove the Boc group, in this way, amino derivatives were produced 9.
Scheme 4 8b For Examples 82-89, piperazine 7 (Scheme 4) was treated with acetoxybenzoic acid in the presence of EDC to provide 8b. A portion of the resulting product was separated and subjected to hydrolysis with LiOH to remove the acetate group, thereby producing hydroxy derivatives 10.
Examples containing the substituted piperazines are prepared using the general procedures depicted in Schemes 5-13.
The substituted piperazines are either commercially available from Aldrich, Co. or are prepared according to literature procedures (Behun et al, Ref. 31 (a), Scheme 5, item 01). Hydrogenation of the alkyl substituted pyracines under 40 to 50 psi pressure in ethanol provided the substituted piperazines. When the substituent was an ester or amide, the pyrazine systems could be partially reduced to the tet rahydropyrazine (Rossen et al, Ref. 31 (b), Scheme 5, eq. 02). The carbonyl substituted piperazines could be obtained under the same conditions as described above using the commercially available dibenzyl piperazines (Scheme 5, Eq 03).
Scheme 5 X «OR. NR, R2 X - OR. NR1R2 2-trifluoromethylpiperazine (Jenneskens et al., Ref. 31c) was prepared by a four-step route (Scheme 6). Using the Lewis acid TiCl 4, N, N'-dibenzylate and lendiamine II was reacted with tri fluoropyruvates 12 to provide hemiacetal 13, which was reduced to room temperature by Et 3 SiH in CF 3 COOH to lactam 14. Treatment with LiAlH 4 after reduced lactam 14 to 1,4-dibenzyl-2-trifluoromethylpiperazine 15. Finally, hydrogenation of compound 15 in HOAc gave the desired product 2 -tri fluoromet i piperazine 16.
Scheme 6 12 L? H. Ether ^ ¿rr M > , 55P * "X -X 'reflux I I Pd-C, MOAc 1. fj J 2KOAC C7 li Mono-benzoylation of the symmetrical substituted piperazines could be achieved using one of the following procedures (Scheme 7). (a) The treatment of a solution of piperazine in acetic acid with acetyl chloride provided the desired mono-benzoic piperazine (Desai et al., Ref. 26, Scheme 7, Eq. 04). (b) The symmetrical piperazines were treated with 2 equivalents of n-butyllithium, followed by the addition of benzoyl chloride at room temperature (Wang et al, Ref. 32, Scheme 7, eq. 05).
Scheme 7 Mono-benzoylation of asymmetric substituted piperazines could be achieved using one of the following procedures (Scheme 8), in which all methods were exemplified by mono-alkyl substituted piperazines. (a) The asymmetric piperazines were treated with 2 equivalents of n-butyl lithium, followed by the addition of benzoyl chloride at room temperature to provide a mixture of two regioisomers, which could be separated by chromatography (Wang et al, Ref. 32 and 33 (b), Scheme 8, Eq. 06); (b) The benzoic acid was converted to its pentaf luorophenyl ester and then the further reaction with 2-alkyl piperazine to provide the mono-benzoyl piperazines with the benzoyl group in the least prevented nitrogen (Adamczyk et al, Ref. 33 (a), Scheme 8, ec. 07); (c) A mixture of piperazine and methyl benzoate was treated with dialkylaluminum chloride in methylene chloride for 2-4 days to produce the mono-benzoylpiperazine with the benzoyl group in the least-hindered nitrogen (Scheme 8, Eq.; (d) The asymmetric piperazines were treated with 2 equivalents of n-butyl lithium, followed by the subsequent addition of triethylsilyl chloride and benzoyl chloride in THF at room temperature to provide the mono-benzoyl piperazines with the benzoyl group in the lower nitrogen. disabled (Wang et al, Ref. 33 (b), Scheme 8, Eq. 09). When the substituent at the 2-position was an ester or amide, mono-benzoylation with benzoyl chloride occurred in the least impeded nitrogen of the piperazine with triethylamine as the base in THF (Scheme 8, Eq.
Scheme 8 1. BUU .9 .. ^^ ßc Q9 C ^ NH 2) TESO. THF L ^. NH 3) Bza X m OR MR, », In the case of tetrahydropyrazines (Scheme 9, Eq. 11), mono-benzoylation occurs in the most impeded nitrogen under the same conditions as those in equation 10 of the Scheme. 8, in the well-introduced way. (Rosen et al, Ref. 31 (b)).
Scheme 9 cox cox i BiCI BxN X • OR. NR, R, ec eleven In addition, the ester group can be selectively reduced by NaBH 4 in the presence of the benzamide (Masuzawa et al, Ref. 34), which is shown in Scheme 10.
Scheme 10 COOR CH.OH I N «BH_, HN ^ X HN ^ I THF. Et, N I 'C, NB2' X ^ .NBl e c. 12 Hydrolysis of the ester group to the acid: The ester groups in the piperazine linkers or in the indole core could be hydrolyzed to the corresponding acid under basic conditions, such as K2C03 (Scheme 11, Eq.13) or NaOMe (Scheme 11, Eq.14) as the bases in MeOH and Water.
Scheme 11 Coupling reaction Scheme 12 18 The reaction of glyoxyl chloride 2 with the substituted benzoyl piperazines or tetrahydropyrazines (17) in CH2C12 using i-Pr2NEt as the base gave the desired products 18.
In the case of coupling reactions using 3-hydroxymethylbenzoylpiperazine, the hydroxyl group was temporarily protected as its TMS (trimethylsilyl) ether with BSTFA (N, 0-bistrimethylsilyl) fluoroacet amide) (Furber et al, Ref. 35) . The unprotected nitrogen atom was then reacted with the glyoxyl 2 chlorides to form the desired diamides. During processing, the masking group TMS was removed to give the free hydroxylmethylpiperazine diamides 19 (Scheme 13).
Scheme 13 Antiviral activity The antiviral activity of the compounds of Examples 1-34 was determined in MT2 cells (a positive T-lymphocytic CD4 cell line) acutely infected by the BRU strain of HIV-1 in the presence of 10 μM of compound. The virus productions were quantified 6 days after infection using a reverse transcriptase test (Potts, Ref. 27). The anti-viral results are summarized in Table 1, shown below. Cytotoxicity was determined by incubating cells in the presence of the serially diluted compound and cell viability was determined using an XTT dye reduction test (Weislow, Ref. 28). 50% of the cytotoxicity concentrations of all the compounds were significantly greater than 10 μm, indicating that the compounds are relatively non-toxic.
The antiviral activity of the compounds of the Examples 35-215 were determined in HeLa CD4 cells CCR5 infected by the simple round infectious HIV-1 reporter virus in the presence of the compound at concentrations <1. 10 μM. The infection by virus was quantified 3 days later by measuring the expression of luciferaza of the viral DNA integrated in the infected cells (Chen et al, Ref. 41). The percent inhibition for each compound was calculated by quantifying the level of expression of luciferase in infected cells in the presence of each compound as a percentage of that observed for the infected cells in the absence of the compound and subtracting such a determined value of 100. The compounds exhibiting anti-viral activity without appreciable toxicity at concentrations < 10 μM are presented in Tables 1-4 and 9-13 Table 1 Table 2 97 4 -Fluoro N AN 97 98 4-C00Me N N 84 HO 99 4-Fluoro N N 89 \ HO- 100 7-COOMe 86 101 4 -Fluoro 74 102 7-COOMe N N > 98 103 7-COOMe N N > 98 104 7-COOMe > 98 N N 105 7-Ome N N> 98 / - \ 106 4, 7-Dif luoro N N > 98 4,5,6,7- 107 N N> 98 tetrafluoro 4.5, 6.7- 108 N N> 98 tetrafluoro \ / 109 7-Nitro N N > 98 / \ 110 7-Ethyl N N > 98 111 7-Ome N N> 98 112 7-Nitro N N \ 84 / \ 113 6-Chlorine N N / - ' 114 5, 6-Dichloro N N 89 115 4-Chlorine N N 79 116 4-Chlorine N N 77 A ^ 117 5, 6-dichloro N N 89 / - \ 118 5-Fluoro N N 69 < X 119 7-Ethyl N N 72 120 4-Bromo N N 58 121 7-COOMe 92 122 4-Br N N 40 123 5-Fluoro N N 95 124 6-Chlorine N N > 98 \ / / \ 125 7-COOMe N N > 98 126 7-COOMe > 98 N N Table 3 Table 4 Experimental procedures biology Abbreviations "Μ..M /" i means micromolar; μci "means microcurie; ml "means milliliter; lμl "means microliter; μm" means microgram; lM 'means molar; 'μm' means micromolar; • "mM" means millimolar; • "a" refers to the * percent inhibition results as representing the mean values of at least two experiments with duplicate determinations in each experiment. • "RT" "refers to reverse transcriptase.
The materials and experimental procedures used to obtain the anti-viral results for Examples 1-34 are described below.
Cells The MT-2 cell lines propagated in the 1640 medium of the Roswell Park Memorial Institute (RPMI) (Life Technologies, Gaithersburg, MD) contain 10% fetal bovine serum (FBS, Sigma, St. Louis, MO).
Virus-BRU from the HIV-1 strain of the laboratory was titrated using an infectivity test (Johnson, V.A. and R.E. Byrington, 1990).
Experiment 1. MT-2 cells (Harada, et al, Ref. 30) were infected by HIV-1 BRU at a multiplicity of infection (MOI) of 0.005 in 1640 RPMI medium containing 10% fetal bovine serum at a concentration of 1 x 105 cells / ml. 2. The compound was added to 100 μl of 1640 RPMI medium containing 10% fetal bovine serum per well in a 96-well plate at a concentration of 20 μM. 3. 100 μl of 1 × 10 5 / ml of infected MT-2 cells were added to each well in such plates, resulting in a final cell concentration of 5 × 10 4 cells / ml and a final compound concentration of 10 μM. 4. The samples were incubated at 37 ° C and harvested for 6 days after infection.
. HIV-1 replication was quantified by measuring reverse transcriptase (RT) activity of HIV-1 present in cell-free supernatants (Potts, et al, Ref. 27). For each sample, 20 μl of the cell-free supernatant was added 40 μi of the RT cocktail [42 μM Tris (hydroxymethyl) aminomethane, pH 7.8 (Sigma, St. Louis, MO), 63 μM potassium chloride (Mallinckrodt, Paris KT), 2 μM dithiothreitol (Sigma, St. Louis MO) magnesium chloride μM (Mallinckrodt, Paris KT), 4 μg / ml polyadenic acid (Pharmacia, Piscataway, NJ), 1.3 μg / ml deoxit imidinai2-i8 oligonucleotide (Pharmacia, Piscataway, NJ), 0.04% (octyl phenoxy) -polyethoxyethanol (Nonidet P-40, Sigma, St. Louis, MO) and 17 μCi / ml of 5'-3H-deoxythine imidine phosphate (NEN, Boston, MA )]. The tests were incubated during 1 hour at 37 ° C and then stained in portions of 1 μl of each reaction on filter paper of diethylaminoethe cellulose (DE-81) (Whatman, Hillsboro, OR), allowed to dry, washed four times with 0.3M sodium chloride (Fisher Scientific, Pittsburg, PA), 30 mM sodium citrate, pH 7.0 (Sigma, St. Louis, MO), were left through two washes in 95% ethanol. The binding reactivity was quantified by scintillation counting. 6. The percent inhibition for each compound was calculated by quantifying the level of HIV-1 replication in the presence of each compound as a percentage without the control compound and subtracting such a determined value of 100. 7. To determine the cytotoxicity of the compounds, uninfected cells were incubated with a series of concentrations of each compound for 3-6 days. The cell variability was determined by the XTT dye reduction method. { 2, 3-bi s (2-methoxy-4-nitro-5-sulfophenyl) -5- [(phenylamino) carbonyl] -2H-tetrazolium hydroxide} (Weislow et al, Ref. 28). The percentage of live cells in the wells containing the compound compared to the untreated controls was determined. 50% of the cytotoxic concentration was calculated as the concentration of the drug that decreased the percentage of living cells to 50% of the untreated cells.
The materials and methods for the determination of antiviral activity are described below for examples 35-215: Cells • Virus Production - The human embryonic kidney cell line, 293, propagated in Dulbecco's modified Eagle's medium (Life Technologies, Gaithersburg, MD) containing 10% fetal bovine serum (FBS, Sigma, St. Louis, MO) ).
• Virus infection - The human epithelial cell line, HeLa, expressing the HIV-1 CD4 and CCR5 receptors was propagated in Dulbecco's modified Eagle's medium (Life Technologies, Gaithersburg, MD) containing 10% fetal bovine serum (FBS, Sigma, St. Louis, MO) and supplemented with 0.2 mg / ml Geneticin (Life Technologies, Gaithersburg, MD) and 0.4 mg / ml Zeocin (Invitrogen, Carlsbad, CA).
