• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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    • 专利摘要:
    The present invention provides drugs and compounds having bio-active properties, pharmaceutical compositions thereof and methods of use thereof. In particular, the present invention relates to indole oxoacetyl piperazine derivatives. These compounds show unique antiviral activity when used alone or in combination with other antiviral, anti-infective, immunomodulatory or HIV influx inhibitors. More specifically, the present invention relates to the treatment of HIV and AIDS.
    公开号:KR20010072471A
    申请号:KR1020017001887
    申请日:2000-05-24
    公开日:2001-07-31
    发明作者:블레어웨이드에스.；데쉬판드밀린드；팡하이콴；린핑-팡；스파이서티모씨피.；월레스오웬비.；왕후이；왕타오；장종싱；용갑-순
    申请人:말라테스티닉 니콜라스 피.；브리스톨-마이어즈 스퀴브 컴페니；
    IPC主号:
    专利说明:

    ANTIVIRAL INDOLEOXOACETYL PIPERAZINE DERIVATIVES}
    [2] It is estimated that 33.4 million people worldwide are infected with HIV-1 (Human Immunodeficiency Virus-1), which is a major medical problem. Currently available HIV drugs include six nucleoside reverse transcriptase (RT) inhibitors (zidovudine, didanosine, stavudine, lamivudine, zalcitabine). , Abacavir], three non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz), and five peptide mimetics (peptidomimetic) ) Protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir and amprenavir). When used alone, these drugs can only temporarily inhibit viral replication. However, when used in combination, these drugs have a great impact on disease progression. Indeed, a significant reduction in mortality in AIDS patients has recently been documented. Despite these results, eventually 30-50% of patients receiving multiple drug therapies fail. Inadequate drug strength, non-compatibility, limited tissue penetration, and drug-specific constraints within certain cell types (such as most nucleoside analogs do not phosphorylate in resting cells) include these sensitive viruses. May explain the incomplete oppression of In addition, rapid turnover of HIV in combination with high replication rates and frequent mutations provided a suboptimal drug concentration. The emergence of drug-resistant variants and failure of treatment (Larder and Kemp, Bulick, Morris-Jones et al., Kuritzkes, Vacca and Condra, Schinazi et al., Flexner, Ref. 6-12). Thus, to provide more therapeutic choices, there is a need for new anti-HIV agents that exhibit distinct patterns of resistance and have desirable pharmacokinetic and safety profiles.
    [3] Currently commercially available HIV-1 agents are usually nucleoside reverse transcriptase inhibitors or peptidomimetic protease inhibitors. Non-nucleoside reverse transcriptase inhibitors are becoming increasingly important in the treatment of HIV infection in recent years. At least 30 different types of NNRTIs have been reported in the literature (DeClercq, Ref. 13). Dipyridodiazepineone (nevirapine), benzoxazinone (apevirens) and bis (heteroaryl) piperazine derivatives (delaladine) have already been approved for clinical use. In addition, some indole derivatives, including indole-3-sulfone, piperazino indole, pyrazino indole, and 5H-indole [3,2-b] [1,5] benzothiazepine derivatives are HIV-1 reverse transcriptase inhibitors. (Ref. 1, Willliams 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 are also known as inhibitors of cell adhesion and HIV infection (Boschelli et al., US Pat. No. 5,424,329, Ref. 4). Finally, 3-substituted indole natural substances (semicocliodinol A and B, didemethylasteryquinone and isococliodinol) have also been described as inhibitors of HIV-1 protease (Fredenhagen et al., Ref. 19). However, none of these documents discloses or suggests novel compounds of the invention and their antiviral infection inhibition uses, including HIV infection.
    [4] 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, their structure is different from that of the compounds of the present invention in that they are symmetrical bis (3-indolylglyoxamide) rather than asymmetric aroyl indoxooxetyl piperazine derivatives, and in therapeutic applications for antiviral infections. No mention is made. Interestingly, the indole moiety present in the compounds disclosed herein is a common feature of many non-nucleoside HIV-1 reverse transcriptase inhibitors, including Upjohn's Delavirdine (Dueweke et al., 1992, 1993, Ref. 22 and 23).
    [5] In addition, the following compounds are commercially available but have never been reported to be useful as chemicals, or particularly for antiviral use in mammals.
    [6] Compound LJ952 (available from Meinai Organics Ltd., Gwynedd, North Wales):
    [7]
    [8] Compound TRI-29586 (available from Tripos):
    [9]
    [10]
    [11]
    [12]
    [13]
    [14]
    [15]
    [16] Summary of the Invention
    [17] Surprisingly, the following compounds of formula (I), pharmaceutically acceptable salts thereof, whether used alone or in combination with other antiviral, anti-infective, immunomodulatory or HIV influx inhibitors, In particular, it has been found to be an effective drug for treating HIV.
    [18] The present invention includes a compound of formula (I), or a pharmaceutically acceptable salt thereof:
    [19]
    [20] During the formula:
    [21] R 1 , R 2 , R 3 , R 4 and R 5 are H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 Alkynyl, halogen, CN, nitro, COOR 6 or XR 7 , wherein said alkyl and cycloalkyl are each optionally substituted with one to three identical or different halogens, amino, OH, CN or NO 2 ;
    [22] R 6 is H, C 1-6 alkyl, or C 3-6 cycloalkyl, benzyl and each of said alkyl, cycloalkyl and benzyl is selected from 1 to 3 same or different halogen, amino, OH, CN or NO 2 Optionally substituted;
    [23] X is O, S or NR 6 R 7 ;
    [24] R 7 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl or C (O) R 8 , said alkyl And cycloalkyl is optionally substituted with 1 to 3 same or different halogens, OH, amino, CN or NO 2 , respectively;
    [25] R 8 is H, C 1-6 alkyl or C 3-6 cycloalkyl;
    [26] -W-
    [27]
    [28] And R9,R10, R11, R12,R13, R14, R15,R16, R17, R18,R19, R20,R21,R22Are each independently H, C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C3-6Cycloalkenyl, C2-6 Alkynyl, CR23R24OR25, COR26, COOR27Or C (O) NR28R29Wherein each of said alkyl and cycloalkyl is one to three same or different halogen, amino, OH, CN or NO2Optionally substituted by;
    [29] R 23, R 24 , R 25, R 26 , R 27 , R 28, R 29 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 Cycloalkenyl or C 2-6 alkynyl;
    [30] Ar is a 4-7 membered aromatic ring which may contain 1 to 5 heteroatoms independently selected from O, S, N or NR 6 , which aromatic ring may optionally be fused to Group B;
    [31] B is a group selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; Or 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-tritianyl, indolinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolininyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, Heteroaryl group selected from 8-naphthyridinyl, putridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl;
    [32] B and the 4-7 membered aromatic ring may each independently contain 1 to 5 substituents selected from R 30 , R 31 , R 32 , R 33 or R 34 ;
    [33] R a and R b are each independently H, C 1-6 alkyl, or phenyl;
    [34] Z is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazolyl, isoxazolyl, 2-methylthiazolyl, thiazolyl , 2-thienyl, 3-thienyl, or pyrimidyl; p is 0-2;
    [35] R 30 , R 31 , R 32 , R 33 and R 34 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, halogen, CN, nitro, C (O) R 35 , COXR 36 , hydroxyl, COOR 6 , hydroxymethyl, trifluoromethyl, trifluoromethoxy, O-[(C 1-4 )-Straight chain or branched alkyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, OC (O) C 1-6 alkyl, SC (O) C 1-6 alkyl, S (O) m C 1-6 alkyl, S (O) 2 NR a R b , amino, carboxyl, OZ, CH 2- (CH 2 ) p -Z, O- (CH 2 ) p -Z, (CH 2 ) p- OZ, CH = CH-Z, or XR 37 , wherein said alkyl and cycloalkyl may each be optionally substituted with 1 to 3 same or different halogen, amino, OH, CN or NO 2 ;
    [36] m is 0-2;
    [37] R 35 and R 36 are each independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
    [38] R 37 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, C (O) R 38 or C (O OR 39 , wherein each of the alkyl and cycloalkyl may be optionally substituted by one to three same or different halogen, amino, OH, CN or NO 2 ;
    [39] R 38 , R 39 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, said alkyl and cycloalkyl being each of 1 to 3 same or different halogens, amino, OH, CN or NO 2 . Optionally substituted by; Provided that R 39 is not H;
    [40] R 40 is (CH 2 ) n -Y and n = 0-6;
    [41] Y is selected from:
    [42] (1) H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, halogen, CN, nitro, Ar, COOR 6 , COOAr, -CONR a R b , TR 6 , NR a R b , -NC (O) R a R b , -OC (O) R 6 , -C [N (R a ) 2 ] = NTR b , XR 6 , C (O) R 6 , -C (O) Ar, -S (O) R a or -S (O) 2 R a , provided that if Y is -S (O) 2 R a then R a is H Not);
    [43] (2) a 4-7 membered heterocyclic ring which may be optionally substituted by R 6 and may contain 1-3 heteroatoms selected from O, S, SO, SO 2 , N, and NR 41 , wherein R 41 is selected from hydrogen, (C 1-4 )-straight chain or branched alkyl, (C 2-4 )-straight chain or branched alkenyl or alkynyl;
    [44] T is S or O;
    [45] Provided that R 1-5 , R 9-16 , and R 30-34 are not all H at the same time and Ar is phenyl;
    [46] Provided that R 1-5 , R 9-16 and R 30-34 are not all H at the same time and Ar is 2-furyl).
    [47] Another embodiment of the invention is a pharmaceutical composition containing an antiviral effective amount of a compound of formula (I).
    [48] Another embodiment of the invention
    [49] (a) AIDS antiviral agents;
    [50] (b) anti-infective agents;
    [51] (c) immunomodulators; And
    [52] (d) HIV influx inhibitors
    [53] A pharmaceutical composition useful for treating HIV infection, which additionally contains an antiviral effective amount of an AIDS therapeutic agent selected from among.
    [54] Another embodiment of the present invention is a method of treating a mammal infected with a virus, wherein the mammal is infected with a virus (such as HIV) by administering an antiviral effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof.