Virus - The replication defective reporter virus was produced by human embryonic kidney 293 cells co-trans ferred with an HIV-1 envelope DNA expression vector and a proviral cDNA containing a cover and host elimination mutation. the reporter gene of luciferase instead of the nef sequences of HIV-1 (Chen, 1994). Transfections were performed using the reagent lipofectAMINE PLUS as described by the manufacturer (Life Technologies, Gaithersburg, MD).
Experiment * 1. The compound was added to HeLa CCR5 CD4 cells plated in 96-well plates at a cell density of 5 X 10 4 cells per well in 100 ul of Dulbecco's modified Eagle's medium containing 10% bovine serum. fetal at a concentration of < 20 u. 2. 100 ul of the replication defective reporter virus in Dulbecco's modified Eagle medium was then added to the cells plated and the compound at a multiplicity of infection (MOI) of 0.01, resulting in a final volume of 200 ul per well and a concentration of the final compound of < 10 uM. 3. Samples were harvested 72 hours after infection.
The viral infection was monitored by measuring luciferase expression of the viral DNA in the infected cells using a luciferase reporter gene test kit (Roche Molecular Biochemicals, Indianapolis, IN). The supernatants of the infected cells were removed and 50 ul of Dulbecco's modified Eagle's medium (without phenol red) and 50 ul of the luciferase test reagent reconstituted by the manufacturer (Roche Molecular Biochemicals, Indianapolis, IN) was added per well. The luciferase activity was then quantified by measuring the luminescence using a Wallac microbeta scintillation counter.
The percent inhibition for each compound was calculated by quantifying the level of luciferase expression in infected cells in the presence of each compound as a percentage of that observed for infected cells in the absence of the compound and subtracting such a determined value of 100.
References Chen, B.K., Saksela, K., Andino, R., and D. Baltimore. 1994. Distinct modes of human immunodeficiency type 1 proviral latency revealed by superinfect ion of nonproduct ively infected celllines with recombinant luciferase-encoding viruses. J. Virol. 68: 654-660 (Ref. 37).
Chemistry General: Unless otherwise noted, the solvents and reagents were used directly as obtained from commercial sources and the reactions were carried out under a nitrogen atmosphere. Flash chromatography was carried out on silica gel 60 (particle size 0.040-0.063, supplied by EM Science). The 1 H NMR spectra were recorded at 500 MHz, unless otherwise noted, and the chemical changes are reported relative to the residual solvent signals. The following standard acronyms were used to describe the multiplicity patterns: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b (width), app (apparent) The coupling constant (J) is in hertz.
All liquid chromatography (LC) results were recorded on a Shimadzu LC-10AS liquid chromatograph using a SPD-10AV UV-Vis detector and the results of mass spectrometry were determined with a micromass platform for LC in the electroatomized form.
CL / MS method (i.e. identification of the compound) Unless otherwise noted, all compounds were analyzed using the following conditions: Column: Column YMC ODS S7 3.0x50 mm Gradient: 100% Solvent A / 0% solvent B at 0% solvent A / 100% solvent B Gradient time: 2 minutes Retention time: 1 minute Flow rate: 5 mL / min Detector of 220 nm wave length Solvent A; 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid Solvent B 10% H2O / 90% MeOH / 0.1% trifluoroacetic acid When observed, the following conditions were used for the HPLC analysis: Method To Column YMC ODS-A C18 S7 3.0x50 min% Start B = 0 /% B finished = 100 Method B YMC Column ODS-A C18 S7 3.0x50 min B% start 30 /% Finished B = 100 Method C Column PHX-LUNA C18 4.6x30 mm B start% = 0 /% B finished = 100 Compounds purified by preparative HPLC were diluted in methanol (1.2 mL) and purified using the following methods in an automated Shimadzu LC-10A preparative HPLC system.
Preparative HPLC method (i.e. purification of the compound) Purification method: Initial gradient (40% of B, 60% of A) increased to the final gradient (100% of B, 0% of A) for 20 minutes, retention for 3 minutes (100% of B, 0% of TO) Solvent At 10% MeOH / 90% H2O / 0.1% tri-fluoroacetic acid Solvent B 10% H2O / 90% MeOH / 0.1% trifluoroacetic acid Column Column YMC C18 S5 20x100 mm 220 nm wave length detector The characters were commercially available or were prepared using known chemistry, such as the Bartoli method (Ref. 36) or as described by Gribble (Ref. 24).
Representative indole syntheses are shown below.
Preparation of 4-fluoro-7-methyl indole STAGE A A flame-dried 50 ml three-necked flask was charged with BC13 (44 mmol, 44 ml, 1M in benzene) and 10 ml of dry benzene at low N2. The mixture was cooled to 0 ° C followed by the dropwise addition of 5-fluoro-2-methylaniline (5 g, 40 mmol) in 10 ml of dry benzene for 10 min, chloroacetonitrile (2.18 g, 48 mmol) for 2 min and A1C13 in one portion. After stirring at 0 ° C for 5 min, the ice bath was removed and the mixture was refluxed for 6 h under N2. The resulting mixture was filtered at rt and poured into EtOAc / IN HCl (300 mL, 50:50 v: v with ice). After separation, the aqueous phase was extracted with EtOAc (2x100 mL). The Combined organic layers were washed with water (100 mL), brine (2x100 mL) and dried with MgSO4. The solvent was removed in vacuo, and the crude intermediate was used directly in the next step without further purification.
STAGE B The above residue was dissolved in 100 mL of EtOH. The mixture was then enriched at 0 ° C, followed by the dropwise addition of NaBH 4 in 2 ml of H20. After stirring at 0 ° C for 1 h, the reaction was quenched with H20 (10 mL). The solvent was removed in vacuo and the residue was dissolved in EtOAc (150 ml) and washed with brine (2x50 ml). The organic layer was dried with MgSO 4, the solvent was removed, and the expected reduced intermediate was used directly in the next cyclization step.
STAGE C The above intermediate, a yellow oil, was dissolved in 100 ml of EtOH, followed by the addition of K2CO3 (11.0 g, 80 mmol). The mixture was refluxed under N2 for 2 h, and cooled to rt. The solids were removed by filtering through celite, and the resulting solution was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL), washed with brine (2x50 mL) and dried with MgSO4. The solvent was removed and a brown oil was given which was purified by flash chromatography (12% EtOAc in hexanes) to yield 2.3 g (39% overall yield) of the pure product. M + H, 150.0; Retention time, 1,297 min.
Synthesis of 4-ethoxyindole A two-necked flask dried in the oven was charged with 5 ml of DMF and NaH (66 mg, 60% in oil, 1.65 mmol). The mixture was cooled to 0 ° C, followed by the dropwise addition of 4-hydroxy indole (200 mg, 1.5 mmol) in 5 ml of DMF for 10 seconds. After stirring for 30 min under N2, 2 ml of DMF was added dropwise, and the reaction was allowed to warm to rt. with continued agitation for 2 h. Removal of the solvent in va cuo, followed by aqueous work up afforded the crude 4-ethoxyindole which was purified by preparative HPLC, to provide 201 mg (83%) of the pure 4-ethoxyindole; HPLC retention time, 1190 min.
Synthesis of 4-fluoro-7-carbomethoxy indole STAGE A: A mixture of 4-fluoro-7-oindole (600 mg, 2.8 mmol) and CuCN (1,004 g, 11.2 mmol) in DMF (4 mL) were added. refluxed for 16 hours. After cooling to room temperature, the reaction mixture was poured into a solution of ammonia in MeOH (30 ml, sat.) And the residue was removed by filtration. The filtrate was added to a mixture of water (20 ml) / ammonia (20 ml, sat aq.) And extracted with EtOAc / ether (1/1) until the analysis by TLC showed no product in the aqueous phase. The combined organic extracts were washed with brine (2x200 ml) and water (200 ml), dried (MgSO4); evaporation i n c uo gave -fluoro-7-cyanoindole as a bright yellow solid (310 mg, 69%).
STAGE B To a solution of KOH (13.04 g, 0.232 mol) in 14% H20 / EtOH (50 ml) was added 4-fluoro-7-cyanoindole (900 mg, 5.60 mmol). The resulting mixture was refluxed for 12 hours, cooled slowly to room temperature, and concentrated in goes to about 30 ml. The residue was acidified to pH 2 with HCl (~ 5.5N aq.). The precipitate was filtered, washed with excess water, and dried under high vacuum to provide 4-fluoro-7-carboxyindole as a white solid (100% conversion). The material was used without further purification.
STAGE C To a suspension of 4-fluoro-7-carboxy indole in a mixture of MeOH (18 ml) / PhH (62 ml) was added (trimethylsilyl) diazomethane (8.8 ml, 17.6 mmol, 2M in hexane). The resulting mixture was stirred at room temperature for 30 min, quenched with excess acetic acid and evaporated in vacuo. The crude oily material was purified by flash chromatography using an elution gradient. (Hexane at 10% EtOAc / Hexane) to provide (4- fluoro) methyl indole-7-carboxylate as a white solid (1.04 g, 83% two-step).
Preparation of 4- luoroindole-7-carboxaldehyde To a solution of -fluoro-7-bromoindole (1.0 g, 4.7 mmol) in THF (5 L) at -78 ° C, n-BuLi (5.6 mL, 2.5M in hexanes) was added dropwise. The mixture was stirred for 15 min at -78 ° C, allowed to warm to 5 ° C for 30 min and then re-cooled to -78 ° C. Then DMF (1.8 mL) was added and the mixture was allowed to warm slowly to room temperature. The reaction was quenched with water and extracted with ether. The organic phase was dried with MgSO 4, filtered and concentrated to provide 4-fluoroindole-7-carboxaldehyde.
General procedure for the preparation of Examples 1-17 in Table 5 STAGE A II To the commercially available indole-3-glyoxylyl chloride I (3 grams, 14.45 mmol) in CH 2 Cl 2 at room temperature was added tert-butyl 1-piperazinecarboxylate (2.7 grams, 14.45 mmol) and diisopropylethylamine (2.76 ml, 15.9 mmol). The light brown solution was stirred for 2 h at room temperature after which time the CL / MS analysis indicated that the reaction was complete. The solvent was removed and the resulting residue was diluted with ethyl acetate (250 ml) and diethyl ether (250 ml). The organic solution was then washed with water (100 ml x 3) and brine (50 ml), dried with MgSO 4, filtered and concentrated. The light yellow solid was then added with 30 ml of 20% trifluoroacetic acid in CH2C12. The solution was concentrated and the light brown solid was dried in vacuo to give 3.5 g (95%) of product II. The CL / MS analysis indicated that this product was 100% pure and used for the next reaction without further purification.
STAGE B II III To piperazine indole-3-glyoxyamide II (0.03 mmol) was added the bound l- (3-dimethylaminopropyl) -3-ylcarbodiimide resin (P-EDC) (0.21 mmol) and carboxylic acid (RCOOH) (0.06 mmol) in dichloromethane (DCE) (1 mL) or DMF (dimethylformamide) (1 mL) in cases where the carboxylic acids are not soluble in DCE. The reaction was stirred for 12 h at room temperature. The product III was filtered and concentrated. Products with purity lower than 70% were diluted in methanol and purified using an automated Shimadzu preparative HPLC system. 2) General Procedure for the preparation of Examples 18-56 in Table 5 Stage A.
IV To a solution of the substituted indole IV (1 eq.) In dry Et20, oxalyl chloride (1.2 eq.) Was added dropwise at 0 ° C. After 15 min., The reaction mixture was warmed to room temperature or heated to ~ 35 ° C overnight if necessary. The substituted indole-3-glyoxylyl chloride V intermediate, which formed as a solid, was filtered and washed with dry ether (2 x 1 ml) to remove excess oxalyl chloride. The product was then dried under vacuum to give the desired glyoxyl V-chlorides.
In the cases where the reaction in Et20 was not successful, the following procedure was adopted: To a solution of the substituted indole IV (1 eq.) In the dry THF (tetrahydrofuran) solvent was added dropwise oxalyl chloride (1.2 eq. .) at 0 ° C.
After 5 min., The reaction was warmed to room temperature, or heated to ~ 70 ° C under nitrogen if necessary. After in va cuo concentration, the resulting crude intermediate V was presented in the next step without further treatment.
Stage B SAW To a solution of the indole glyoxyl chloride V (1 eq.) In dry THF was added benzoylpiperazine (1 eq.) At room temperature. The mixture was then cooled to 0 ° C, followed by the dropwise addition of diisopropylamine (1.3 eq.). After 5 min, the reaction mixture was warmed to room temperature and stirred for 3 h. The resulting crude VI products were purified by preparative HPLC and characterized as shown in Table 5.