    [55]
    [56] During the formula:
    [57] R 1 , R 2 , R 3 , R 4 and R 5 are H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 Alkynyl, halogen, CN, nitro, COOR 6 or XR 7 , wherein said alkyl and cycloalkyl are each optionally substituted with one to three identical or different halogens, amino, OH, CN or NO 2 ;
    [58] R 6 is H, C 1-6 alkyl, or C 3-6 cycloalkyl, benzyl and each of said alkyl, cycloalkyl and benzyl is selected from 1 to 3 same or different halogen, amino, OH, CN or NO 2 Optionally substituted;
    [59] X is O, S or NR 6 R 7 ;
    [60] R 7 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl or C (O) R 8 , said alkyl And cycloalkyl is optionally substituted with 1 to 3 same or different halogens, OH, amino, CN or NO 2 , respectively;
    [61] R 8 is H, C 1-6 alkyl or C 3-6 cycloalkyl;
    [62] -W-
    [63]
    [64] And R9,R10, R11, R12,R13, R14, R15,R16, R17, R18,R19, R20,R21,R22Are each independently H, C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C3-6Cycloalkenyl, C2-6 Alkynyl, CR23R24OR25, COR26, COOR27Or C (O) NR28R29Wherein each of said alkyl and cycloalkyl is one to three same or different halogen, amino, OH, CN or NO2Optionally substituted by;
    [65] R 23, R 24 , R 25, R 26 , R 27 , R 28, R 29 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 Cycloalkenyl or C 2-6 alkynyl;
    [66] Ar is a 4-7 membered aromatic ring which may contain 1 to 5 heteroatoms independently selected from O, S, N or NR 6 , which aromatic ring may optionally be fused to Group B;
    [67] B is a group selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; Or 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-tritianyl, indolinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolininyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, Heteroaryl group selected from 8-naphthyridinyl, putridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl;
    [68] B and the 4-7 membered aromatic ring may each independently contain 1 to 5 substituents selected from R 30 , R 31 , R 32 , R 33 or R 34 ;
    [69] R a and R b are each independently H, C 1-6 alkyl, or phenyl;
    [70] Z is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazolyl, isoxazolyl, 2-methylthiazolyl, thiazolyl , 2-thienyl, 3-thienyl, or pyrimidyl; p is 0-2;
    [71] R 30 , R 31 , R 32 , R 33 and R 34 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, halogen, CN, nitro, C (O) R 35 , COXR 36 , hydroxyl, COOR 6 , hydroxymethyl, trifluoromethyl, trifluoromethoxy, O-[(C 1-4 )-Straight chain or branched alkyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, OC (O) C 1-6 alkyl, SC (O) C 1-6 alkyl, S (O) m C 1-6 alkyl, S (O) 2 NR a R b , amino, carboxyl, OZ, CH 2- (CH 2 ) p -Z, O- (CH 2 ) p -Z, (CH 2 ) p- OZ, CH = CH-Z, or XR 37 , wherein said alkyl and cycloalkyl may each be optionally substituted with 1 to 3 same or different halogen, amino, OH, CN or NO 2 ;
    [72] m is 0-2;
    [73] R 35 and R 36 are each independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
    [74] R 37 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, C (O) R 38 or C (O OR 39 , wherein each of the alkyl and cycloalkyl may be optionally substituted by one to three same or different halogen, amino, OH, CN or NO 2 ;
    [75] R 38 , R 39 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, said alkyl and cycloalkyl being each of 1 to 3 same or different halogens, amino, OH, CN or NO 2 . Optionally substituted by; Provided that R 39 is not H;
    [76] R 40 is (CH 2 ) n -Y and n = 0-6;
    [77] Y is selected from:
    [78] (1) H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, halogen, CN, nitro, Ar, COOR 6 , COOAr, -CONR a R b , TR 6 , NR a R b , -NC (O) R a R b , -OC (O) R 6 , -C {N (R a ) 2 ] = NTR b , XR 6 , C (O) R 6 , -C (O) Ar, -S (O) R a or -S (O) 2 R a , provided that if Y is -S (O) 2 R a then R a is H Not);
    [79] (2) a 4-7 membered heterocyclic ring which may be optionally substituted by R 6 and may contain 1-3 heteroatoms selected from O, S, So, SO 2 , N, and NR 41 ′ , wherein R 41 is selected from hydrogen, (C 1-4 )-straight chain or branched alkyl, (C 2-4 )-straight chain or branched alkenyl or alkynyl;
    [80] T is S or O;
    [81] In a preferred embodiment, the compounds of formulas I and II are those wherein Ar is phenyl, furyl, isoxazolyl, thiophenyl, pyrazolyl, pyridyl, benzofuryl, benzothiophenyl, indolyl, pyrazinyl, thiazolyl, imidazolyl And thiazozolyl compounds.
    [82] W also
    [83]
    [84] And R9, R10, R11, R12, R13, R14 And R15Are each H;
    [85] Also preferred are compounds of formula I and II, wherein R 16 is methyl.
    [86] Also preferred are compounds of formula I and II, wherein R 2 is H, fluoro or methoxy.
    [87] Also preferred are compounds of formula I and II, wherein R 1 , R 3, and R 4 are each H.
    [1] The present invention relates to compounds having drug and bio-effect properties, pharmaceutical compositions thereof and methods of use thereof. More specifically, the present invention relates to indole oxoacetyl piperazine derivatives. These compounds, either alone or in combination with other antiviral, anti-infective, immunomodulatory or HIV influx inhibitors, etc., have unique antiviral activity. More specifically, the present invention relates to methods of treating HIV and AIDS.
    [88] The synthesis and anti-HIV-1 activity of the novel indoleoxoacetyl piperazine homologue of formula I is summarized below.
    [89] chemistry
    [90] The present invention encompasses the compounds of formula (I), pharmaceutical compositions thereof, and the use of such compositions in patients infected with or susceptible to HIV. Compounds of formula I, including pharmaceutically acceptable salts thereof, have the following structure:
    [91]
    [92] In this specification and in the claims, “C 1-6 alkyl” (unless otherwise stated) refers to straight or branched chains such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, and the like. It means an alkyl group. Likewise, "C 2-6 alkynyl" includes straight or branched groups.
    [93] "Pharmaceutically acceptable salts" in this specification and claims include nontoxic base addition salts. Suitable salts are derived from organic and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, actic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, and the like. And the like, but are not limited to these.
    [94] "Halogen" refers to chlorine, bromine, iodine or fluorine.
    [95] By “antiviral effective amount” in the methods of the present invention is meant the total amount of each active serving sufficient to present a significant benefit to the patient, such as the healing of acute symptoms, characterized by the inhibition of viral infections including HIV infection. . Alone, when administered in separate active ingredients, the term refers to that ingredient alone. Only when administered in combination, the term refers to the combined amount of active ingredients that result in the desired antiviral effect, whether administered in combination, continuously or simultaneously. The term "treat, therapeutic, cure" in this specification and claims means preventing or alleviating a disease associated with a viral infection, including HIV infection.
    [96] The invention also relates to complexes of the compounds of the invention with one or more agents useful for treating AIDS. For example, the compounds of the present invention can be effectively administered in pre- and / or post-exposure periods in combination with an effective amount of an AIDS antiviral agent, immunomodulator, anti-infective agent or vaccine as described in the following table.
    [97] Antiviral agents
    [98] Drug name manufacturer Usage 097 Hoechst / bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor) Amprenivir141 W94GW 141 Glaxo wellcome HIV infection, AIDS, ARC (protease inhibitor) Abacavir (1592U89) GW 1592 Glaxo wellcome HIV infection, (AIDS, ARC (RT inhibitor) Acemannan Carrington Labs (Irving, TX) ARC Acyclovir Burroughs wellcome Combination with HIV infection, AIDS, ARCAZT AD-439 Tanox biosystems HIV infection, AIDS, ARC
    [99] AD-519 Tanox biosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead sciences HIV infection AL-721 Ethigen (Los Angeles, CA) ARC, PGLHIV Infection, AIDS Alpha interferon Glaxo wellcome HIV combined with Kaposi's sarcoma w / Retrovir Ansamycin LM 427 Adria Laboratories (Dublin, OH) Erbamont (Stamford, CT) ARC Antibodies to Neutralize pH-Stable Alpha Abnormal Interferon Advanced Biotherapy Concepts (Rockville, MD) AIDS, ARC AR177 Aronex pharm HIV infection, HIV, ARC Beta-fluoro-ddA Nat'l Cancer Institute AIDS-Related Diseases BMS-232623 (CGP-73547) Bristol-myers squibb / novivartis HIV infection, AIDS, ARC (protease inhibitor) BMS-234475 (CGP-61755) Bristol-myers squibb / novivartis HIV infection, AIDS, ARC (protease inhibitor) CI-1012 Warner-lambert HIV-1 infection Cidovofir Gilead science CMV retinitis herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus Immune Globin MedImmune CMV retinitis Cytovene Ganciclovir Syntex Vision threatening CMV Peripheral CMV retinitis Delaviridine Pharmacia-upjohn HIV infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem. Ind. Ltd. (Osaka, Japan) AIDS, AR, HIV positive asymptomatic ddC dideoxycytidine Hoffman-la roche HIV infection, AIDS, ARC ddI dideoxyinosine Bristol-myers squibb Combined with HIV infection, AIDS, ARC: AZT / d4T DMP-450 AVID (Camden, NJ) HIV infection, AIDS, ARC (protease inhibitor) Efavirenz (DMP 266) (-) 6-chloro-4- (S) -cyclopropylethynyl-4 (S) -trifluoromethyl-1,4-dihydro2H-3,1-benzoxazine-2- ON, STOCRINE DuPont Merck HIV infection, AIDS, ARC (non-nucleoside RT inhibitor) EL-10 Elan Corp, PLC (Gainesville, GA) HIV infection Famciclovir Smith kline Herpes zoster, herpes simplex FTC Emory university HIV infection, AIDS, ARC (reverse transcriptase inhibitor)
    [100] GS840 Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 Hoechst marion roussel HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human Interferon Beta Triton Biosciences (Almeda, CA) AIDS, Kaposi's Breeding ARC Interferon alfa-n3 Interferon sciences ARC, AIDS Indinavir Merk Combined use with HIV infection, AIDS, ARC, asymptomatic HIV positive, AZT / ddI / ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-related diseases Lamivudine, 3TC Glaxo wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); in combination with AZT Lobucavir Bristol-myers squibb CMV infection Nelfinavir Agouron pharmaceuticals AIDS infection, AIDS, ARC (protease inhibitor) Nevirapine Boeheringer Ingleheim AIDS infection, AIDS, ARC (RT preparation) Novapren Novaferon Labs, Inc (Akron, OH) HIV inhibitor Peptide T OctapeptideSequcnce Peninsula Labs (Belmont, CA) AIDS TrisodiumPhosphonoformate Astra Pharm.Products, Inc. CMV retinitis, HIV infection, and other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor) Probucol Virex HIV infection, AIDS RBC-CD4 Sheffield Med. Tech (Houston, TX) HIV infection, AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor) Saquinavir Hoffmann-laroche HIV infection AIDS, ARC (protease inhibitor) Stavudine; d4T didehydrodeoxythymidine Bristol-myers squibb HIV infection AIDS, ARC Valaciclovir Glaxo wellcome Genital HSV & CMV Infection Virazole Ribavirin Viratek / ICN (Costa Mesa, CA) Asymptomatic HIV positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-laroche HIV infection AIDS, ARC, AZT combination Zidovudine; AZT Glaxo wellcome HIV infection AIDS, ARC, Kaposi 'sarcoma, in combination with other therapies