General Procedure for the preparation of Examples 58-63 in Table 5 STAGE A Vile To the glyoxyl chloride V (1 equiv.) In CH2C12 at room temperature was added tert-butyl 1-piperazinecarboxylate (1 equiv.) And diisopropylethylamine (1.2 equiv.). The solution was stirred for 2 h at room temperature after which time the CL / MS analyzes indicated that the reaction was complete. The solvent was removed in vacuo and the resulting residue was diluted with ethyl acetate and diethyl ether. The organic solution was then washed with water (100 ml x 3) and brine (50 ml), dried with MgSO4, filtered and concentrated. Then 30 ml of 20% trifluoroacetic acid in CH2C12 was added to the solid. The solution was concentrated and the solid, light brown dried in va cuo to give glyoxamide VII.
STAGE B C Vile VIII To the piperazine glyoxamide VII (0.1 mmol, 1 eq.) In DMF (1 mL) at room temperature was added EDC (1.5 eq.) And Boc-aminobenzoic acid (1.5 eq.). The reaction mixture was stirred at room temperature for 16 hours. The crude product was then purified by preparative HPLC to provide product VIII.
General Procedure for the preparation of Examples 65-73 in Table 5 VIII IX To the protected Boc VIII derivative (0.03 mmol) was added 50% TFA / CH2C12 (1.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The product was then concentrated to give the product IX as its TFA salt. The purity of IX was sufficient that no further purification was necessary.
General Procedure for the preparation of Examples 82-86 in Table 5 VII To the piperazine glyoxamide VII (0.1 mmol, 1 eq.) In DMF (1 mL) at room temperature was added EDC (1.5 eq.) And acetoxybenzoic acid (1.5 eq.). The reaction mixture was stirred at room temperature for 16 hours. The crude product was then purified by preparative HPLC to provide product X.
General Procedure for the preparation of Examples 87-89 in Table 5 XI To the protected acetate derivative X (0.03 mmol, 1 eq.) Was added aqueous LiOH (3 eq.) In THF / MeOH (1.5 L, 1: 1). The reaction mixture was stirred at room temperature for 16 hours. The crude product was then purified by preparative HPLC to provide product XI.
General Procedure for the preparation of Examples 64 and 74-81 in Table 5 STAGE A XII To a solution of the protected Boc amino benzoic acid (5 mmol) in DMF (10 mL) at room temperature was added pentafluorophenol (5 mmol) followed by EDC (5 mmol). The reaction mixture was stirred at room temperature for 3 h. The crude product was diluted with CH2Cl2 and washed with water, 0.1M HCl. The organic phase was dried with MgSO 4, filtered and concentrated. The pentafluorophenyl ester XII was used in the next reaction without further purification.
STAGE B XIII To a stirred solution DE (R) -2-methyl-piperazine in DMF (15 mL) at room temperature was added dropwise a solution of pentafluorophenyl ester XII in DMF (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The crude product was diluted with CH2Cl2 and washed with Na2CO3 (sat) and brine. The organic phase was dried with MgSO 4, filtered and concentrated. The crude product was purified by flash chromatography (50% EtOAc / Hexane-10% MeOH / EtOAc) to provide product XIII.
STAGE C XIV To the indole-3-glyoxyl chloride V (1 eq.) In CH2C12 was added acylpiperazine XII followed by i-Pr2NEt (3 eq.). The reaction mixture was stirred at room temperature for 5 hours, then diluted with methanol and the XIV product was purified by preparative HPLC.
STAGE D To the protected XIV Boc derivative (-0.03 mmol) was added 50% TFA / CH2C12 (1.5 L). The reaction mixture was stirred at room temperature for 16 hours. The product was then concentrated to give the product XV. The purity of XV was sufficient that no further purification was necessary.
Procedure for the synthesis of Examples 57 and 90 in Table 5.
STAGE A IV XVI To the substituted indole IV (1 equiv.) In CH2C12 at 0 ° C was added ethyl chloroxalate (2 equiv.) Dropwise followed by the addition of A1C13 (2 equiv.). The reaction was stirred at 0 ° C and then allowed to warm to room temperature overnight. The reaction was quenched by the dropwise addition of HCl (IN). The crude material was extracted with EtOAc and washed with water, dried with MgSO 4, filtered and concentrated. The crude product was then recrystallized from EtOAc / Hexanes to provide ester XVI.
STAGE B XVI XVII To the ester XVI (1 equiv.) In EtOH was added dropwise NaOH (2.5 equiv, ION). The reaction mixture was stirred at rt for 30 min and then heated at 45 ° C for an additional 90 min. The product was concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The organic layer was separated and washed with water, dried with MgSO 4, filtered and concentrated to provide the acid XVII.
STAGE C To the XVII acid (1 equiv.) In DMF was added benzoyl pierazine (1.2 equiv.) Followed by DEPBT (1.2 equiv.) And i-Pr2NEt (2 equiv.). The reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc, washed with water and brine, dried with MgSO 4, filtered and concentrated. The crude product was then purified by flash chromatography (EtOAc / MeOH, 95: 5) to provide the desired product XVIII.
Table 5 (M + H) + refers to the molecular ion peak in the positive ionization form. ND means not determined.
Procedure for the synthesis of the compounds in Table 6 A. Preparation of substituted piperazines Preparation of 2-alkylpiperazines g of 2-alkyl pyrazine (46.3 mmol, from Pirazine Specialties, Inc.) was dissolved in 200 ml of 95% ethanol with 500 mg of 10% palladium in active carbon. The reaction mixture was hydrogenated under pressure (40-50 psi) for 2 days. The solid was filtered and stirred. The filtrate was concentrated to provide 2-alkyl piperazine, which did not require further purification. 2-ethylpiperazine XIX: 1 H NMR (500 MHz, CD30D) d 2. 89 (t, J = 15.05 Hz, 1H), 2.85 (d, J = 15.11 Hz, 2H), 2.75 (t, J = 11.80 Hz, 1H), 2.65 (t, J = 11.90 Hz, 1H), 2.48 ( m, 1H), 2.28 (t, J = 6.12 Hz, 1H), 1.35 (m, 2H), 0.93 (t, J = 7.55 Hz, 3H).
XIX 2-propylpiperazine XX: XH NMR (300 MHz, CD3C13) d 3.00-2.60 (m, 6H), 2.65 (t, J = 10.20 Hz, 1H), 1.70 (m, 2H), 1.30 (m, 2H), 0.92 (t, J = 6.9 Hz, 3H).
XX 2-iso-propylpiperazine XXI: 1 NMR (300 MHz, CD3C13) d 3.03-2.30 (m, 7H), 1.50 (m, 1H), 0.91 (dd, J = 6.60 &6.60 Hz, 3H).
Y ^ H XXI 2-iso-butylpiperazine XXII: 1 H NMR (500 MHz, CD3OD) d 3.00-2.62 (m, 6H), 2.28 (t, J = 10.55 Hz, 1H), 1.68 (m, 1H), 1.38 (m, 2H), 0.92 (dd, J = 6.65 &6.55 Hz, 3H).
XXII 2-tert-butylpiperazine XXIII: ** H NMR (500 MHz, CD3OD) d 2.96 (d, J = 11.85 Hz, 2H), 2.80 (d, J = 12.05 Hz, 1H), 2.74 (t, J = 11.75 Hz , 1H), 2.63 (t, J = 11.95 Hz, 1H), 2.41 (t, J = 11.85 Hz, 1H), 2.31 (d, J = 13.91 Hz, 1H), 0.92 (s, 9H). xx i 2-Pentylpiperazine XXIV: 1 H NMR (500 MHz, CD 3 OD) d 2.89 (m, 2 H), 2.83 (d, J = 11.95 Hz, 1 H), 2.75 (t, J = 11.80 Hz, 1H), 2.65 (t, J = 11.85 Hz, 1H), 2.56 (m, 1H), 2.28 (t, J = 12.3 Hz, 1H), 1.35 (m, 8H), 0.90 (t, J = 7.15 Hz, 3H). xxrv Preparation of 2-methoxycarbonyltet rahydropyrazine XXV: XXV 5g of methyl ester of pyrazole carboxylic acid (36.2 mmol, from Lancaster, Inc.) was dissolved in 200 ml of 95% ethanol with 500 mg of 10% palladium on active carbon. The reaction mixture was hydrogenated under pressure (40-50 psi) for 2 days. The solid was filtered and removed. The filtrate is concentrated to provide methoxycarbonyltetrahydropyrazine XXV which was sufficiently pure for the subsequent reactions. 2-Methoxycarbonyltetrahydropyrazine XXV: 1H NMR (300 MHz, CD3OD) d7.10 (s, 1H), 4.84 (b, 2H), 3.66 (s, 3H), 3.29 (t, J = 6.0 Hz, 2H), 3.08 (t, J = 6.0 Hz, 2H); 13 C NMR (75 MHz, CD3OD) dl66.1, 130.8, 105.4, 48.4, 40.6, 40.0; MS m / z: (M + H) + calculated for C6HnN202: 143.08, found 143.09. HPLC retention time 0.11 (Method C). xxv Preparation of 2-ethoxycarbonylpiperazine XXVI XXVI g of N, N'-dibenzylpiperazine carboxylic acid ethyl ester (14.8 mmol, from Maybridge Chemical Company Ltd.) was dissolved in 200 ml of 95% ethanol with 500 mg of 10% palladium on active carbon. The reaction mixture was hydrogenated under pressure (40-50 psi) for 2 days. The solid was filtered and removed. The filtrate was concentrated to provide 2-ethoxycarbonylpiperazine XXVI, which was sufficiently pure for the subsequent reactions. 2-Ethoxycarbonylpiperazine XXVI: 1 H NMR (300 MHz, CD 3 OD) d 4.20 (q, J = 7.20 Hz, 2H), 3.46-2.60 (m, 7H), 1.27 (t, J = 6.9 Hz, 3H).
XXVI Preparation of 2-trifluoromethylpiperazine XXVII Stage 1 To a solution of N, N '-dibencilet ilendiamine (1.51 ml, 6.41 mmol), 3, 3, 3-t-rifluoro-2-oxopropanat or methyl (1.0 g, 6.41 mmol) and triethylamine (1.78 ml, 12.8 mmol) in dichloromethane (100 ml) were added to a titanium chloride syringe (1M in CH2C12, 3. 21 ml, 3.21 mmol). The reaction was stirred for 8 hours and the solvents removed in vacuo. The residue was taken to the next step without further purification.
Stage 2 The crude product (200 mg, < 0.55 mmol) from the previous step was dissolved in TFA (5 mL). Then an excess of triethylsilane (0.88 ml, 5.5 mmol) was added. After 30 minutes, the TFA was removed in vacuo and the residue was taken to the next step without further purification.
Stage 3: The crude product (< 0.55 mmol) from step 2 was suspended in ether. LiAlH4 (1M in THF, 0.55 ml, 0.55 mmol) was then added at room temperature. After stirring for 8 hours, the reaction was quenched with saturated NaHCO 3 solution. The aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated to give a residue, which was taken to the next step without purification.
Stage : The crude product from step 3 was dissolved in HOAc (20 ml) with 10 mg of 10% palladium on active carbon. The reaction mixture was hydrogenated under pressure (40-50 psi) for 8 hours. The solid was filtered and removed. The filtrate was concentrated to give 2-tri f luoromet ilpiperazine XXVII as a HOAc salt, which was sufficiently pure for further reactions. 2-Trifluoromethylpiperazine XXVII as its HOAc salt (2 equivalents): XH NMR (300 MHz, CD3OD) d 3.80-2.80 (m, 7H), 1.95 (s, 6H); 13 C NMR (75 MHz, CD3OD) dl74.5, 53.8, 53.3, 42.7, 41.3, 40.8, 19.8; HRMS m / z: (M + H) + calculated for C5H? 0F3N2: 155.0796, found 155.0801.
B. Mono-benzoylation of Piperazine Derivatives: Unless otherwise stated, the substituted piperazine was mono-benzoylated using the following procedures: Preparation of benzoylpiperazines XXVIII and XXIX: To a stirred solution of the substituted piperazine (1.0 g, 11.6 mmol) in dry THF (50 ml) under argon was added n-BuLi 2.5M in THF (10.23 ml, 25.5 mmol) at room temperature. After stirring for 1 hour at room temperature, benzoyl chloride (1.27 ml, 11.0 mmol) was added to the dianion solution and the reaction mixture was stirred for an additional 10 minutes. The reaction mixture was quenched with MeOH, and the solvents were evaporated. The residue was partitioned between EtOAc (50 mL) and sat. NaHCO 3. The aqueous layer was saturated with NaCl and extracted with EtOAc (2 X 30 ml). The organic layer was dried with MgSO 4 and concentrated to provide the crude product benzoylpiperazine, which was generally of sufficient purity to be used directly without further purification. Chromatography on a column of silica gel (EtOAc / MeOH / Et 3 N, 7: 3: 1) gave the purified product.