    [101] Immunomodulators
    [102] Drug name manufacturer Usage AS-101 Wyeth-ayerst AIDS Bropirimine Pharmacia Upjohn Advanced AIDS Acemannan Carrington Labs, Inc. (Irving, TX) AIDS, ARC CL246,738 American CyanamidLederle Labs AIDS, Kaposi 'Breeding EL10 Elan Corp, PLC (Gainesville, GA) HIV infection FP-21399 Fuki ImmunoPharm Blocking Fusion of HIV and CD4 + Cells Gamma interferon Genentech Combined with ARC, w / TNF (Tumor Necrosis Factor) Granulocyte MacrophageColony Promotes Cognition Genetics Institute Sandoz AIDS Granulocyte MacrophageColony Promotes Cognition Hoechst-Roussel Immunex AIDS Granulocyte MacrophageColony Promotes Cognition Schering-Plough AIDS, w / AZT combination HIV Core particle Immunistimulant Rorer Seropositive HIV IL-2 Interleukin-2 Cetus Combined with AIDS, w / AZT IL-2 Interleukin-2 Hoffman-LaRoche Immunex Combined with AIDS, ARC, HIV, w / AZT IL-2 interleukin-2 Chiron AIDS increases CD4 cell count Immune GlobulinIntravenous (Human) Cutter Biological (Berkeley, CA) Combination with Pediatric AIDS, w / AZT IMREG-1 Imreg (New Orleans, LA) AIDS, Kaposi 'Breeding, ARC, PGL IMERG-2 Imreg (New Orleans, LA) AIDS, Kaposi 'Breeding, ARC, PGL Imuthiol Diethyl DithioCarbamate Merieux Institute AIDS, ARC Alpha-2 Interferon Schering Plow Kaposi 'sarcoma, combined with w / AZT Methionine-Enkephalin TNI Pharmaceutical (Chicago, IL) AIDS, ARC MTP-PEMuramyl-Tripeptide Ciba-Geigy Corp. Kaposi 'Sarcoma Granulocyte ColonyStimulating Factor Amgen Combined with AIDS, w / AZT Remune Immune Response Corp. Immunotherapy rCD4 Recombinant SolubleHuman CD4 Genentech AIDS, ARC rCD4-IgG hybrids AIDS, ARC Recombinant SolubleHuman CD4 Biogen AIDS, ARC Interfetron Alfa 2a Hoffmann-la roche Kaposi 'breeding, combined with AIDS and ARCw / AZT SK & F106528 Soluble T4 Smith kline HIV infection
    [103] Thymopentin Immunobiology Research Institute (Annandale, NJ) HIV infection Tumor necrosis Factor; TNF Genentech Combined with ARC, w / gamma interferon
    [104] Anti-infective
    [105] Drug name manufacturer Usage Clindamycin with Primaquine Pharmacia Upjohn PCP Fluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille-Nystatin Pastille Squibb Corp. Prevention of Oral Candidiasis Ornidyl Eflornithine Merrell Dow PCP Pentamidine Isethionate (IM & IV) Lypho Med (Rosemont, IL) PCP Therapy Trimethoprim Antibacterial Trimethoprim / sulfa Antibacterial Piritrexim Burroughs wellcome PCP Therapy Pentamidine Isethionate for Inhalation Fisons Corporation PCP Prevention Spiramycin Rhone-poulenc Cryptosporidium diarrhea Intraconazole-R51211 Janssen-Pharm. Histoplasmosis; cryptococcal meningitis Trimetrexate Warner-lambert PCP Daunorubicin NeXstar, Sequus Kapos' Breeding Recombinant HumanErythropoietin Ortho Pharm. Corp. Pernicious anemia. Combination with AZT Therapy Recombinant HumanGrowth Hormone Serono AIDS-related wasting, cachexia Megestrol Acetate Bristol-myers squibb w / AIDS-related anorexia treatment Testosterone Alza, Smith Kline AIDS-related wasting diseases Total Enteral Nutrition Norwich EatonPharmaceuticals Diarrhea and malabsorption associated with AIDS
    [106] In addition, the compounds of the present invention may be used in combination with another class of AIDS therapeutics called HIV entry inhibitors. Examples of such HIV influx inhibitors are described 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.
    [107] The range of combinations of the compounds of the invention with AIDS antiviral agents, immunomodulators, anti-infective agents, HIV inhibitors or vaccines is not limited to those listed in the table above, and any combination with any pharmaceutical composition useful for treating AIDS is in principle. Included.
    [108] Preferred combinations are simultaneous or alternation treatment with compounds of the invention and inhibitors of HIV proteases and / or non-nucleoside inhibitors of HIV reverse transcriptase. Any fourth component available for combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3Tc, ddC or ddI. Preferred inhibitors of HIV protease are N-2 (R) -hydroxy-1- (S) -indanyl) -2- (R) -phenylmethyl-4- (S) -hydroxy-5- (1- ( As indinavir, a sulfate salt of 4- (3-pyridyl-methyl) -2- (S) -N '-(t-butylcarboxamido) -piperazinyl))-pentanamide ethanolate, It is synthesized according to the method of US 5,413,999. Indinanus are generally administered in a dosage of 800 mg three times daily. Other preferred protease inhibitors include Nelpinaber and Ritonaber. Another preferred inhibitor of HIV protease is saquinaber, which is administered at a dosage of 600 or 1200 mg three times a day. Preferred non-nucleoside inhibitors of HIV reverse transcriptases include epavirens. The preparation of ddC, ddI and AZT is described in EPO 0,484,071. Such a combination can have unexpected effects of limiting HIV infection and spread. Preferred combinations include (1) indinaver and efavirens, and optionally, AZT and / or 3TC and / or ddI and / or ddC; (2) indinaver and AZT and / or ddI and / or ddC and / or 3TC, in particular indinaver and AZT and 3TC; (3) stavudine and 3TC and / or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) includes combinations of zidovudine and lamivudine.
    [109] In such combinations the compounds of the invention and other active agents can be administered separately or in combination. In addition, one component may be administered prior to, simultaneously with, or after the other component (s).
    [110] Methods for preparing compounds of Formula I are shown in Schemes 1-13 and exemplified in Tables 5-8.
    [111]
    [112] Starting indole 1 (Scheme 1) is known or readily prepared according to the process as described in Gribble, G. (Ref. 24) or Bartoli et al. (Ref. 36). According to the literature process (Lingens, F. et al., Ref. 25), indole 1 is treated with oxalyl chloride or ether in THF (tetrahydrofuran) to give the desired glyoxyl chloride 2. Intermediate glyoxyl chloride 2 is coupled with benzoyl piperazine 3 (Desai, M. et al., Ref. 26) under basic conditions to give 4.
    [113]
    [114] Indole-3-glyoxyl chloride 2 (Scheme 2) is treated with tert-butyl 1-piperazinecarboxylate 5 to obtain coupling product 6. The Boc group of 6 is deprotected with 20% (trifluoroacetic acid) TFA / CH 2 Cl 2 to give 7. This product is coupled with carboxylic acid in the presence of polymer reinforced 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (P-EDC) to afford product 8.
    [115]
    [116] For Examples 58-81, piperazine 7 (Scheme 3) is treated with Boc-protected aminobenzoic acid in the presence of EDC to give 8a. A portion of the obtained product is isolated and treated with TFA to remove the Boc group, giving amino derivative 9.
    [117]
    [118] For Examples 82-89, piperazine 7 (Scheme 4) was treated with acetoxybenzoic acid in the presence of EDC to give 8b. A portion of the obtained product is separated and treated with LiOH to remove the acetate groups, giving hydroxy derivative 10.
    [119] Examples containing substituted piperazine are prepared using the general process outlined in Schemes 5-13.
    [120] Substituted piperazine is purchased from Aldrich, Co. or prepared according to the methods described in the literature (Behun et al., Ref. 31 (a), Scheme 5, eq. 0.1). Substituted piperazine was obtained by hydrogenating alkyl substituted pyrazine at 40-50 psi in ethanol. When the substituent was an ester or an amide, the pyrazine system could be partially reduced to tetrahydropyrazine (Rossen et al., Ref. 31 (b), Scheme 5, eq. 02). Carbonyl substituted piperazine can be obtained under the same conditions as above by using a commercially available dibenzyl piperazine (Scheme 5, eq. 03).
    [121]
    [122] 2-trifluoromethylpiperazine (Jenneskens et al., Ref. 31c) was prepared via a four step route (Scheme 6). Using Lewis acid TiCl 4 , N, N′-dibenzylethylenediamine 11 was reacted with trifluoropyruvate 12 to obtain hemiacetal 13 which was reduced by Et 3 SiH in CF 3 COOH at room temperature at lactam 14 Got. Subsequently, 1,4-dibenzyl-2-trifluoromethylpiperazine 15 was obtained for lactam 14 by LiAlH 4 treatment. Finally, Compound 15 in HOAc was hydrogenated to afford the desired product 2-trifluoromethylpiperazine 16.
    [123]
    [124] Any of the following processes could be used to achieve mono-benzoylation of symmetrically substituted piperazine (Scheme 7). (a) The piperazine solution in acetic acid was treated with acetyl chloride to give the desired mono-benzoylated piperazine (Desai et al., Ref. 26, Scheme 7, eq. 04). (b) Symmetric piperazine was treated with 2 equivalents of n-butyllithium followed by benzoyl chloride at room temperature (Wang et al., Ref. 32, Scheme 7, eq. 05).
    [125]
    [126] Any of the following processes could be used to achieve mono-benzoylation of asymmetrically substituted piperazine (Scheme 8), all of which were illustrated by mono-alkyl substituted piperazine. (a) Asymmetric piperazine was treated with 2 equivalents of n-butyllithium followed by addition of benzoyl chloride at room temperature to obtain a mixture of two regioisomers which could be separated by chromatography (Wang et al., Ref. 32 and 33 (b), scheme 8 eq 06); (b) benzoic acid was converted to its pentafluorophenyl esters and then further reacted with 2-alkylpiperazine to give mono-benzoylpiperazine with benzoyl groups in less hindered nitrogen (Adamczyk et al., Ref. 33 (a), Scheme 8, eq 07;) (c) piperazine and methyl benzoate in methylene chloride for 2-4 days with dialkylaluminum chloride to give mono-benzoylpiperazine with benzoyl groups in less interfering nitrogen Obtained (Scheme 8, eq. 08); (d) Asymmetric piperazine was treated with 2 equivalents of n-butyllithium, followed by addition of triethylsilyl chloride and benzoyl chloride in THF at room temperature to give mono-benzoylpiperazine with benzoyl groups at more interfering nitrogen (Wang Et al., Ref. 33 (b), Scheme 8, eq 09). When the substituent at position 2 was an ester or an amide, mono-benzoylation with benzoyl chloride occurred at less interfering nitrogen of piperazine by the use of triethylamine as the base in THF (Scheme 8, eq. 10) .
    [127]
    [128] In the case of tetrahydropyrazine (Scheme 9, eq. 11), mono benzoylation occurred in a well-precedented manner in more interfering nitrogen under the same conditions as in Scheme 10 of Scheme 8 (Rossen et al., Ref. )).
    [129]
    [130] In addition, as shown in Scheme 10, the ester group can be selectively reduced by NaBH 4 in the presence of benzamide (Masuzawa et al., Ref. 34).
    [131]
    [132] Hydrolysis of ester groups to acids:
    [133] The piperazine linker or ester groups on the indole nucleus can be hydrolyzed with the corresponding acid under basic conditions such as K 2 CO 3 (Scheme 11, eq.13) or NaOMe (Scheme 11, eq. 14) in MeOH and water. have.
    [134]
    [135] Coupling reaction
    [136]
    [137] Glyoxyl chloride 2 was reacted with substituted benzoyl piperazine or tetrahydropyrazine (17) in CH 2 Cl 2 using i-Pr 2 NEt as the base to give the desired product 18.
    [138] For coupling reactions with 3-hydroxymethyl-benzoylpiperazine, the hydroxyl group is temporarily protected as its TMS (trimethylsilyl) ether using BSTFA (N, O-bistrimethylsilyl) fluoroacetamide) (Furber et al., Ref. 35). The unprotected nitrogen atom was then reacted with glyoxyl chloride 2 to form the desired diamide. During work-up, the TMS protecting group was removed to give free hydrigomethylpiperazine diamide 19 (Scheme 13).
    [139]
    [140] Antiviral activity
    [141] Antiviral activity of the compounds of Examples 1-34 was measured against MT-2 cells (CD4-positive T-lymphocyte cell line) acutely infected by HIV-1 dml BRU strain in the presence of 10 μM compound. Virus yield was quantified 6 days after infection using reverse transcriptase assay (Potts, Ref. 27). Anti-viral results are summarized in Table 1 below. Cytotoxicity was measured by incubating cells in the presence of passaged compounds and the survival of cells was examined using XTT staining reduction assay (Weislow, Ref. 28). The 50% cytotoxic concentration of all compounds was much higher than 10 μM, indicating that these compounds are relatively non-toxic.
    [142] Antiviral activity of the compounds of Examples 35-215 was measured in HeLa CD4CCR5 cells infected with single-round infectious HIV-1 reporter virus in the presence of a compound at a concentration of ≦ 10 μM. Viral infection was quantified 3 days after infection by measurement of luciferase expression from DNA of the virus integrated in infected cells (Chen et al., Ref. 41). Percent inhibition of each compound quantified luciferase expression levels in cells infected in the presence of each compound as a percentage of the observed value for cells infected in the absence of compounds and subtracted this value from 100. Compounds that exhibit anti-viral activity without showing appreciable toxicity at concentrations of ≦ 10 μM are shown in Tables 1-4 and 9-13.
    [143] TABLE 1
    [144]
    [145]
    [146]
    [147]
    [148] TABLE 2
    [149]
    [150]
    [151]
    [152]
    [153]
    [154]
    [155] TABLE 3
    [156]
    [157]
    [158]
    [159] TABLE 4
    [160]
    [161]
    [162] Experimental process
    [163] biology
    [164] Abbreviation
    [165] "ΜM" means micromolar;
    [166] "Μci" means microcurie;
    [167] "Ml" means milliliters;
    [168] "Μl" refers to microlliters;
    [169] "Μg" means microgram;
    [170] "M" means molar;
    [171] "Μm" means micromolar;
    [172] "MM" means millimolar;
    [173] "A" refers to percentage inhibition data representing the average of at least two experiments, measured twice per experiment.
    [174] "RT" refers to reverse transcriptase.
    [175] The materials and experimental procedures used to obtain the anti-viral results of Examples 1-34 are described below.
    [176] Cells -MT-2T cell lines were propagated in Roswell Park Memorial Institute (RPMI) 1640 medium (Life Technologies, Gaithersburg, MD) containing 10% fetal bovine serum (FBS, Sigma, St. Louis, Mo.).
    [177] Virus -infectivity assays were used to titrate laboratory HIV-1 strain BRUs (Johnson, VA and RE Byrington, 1990).
    [178] Experiment
    [179] 1. In a RPMI 1640 medium containing 10% fetal bovine serum, MT-2 cells (Harada et al., Ref. 30) were added at a concentration of 0.005 multiplicity of infection (MOI) at 1 × 10 5 cells / ml. Infected with HIV-1 BRU.
    [180] 2. Compounds were added at a concentration of 20 μM to 100 μl of RPMI 1640 medium containing 10% fetal bovine serum per well in a 96 well plate.
    [181] 3. 100 μl of 1 × 10 5 / ml infected MT-2 cells were added to each well of the porcelain plate, the final cell concentration was 5 × 10 4 cells / ml, and the final compound concentration was 10 μM.
    [182] 4. Samples were incubated at 37 ° C. and then harvested 6 days after infection.
    [183] 5. HIV-1 replication was quantified by measuring HIV-1 reverse transcriptase (RT) activity present in the cell-free supernatant (Potts et al., Ref. 27). For each sample, 20 μl of cell-free supernatant was added to 40 μl 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), 4 μM magnesium chloride (Mallinckrodt, Paris KT), 4 μg / ml polyadenylic acid (Pharmacia, Piscataway, NJ), 1.3 μg / ml oligonucleotide deoxythymidine 12-18 (Pharmacia, Piscataway , NJ), 0.04% (octylphenoxy) -polyethoxyethanol (Nonidet P-40, Sigma, St. Louis, MO), and 17 μCi / ml 3H-deoxythymidine 5′-triphosphate (NEN, Boston , MA)]. The analytes were incubated at 37 ° C. for 1 hour, then 1 μl of each reactant was dried on diethylaminoethyl cellulose (DE-81) filter paper (Whatman, Hillsboro, OR) and dried, followed by 0.3 M sodium chloride (Fisher Scientific, Pittsburgh, PA), 30 mM sodium citrate pH 7.0 (Sigma, St. Louis, MO), followed by 4 washes, followed by 2 washes in 95% ethanol. Bound radioactivity was quantified by scintillation counting.
    [184] 6. The percentage inhibition of each compound was calculated by quantifying HIV-1 replication levels in the presence of each compound as a percentage of the uncompounded control group and then subtracting these measurements from 100.
    [185] 7. To measure the cytotoxicity of the compounds, uninfected cells were incubated with various concentrations of each compound for 3-6 days. Cell viability was XTT {2,3-bis (2-methoxy-4-nitro-5-sulfophenyl) -5-[(phenylamino) carbonyl] -2H-tetrazolium hydroxide} dye reduction method (Weislow And Ref. 28). The percentage of live cells in compound containing wells relative to untreated control was measured. 50% cytotoxicity concentration was calculated as the drug concentration which reduced the percentage of survival of untreated cells to 50%.
    [186] Methods and materials for measuring anti-viral activity of Examples 35-215 are described below:
    [187] cell:
    [188] Virus Production —Proliferated in Dulbecco's Modified Eagle Medium (Life Technologies, Gaithersburg, MD) containing human embryonic kidney cell line, 293, 10% fetal bovine serum (FBS, Sigma, St. Louis, MO).
    [189] Virus infections -containing 0.2% fetal bovine serum (FBS, Sigma, St. Louis, MO) and 0.2 mg / ml geneticin (Life Technologies, Gaithersburg, MD) and 0.4 mg / ml zeocine (Invitrogen, Carlsbad, Human epithelial cell lines HeLa expressing HIV-1 receptor CD4 and CCR5 were propagated in Dulbecco's modified Eagle's medium (Life Technologies, Gaithersburg, Md.) Supplemented with CA).
    [190] Virus -human embryonic kidney 293 cells are co-transformed with an HIV-1 envelope DNA expression vector and a proviral cDNA comprising an envelope deletion mutation and a luciferase reporter gene inserted in place of the HIV-1 nef sequence Replication defective reporter virus was prepared (Chen, 1994). Transformation was performed using lipofect AMINE PLUS reagent as described by the manufacturer (Life Technologies, Gaithersburg, MD).
    [191] Experiment
    [192] 1. Add compound at a concentration of <20 uM to HeLa CD4 CCR5 cells plated in 96-well plates at a cell concentration of 5 x 10 4 cells per well in 100ul of Dulbecco modified Eagle's medium containing 10% fetal bovine serum. It was.
    [193] 2. Add 10ul replication deficient reporter virus in Dulbecco 'modified Eagle's medium to plated cells and compound with multiplicity of infection (MOI) of 0.01 to a final concentration of 200 ul per well and a final compound concentration of <10 uM. It was.
    [194] 3. Samples were harvested 72 hours after infection.
    [195] 4. Viral infections were monitored by measuring luciferase expression from viral DNA in infected cells using the Luciferase Reporter Gene Analysis Kit (Roche Molecular Biochemicals, Indianapolis, IN). Supernatant of infected cells was removed and 50 ul of Dulbecco 'modified Eagle's medium (no phenol red) and 50 ul of luciferase assay reagent reconstituted as described by the manufacturer (Roche Molecular Biochemicals, Indianapolis, IN) per well were added. It was. Luciferase activity was then measured by measuring luminescence using a Wallac microbeta scintillation counter.
    [196] 5. Luciferase expression levels in infected cells in the presence of each compound were quantified as a percentage of the observed value for cells infected in the absence of conjugates and then subtracted from 100 to calculate the percentage inhibition for each compound.
    [197] references
    [198] Chen, B.K., Saksela, K., Andino, R., and D. Baltimore. 1994. Distinct modes of immunodeficiency type 1 proviral latency revealed by superinfection of nonproductively infected cell lines with recombinant luciferase-encoding viruses. J. Virol. 68: 654-660 (Ref. 37).
    [199] chemistry
    [200] General : Unless stated otherwise, solvents and reagents were used as purchased from the manufacturer and the reaction was carried out under a nitrogen atmosphere. Flash chromatography was performed on Silica gel 60 (0.040-0.063 particle size; EM Science supply). Unless stated otherwise, 1 H NMR spectra were recorded at 500 MHz and chemical shifts were reported relative to residual solvent signal. Multiplicity patterns were recorded using the following standard acronyms; s (single), d (double), t (triple), q (quad), m (multiple), b (wide), app (clear), and the coupling constant (J) is in hertz.
    [201] All liquid chromatography (LC) data was recorded on a Shimadzu LC-10AS liquid chromatograph using a SPD-10AV UV-Vis detector, and mass spectrophotometer (MS) data were measured using an electrosprayed Micromass Platform for LC. It was.
    [202] LC / MS method (i.e. compound identification)
    [203] Unless stated otherwise, all compounds were analyzed using the following conditions:
    [204] Column: YMC ODS S7 3.0 x 50 mm Column
    [205] Gradient: 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B
    [206] Draft time: 2 minutes
    [207] Retention time: 1 minute
    [208] Flow rate: 5mL / min
    [209] Detector wavelength: 220nm
    [210] Solvent A: 10% MeOH / 90% H 2 O / 0.1% trifluoroacetic acid
    [211] Solvent B: 10% H 2 O / 90% MeOH / 0.1% trifluoroacetic acid
    [212] Where specifically mentioned, the following conditions were used for HPLC analysis:
    [213] Method A: Column YMC ODS-A C18S7 3.0 x 50 minutes
    [214] Start% b = 0 / final% b = 100
    [215] Method B: Column YMC ODS-A C18S7 3.0 x 50 minutes
    [216] Starting% b = 30 / final% b = 100
    [217] Method C: Column PHX-LUNA C18 4.6 x 30 mm
    [218] Start% b = 0 / final% b = 100
    [219] Compounds purified by preparative HPLC were diluted in methanol (1.2 ml) and purified using the following method on a Shimadzu LC-10A automated preparative HPLC system.