Preparation of benzoylpiperazine XXXIII and XLIII XXXIII XLIII To a solution of 2-isopropylpiperazine (1.0 g, 7.81 mmol) in dry THF (50 mL), maintained at room temperature under an argon atmosphere, a solution of n-BuLi 2.5 M in THF (6.88) was added. mL, 17.2 mmol). After stirring for 30 minutes at room temperature, benzoyl chloride (0.86 ml, 7.42 mmol) was added and the reaction mixture was stirred for an additional 10 minutes. The reaction mixture was then quenched with MeOH, the solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica gel. Elution with a mixture of EtOAc and MeOH (1: 1) gave the product XXXIII (0.62 g, yield 36%) and XLIII (0.3 g, yield 17%). The benzoyl piperazines XXXIII, XXXIV, XXXV, XXXVI, XXXVII were prepared using the same procedure as the one depicted above.
Preparation of benzoylpiperazines XXXI, XXXII, XXXVIII ,: Commercially available benzoic acid (4.8 g, 40 mmol), pentafluorophenol (7.4 g, 40 mmol) and EDAC (7.6 g, 40 mmol) were combined in 60 mL of dry DMF. The mixture was stirred at room temperature for 2 hours. To this solution, 2-methyl-piperazine (4.0 g, 40 mmol) in 30 ml of DMF was slowly added and the reaction mixture was stirred at room temperature for 12 hours.
Evaporation of DMF gave a residue which was diluted with 400 mL of EtOAc and washed with water (2 X 100 mL). The organic phase was dried with anhydrous MgSO 4 and concentrated in vacuo to provide a crude product, which was purified by column chromatography with EtOAc / MeOH (100: 1) and then EtOAc / MeOH (10: 1) to give 4.8 g of product XX in 60% yield.
Preparation of benzoylpiperazine XXX: To a stirred solution of 2-methypiperazine (10.0 g, 0.1 mol) in dry CH2C12 (500 ml) under argon was added a solution of 1.0 M Me2AlCl or Et2AlCl in hexanes (100 ml, 0.1 mmol) and methyl benzoate (12.4 ml, 0.1 mmol) at room temperature. The reaction mixture was then stirred for 2 days before 2N NaOH (200 ml) was added. The aqueous layer was extracted with EtOAc (3 X 100 mL). The combined organic layer was dried with MgSO4 and the concentration of the solution gave 20.0 g of the crude product (98%), which was sufficiently pure for further reactions.
Preparation of N-benzoyl-cis-2,6-dimetylpiperazine XLVII: XLVII To a stirred solution of 2,6-di-methypiperazine (0.82 g, 7.2 mmol) in dry THF (50 mL), maintained at room temperature under an argon aphere, added a solution of n-BuLi 2.5 M in THF (6.3 mL, 15.8 mmol). After stirring for 30 minutes at room temperature, trimethylsilyl chloride (1.0 mL, 7.9 mmol) was added and the reaction mixture was stirred for one hour before the addition of benzoyl chloride (0.80 mL, 6.9 mmol). After 10 minutes, the reaction mixture was quenched with MeOH and the solvents evaporated in vacuo. The residue was purified by flash column chromatography with silica gel eluting with a mixture of EtOAc and MeOH (1: 1) to give product XLVII (1.48 g, 99% yield). The benzoyl piperazines XL, XLI, XLII, XLIII, XLIV, XLV and XLVI were synthesized using the same procedure as depicted above.
Preparation of benzoylpiperazine XXXIX: XXXIX To a stirred solution of 2-ethoxycarbonylpiperazine (4.6 g, 29.1 mmol) in dry methylene chloride (200 L), benzoyl chloride (3.55 ml, 29.1 mmol) and triethylamine (2 ml) were added sequentially. After stirring for 8 hours at room temperature, a saturated NaHCO 3 solution was added and the aqueous phase was extracted with ethyl acetate (3 X 200 ml). The organic layers were combined, dried with MgSO4 and concentrated to give a crude mixture, which included the desired product XXXIX. The crude was then used for the additional reaction without purification.
Preparation of benzoylpiperazine XLVIII To a stirred solution of 2-methoxycarbonyltet rahidropi racin (1.0 g, 7.0 mmol) in dry methylene chloride (50 ml), benzoyl chloride (0.76 ml, 6.7 mmol) was added and triethylamine (5 ml) sequentially. After stirring for 8 hours at room temperature, a saturated NaHCO 3 solution was added and the aqueous phase was extracted with ethyl acetate (3 X 20 ml). The organic layers were combined, dried with MgSO4 and concentrated to give a crude mixture, which included the desired product XLVII. The crude was then used for the additional reaction without purification.
Preparation of 3-hydroxylmethylbenzoylpiperazine XLIX: To a stirred solution of 3-ethoxycarbonyl-benzoylpiperazine XLIX (200 mg, 0.76 mmol) in THF (5 ml), lithium chloride (36 mg, 0.84 mmol), NaBH 4 (32 mg, 0.84 mmol) and EtOH (5 mg) were added. ml) sequentially. After stirring for 8 hours at room temperature, a saturated NaHCO 3 solution it was added and the aqueous phase was extracted with ethyl acetate (3 X 20ml). The organic layers were combined, dried over MgSO4 and concentrated to give a crude mixture, which was used for the further reaction without purification.
Characterization of Mono-Benzollated Piperazine Derivatives N-Benzoylpiperazine XXVIII: XH NMR (300 MHz, CD3OD) d7.37 (m, 5H), 3.73 (br s, 2H), 3.42 (br s, 2H), 2.85 (br s, 4H); 13 C NMR (75 MHz, CD 3 OD) dl 70.9, 135.0, 129.6, 128.2, 126.5, 44.5; HRMS m / z: (M + H) + calculated for C 11 H 15 N 2 O 191.1184, found 191.1181.
XX VIII N- (Benzoyl) -trans-2, 5-dimethylpiperazine XXIX. XH NMR (300 MHz, CD3OD) d7.50-7.28 (m, 5H), 4.38 (br s, 1H), 3.70 (br s, 1H), 3.40-3.20 (m, 3H), 2.57 (dd, 1H, J = 12.96, 1.98 Hz), 1.35 (d, 3H, J = 6.87 Hz), 1.22 (d, 3H, J = 6.78 Hz); 13C NMR (75 MHz, CD30D) dl71.9, 135. 9, 129.3, 128.3, 126.0, 47.6, 46.7, 43.8, 42.3, 14.7, 14.3; HRMS m / z: (M + H) + calculated for d3H19N20 219.1497, found 219.1499.
XXIX N- (Benzoyl) -3-methylpiperazine XXX. XH NMR (300 MHz, CD3OD) d7.45 (m, 5H), 4.50 (d, 1H, J = 10.8 Hz), 3.60 (b, 1H), 3.33-2.60 (m, 5H), 1.16-0.98 (m, 3H); 13 C NMR (75 MHz, CD3OD) 6170.9, 135.3, 129.6, 128.3, 126.5, 54.0, 50.6, 50.1, 45.0, 44.1, 41.7, 17.50; HRMS m / z: (M + H) + calc'd for C? 2H? 7N20 205.1341, found 205.1336.
XXX N- (Benzoyl) -3-ethylpiperazine XXXI. X H NMR (300 MHz, CD 3 OD) 67.47 (m, 5 H), 4.55 (b, 1 H), 3.64 (b, 1 H), 3. 36-2.59 (m, 5H), 1.51-0.82 (m, 5H); 13C NMR (75 MHz, CD3OD) 6171.5, 135.8, 130.1, 128.8, 126.9, 57.2, 56. 7, 52.9, 47.1, 45.5, 42.5, 26.4, 26.0, 9.3; HRMS m / z: (M + H) + calculated for C? 3H19N20 219.1497, found 219.1495.
XXXI N- (Benzoyl) -3-propylpiperazine XXXII. XH NMR (300 MHz, CD3OD) 67.45 (m, 5H), 4.53 (t, 1H, J = 13.44 Hz), 3.64 (b, 1H), 3.17-2.64 (m, 5H), 1.46-0.86 (m, 7H); 13 C NMR (75 MHz, CD3OD) 6171.4, 135.9, 130.1, 128.8, 126.9, 55.4, 54.9, 53.2, 45.6, 45.0, 42.6, . 8, 35.3, 18.8, 13.4; HRMS m / z: (M + H) + calculated for C? H2? N20 233.1654, found 233.1652 XXXII N- (Benzoyl) -3-iso-propylpiperazine XXXIII. 1H NMR (300 MHz, CD3OD) d7.45 (m, 5H), 4.30 (m, 1H), 3.64 (m, 1H), 3.10-2.40 (m, 5H), 1.70-0.75 (m, 7H! 13, NMR (75 MHz, CD3OD) 6171.5, 135.9, 130.5, 129.3, 126.9, 61.7, 61.1, 51.2, 45.9, 45.4, 42.5, 31.2, 30.7, 18.3; HRMS m / z: (M + H) + calculated for C? 4H2? N20 233.1654, found 233.1654.
XXX11I N- (Benzoyl) -3-pentylpiperazine XXXIV. ? H NMR (300 MHz, CD30D) 67.47 (m, 5H), 4.50 (t, 1H, J = 17.85 Hz), 3.62 (b, 1H), 3.17-2.64 (m, 5H), 1.46-0.87 (m, 11H); 13 C NMR (75 MHz, CD3OD) 6171.4, 135.9, 130.1, 129.3, 126.8, 55.6, 55.2, 53.1, 45.6, 45.0, 42.5, 33.6, 33.0, 32.0, 28.9, 25.9, 25.3, 22.6, 13.4; HRMS m / z: (M + H) + calculated for C? 6H25N20 261.1967, found 261.1969. xxxiv N- (Benzoyl) -3-iso-butylpiperazine XXXV. MS m / z: (M + H) + calculated for C? 5H23N20: 247.22. HPLC retention time: 1.04 minutes (Method C).
XXXV N- (Benzoyl) -3-tert-butylpiperazine XXXVI. 1ti NMR (300 MHz, CD3OD) 67.45 (m, 5H), 4.70 (m, 1H), 3.66 (m, 1H), 3.17-2.43 (m, 5H), 1.17-0.84 (m, 9H); 13 C NMR (75 MHz, CD 3 OD) 6171.6, 135.9, 131.0, 129.4, 126.9, 65.3, 64.6, 49.6, 46.5, 45.9, 43.7, 42.3, 32.7, 25.7; HRMS m / z: (M + H) + calculated for d5H23N20 247. 1810, found 247.1815.
XXXVI N- (Benzoyl) -cis-3, 5-di-methylpiperazine XXXVII. XH NMR (300 MHz, CD3OD) d7.43 (m, 5H), 4.55 (d, 1H, J = 12.0 Hz), 3.55 (d, 1H, J = 9.60 Hz), 2.74-2.38 (m, 5H), 1.13-0.94 (m, 6H); 13C NMR (75 MHz, CD3OD) 6170.5, 135. 5, 129.6, 128.3, 126.6, 53.4, 50.9, 50.2, 17.7, 17. 3; HRMS m / z: (M + H) + calculated for C? 3H19N20 219.1497, found 219.1492.
XXXVII N- (Benzoyl) -3-trif luoromethylpiperazine XXXVIII. MS m / z: (M + H) + calculated for C? H? 4F3N20: 259.11, found 259.05. HPLC retention time: 0.65 minutes (Method A).
XXXVIII N- (Benzoyl) -3-ethoxycarbonylpiperazine XXXIX. MS m / z: (M + H) + calculated for C? 4H? 9N203: 263.14, found 263.14. HPLC retention time: 0.80 minutes (Method C).
XXXIX N- (Benzoyl) -2-methylpiperazine XL. "? NMR (300 MHz, CD30D) 67.47 (m, 5H), 3.30-2.70 (m, 7H), 1.36 (d, 3H, J = 6.90 Hz); 13C NMR (75 MHz, CD3OD) 6171.0, 135.4, 129.7 , 128.5, 126.3, 48.5, 44.3, 14.5; HRMS m / z: (M + H) + calculated for C? 2H? 7N20 205.1341, found 205. 1341 ) XL N- (Benzoyl) -2-ethylpiperazine XLI. X H NMR (300 MHz, CD3OD) 67.49 (m, 5H), 3.34-2.80 (m, 7H), 2.10-1.70 (m, 2H), 0.85 (b, 3H); 13 C NMR (75 MHz, CD 3 OD) 6171.5, 135.1, 129.8, 128.5, 126.5, 48.5, 46.0, 43.9, 21.8, 9.6; HRMS m / z: (M + H) + calculated for C? 3H? 9N20 219.1497, found 219.1501. x N- (Benzoyl) -2-propylpiperazine XLII. 1 H NMR (300 MHz, CD3OD) 67.50 (m, 5H), 3.60-2.80 (m, 7H), 2.10-0.70 (m, 7H); iJC NMR (75 MHz, CD3OD) 6172.5, 135.0, 129.9, 128.6, 126.7, 48.7, 46.2, 43.8, 30.9, 18.9, 13. 1; HRMS m / z: (M + H) + calculated for C 14 H 2? N 20 233.1654, found 233.1650.