    [220] Preparative HPLC Method (i.e. Compound Purification)
    [221] Purification Method: 10 min, 3 min residence (100% B, 0% A) from initial gradient (40% B, 60% A) ramp to final gradient (100% B, 0% A).
    [222] Solvent A: 10% MeOH / 90% H 2 O / 0.1% trifluoroacetic acid
    [223] Solvent B: 10% H 2 O / 90% MeOH / 0.1% trifluoroacetic acid
    [224] Column: YMC C18 S5 20 x 100 mm zjffja
    [225] Detection wavelength: 220 nm
    [226] Indole is commercially available or prepared using known chemistry according to the method of Bartoli (Ref. 36) or the method of Gribble (Ref. 24).
    [227] Representative indole synthesis was as follows.
    [228] Preparation of 4-fluoro-7-methyl indole
    [229] A step
    [230]
    [231] In a flame-dried 50 ml three-necked flask, BCl 3 (44 mmole, 44 ml, 1M in benzene) and 10 ml of dry benzene were placed under N 2 at room temperature. The mixture was cooled to 0 ° C., then 5-fluoro-2-methylaniline (5 g, 40 mmol) in 10 ml of dry benzene was added dropwise over 10 minutes and chloroacetonitrile (2.18 g, 48 mmol) was added in 2 minutes. Over dropwise, AlCl 3 was added in one portion. After 5 min stirring at 0 ° C., the ice-bath was removed and the mixture was refluxed under N 2 for 6 h. The resulting mixture was cooled to rt and poured into EtOAc / 1N HCl (300 ml, for 50:50 v / v ice). After separation, the aqueous phase was extracted with EtOAc (2x100ml). The combined organic layer was washed with water (100 ml), brine (2 × 100 ml) and then dried over MgSO 4 . The solvent was removed in vacuo and the crude intermediate was used directly in the next step without further purification.
    [232] Step B:
    [233]
    [234] The residue was dissolved in 100 ml EtOH. The mixture was then cooled to 0 ° C. and then NaBH 4 in 2 ml H 2 O was added dropwise. After 1 h of stirring at 0 ° C., the reaction was stopped with H 2 O (10 ml). The solvent was removed in vacuo and the residue was dissolved in EtOAc (150 ml) and washed with brine (2 × 50 ml). The organic layer was dried over MgSO 4 , the residue was removed and the expected reducing intermediate was used directly in the next cyclization step.
    [235] Step C:
    [236]
    [237] The intermediate, yellow oil, was dissolved in 100 ml EtOH and then K 2 CO 3 (11 g, 80 mmol) was added. The mixture was refluxed under N 2 for 2 hours and cooled to room temperature. The solid was filtered off through celite and the resulting solution was concentrated in vacuo. The residue was dissolved in EtOAc (200 ml), washed with brine (2 × 50 ml) and dried over MgSO 4 . The solvent was removed in vacuo to give a brown oil which was purified by flash chromatography (12% EtOAc in hexane) to give 2.3 g (39% total yield) of pure product. M + H, 150.0: retention time, 1.297 minutes.
    [238] Synthesis of 4-ethoxyindole:
    [239]
    [240] 5 ml of DMF and NaH (66 mg, 60% in oil, 1.65 mmol) were added to an oven dried flask with eggplant. The mixture was cooled to 0 ° C. and then 4-hydroxy indole (200 mg, 1.5 mmol) in 5 ml DMF was added dropwise for 10 seconds. After stirring for 30 min under N 2 , bromoethane in 2 ml DMF was added dropwise and the reaction was allowed to warm to room temperature with continued stirring for 2 h. The solvent was removed in vacuo and then aqueous work up to afford crude 4-ethoxyindole which was purified by preparative HPLC to give 201 mg (83%) of pure 4-ethoxyindole: HPLC retention time, 1.190 min.
    [241] Synthesis of 4-fluoro-7-carbomethoxy indole
    [242] Step A :
    [243]
    [244] A mixture of 4-fluoro-7-bromoindole (600 mg, 2.8 mmol) and CuCN (1.004 g, 11.2 mmol) in DMF (4 ml) was refluxed for 16 h. After cooling to room temperature, the reaction mixture was poured into ammonia solution in MeOH (30 ml, saturated) and the residue was removed by filtration. The filtrate was added to a mixture of water (20 ml) / ammonia (20 ml, saturated aqueous) and extracted with EtOAc / ether (1/1) until no product was seen in the aqueous phase by TLC analysis. The combined organic extracts were washed with brine (2x200ml) and water (200ml), dried (MgSO 4 ) and then evaporated in vacuo to give 4-fluoro-7-cyanoindole as a tanish yellow solid (310 mg, 69 %).
    [245] Step B
    [246]
    [247] A solution of KOH (13.04 g, 0.232 mmol) in 14% H 2 O / EtOH (50 ml) was added to 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 vacuo to about 30 ml. The residue was acidified to pH 2 with HCl (˜5.5 N aq.). The precipitate was filtered off, washed with excess water and dried under high vacuum to afford 4-fluoro-7-carboxyindole as a white solid (100% conversion). This material was used without further purification.
    [248] C stage
    [249]
    [250] To a suspension of 4-fluoro-7-carboxyindole in a mixture of MeOH (18 ml) / PhH (62 ml) (trimethylsilyl) diazomethane (8.8 ml, 17.6 mmol, 2 M in hexane) was added. The resulting mixture was stirred at rt for 30 min, quenched with excess acetic acid and then evaporated in vacuo. The crude oily material was purified by flash chromatography using gradient elution (hexanes to 10% EtOAc / hexanes) to afford methyl (4-fluoro) indole-7-carboxylate as a white solid (1.04 g, 83% Step 2).
    [251] 4-fluoroindole-7-carboxaldehyde
    [252]
    [253] N-BuLi (5.6 ml in hexane, 2.6 M) was added dropwise to a solution of 4-fluoro-7-bromoindole (1.0 g, 4.7 mmol) in THF (5 ml) at −78 ° C. The mixture was stirred at -78 ° C for 15 minutes, warmed to 5 ° C for 30 minutes and then cooled back to -78 ° C. DMF (1.8 ml) was added and the mixture was slowly warmed to room temperature. The reaction was quenched with water and extracted with ether. The organic phase was dried over MgSO 4 , filtered and concentrated to give 4-fluoroindole-7-carboxaldehyde.
    [254] General Process for Preparation of Examples 1-17 in Table 5
    [255] A step
    [256]
    [257] Tert-butyl 1-piperazinecarboxylate (2.7 g, 14.45 mmol) and diisopropylethylamine (3 g, 14.45 mmol) commercially available in CH 2 Cl 2 in CH 2 Cl 2 at room temperature. 2.76 ml, 15.9 mmol) was added. The light brown solution was stirred for 2 hours at room temperature and LC / MS analysis showed the reaction to be complete. The solvent was removed in vacuo and the residue obtained was diluted with ethyl acetate (250 ml) and diethyl ether (250 ml). The organic solution was washed with water (100mlx3) and brine (50ml), dried over MgSO 4 , filtered and concentrated. To this light yellow solid was added 30 ml of 20% trifluoroacetic acid in CH 2 Cl 2 . The solution was concentrated and the light brown solid was dried in vacuo to yield 3.5 g (95%) of product II. LC / MS analysis showed this product to be 100% pure and used in the next step without further purification.
    [258] Step B
    [259]
    [260] Dichloroethane (DCE) (1 ml) in piperazine indole-3-glyoxylamide II (0.03 mmol) or carboxylic acid (ROOH) (0.06 mmol) in DMF (dimethylformamide) when carboxylic acid is not soluble in DCE And resin-bonded 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (P-EDC) (0.21 mmol) were added. The reaction was shaken for 12 hours at room temperature. Product III was filtered and concentrated. The product with less than 70% purity was diluted in methanol and purified by Shimadzu automated preparative HPLC system.
    [261] 2) General Process for Preparation of Examples 18-56 in Table 5
    [262] Step A.
    [263]
    [264] Oxalylchloride (1.2eq) was added dropwise to a substituted indole IV (1eq) solution in dry Et 2 O at 0 ° C. After 5 minutes, the reaction mixture was warmed to room temperature and heated to ˜35 ° C. overnight if necessary. Substituted-indole-3-glyoxylyl chloride V, the intermediate produced as a solid, was filtered and washed with dry ether (2 × 1 ml) to remove excess oxalyl chloride. The product was dried under vacuum to afford the desired glyoxyl chloride V.
    [265] If the reaction in Et 2 O failed, the following process was adopted: oxalyl chloride (1.2 eq) was added dropwise at 0 ° C. to a solution of chiled indole IV (1 eq) in dry THF (tetrahydrofuran) solvent. It was. After 5 minutes, the reaction was allowed to warm to room temperature or, if necessary, heated to ˜70 ° C. under nitrogen. After concentration in vacuo, the crude intermediate V obtained was used in the next step without further treatment.
    [266] Step B
    [267]
    [268] To a solution of indole glyoxylyl chloride V (1 eq) in dry THF was added benzoylpiperazine (1 eq) at room temperature. The mixture was then cooled to 0 ° C. and diisopropylamine (1.3eq) was added dropwise. After 5 minutes, the reaction mixture was warmed to room temperature and shaken for 3 hours. The crude product VI obtained was purified by preparative HPLC and characterized as shown in Table 5.
    [269] General Process for Preparation of Examples 58-63 in Table 5
    [270] A step
    [271]
    [272] To glyoxyl chloride V (1 equiv) in CH 2 Cl 2 at room temperature was added tert-butyl 1-piperazinecarboxylate (1 equiv) and diisopropylethylamine (1.2 equiv). The solution was stirred at room temperature for 2 hours and then LC / MS analyzed to indicate that the reaction was complete. The solvent was removed in vacuo and the residue obtained was diluted with ethyl acetate and diethyl ether. The organic solution was washed with water (100mlx3) and brine (50ml), dried over MgSO 4 , filtered and concentrated. To this solid was added 30 ml of 20% trifluoroacetic acid in CH 2 Cl 2 . The solution was concentrated and the light brown solid was dried in vacuo to give glyoxamide VII.
    [273] Step B
    [274]
    [275] EDC (1.5 eq) and Boc-aminobenzoic acid (1.5eq) were added to piperazine glyoxamide VII (0.1 mmol, 1eq) in DMF (1 ml) at room temperature. The reaction mixture was stirred at rt for 16 h. The crude product was purified by preparative HPLC to give crude VIII.