N- (Benzoyl) -2-iso-propylpiperazine XLIII. 1 H NMR (300 MHz, CD 3 OD) 67.50 (b, 5 H), 4.40 (m, 1 H), 3.60-2.50 (m, 6H), 1.10-0.70 (m, 7H); 13C NMR (75 MHz, CD3OD) 6171. 1, 135.0, 130.0, 128.7, 127.0, 60.6, 54.1, 43. 9, 42.3, 25.4, 19.3, 18.4; HRMS m / z: (M + H) + calculated for C? 4H2iN20 233.1654, found 233. 1653 XLUI N- (Benzoyl) -2-pentylpiperazine XLIV. 1 H NMR (300 MHz, CD 3 OD) 67.47 (b, 5H), 3.40-2.80 (m, 7H), 2.10-0.70 (m, 11H); 13 C NMR (75 MHz, CD3OD) 6171.2, 135.0, 129.9, 128.6, 126.7, 48.7, 46.2, 43.8, 31.0, 28.8, 25.3, 22.2, 13.4; HRMS m / z: (M + H) + calculated for C 16 H 25 N 2 O 261.1967, found 261.1970.
N- (Benzoyl) -2-iso-butylpiperazine XLV. MS m / z: (M + H) + calculated for C15H23N2O: 247.18, found 247.23. HPLC retention time: 1.06 minutes (Method C).
N- (Benzoyl) -2-tert-butylpiperazine XLVI. *? NMR (300 MHz, CD30D) 67.45 (m, 5H), 4.53 (t, 1H, J = 5.70 Hz), 3.60-2.60 (m, 6H), 1.14 (s, 9H); 13 C NMR (75 MHz, CD30D) 6173.5, 136.7, 129.9, 128.9, 126.6, 55.9, 44.8, 44.5, 42.7, 36.5, 27.8; HRMS m / z: (M + H) + calculated for C? 5H23N20 247.1810, found 247. 1808 XLVI N- (Benzoyl) -cis-2,6-di-methylpiperazine XLVII. *? NMR (300 MHz, CD3OD) 67.45 (m, 5H), 4.18 (b, 2H), 2.85 (m, 4H), 1.33 (d, 6H, J = 6.90 Hz); 13 C NMR (75 MHz, CD3OD) 6172.0, 136.7, 128.9, 128.3, 125.8, 49.1, 47. 1, 19.2; HRMS m / z: (M + H) + calculated for C? 3H? 9N20 219. 1497, found 219.1491.
XX XLV1I N- (Benzoyl) -3-methoxycarbonyltetrahydropyrazine XLVIII. MS m / z: (M + H) + calculated for C? 3H? 5N203: 247.11, found 247.13. HPLC retention time: 1.00 minutes (Method C).
XLVlll 3-Hydroxymethyl-benzoylpiperazine XLIX. MS m / z: (M + H) + calculated for Ci2H17N202: 221.13, found 221.17. HPLC retention time: 0.32 minutes (Method C).
XLIX C. Coupling of mono-benzoyl piperazines with glyoxyl chlorides To a solution of indole glyoxoyl chloride V (1 eq) in dry CH 2 C 12, substituted benzoylpiperazine (1 eq) was added at room temperature. The mixture was then cooled to 0 ° C, followed by the dropwise addition of diisopropylamine (1.3 eq). After 5 min., The reaction mixture was warmed to room temperature and stirred for 3 h. The resulting crude XL products were purified by preparative HPLC and characterized as shown in Table 6.
Preparation of N- (Benzoyl) -3-hydroxymethyl-N '- [(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine Example 98: To a stirred solution of 3-hydroxymethylbenzoylpiperazine XLIX (8.0 mg, 0.036 mmol) in acetonitrile (5 ml) was added BSTFA (8.1 mg, 0.036 mmol). After stirring for 30 minutes at room temperature, (7-methoxycarbonyl-indol-3-yl) -oxoacetyl chloride (8.1 mg, 0.036 mmol) and pyridine (0.5 ml) were added. The reaction was stirred for another 2 hours at room temperature. Concentration in vacuo provided a residue, which was then purified by Shimazu HPLC purification system to give 2 mg of N- (benzoyl) -3-hydroxymethyl-N '- [(7-methoxycarbonyl-indol-3-yl) -oxoacetyl ] -piperazine (Example 98).
Hydrolysis of the Ester Group to the Acid Group Preparation of N- (Benzoyl) -3-hydroxycarbonyl-N '- [(4-fluoro-indol-3-yl) -oxoacetyl] -piperazine (Example 101): To a stirred solution of N- (benzoyl) -3-ethoxycarbonyl-N '- [(4-fluoro-indol-3-yl) -oxoacetyl] -piperazine (10 mg, 0.02 mmol) in methanol (1 ml) and water (1 ml), potassium carbonate (9 mg, 0.06 mmol) was added. After stirring for 8 hours at room temperature, the product was concentrated in vacuo to give a residue which was purified by preparative HPLC to yield 2 mg of N- (benzoyl) -3-hydroxycarbonyl-N '- [(4 - fluoro-indol-3-yl) -oxoacetyl] -piperazine (Example 101).
Preparation of N- (ben zoi 1) -3- (R) -met i 1 -N '- [(7 • hydroxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (Example 137).
To a stirred solution of N- (benzoyl) -3- (R) -methyl-N '- [(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (20 mg, 0.05 mmol) in sodium methoxide 0.5N in methanol (5 ml), 0.5 ml of water was added. After stirring for 8 hours at room temperature, 10% HCl was added to the reaction mixture at pH = 6. N- (benzoyl) -3- (R) -met il-N '- [(7-hydroxycarbonyl- indol-3-yl) -oxoacetyl] -piperazine (Example 137) precipitated from the solution, which was collected by filtration.
Table 6 109 7-Nitro 1.48 421 110 7-Ethyl N N 1.58 404 111 7-Ome N N 1.39 406 112 7-Nitro N N 1.49 421 / \ 113 6-Chlorine N N 1.55 411 114 5, 6-dichloro N N 1.71 446 115 4-Chlorine N N 1.45 410 116 -. 116 -Cloro N N 1.45 410 117 5, 6-dichloro N N 1.72 446 118 5-Fluoro N N 1.43 394 A Observe in Table 6, and other tables here, in the HPLC column, the superscript numbers "A", "B" or "C" refer to the HPLC method used (ie Methods A, B or C, respectively) .
Preparation of Examples 148-194 in Table 7 STAGE A.
To the substituted indol-3-glyoxioxy chloride V (1 eq.) In CH 2 Cl 12 at room temperature was added tert-butyl 1-piperazinecarboxylate (1 eq.) And diisopropylethylamine (1.5 eq.). The solution was stirred for 2 h at room temperature, time after which the CL / MS analysis indicated that the reaction was complete. The solvent was removed and the resulting residue was diluted with ethyl acetate (250 ml) and diethyl ether (250 ml). The organic solution was then washed with water (100 ml x 3) and brine (50 ml. ml), was added with MgSO 4, filtered and concentrated. The light yellow solid was then added with 30 ml of 20% trifluoroacetic acid in CH2C12. The solution was concentrated and dried in vacuo to give the desired product VII. The CL / MS analyzes indicated that this product was 100% pure and was used for the next reaction without further purification.
STAGE B.
To the piperazine indole-3-glyoxylamide (1 eq.) Was added the linked 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (P-EDC) by resin (7 eq.) And carboxylic acid (RCOOH) (2). eq.) in dichloroethane (DCE) or DMF (dimethylformamide) in cases where the carboxylic acids are not soluble in DCE. The reaction was stirred for 12 h at room temperature. The XLI product was filtered and concentrated. Products with purity less than 70% were diluted in methanol and purified using the system Preparative HPLC Shimadzu.
Preparation of Example 195 in Table 7 STAGE A XL1I To a solution of tert-butyl-1-piperazine carboxylate (601 mg, 3.23 mmol) and imidazole of the acid 4-acetic acid (330 mg, 2.94 mmol) in dichloromethane (30 ml), DMAP (394 mg, 3.22 mmol) and EDC were added. (616 mg, 3.22 mmol). The reaction mixture was stirred at room temperature for 21.5 hours. Removal of the solvent gave a white solid, which was subjected to flash chromatography using an elution gradient (100% EtOAc, 2% to 5% MeOH / EtOAc, 1/5/95 NH 3 (sat. ) / MeOH / EtOAc) to give XLII as a white solid.
STAGE B XLIII XLII To the compound XXLII (130 mg, 0.464 mmol) was added a solution of HCl in dioxane (4M, 5 ml) and the mixture was stirred at room temperature for 3 hours. Removal of excess in va reagent gave the XLIII hydrochloride salt as a white solid (100% conversion).
STAGE C 4-Fluoroindole glyoxyl chloride was coupled with XLIII as previously described.
Table 7 Synthesis of Examples 195-215 in Table 8 STAGE A To pentafluorophenol (1.84 g, 10 mmol) in DMF (15 mL) was added picolinic acid (1.23 g, 10 mmol) and EDC (1.91 g, 10 mmol) at room temperature for 4 h. The crude product XLIV was diluted with CH2C12 and washed with water, 0.1M HCl and brine. The organic phase was dried with MgSO 4, filtered and concentrated. The crude material was used without further purification.
STAGE B XUV XLV To a solution of (R) -methyl pierazine (1.0 g, 10 mmol) in DMF (20 ml) at room temperature was slowly added a solution of pentafluorophenylester of picolinic acid XLIV in DMF (20 ml). The reaction mixture was stirred at room temperature for 16 h. The product was diluted with CH2C12 and washed with water and brine, dried with MgSO4, filtered and concentrated. The XLV product was then purified by flash chromatography (100% EtOAc-50% MeOH / EtOAc).
Piperazine XLVI was prepared using the methodology similar to that represented in STAGE A and STAGE B above.
XLVI E TA PA C XLVII To the mixture of indole glyoxochloride V (1 eq.) And 3- (R) -methyl-1-piperazinecarboxylate XLV or XLVI (1 eq.) In THF was added diisopropylethylamine (1.5 eq.) Dropwise at 0 ° C. . The solution was stirred for an additional 2 h at room temperature and the resulting crude compounds were purified by preparative HPLC.
Table 8 (M-H) measured in the negative ionization form Additional Analytical Results 2 ± to the Selected Compounds 1- (4-methylbenzoyl) -4- [(1H-indol-3, 11) oxoacetyl] piperazine (Example 15) MS (ESI): 376 (M + H) +; IR (KBr): 3150, 3104, 2922, 2868, 1780, 1629, 1519, 1433, 1272, 1158, 1006, 829, 775, 753, 645 cm "1; XH NMR (CDC13) d 2.40 (s, 3H), 3.60-3.79 (m, 8H), 7.23-7.45 (m, 7H), 7.99 (d, J = 3.1 Hz, 1H), 8.34 (m, 1H), 9.10 (s, 1H). 1- (benzoyl) -4- [(1H-4-fluoroindol-3-1) oxoacetyl] piperazine (Example 19) MS (ESI): 380 (M + H) + HRMS calculated for C2? H? 8FN303 [(M + H)] +, 380.14105; found, 380.1412. lH NMR (DMF-d7) 6 12.71 (s, 1H), 8.02 (s, 1H), 7.46-7.56 (m, 6H), 7.31 (ddd, J = 4.71, 7.99 Hz, 1H), 7.03 (dd, J = 7.84, 10.98 Hz, 1H), 3.77 (br. S, 4H), 3.57 (br, s, 4H). 1- (benzoyl) -4- [(1H-4-chloroindol-3-yl) oxoacetyl] piperazine (Example 20) S (ESI): 396 (M + H) + HRMS calculated for C21H18C1N303 [(M + H)] +, 396.11150; found, 396.1105.
XH NMR (DMF-d7) 6 12.74 (br.s, 1H), 8.03 (s, 1H), 7.57-7.65 (m, 1H), 7.50 (s, 5H), 7.28-7.38 (m, 1H), 3. 42-3.83 (m, 8H). 1- (benzoyl) -4- [(1H-6-fluoroindol-3-yl) oxoacetyl] piperazine (Example 28) MS (ESI): 380 (M + H) HRMS calculated for C2? H? 8FN303 [(M + H)] +, 380.14105; found, 380.1414.
? H NMR (DMF-d7) 6 12.09 (s, 1H), 7.81 (dd, J = 5.64, 8.46 Hz, 1H), 7.62 (s, 1H), 7.08 (s, 5H), 7.01 (dd, J = 2.28, 9.61 Hz, 1H), 2.86-3.52 (m, 8H).