    [276] General Process for Preparation of Examples 65-73 in Table 5
    [277]
    [278] To Boc-protected derivative VIII (0.03 mmol) 50% TFA / CH 2 Cl 2 (1.5 ml) was added. The reaction mixture was stirred at rt for 16 h. This product was then concentrated in vacuo to give the product IX as a TFA salt. The purity of IX was sufficient so no further purification was necessary.
    [279] General Process for Preparation of Examples 82-86 in Table 5
    [280]
    [281] EDC (1.5ea) and acetoxybenzoic acid (1.5ez) were added to piperazine glyoxamide VII (0.1 mmol, 1ea) in DMF (1 ml) at room temperature. The reaction mixture was stirred at rt for 16 h. The crude product was purified by preparative HPLC to give product X.
    [282] General Process for Preparation of Examples 87-89 in Table 5
    [283]
    [284] To the acetate-protected derivative X (0.03 mmol, 1 eq) was added aqueous LiOH (3 eq) in THF / MeOH (1.5 ml, 1: 1). The reaction mixture was stirred at rt for 16 h. The crude product was purified by preparative HPLC to give product XI.
    [285] General Process for Preparation of Examples 64 and 74-81 in Table 5
    [286] A step
    [287]
    [288] To a solution of Boc-protected aminobenzoic 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 rt for 3 h. The crude product was diluted with CH 2 Cl 2 and washed with water, 0.1M HCl and brine. The organic phase was dried over MgSO 4 , filtered and concentrated. Pentafluorophenyl ester XII was used in the next reaction without further purification.
    [289] Step B
    [290]
    [291] To a stirred solution of (R) -2-methylpiperazine 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 rt for 16 h. The crude product was diluted with CH 2 Cl 2 and washed with Na 2 CO 3 (saturated) and brine. The organic phase was dried over MgSO 4 , filtered and concentrated. The crude product was purified by flash chromatography (50% EtOAc / hexanes-10% MeOH / EtOAc) to give product XIII.
    [292] C stage
    [293]
    [294] To indole-3-glyoxyl chloride V (1 eq) in CH 2 Cl 2 was added acyl piperazine XII followed by i-Pr 2 NEt (3 eq). The reaction mixture was stirred at rt for 5 h, then diluted with methanol and the product XIV was purified by preparative HPLC.
    [295] D stage
    [296]
    [297] To the Boc-protected derivative XIV (˜0.03 mmol) was added 50% TFA / CH 2 Cl 2 (1.5 ml). The reaction mixture was stirred at rt for 16 h. The product was concentrated in vacuo to give the product XV. The purity of XV was sufficient to require no further purification.
    [298] Process for the synthesis of Examples 57 and 90 in Table 5
    [299] A step
    [300]
    [301] Ethyl chloroxalate (2 equiv) was added dropwise to substituted indole IV (1 equiv) in CH 2 Cl 2 at 0 ° C. followed by addition of AlCl 3 (2 equiv). The reaction was stirred at 0 ° C. and then warmed to room temperature overnight. The reaction was stopped by the dropwise addition of HCl (1N). The crude material was extracted with EtOAc, washed with water and then dried over MgSO 4 , filtered and concentrated. The crude product was recrystallized from EtOAc / hexanes to give ester XVI.
    [302] Step B
    [303]
    [304] To the ester XVI (1 equiv) in EtOH was added dropwise NaOH (2.5 equiv, 10N). The reaction mixture was stirred for 30 minutes at room temperature and then heated back to 45 ° C. for 90 minutes. The product was concentrated in vacuo. The obtained residue was partitioned between EtOAc and water. The organic layer was separated, washed with water, dried over MgSO 4 , filtered and concentrated to give acid XVII.
    [305] C stage
    [306]
    [307] To acid XVII (1 equiv) in DMF was added benzoyl piperazine (1.2 equiv) followed by DEPBT (1.2 equiv) and i-Pr 2 NEt (2 equiv). The reaction mixture was stirred at rt for 2 h. It was then sparged with EtOAc, washed with water and brine, dried over MgSO 4 , filtered and concentrated. The crude product was subjected to flash chromatography (EtOAc / MeOH, 95: 5) to afford the desired product XVIII.
    [308] TABLE 5
    [309]
    [310]
    [311]
    [312]
    [313] Synthesis Process of Compounds in Table 6
    [314] A. Preparation of Substituted Piperazine:
    [315] Preparation of 2-alkylpiperazine:
    [316]
    [317] 5 g of 2-alkyl pyrazine (46.3 mmol, Pyrazine Specialties, Inc.) was dissolved in 200 ml of 95% ethanol with 500 mg of 10% palladium on activated carbon. The reaction mixture was hydrogenated for 2 days under pressure 940-50 psi). The solid was filtered and removed. The filtrate was concentrated to give 2-alkyl piperazine, which needed no further purification.
    [318]
    [319]
    [320] Preparation of 2-methoxycarbonyltetrahydropyrazine XXV:
    [321]
    [322] 5 g of pyrazine carboxylic acid methyl ester (36.2 mmol, Lancaster, Inc.) was dissolved in 200 ml of 95% ethanol with 500 mg of 10% palladium on activated carbon. The reaction mixture was hydrogenated for 2 days under pressure (40-50 psi). The solid was filtered and removed. The filtrate was concentrated to give methoxycarbonyltetrahydropyrazine XXI. It was pure enough to be used as is for subsequent reactions.
    [323]
    [324] 40.0; MS m / z: (M + H) + C 6 H 11 N 2 O 2 calc: 143.08, found 143.09, HPLC retention time 0.11 (method C)
    [325]
    [326] Preparation of 2-ethoxycarbonylpiperazine XXVI
    [327]
    [328] 5 g of N, N'-dibenzylpiperazine carboxylic acid ethyl ester (14.8 mmol, Maybridge Chemical Company Ltd.) were dissolved in 200 ml of 95% ethanol with 500 mg of 10% palladium on activated carbon. The reaction mixture was hydrogenated for 2 days under pressure (40-50 psi). The solid was filtered and removed. The filtrate was concentrated to give 2-ethoxycarbonylpiperazine XXVI. It was pure enough to be used as is for subsequent reactions.
    [329]
    [330] Preparation of 2-trifluoromethylpiperazine XXVII
    [331] Stage 1:
    [332]
    [333] N, N'-dibenzylethylenediamine (1.51ml, 6.41mmol), methyl 3,3,3-trifluoro-2-oxopropanoate (1.0g, 6.41mmol) and triethyl in dichloromethane (100ml) To a solution of amine (1.78 ml, 12.8 mmol) was added titanium chloride (1M in CH 2 Cl 2 , 3.21 ml, 3.21 mmol) via syringe. The reaction was stirred for 8 hours and the solvent was removed in vacuo. The residue was used for next step without further purification.
    [334] Step 2:
    [335]
    [336] The crude product (200 mg, 0.55 mmol) from the previous step was dissolved in TFA (5 ml). Excess triethylsilane (0.88 ml, 5.5 mmol) was added. After 30 minutes, TFA was removed in vacuo and the residue used in the next step without further purification.
    [337] STEP 3:
    [338]
    [339] The crude product (<0.55 mmol) from step 2 was suspended in ether. LiAlH 4 (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 MgSO 4 and concentrated to give a residue, which was used without further purification in the next step.
    [340] STEP 4:
    [341]
    [342] The crude product from step 3 was dissolved in HOAc (20 ml) with 10 mg of 10% palladium on activated carbon. The reaction mixture was hydrogenated for 8 hours under pressure (40-50 psi). The solid was filtered and removed. The filtrate was concentrated to give 2-trifluoromethylpiperazine XXVII as HOAc salt, which was high enough to be used as is for subsequent reactions.
    [343] 2-trifluoromethylpiperazine XXVII as HOAc (2 equiv) salt:
    [344]
    [345] Calcd for C 5 H 10 F 3 N 2 : 155.0796, found 155.0801
    [346]
    [347] B. Mono-benzoylation of Piperazine Derivatives
    [348] Unless stated otherwise, substituted piperazine was mono-benzoylated according to the following procedure:
    [349] Preparation of benzoylpiperazine XXVIII and XXIX:
    [350]
    [351] To a stirred solution of substituted piperazine (1.0 g, 11.6 mmol) in dry THF (50 ml) was added 2.5M n-BuLi in TFH (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 another 10 minutes. The reaction mixture was quenched with MeOH and the solvent was evaporated. The residue was partitioned between EtOAc (50 ml) and NaHCO 3 . The aqueous layer was saturated with NaCl and extracted with EtOAc (2 × 30 ml). The organic layer was dried over MgSO 4 and concentrated to afford the crude product benzoylpiperazine. It was generally pure enough to be ready for use without further purification. Chromatography on a silica gel column (EtOAc / MeOH / Et 3 N, 7: 3: 1) afforded the purified product.
    [352] Preparation of benzoylpiperazine XXXIII and XLIII:
    [353]
    [354] A solution of 2.5M n-BuLi in THF (6.88ml, 17.2mmol) was added to a stirred solution of 2-isopropylpiperazine (1.0g, 7.81mmol) in dry THF (50ml) maintained under room temperature argon atmosphere. . 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 another 10 minutes. The reaction mixture was then quenched with MeOH, the solvent was removed in vacuo and the residue was purified by silica gel flash chromatography. Elution with a mixture of EtOAc and MeOH (1: 1) gave the product XXXIII (0.62 g, 36% yield) and XLIII (0.3 g, 17% yield). Benzoyl piperazine XXXIII, XXXIV, XXXV, XXXVI, XXXVII were prepared following the same process as outlined above.
    [355] Preparation of Benzoyl Piperazine XXXI, XXXII, XXXVIII:
    [356]
    [357] 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 rt for 2 h. To this solution was added slowly 2-methylpiperazine (4.0 g, 40 mmol) in 30 ml of DMF and the reaction mixture was stirred for 12 hours.
    [358] DMF was evaporated to give a residue, which was diluted with 400 ml of EtOAc and washed with water (2 × 100 ml). The organic phase was dried over anhydrous MgSO 4 and concentrated in vacuo to afford the crude product which was purified by column chromatography (EtOAc / MeOH (100: 1) followed by EtOAc / MeOH (10: 1)) to give 4.8 g of Product XX. Obtained in% yield.
    [359] Preparation of Benzolylpiperazine XXX
    [360]
    [361] To a stirred solution of 2-methylpiperazine (10.0 g, 0.1 mol) in CH 2 Cl 2 (500 ml) dried under argon at room temperature 1.0 M in methyl benzoate (12.4 ml, 0.1 mmol) and hexane (100 ml, 0.1 mmol) Me 2 AlCl or Et 2 AlCl was added. The reaction mixture was stirred for 2 days before adding 2N NaOH (200 ml). The aqueous layer was extracted with EtOAc (3x100 ml). The combined organic layer was dried over MgSO 4 and the solution was concentrated to give 20.0 g (98%) of crude product. This was pure enough and used as such in the subsequent reaction.