Anal. Calculated for C2? H? 8FN303: C, 66.48; H, 4.78, N, 11.08. Found: C, 66.09, H, 4.78, N, 10.94. 1- (benzoyl) -4- [(1H-4,6-difluoroindol-3-11) oxoacetyl] piperazine (Example 42) X H NMR (DMSO-d 6) 6 3.40 (br s, 4 H), 3.65 (br s, 4 H), 7.06 (t, 1 H), 7.20 (d, J = 8.49 Hz, 1 H), 8.27 (s, 1 H), 12.65 (br s, 1H).
Analysis Calculated for C2? H17F2N3 O3 * 0.322 H20 C, 62.57; H, 4.41; N, 10.42 Found C, 62.56; H, 4.46; N, 10.11 1 - . 1 - (benzoyl) -4- [(lH-5-f luoro-7-bromoindol-3, 11) oxoacetylpiperazine (Example 48) * H NMR (DMSO-d6) d 3.40 (br s, 4H), 3.67 (br s, 4H), 7.43 (br s, 5H), 7.54 (dd, J = 2.25, 8.97 Hz, 1H), 7. 83 (d, J = 8.4 Hz, 1H), 8.29 (s, 1H), 12.79 (br s, 1H).
Analysis Calculated for C2? H? 7N3 BrF 03 »1.2 H20: C, 52.56; H, 4.07; N, 8.76. Found: C, 52.33; H, 3. 69; N, 8.50. 1 (benzoyl) -4- [(1H-4-fluoro-7-trifluoroethoxyindol-3-yl) oxoacetyl] piperazine (Example 51) 1R NMR (DMSO-de) 6 3.61 (br m, 4H), 3.80 (br m, 4H), 4. 52 (m, 2H), 6.68 (m, 1H), 6.91 (m, 1H), 7.45 (s, 5H), 8.07 (d, J = 2.91 Hz, 1H), 9.37 (s, 1H).
Analysis Calculated for C23H? 9F4N3 04 «0.59 H20, 0.47 ethyl acetate C, 56.44; H, 4.56; N, 7.94 Found: C, 56.44; H, 4.16; N, 8.19 1 (Benzoyl) -4- [(1H-4-bromo-7-fluoroindol-3-oxo-oxacetyl] piperazine (Example 55) : H NMR (CDC13) d 3.6-3.9 (br, 8H), 6.92 (t, 1H), 7.42 (br s, 6H), 8.09 (s, 1H), 9.5 (br s, 1H).
Analysis Calculated for C2? H? 7BrFN303 «0.25 H20, 0.21 ethyl acetate: C, 54.5; H, 4.02; N, 16.6 Found C, 54.50; H, 4.09; N, 8.44 Example 90 XH NMR (DMSO-dg) d 3.66 (br s, 4H), 7.27 (t, J = 8.31 Hz, 1H), 7.43 (br. S, 7H), 8.01 (m, 1H), 8.14 (s, 1H) , 10.14 (s, 1H), 12.42 (br. S, 1H) MS: (M + H) + 480.00, (MH) 406.02 IR: 1636, 1592 cm "1 N- (benzoyl) - (R) -3-methyl-N '- [(4-f luoro-indol-3-yl) -oxoacetyl] -piperazine (Example 93) 2 H NMR (300 MHz, CD 3 OD) 68.20 (s, 0.5H), 8.15 (s, 0.5H), 7.48-6.90 (m, 8H), 5.00-3.00 (m, 7H), 1.30 (b, 3H). MS m / z (M + H) + calculated for C22H2iFN303: 394. 16; found 394.23. HPLC retention time: 0.92 minutes (Method B).
N- (benzoyl) - (S) -3-methyl-N '- [(4-fluoro-indol-3-yl) -oxoacetyl] -piperazine (Example 94) XH NMR (300 MHz, CD3OD) 68.20 (s, 0.5H), 8.13 (s, 0.5H), 7.48-6.90 (m, 8H), 5.00-3.00 (m, 7H), 1.30 (b, 3H). MS m / z: (M + H) + calculated for C 22 H 21 FN 303: 394.16; found 394.25. HPLC retention time: 1.32 minutes (Method A).
N- (benzoyl) -2-methyl-N '- [(4-fluoro-indol-3-yl) -oxoacetyl] -piperazine (Example 95) 1 H NMR (300 MHz, CD30D) 68.20 (s, 0.5H), 8.13 (s, 0. 5H), 7.48-6.90 (m, 8H), 5.00-3.00 (m, 7H), 1.37 (d, J = 6.78 Hz, 1.5H), 1.27 (d, J = 6.84 Hz, 1.5H). MS m / z: (M + H) + calculated for C22H2? FN303: 394.16; found 394.23. HPLC retention time: 1.32 minutes (Method A).
N- (benzoyl) -3-hydroxymethyl-N '- [(4-fluoro-indol-3-11) -oxoacetyl] -piperazine (Example 99) 1 H NMR (300 MHz, CD 3 OD) 67.50 (b, 5H), 7.39-6.72 (m, 4H), 5.00-2.80 (m, 9H). MS m / z: (M + Na) + calculated for C22H2oFN3Na04: 432.13; found 432.19. HPLC retention time: 1.23 minutes (Method A).
N- (benzoyl) - (R) -3-methyl-N '- [(7-methoxycarbonyl-indol-3-11) -oxoacetyl] -piperazine (Example 102) XH NMR (300 MHz, CD30D) 6 8.50 (d, J = 48 Hz, 1H), 8.15 (s, 0.5H), 8.10 (s, 0.5H), 8.00 (d, J = 7.38 Hz, 1H), 7.42 (m, 6H), 5.00-3.00 (m, 7H), 4.02 (s, 3H), 1.34 (b, 3H); 13 C NMR (75 MHz, CD3OD) 6186.2, 166.9, 137.9, 135.3, 130.3, 128.8, 127.2, 126.9, 126.4, 122.7, 114.5, 114.0, 5 1.6, 50.7, 45.6, 15.4, 14.2. MS m / z: (M + H) + calculated for C 24 H 24 N 305: 434.17; found 434.24. HPLC retention time: 1.41 minutes (Method B).
N- (benzoyl) -3-hydroxymethyl-N '- [(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (Example 98) XH NMR (300 MHz, CD3OD) 68.54 (b, 1H), 8.24 (s, 0. 5H), 8.16 (s, 0.5H), 8.00 (m, 1H), 7.47 (m, 6H), 5.00-3.00 (m, 9H), 4.02 (s, 3H). MS m / z: (M + H) + calculated for C 24 H 2 N 306: 450.17; Found 450.24. HPLC retention time: 1.44 minutes (Method-A).
N- (benzoyl) -2-methoxycarbonyl-N '- [(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -tetrahydropyrazine (Example 121) H NMR (500 MHz, CD3OD) 68.50 (m, 1H), 8.21 (s, 1H), 7.93 (m, 1H), 7.44 (m, 7H), 4.00 (s, 6H), 4.00-3.30 (m, 4H); 13 C NMR (125 MHz, CD 3 OD) 6184.7, 167.9, 166.1, 165.3, 165.1, 164.9, 140.2, 137.2, 132.5, 129. 6, 128.3, 128.2, 127.6, 125.1, 123.9, 116.0, 115.6, 115.0, 52.8, 52.6, 47.0, 43.8. MS m / z: (M + H) + calculated for C 25 H 22 N 307: 476.15; found 476.21. HPLC retention time: 1.62 minutes (Method A).
N- (Benzoyl) -2-propyl-N '- [(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (Example 126) XH NMR (300 MHz, CD30D) 68.50 (d, J = 6.93 Hz, 1H), 8.17 (s, 0.5H), 8.08 (s, 0.5H), 7.98 (d, J = 6.00 Hz, 1H), 7.45 ( m, 6H), 5.00-2.90 (m, 7H), 4.02 (s, 3H), 1.70-0.60 (m, 7H); 13 C NMR (75 MHz, CD3OD) 6186.0, 167.6, 166.9, 138.0, 136.1, 135.8, 130.2, 128.9, 127.2, 126.9, 126.4, 122.7, 114.5, 114.1, 51.7, 46.2, 44.0, 41.3, 31.5, 19.2, 13.2, 12.9. MS m / z: (M + H) + calculated for C 26 H 28 N 305: 462.20; found 462.30. HPLC retention time: 1.69 minutes (Method A).
N- (benzoyl) - (R) -3-methyl-N '- [(7-hydroxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (Example 137) XH NMR (300 MHz, CD30D) 68.46 (b, 1H), 8.14 (s, 0. 5H), 8.09 (s, 0.5H), 8.00 (d, J = 7.17 Hz, 1H) 7. 43, m, 6H) 5.00-2.90 m, 7H) 1.32 (b, 3H) 13, NMR (75 MHz, CD3OD) 6186.3, 168.2, 167.1, 137.8, 135. 3, 130.3, 128.8, 127.1, 126.9, 126.7, 122.7, 115. 4, 113.9, 50.7, 45.6, 15.4, 14.2. MS m / z: (M + H) + calculated for C27H3oN305: 420.16; found 420.16. HPLC retention time: 1.43 minutes (Method A).
N- (benzoyl) -3-trif luoromethyl-N '- [(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine (Example 142) - XH NMR (300 MHz, CD3OD) 68.52 (b, 1H), 8.02 (d, J = 7.56 Hz, 1H), 7.45 (m, 6H), 5.00-3.00 (m, 7H), 4.03 (s, 3H). MS m / z: (M + H) + calculated for C 24 H 2? F 3 N 305: 488.14; found 488.15. HPLC retention time: 1.65 minutes (Method A).
N- (benzoyl) -3-trif luoromethyl-N '- [(4-f luoro-indol-3-yl) -oxoacetyl] -piperazine (Example 143) ** H NMR (300 MHz, CD30D) 68.11 (s, 1H), 7.50-6.90 (m, 9H), 5.00-3.00 (m, 7H). MS m / z: (M + H) + calculated for C 24 H 2? F 3 N 305: 488.14; found 488.12. HPLC retention time: 1.42 minutes (Method A).
N- (benzoyl) - (R) -3-methyl-N '- [(4-f luoro-7-bromoindol-3-yl) -oxoacetyl] -piperazine (Example 144) 1 H NMR (CDC13) d 1.31 (br.s, 3H), 3.34 (br.s, 3H), 6.90 (t, J = 8.7 Hz, 1H), 7.38 (br.s, 6H), 8.05 (br. , 1H), 9.46 (br. S, 1H) S: (M + H) + 473.80, (MH) 470.02 Analysis calculated for C22H19N303BrF. 0.6H20 C, 54.68; H, 4.21; N, 8.7. Found C, 54.46; H, 4.14; N, 8.56. 1- [(Pyrid-2-yl) oxo] -4- [(lH-4-f luoro-indol-3-yl) oxoacetylpiperazine (Example 166) MS (ESI): 381 (M + H) +; 1ti NMR (CDC13) 6 3.56 (m, 2H), 3.66 (m, 2H), 3.82-3.94 (m, 4H), 6.97 (m, 1H), 7.33 (m, 2H), 7.57 (m, 1H), 7.70 (m, 1H), 8.01 (m, 1H), 8.20 (s, 1H), 8.66 (, 1H). 1- [(Pyrid-2-yl) oxo] -4- [(1 H-4,7-difluoro-indol-3-yl) oxoacetyl] piperazine (Example 191) MS (ESI): 413 (M + H) X H NMR (CDCl 3) d 3.54-3.65 (m, 4 H), 3.76-3.93 (m, 4 H), 6.95 (m, 2 H), 7.52 (m, 1 H), 7.66 (m, 1 H), 7.96 (m, 1 H) ), 8.20 (m, 1H), 8.60 (m, 1H).
Example 195 MS (ESI): 370 (M + H) + X H NMR: (CD3OD, 6 = 3.30 ppm) 8.82 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.37-7.26 (m, 2H), 7.02-6.96 (m, 1H), 3.97 (bs, 2H), 3.86 (app dd, J = 6.4, 3.3, 4H), 3.64 (app dd, J = 6.3, 4.0, 2H); LC / MS: (ES +) m / z (M + H) + = 370, Analytical HPLC (Rt = 0.810 min) purity: 100%.
Example 212 MS (ESI): 402 (M + H) + XH NMR: (CD3OD, 6 = 3.30 ppm) 8.65-8.51 (m, 2H), 8. 24-8.19 (m, 1H), 8.02-7.94 (m, 1H), 7.73-7.68 (m, 2H), 7.56-7.39 (m, 2H), 4.63-3.09 (bm, 7H), 1.35 (m, 3H) The processes for making the compounds of the formula I are shown in Schemes 14-22, and are further exemplified in Tables 14-18.
Scheme 14 The initiator characters 1 (Scheme 14) are known or easily prepared according to the procedures of the literature, such as those described in Gribble, G. (Ref. 24) or Bartoli et al (Ref. 36). The indoles 1 are treated with oxalyl chloride in THF (tetrahydrofuran) or ether to provide the desired glyoxyl 2 chlorides according to the procedures of the literature (Lingens, F. et al, Ref. 25). The intermediate glyoxyl 2 chlorides are then coupled with benzoyl piperazine 3 (Desai, M. et al, Ref. 26) under basic conditions to provide 4.