    [362] Preparation of N-benzoyl-cis-2,6-dimethylpiperazine XLVII:
    [363]
    [364] To a stirred solution of 2,6-dimethyl piperazine (0.82 g, 7.2 mmol) in dry THF (50 ml) maintained at room temperature under argon atmosphere was added a 2.5 M n-BuLi solution 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 1 hour before the addition of benzoyl chloride (0.80 ml, 6.8 mmol). After 10 minutes, the reaction mixture was quenched with MeOH and the solvent was evaporated in vacuo. The residue was purified by silica gel flash column chromatography eluting with a mixture of EtOAc and MeOH (1: 1) to afford product XLVII (1.48 g, 99% yield). Benzoyl piperazine XL, XLI, XLII, XLIII, XLI, XLV and XLVI were synthesized as outlined above using a sample process.
    [365] Preparation of Benzoyl Piperazine XXXIX:
    [366]
    [367] To a stirred solution of 2-ethoxycarbonylpiperazine (4.6 g, 29.1 mmol) in dry methylene chloride (200 ml) was added successively benzoyl chloride (3.55 ml, 29.1 mmol) and triethylamine (2 ml). After stirring for 8 hours at room temperature, saturated NaHCO 3 solution was added and the aqueous phase was extracted with ethyl acetate (3 × 200 ml. The organic layers were combined, dried over MgSO 4 and concentrated to give a crude mixture containing the desired product XXXIX. This mixture was used in the next step without purification.
    [368] Preparation of Benzoylpiperazine XLVIII:
    [369]
    [370] To a stirred solution of 2-methoxycarbonyltetrahydropyrazine (1.0 g, 7.0 mmol) in dry methylene chloride (50 ml) was added successively benzoyl chloride (0.76 ml, 6.7 mmol) and triethylamine (5 ml). After stirring for 8 hours at room temperature, saturated NaHCO 3 solution was added and the aqueous phase was extracted with ethyl acetate (3 × 200 ml. The organic layers were combined, dried over MgSO 4 and concentrated to give a crude mixture containing the desired product XLVII. This mixture was used in the next step without purification.
    [371] Preparation of 3-hydroxymethyl-benzoylpiperazine XLIX:
    [372]
    [373] To a stirred solution of 3-ethoxycarbonyl-benzoylpiperazine XLIX (200 mg, 0.76 mmol) in THF (5 ml) successively added lithium chloride (36 ml, 0.84 mmol), NaBH 4 (32 mg, 0.84 mmol) and EtOH (5 ml) Was added. After stirring for 8 hours at room temperature, saturated NaHCO 3 solution was added and the aqueous phase was extracted with ethyl acetate ( 3 × 20 ml). The organic layers were combined, dried over MgSO 4 and concentrated to give a crude mixture. This mixture was used in the next step without purification.
    [374] Characterization of Mono-benzoylated Piperazine Derivatives
    [375]
    [376]
    [377]
    [378]
    [379]
    [380]
    [381]
    [382]
    [383]
    [384] C. Coupling of Mono-benzoyl Piperazine with Glyoxyl Chloride
    [385]
    [386] To a solution of indole glyoxyl chloride V (1 eq) in dry CH 2 Cl 2 was added substituted benzoylpiperazine (1 eq) at room temperature. The mixture was cooled to 0 ° C. and diisopropylamine (1.3eq) was added dropwise. After 5 minutes, the reaction mixture was cooled to room temperature and shaken for 3 hours. The crude product XL obtained was purified by preparative HPLC and characterized as shown in Table 6.
    [387] Preparation of N- (benzoyl) -3-hydroxymethyl-N '-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine Example 98:
    [388]
    [389] To a stirred solution of 3-hydroxymethyl-benzoylpiperazine 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 again at rt for 2 h. Concentration in vacuo to give a residue which was purified by Shimazu HPLC purification system to give N- (benzoyl) -3-hydroxymethyl-N '-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -Piperazine was obtained (Example 98).
    [390] D. Hydrolysis of ester groups to acid groups
    [391] N- (benzoyl) -3-hydroxycarbonyl-N '-[(4-fluuro-indol-3-yl) oxoacetyl] piperazine (Example 101) :
    [392]
    [393] N- (benzoyl) -3-ethoxycarbonyl-N '-[(4-fluoroindol-3-yl) -oxoacetyl] -piperazine (10 mg, 0.02 mmol in methanol (1 ml) and water (1 ml) To a stirred solution of) potassium carbonate (9 mg, 0.06 mmol) was added. After stirring for 8 h at room temperature the product was concentrated in vacuo and the residue was purified by preparative HPLC to give N- (benzoyl) -3-hydroxycarbonyl-N '-[(4-fluoro-indol-3-yl)- Oxoacetyl] -piperazine was obtained (Example 101).
    [394] N- (benzoyl) -3- (R) -methyl-N '-[(7-hydroxycarbonyl-indol-3-yl) oxoacetyl] piperazine (Example 137) :
    [395]
    [396] N- (benzoyl) -3- (R) -methyl-N '-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl] -piperazine in 0.5N sodium methoxide in methanol (5 ml) 0.5 ml of water was added to a stirred solution of (20 mg, 0.05 mmol). After stirring for 8 hours at room temperature, 10% HCl was added to the reaction mixture to pH = 6. N- (benzoyl) -3- (R) -methyl-N '-[(7-hydroxycarbonyl-indol-3-yl) oxoacetyl] piperazine (Example 137) was precipitated from the solution and was collected by filtration. It was.
    [397] TABLE 6
    [398]
    [399]
    [400]
    [401]
    [402]
    [403]
    [404] In the HPLC column of Table 6 and other tables, the superscript "A", "B" or "C" indicates the HPLC method used (ie, each refers to method A, B, or C).
    [405] Preparation of Examples 148-194 in Table 7
    [406] Step A.
    [407]
    [408] Tertiary-butyl 1-piperazinecarboxylate (1eq) and diisopropylethylamine (1.5eq) were added to substituted indole-3-glyoxylyl chloride V (1eq) in CH 2 Cl 2 at room temperature. The solution was stirred at room temperature for 2 hours and then analyzed by LC / MS to indicate the reaction was complete. The solvent was removed in vacuo and the residue obtained was diluted with ethyl acetate (250 ml) and diethyl ether (250 ml). The organic solution was washed with water (100mlx3) and brine (50ml), dried over MgSO 4 , filtered and concentrated. To the pale yellow solid was added 30 ml of 20% trifluoroacetic acid in CH 2 Cl 2 . The solution was concentrated and vacuum dried to afford the desired product VII. LC / MS analysis showed that this product was 100% pure and was used without further purification in the next step.
    [409] Step B.
    [410]
    [411] Dichloroethane (DCE) (1 ml) in piperazine indole-3-glyoxylamide (1 eq) or carboxylic acid (ROOH) (2 eq) and resin in DMF (dimethylformamide) when carboxylic acid is not soluble in DCE Combined 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (P-EDC) (0.21 mmol) was added. The reaction was shaken for 12 hours at room temperature. The product XLI was filtered and concentrated. The product with less than 70% purity was diluted in methanol and purified by Shimadzu automated preparative HPLC system.
    [412] Preparation of Example 195 in Table 7
    [413] A step
    [414]
    [415] DMAP (394 mg, 3.22 mmol) and EDC (616 mg) in a solution of tert-butyl-1-piperazine carboxylate (601 mg, 3.23 mmol) and 4-acetate imidazole (330 mg, 2.94 mmol) in dichloromethane (30 ml) , 3.22 mmol) was added. The reaction mixture was stirred at rt for 21.5 h. The solvent was removed in vacuo to give a white solid which was subjected to flash chromatography using gradient elution (100% EtOAc to 2% to 5% MeOH / EtOAc, sowl 1/5/95 / NH 3 (saturated solution) / MEOH / ETOAc). Purification by to give XLII as a white solid.
    [416] Step B
    [417]
    [418] To compound XXLII (130 mg, 0.464 mmol) was added a solution of HCl in dioxane (4M, 5 ml) and the mixture was stirred at rt for 3 h. Excess reagent was removed in vacuo to afford hydrochloride XLIII as a white solid (100% conversion).
    [419] C stage
    [420]
    [421] 4-fluoroindole glyoxyl chloride was coupled with XLIII as described above.
    [422] TABLE 7
    [423]
    [424]
    [425]
    [426] Synthesis of Examples 195-215 in Table 8
    [427] A step
    [428]
    [429] 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 hours. The crude product XLIV was diluted with CH 2 Cl 2 and washed with water, 0.1M HCl and brine. The organic phase was dried over MgSO 4 , filtered and concentrated. The crude material was used without further purification.
    [430] Step B
    [431]
    [432] To a solution of (R) -methyl piperazine (1.0 g, 10 mmol) in DMF (20 mL) was added a solution of pentafluorophenylester XLIV picolinic acid in DMF (2 mL) at room temperature. The reaction mixture was stirred at rt for 16 h. The product was diluted with CH 2 Cl 2 , washed with water and brine, dried over MgSO 4 , filtered and concentrated. The fresh XLV was purified by flash chromatography (100% EtOAc-50% MeOH / EtOAc).
    [433] Piperazine XLVI was prepared by a method similar to that outlined in steps A and B above.
    [434]
    [435] Diisopropylethylamine (1.5eq) was added dropwise at 0 ° C. to a mixture of 3- (R) -methyl-1-piperazincarboxylate XLV or XLVI with indole glyoxylchloride V (1eq) in THF. The solution was stirred again for 2 hours at room temperature and the crude compound obtained was purified by preparative HPLC.
    [436] TABLE 8
    [437]
    [438]
    [439] * (M-H) is measured in negative ionization mode.