Scheme 15 The treatment of indole glyoxamide 4 (Scheme 15) with an alkylating agent (R40X) under basic conditions (BEMP or NaH) provides 5 N-alkylated derivatives.
Scheme 16 The 6 N-acyl derivatives are prepared by treating indole giloxamide 4 with an acid chloride (R40aCOCl) in the presence of i-Pr2NEt (Scheme 16).
Alternatively, the bis-acylated products are prepared as shown in Scheme 17.
Scheme 17 Treatment of indole-3-glyoxyl chloride 2 (Scheme 17) with tert-butyl 1-piperazinecarboxylate 7 provides the coupled product 8. Removal of the Boc protecting group of 8 is carried out with 20% TFA / CH2C12 to produce 9. This product then it is coupled with acid chloride (R40cCOCl) to give the bis-acyl products.
Scheme 18 eleven Carbamates 11 are synthesized by the reaction of indole glyoxamide 4 with chloroformate (R40dOCOCl) in the presence of i-Pr2NEt or NaH (Scheme 18).
Scheme 19 12 Ureas are prepared by three methods. Direct treatment of indole glyoxamide 4 with carbamoyl chloride (RaRbNCOCl) in the presence of i-Pr2NEt provides the desired ureas 12 (Scheme 19). 13 14 Alternatively, the treatment of 4 (Scheme ) with p-nitrophenyl chloroformate and i-Pr2NEt provides p-nitrophenyl carbamate 13 which, upon exposure to the amine (RaRbNH), provides the desired urea 14.
Scheme 21 fifteen Finally, the reaction of indole glyoxamide 4 with isocyanate (RaNCO) in the presence of i-Pr2NEt provides urea 15 (Scheme 21).
Scheme 22 The indole sulfonamides 15 (Scheme 22) are readily prepared by treating indole glyoxamide 4 with sulfonyl chloride (RaS02Cl) in the presence of i-Pr2NEt.
Table 9 4, 7-Dif luoro ^ -CH3 > 98 4, 7-Dif luoro 93 OH , 7-Dif luoro // -NH2 89 OH 4, 7-Dif luoro 98 4 - . 4 - . 4 - . 4 -Fluoro / 91 4-Fluoro 92 -Cl 4 -Fluoro 95 4 -Fluoro 98 co2e 4-Fluoro X. 96 C02Et 4-Fluoro X 93 // "N Table 10 Table 11 Table 12 Table 13 EXPERIMENTS 3) General Procedure for the preparation of Examples 1-34 Stage A.
IV To a solution of the substituted indole IV (1 eq.) In dry Et20, oxalyl chloride (1.2 eq.) Was added dropwise at 0 ° C. After 5 min., The reaction mixture was warmed to room temperature or heated to ~ 35 ° C overnight if necessary. The substituted indole-3-glyoxyl V chloride intermediate, which formed as a solid, was filtered and washed with dry ether (2.1 ml) to remove excess oxalyl chloride. The product was then dried under vacuum to give the desired glyoxyl V-chlorides.
In the cases where the reaction in Et20 was not successful, the following procedure was adopted: To a solution of the substituted indole IV (1 eq.) In the dry THF (tetrahydrofuran) solvent, oxalyl chloride was added dropwise (1.2. eq.) at 0 ° C. After 5 min, the reaction was warmed to room temperature, or heated to ~ 70 ° C under nitrogen if necessary. After concentration in vacuo, the resulting crude intermediate V was presented in the next step without further treatment.
Stage B To a solution of indole glyoxyl chloride V (1 eq.) In dry THF was added benzoylpiperazine (1 eq.) At room temperature. The mixture was then cooled to 0 ° C, followed by the dropwise addition of diisopropylamine (1.3 eq.). After 5 min, the The reaction mixture was warmed to room temperature and stirred for 3 h. The resulting crude VI products were purified by preparative HPLC and characterized as shown in Table 14.
Stage C The glyoxamide Via (0.0416 μM), the alkyl or aryl halide R2X (0.0478 μM), the dry DMF (2 ml) were added to a pre-dried 5 ml ampule.
BEMP (0.0541 μM) at rt. The reaction was stirred to 70 ~ 80 ° C in a heating block under nitrogen for 4 h. After evaporation of the in va cuo solvent, the crude compound was purified by preparative HPLC and characterized as shown in Table 14.
For Examples 33 and 34, the reactions were carried out in NMP and heated at 80 ° C for 16 h before purification by preparative HPLC.
Preparation of Example 19 To the indole glyoxamide Vlld (200 mg, 0.5 mmol) in THF (1 mL) in a sealed tube was added BEMP (0.2 equiv.) And t-butyl acrylate (0.37 mL, 2.5 mmol). The reaction mixture was heated at 90 ° C overnight. The crude product was poured into 1M HCl and extracted with EtOAc. The organic phase was washed with sat. NaCl. and dried with MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc / Hexane 2:!) To provide 195 mg of the alkylated product 19.
Preparation of Example 21 To ester 19 (956 mg) was added CH2C12 (4 mL) followed by TFA (4 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the product was triturated with ether to provide the acid 21 (802 mg) as a white solid.
Preparation of Example 22 17 22 To the nitrile 17 (330 mg, 0.76 mmol) in EtOH / H20 (18 mL, 2: 1) was added hydroxylamine (189 mg, 2.72 g. mmol) followed by K2CO3 (209 mg, 1.5 mmol). The reaction mixture was heated at 65 ° C overnight. The solvent was then removed i n va c uo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine, dried with MgSO 4, filtered and concentrated. The product was then triturated with ether to provide 22 (276 mg) as a white solid.
Preparation of Example 23 22 23 To glyoxamide 22 (100 mg, 0.21 mmol) was added toluene (1.5 mL) followed by K2C03 (35 mg, 0.26 mmol) and phosgene in toluene (1.09 mL, 20% solution). The reaction mixture was heated to reflux for 2.5 h. The mixture was then cooled to rt and stirred overnight. The product was filtered, concentrated and triturated with ether to produce (89 mg) as a gold-colored solid. Table 14 4-Fluoro 2.08 494 C02Et 4-Fluoro 2.14 522 -C02Et 4 - . 4 - . 4 -Fluoro x 2.00 466 C02Et 4-Fluoro 1.24 471 4-Fluoro 1.09 471 4-Fluoro 1.39 471 4 -Fluoro 1.67 494 -Fluoro 2.03 528 \\ A-00 * 4-Fluoro J "NO, 1.79 501 General Procedure for the Preparation of Examples 35-56 STAGE A II To the indole-3-glyoxyl ilo I chloride (3 grams, 14.45 mmol) in CH 2 Cl 12 at room temperature was added tert-butyl 1-piperazinecarboxylate (2.7 grams, 14.45 mmol) and diisopropylethylamine (2.76 mL, 15.9 mmol). The light brown solution was stirred for 2 h at room temperature, time after which the CL / MS analysis indicated that the reaction was complete. The solvent was removed in vacuo and the resulting residue was diluted with ethyl acetate (250 ml) and diethyl ether (250 ml). The organic solution was then washed with water (100 ml x 3) and brine (50 ml), dried with MgSO 4, filtered and concentrated.
The light yellow solid was then added with 30 ml of 20% trifluoroacetic acid in CH2C12. The The solution was concentrated and the light brown solid was dried in vacuo to give 3.5 g (95%) of product II. The CL / MS analysis indicated that this product was 100% pure and was used for the next reaction without further purification.
STAGE B III To the piperazine glyoxamide II (1 equiv.) In dichloromethane (DCE) was added substituted benzoyl chloride (3 equiv.) Followed by i-Pr2NEt (4 equiv.). The reaction mixture was stirred at room temperature for 16 h and the product III was then purified by preparative HPLC.
General Procedure for the Preparation of Examples 35-56 To the indole glyoxamide VIb (1 equiv.) In DCE was added the substituted acid chloride (3 equiv.) Followed by i-Pr2NEt (4 equiv.). The reaction mixture was stirred at room temperature for 16 h and the Vlla product was then purified by preparative HPLC.
Table 15 General Procedure for the Preparation of Examples 57-64 To the indole glyoxamide VI (1 equiv.) In DCE was added the chloroformate R OCOCl (3 equiv.) Followed by i-Pr2NEt (4 equiv.). The reaction mixture was stirred at room temperature for 16 h and the carbamate Vllb. It was then purified by preparative HPLC.
Table 16 General Procedure for the Preparation of Examples 65-69 To the indole glyoxamide VIe (1 equiv.) In NMP was added carbamoyl chloride R? R2NCOCl (2 equiv.) Followed by i-Pr2NEt (4 equiv.). The reaction mixture was stirred at room temperature for 16 h and the Vlle urea was then purified by preparative HPLC.
General Procedure for the Preparation of Examples 65-69 STAGE A To indol glyoxamide Vlle (1 equiv.) In DCE was added p-nitrophenyl chloroformate (1.1 equiv.) Followed by i-Pr2NEt (3 equiv.). The reaction mixture was stirred at room temperature for 3 h and the crude product was used in the next reaction without further work-up or purification.
STAGE B Vllle To p-nitrophenyl carbamate Vllle the secondary amine R? R2NH was added. The reaction mixture was stirred for 16 h at room temperature and the urea IXe was then purified by preparative HPLC.
Preparation of Examples 65-69 in Table 17 Isocyanate (RiNCO) was added to the indole glyoxamide Vlle (1 equiv.) In CH2C12 at room temperature. (2 equiv.) Followed by i-Pr2NEt (3 equiv.). The reaction mixture was stirred at room temperature during 18 h and the crude product Xe was purified by preparative HPLC Table 17 Preparation of Examples 70-71 in Table 18 To the indole glyoxamide XIf (1 equiv.) In DCE was added p-sulfonyl chloride (2 equiv.) Followed by i-Pr2NEt (3 equiv.). The reaction mixture was stirred at room temperature for 3 h and the crude product Xllf was purified by preparative HPLC.
Table 18 Additional analytical results for the selected compounds 1 H NMR (300 MHz, DMF-d 7): d 8.30 (s, 1H), 8.22 (d, 1H, J = 7.26 Hz), 7.84 (d, 1H, J = 7.26 Hz), 7.30-7.54 (m, 7H ), 4.99 (s, 3H), 3.52-3.92 (m, 8H).
H NMR (300 MHz, CD3OD): d 8.28 (d, 1H, J = 8.37 Hz), 8.22 (s, 1H), 7.64 (d, 1H, J = 7.26 Hz), 7.27-7.56 (m, 7H), 5.16 (d, 2H,? J = 2.52 Hz), 3.36-4.02 (m, 8H), 3.02 (t, 1H, J = 2.55 Hz). 17 lH NMR (500 MHz, CD3C1): 6 8.05 (s, 1H), 7.45 (br, s, 5H), 6.88-7.01 (m, 2H), 5.04 (s, 2H), 3.79 (br, m, 4H), 3.59 (br, m, 4H).
Analysis calculated for C23H? 8F2N403: C 63.30; H 4.16; N 12.84; F 8.71; Or 11.00. Found C 62.33; H 4.52; N 12.05. MS 437 (M + H) X 18 X H NMR (500 MHz, CD 3 Cl): d 7.99 (s, 1 H), 7.44 (br, s, 5 H), 6.74-6.85 (m, 2 H), 4.90 (s, 2 H), 3.79 (br, m, 4 H) , 3.57 (br, m, 4H), 3.45 (q, J = 11.4 Hz, 4H), 1.35 (t, J = 11.4 Hz, 3H), 1.21 (t, J = 11.4 Hz, 3H).
Analysis calculated for C2 H28F2N404: C 63.52; H 5.54; N 10.97. Found C 62.75; H 5.54; N 10.80. twenty XH NMR (500 MHz, DMSO-de): d 8.32 (s, 1H), 7.44 (br, s, 6H), 7.12 (app.t, 1H), 3.87 (s, 3H), 3.2-3.7 (br, m, 8H). MS 412 (M + H) + Analysis calculated for C22H? 9F2N303: C 64.23; H 4.65; N 10.01. Found C 64.58; H 4.74; N 9.63.
** H NMR (500 MHz, DMSO-d6): d 8.40 (s, 1H), 7.44 (br, s, 6H), 7.14 (app.t, 1H), 5.01 (br, s, 2H), 3.2- 3.7 (br, m). MS 470 (M + H) + Analysis calculated for C23H2? F2N504: C 58.85; H 4.51; N 14.92. Found C 58.17; H 5.06; N 13.85. 2. 3 * H NMR (500 MHz, DMSO-d6): d 8.40 (s, 1H), 7.4-7.55 (m, 6H), 7.16 (app.t, 1H), 5.61 (br, s, 2H), 3.2-3.7 (br, m) MS 496 (M + H) + The compounds of the present invention could be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation or rectally spray, in dosage unit formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles not conventional toxins.
Thus, in accordance with the present invention, there is provided a method of treatment and a pharmaceutical composition for treating viral infections, such as HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention.
The pharmaceutical composition could be in the form of suspensions or tablets administered orally; nasal sprays, sterile injectable preparations, for example, as injectable sterile injectable aqueous or oleaginous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well known in the art of pharmaceutical formulation and could contain microcrystalline cellulose to impart volume, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity improver and sweetening / flavoring agents known in the art. As the immediate release tablets, these compositions could contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, extenders, disintegrators, diluents and lubricants known in the art.
The injectable solutions or suspensions could be formulated according to the known art, using the appropriate parenterally acceptable non-toxic diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution or the agents suitable dispersion or humidification and suspension, such as sterile, soft, fixed oils, including synthetic mono or diglycerides and fatty acids, including oleic acid.
The compounds of this invention can be administered orally to humans in a dosage range of 1 to 100 mg / kg body weight in divided dosages. A preferred dosage range is 1 to 10 mg / kg of body weight orally in divided dosages. Another preferred dosage range is 1 to 20 mg / kg body weight orally in divided dosages. However, it will be understood that the specific dosage level and frequency of dosing for any particular patient could be varied and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and the duration of the action. of such compound, age, body weight, general health, sex, diet, form and time of administration, the rate of excretion, the pharmacological combination, the severity of the particular condition and the therapy to which the host submits.
Abbreviations TFA Trifluoroacetic acid P-EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide supported by polymer EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide DCE 1,2-dichloroethane DMF N, N-dimethylformamide THF Tetrahydrofuran NMP N-methylpyrrolidone BEMP 2-tert-butylimino-2-diethylamino-1, 3-dimethyl-1-yl-perhydro-1,3, 2-diazaphosphorine It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.

Claims (13)

1. A compound of the formula I, which includes the pharmaceutically acceptable salts thereof, characterized because R?, R2, R3, R4 and Rs are each independently H, C? C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, cycloalkenyl C3-C6 alkenyl, C2-Ce, halogen, CN, nitro, COOR6 or XR, each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different halogen, amino, OH, CN or N02; Re is H, C? -C6 alkyl, or C3-C? Cycloalkyl, benzyl, each alkyl, cycloalkyl and benzyl is optionally substituted with one to three of the same or different halogen, amino, OH, CN, or N02; X is O, S or NR6R7; R is H, C?-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-Ce cycloalkenyl, C2-Cß alkynyl or C (0) R8 each of alkyl and cycloalkyl is optionally substituted with one to three thereof or different halogen, amino, OH, CN, or N02; R8 is H, Ci-Ce alkyl or C3-C6 cycloalkyl; -W- is R9, RIO, Rll, RL2, RL3, l4, RL5, Rl6- RL7 - RL8, RL9, R2O, R2 ?, R22 are each independently H, C C6 alkyl, C3-C6 cycloalkyl, C2-C6,? C3-C3 alkynyl C2-C6 cycloalkenyl, CR23R240R25, COR26, COOR27 or C (0) NR28R29 each of alkyl and cycloalkyl is optionally substituted with each other three of the same or different halogen, amino, OH, CN, or N02; R23, R2, R25, R26, R27, R2s, R29 are each independently H, Ci-Cß alkyl, C3-C cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, or C2-C6 alkynyl; Ar is a 4-7 membered aromatic ring that could contain one to five heteroatoms independently selected from the group consisting of O, S, N or NR6, wherein the aromatic ring is optionally fused to group B; B is an aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; or a heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-tiadia zolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trityanil, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl; B and the aromatic ring of 4-7 members could each independently contain one to five substituents each independently selected from R30 R3 ?, R32, R33 or R34; Ra and Rb are each independently H, C? -6 alkyl or phenyl; Z is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimeth i 1 zoilo isoxa, isoxazoyl, 2-met iltiazoilo, thiazoyl, 2-thienyl, 3-thienyl or pyrimidyl; and p is 0-2; R30 R31, R32, R33 and R34 are each independently H, Ci-Cß alkyl, C3- cycloalkyl C6, C2-C6 alkenyl, C3-C6 cycloalkenyl, alkynyl C2-C6, halogen, CN, nitro, C (0) R35, COXR36, hydroxyl, COOR6, hydroxymethyl, trifluoromethyl, trifluoromethoxy, 0- [straight or branched chain (C? -C) alkyl], O-benzyl, O -phenyl, 1,2-methylenedioxy, OC (0) alkyl C? _6, SC (0) alkyl C? -6, S (0) malkyl C? _6, S (0) 2NRaRb, amino, carboxyl, OZ, CH2 - (CH2) PZ, 0- (CH2) pZ, (CH2) p-0-Z, CH = CH-Z or XR37, each of alkyl and cycloalkyl is optionally substituted with one to three the same or different from halogen, amino, OH, CN or NO2; m is 0 -2; R35 and R36 are each independently H, Ci-Ce alkyl or C3-C6 cycloalkyl; R3-7 is H, C? -C6 alkyl, C3-C6 cycloalkyl, C-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, C (0) R38 or C (0) OR39, each of alkynyl and cycloalkyl it is optionally substituted with one to three of the same or different from halogen, amino, OH, CN or N02; R38, R39 are each independently H, Ci-Cβ alkyl or C3-C6 cycloalkyl, each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different from halogen, amino, OH, CN or N02; with the proviso that R39 is not H; R 40 is (CH 2) n-Y, where n is 0-6; And it is selected from: (1) H, C? -C6 alkyl, C3-C6 cycloalkyl, C2-6 alkenyl, C3-6 cycloalkenyl, C2-6 alkynyl, halogen, CN, nitro, Ar, COOR6, COOAr, -CONRaR, TR6, NRaRb, -NC (0) NRaRb, -OC (0) R6, -C [N (Ra) 2] = NT-Rb, XR6, -C (0) R6, -C (0) Ar, -S (0) Ra or -S (0) 2Ra, with the proviso that when Y is -S (0) Ra or -S (0) 2Ra then Ra is not H; Y (2) a 4-7 membered heterocyclic ring, optionally substituted with R6, which could contain 1-3 heteroatoms selected from the group consisting of O, S, SO, S02, N and NR4i, wherein R4? is selected from the group consisting of straight-chain or branched, straight-chain or branched (C? -C4) alkyl, alkenyl or (C2-C4) alkynyl straight chain or branched T is S or O; with the proviso that R1-R5, R9-R16 and R30-R34 are not all H at the same time and Ar is phenyl; Y with the proviso that R1-R5, R9-Ri6 and R30-R34 are not all H at the same time and Ar is 2-furyl.
2. A compound of claim 1, characterized in that Ar is phenyl, furyl, isoxazolyl, thiophenyl, pyrazolyl, pyridyl, benzofuryl, benzothiophenyl, indolyl, pyrazinyl, thiazolyl, imidazolyl, thiadiazolyl.
3. A compound of claim 1, characterized in that: W is Rg, Rio, Rn, R12, R13, R1 and R15 are each H; Y Ri e e s met i l o.
4. A compound of claim 1, characterized in that: R2 is H, fluoro or methoxy.
5. A compound of claim 1, characterized in that: Ri, R3 and R4 are each H.
6. A pharmaceutical formulation, characterized in that it comprises an antiviral effective amount of a compound as claimed in any of claims 1-5.
The pharmaceutical formulation of claim 6, useful for the treatment of HIV infection, further comprising an antiviral effective amount of an AIDS treatment agent, characterized in that it is selected from the group consisting of: (a) an AIDS antiviral agent; ! b) an anti-infective agent; c) an immunomodulator; Y (d) inhibitors of HIV entry
8. A method for treating mammals infected with a virus, characterized in that it comprises administering to the mammal an antiviral effective amount of a compound of the formula II, or the pharmaceutically acceptable salts thereof, where R?, R2, R3, R4 and 5 are each independently H, C? -C6 alkyl, C3-C6 cycloalkyl, C2-Ce alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, halogen, CN, nitro, COOR6 or XR7, each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different halogen, amino, OH, CN or N02; Re is H, Ci-Cß alkyl, or C3-C6 cycloalkyl, benzyl, each of alkyl, cycloalkyl and benzyl is optionally substituted with one to three of the same or different halogen, amino, OH, CN, or N02; X is O, S or NR6R7; R7 is H, Ci-Cß alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl or C (0) R8 each of alkyl and cycloalkyl is optionally substituted with one to three thereof or different halogen, amino, OH, CN, or N02; is H, C? -C6 alkyl or C3-C6 cycloalkyl,? -W- is Rg, Rio, Rll, Rl2, Rl3, Rl4, Rl5, Rl6-Rl-Rl8, Rl9, R20, R21, R22 are each independently H, Ci-Cß alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, CR23R24OR2s, COR26, COOR27 or C (0) NR28R29 each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different halogen, amino, OH, CN, or N02; R 23, R 24, R 25, R 26, R 27, R 28, R g are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkenyl, or C 2 -C 6 alkynyl; Ar is a 4-7 member aromatic ring that could contain one to five heteroatoms selected independently of the group that consists of 0, S, N or NR6, wherein the aromatic ring is optionally fused to group B; B is an aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; or a heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1, 3, 5-tritylanyl, indolyl zinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl , 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl; B and the aromatic ring of 4-7 members could each contain independently from one to five substituents that are each independently selected from R3 or R3 ?, R32, R33 or R34; R a and R b are each independently H, C 1-6 alkyl or phenyl; Z is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethyl-isoxazoyl, isoxazoyl, 2-methylathiazoyl, thiazoyl, 2-thienyl, 3-thienyl or pyrimidyl; and p is 0-2; R3o R31, R32, R33 and R34 are each independently H, C? -C6 alkyl, C3-Ce cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, halogen, CN, nitro, C (0) R35, COXR36, hydroxyl, COORß, hydroxymethyl, trifluoromethyl, trifluoromethoxy, 0- [straight or branched chain (C? -C) alkyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, OC (0) alkyl C? -6, SC (0) alkyl C? -6, S (0) malzyl C? _6, S (0) 2NRaRb, amino, carboxyl, OZ, CH2- (CH2) pZ, 0- (CH2) pZ, (CH2) p-0-Z, CH = CH-Z or XR37, each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different from halogen, amino, OH, CN or N02; m is O -2; R35 and R36 are each independently H, Ci-Cß alkyl or C3-Cd cycloalkyl; R37 is H, C? -C6 alkyl, C3-C6 cycloalkyl, C? -Ce alkenyl, C3-C6 cycloalkenyl, C2-C? Alkynyl, C (0) R38 or C (0) OR39, each of alkynyl and cycloalkyl are optionally substituted with one to three of the same or different from halogen, amino, OH, CN or N02; R38, R3g are each independently H, C? -C6 alkyl or C3-C6 cycloalkyl, each of alkyl and cycloalkyl is optionally substituted with one to three of the same or different from halogen, amino, OH, CN or N02; with the proviso that R3g is not H; ^ 40 is (CH2) n-Y, where n is 0-6; And it is selected from (1) H, C? -C6 alkyl, C3-C6 cycloalkyl, C2.6 alkenyl, C3_6 cycloalkenyl, C2_6 alkynyl, Halogen, CN, nitro, Ar, COOR6, COOAr, -CONRaRb, TR6, NRaRb, -NC (0) NRaRb, -OC (0) R6, -C [N (Ra) 2] = NT-Rb, XR6, -C (0) R6, -C (0) Ar, -S (0 ) Ra or -S (0) 2Ra, with the proviso that when Y is -S (0) Ra or -S (0) 2Ra then Ra is not H; Y (2) a 4-7 membered heterocyclic ring, optionally substituted with R6, which could contain 1-3 heteroatoms selected from the group consisting of O ', S, SO, S02, N and NR4 ?, wherein R4? is selected from the group consisting of straight or branched chain (C? -C4) alkyl, straight or branched alkyl, alkenyl or (C2-C4) alkynyl of straight or branched chain; T is S or O;
9. The method of claim 8, characterized in that the virus is HIV.
10. The method of claim 8, characterized in that Ar is phenyl, furyl, isoxazolyl, thiophenyl, pyrazolyl, pyridyl, benzofuryl, benzothiophenyl, indolyl, pyrazinyl, thiazolyl, imidazolyl, thiadiazolyl.
The method of the claim characterized in that it is Rg, Rio, Rii, R? 2, R13, R1 and Ris are each H; and Ri6 is methyl.
12. The method of claim 8, characterized in that R2 is H, fluoro or methoxy.
13. The method of claim 8, characterized in that Ri, R3 and R4 are each H.
MXPA/A/2001/001465A 1999-06-15 2001-02-08 Antiviral indoleoxoacetyl piperazine derivatives MXPA01001465A (en)

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