    [440] Additional Analytical Data for Selected Compounds
    [441] 1- (4-methylbenzoyl) -4-[(1H-indol-3-yl) oxoacetyl] piperazine (Example 15)
    [442]
    [443] 1- (benzoyl) -4-[(1H-4-fluoroindol-3-yl) oxoacetyl] piperazine
    [444] (Example 19)
    [445]
    [446]
    [447] 1- (benzoyl) -4-[(1H-4,6-difluoroindol-3-yl) oxoacetyl] piperazine
    [448] (Example 42)
    [449]
    [450] 1- (benzoyl) -4-[(1H-5-fluoro-7-bromoindol-3-yl) oxoacetyl] piperazine
    [451] (Example 48)
    [452]
    [453] 1- (benzoyl) -4-[(1H-4-fluoro-7-trifluoroethoxyindol-3-yl)-
    [454] Oxoacetyl] piperazine (Example 51)
    [455]
    [456] 1- (benzoyl) -4-[(1H-4-bromo-7-fluoroindol-3-yl) oxoacetyl]
    [457] Piperazine (Example 55)
    [458]
    [459] Example 90
    [460]
    [461] N- (benzoyl)-(R) -3-methyl-N '-[(4-fluoro-indol-3-yl) -oxoacetyl] piperazine (Example 93)
    [462]
    [463] N- (benzoyl)-(S) -3-methyl-N '-[(4-fluoro-indol-3-yl) -oxoacetyl] piperazine (Example 94)
    [464]
    [465] N- (benzoyl) -2-methyl-N '-[(4-fluoro-indol-3-yl) -oxoacetyl] piperazine
    [466] (Example 95)
    [467]
    [468] N- (benzoyl) -3-hydroxymethyl-N '-[(4-fluoro-indol-3-yl) -oxoacetyl]
    [469] Piperazine (Example 99)
    [470]
    [471] N- (benzoyl)-(R) -3-methyl-N '-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl]
    [472] Piperazine (Example 102)
    [473]
    [474]
    [475] N- (benzoyl) -3-benzoylmethyl-N '-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl]
    [476] Piperazine (Example 98)
    [477]
    [478] N- (benzoyl) -2-methoxycarbonyl-N '-[(7-methoxycarbonyl-indol-3-yl)-
    [479] Oxoacetyl] -tetrahydropyrazine (Example 121)
    [480]
    [481]
    [482] N- (benzoyl) -2-propyl-N '-[(7-methoxycarbonyl-indol-3-yl) -oxoacetyl]
    [483] Piperazine (Example 126)
    [484]
    [485] N- (benzoyl)-(R) -3-methyl-N '-[(7-hydroxycarbonyl-indol-3-yl) -oxoacetyl]
    [486] Piperazine (Example 137)
    [487]
    [488] C 27 H 30 N 3 0 5 : calc. 420.16; Found 420.16. HPLC retention time: 1.43 min (Method A)
    [489] N- (benzoyl) -3-trifluoromethyl-N '-[(7-methoxycarbonyl-indol-3-yl)-
    [490] Oxoacetyl] -piperazine (Example 142)
    [491]
    [492] N- (benzoyl) -3-trifluoromethyl-N '-[(4-fluoro-indol-3-yl) oxoacetyl]-
    [493] Piperazine (Example 143)
    [494]
    [495] N- (benzoyl)-(R) -3-methyl-N '-[(4-fluoro-7-bromoindol-3-yl) -oxoacetyl]
    [496] Piperazine (Example 144)
    [497]
    [498] 1-[(pyri-2-yl) oxo] -4-[(1H-4-fluoro-indol-3-yl) -oxoacetyl] piperazine
    [499] (Example 166)
    [500]
    [501] 1-[(pyri-2-yl) oxo] -4-[(1H-4,7-difluoro-indol-3-yl) -oxoacetyl]-
    [502] Piperazine (Example 191)
    [503]
    [504] Example 195
    [505]
    [506] Example 212
    [507]
    [508] Methods for preparing compounds of Formula I are shown in Schemes 14-22 and further illustrated in Tables 14-18.
    [509]
    [510] Starting material Indole 1 (Scheme 14) is well known or can be readily prepared according to the methods of literature as described in Gribble, G (Ref. 24) or Bartoli et al. (Ref. 36). Indole 1 was treated with oxalyl chloride in THF (tetrahydrofuran) or ether according to the literature method (Lingens, F. et al., Ref. 25) to obtain the desired glyoxylchlorlai 2. The intermediate glyoxyl chloride 2 was coupled with benzoyl piperazine 3 under basic conditions (Desai, M. et al., Ref. 26) to afford compound 4.
    [511]
    [512] Indole glyoxamide 4 (Scheme 15) was treated with alkylating agent (R 40 X) under basic conditions (BEMP or NaH) to give N-alkylated derivative 5.
    [513]
    [514] N-acyl derivative 6 was prepared by treating indole glyoxamide 4 with acid chloride (R 40a COCl) in the presence of i-Pr 2 NEt (Scheme 16). On the other hand, bis-acylated products were prepared as shown in Scheme 17.
    [515]
    [516] Indole-3-glyoxyl chloride 2 was treated with tert-butyl 1-piperazinecarboxylate 7 to give a coupled product 8. Compound 9 was obtained by removing the Boc protecting group of compound 8 using 20% TFA / CH 2 Cl 2 . This product was coupled with acid chloride (R 40c COCl) to give bis-acyl product 10.
    [517]
    [518] Carbamate 11 was synthesized by treatment of indole glyoxamide 4 with chloroformate (R 40d OCOCl) in the presence of i-Pr 2 NEt or NaH (Scheme 18).
    [519]
    [520] Urease is prepared in three ways. Treatment of indole glyoxamide 4 directly with carbamoyl chloride (R a R b NCOCl) in the presence of i-Pr 2 NEt affords the desired urease 12 (Scheme 19)
    [521]
    [522] On the other hand, product 4 (Scheme 20) was treated with p-nitrophenylchloroformate and i-Pr 2 NEt to obtain p-nitrophenylcarbamate 13 which was exposed to amine (R a R b NH) to give the desired urea Gets 14
    [523]
    [524] Finally, indole glyoxamide 4 is reacted with isocyanate (R a NCO in the presence of i-Pr 2 NEt to give urea 15 (Scheme 21).
    [525]
    [526] Indole sulfonamide 15 (Scheme 22) is readily obtained by reacting indole glyoxamide 4 with sulfonyl chloride (R a SO 2 Cl) in the presence of i-Pr 2 NEt.
    [527] TABLE 9
    [528]
    [529]
    [530]
    [531] TABLE 10
    [532]
    [533]
    [534]
    [535] TABLE 11
    [536]
    [537] TABLE 12
    [538]
    [539] TABLE 13
    [540]
    [541] General Process for Preparation of Examples 1-34
    [542] Step A.
    [543]
    [544] To a solution of substituted Indole IV (1eq) in dry Et 2 O was added dropwise oxalylchloride (1.2eq) at 0 ° C. After 5 minutes, the reaction mixture was warmed to room temperature or heated to ˜35 ° C. overnight if necessary. Substituted indole-3-glyoxyl chloride V, an intermediate formed as a solid, was filtered and washed with dry ether (2 × 1 ml) to remove excess oxalyl chloride. The product was dried under vacuum to afford the desired glyoxyl chloride V.
    [545] If the reaction in Et 2 O was unsuccessful, the following process was adopted: Oxalylchloride (1.2 eq) was added dropwise at 0 ° C. to a solution of substituted Indole IV (1 eq) in dry THF. After 5 minutes, the reaction mixture was allowed to warm to room temperature or, if necessary, heated to ˜70 ° C. overnight under nitrogen atmosphere. After concentration in vacuo, the crude intermediate V obtained was used in the next step without further processing.
    [546] Step B
    [547]
    [548] To a solution of indole glyoxyl chloride IV (1 eq) in dry THF was added benzoylpiperazine (1 eq) at room temperature. The mixture was then cooled to 0 ° C. and then diisopropylamine (1.3eq) was added dropwise. After 5 minutes, the reaction mixture was warmed to room temperature and shaken for 3 hours. The crude product VI obtained was purified by preparative HPLC and characterized as shown in Table 14.
    [549] C stage
    [550]
    [551] To 5 ml vials that were dried beforehand, indole glyoxamide VIa (0.0416 μM), alkyl or aryl halide R 2 X (0.0478 μM), dry DMF (2 mL) and BEMP (0.0541 μM) were added at room temperature. The reaction was shaken at 70-80 ° C. for 4 hours in a heating block under a nitrogen atmosphere. After evaporation of the solvent, the crude compound was purified by preparative HPLC and characterized as shown in Table 14.
    [552] For Examples 33 and 34 the reaction was carried out in NMP and heated to 80 ° C. for 16 h before purification by preparative HPLC.
    [553] Preparation of Example 19
    [554]
    [555] To indole glyoxamide VIId (200 mg, 0.5 mmol) in THF (1 ml) in a sealed tube was added BEMP (0.2 equiv) and t-butylacrylate (0.37 ml, 2.5 mmol). The reaction mixture was heated to 90 ° C. overnight. The crude product was poured into 1M HCl and extracted with EtOAc. The organic phase was washed with saturated NaCl and dried over MgSO 4 , filtered and concentrated. The crude product was purified by flash chromatography (2: 1 EtOAc / hexanes) to give 195 mg of alkylated product 19.
    [556] Preparation of Example 21
    [557]
    [558] To ester 19 (956 mg) was added CH 2 Cl 2 (4 ml) followed by TFA (4 ml). The reaction mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the product was triturated with ether to give acid 21 (802 mg) as a white solid.
    [559] Preparation of Example 22
    [560]
    [561] To nitrile 17 (330 mg, 0.76 mmol) in EtOH / H 2 O (18 ml, 2: 1) was added hydroxyamine (189 mg, 2.72 mmol) followed by K 2 CO 3 (209 mg, 1.5 mmol). The reaction mixture was heated to 65 ° C. overnight. The solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine, dried over MgSO 4 , filtered and concentrated. The product was triturated with ether to give compound 22 (276 mg) as a white solid.
    [562] Preparation of Example 23
    [563]
    [564] To glyoxamide 22 (100 mg, 0.21 mmol) was added sequentially toluene (1.5 ml) and K 2 CO 3 (35 mg, 0.26 mmol) and phosgene in toluene (1.09 ml, 20% solution). The reaction mixture was heated to reflux for 2.6 hours. The mixture was then cooled to rt and stirred overnight. The product was filtered, concentrated and triturated with ether to give compound 23 (89 mg) as a golden solid.
    [565] TABLE 14
    [566]
    [567]
    [568]
    [569] General Process for the Preparation of Examples 35-56
    [570] A step
    [571]
    [572] Tert-butyl 1-piperazinecarboxylate (2.7 g, 14.45 mmol) and diisopropylethylamine (2.76 ml) in indole-3-glyoxylyl chloride I (3 g, 14.45 mmol) in CH 2 Cl 2 at room temperature , 15.9 mmol) was added. LC / MS analysis of the light brown solution after stirring for 2 hours at room temperature indicated the reaction to be complete. The solvent was removed in vacuo and the residue obtained was diluted with ethyl acetate (250 ml) and diethyl ether (250 ml). The organic solution was diluted with water (100 ml x 3) and diethyl ether (250 ml). The organic solution was washed with water (100mlx3) and brine (50ml), dried over MgSO 4 , filtered and concentrated. To this pale yellow solid was added 30 ml of 20% trifluoroacetic acid in CH 2 Cl 2 . The solution was concentrated and the light brown solid was dried in vacuo to give 3.5 g (95%) of product II. LC / MS analysis showed the product to be 100% pure and used as such without further purification in the next step.
    [573] Step B
    [574]
    [575] Substituted benzoyl chloride (3 equiv) followed by piperazine glyoxamide II (1 equiv) in dichloroethane (DCE) followed by i-Pr 2 NEt (4 equiv). The reaction mixture was stirred at rt for 16 h and then product III was purified by preparative HPLC.
    [576] General Process for the Preparation of Examples 35-56
    [577]
    [578] Acid chloride (3 equiv) substituted to indole glyoxamide VIb (1 equiv) in DCE was added followed by i-Pr 2 NEt (4 equiv). The reaction mixture was stirred at rt for 16 h and the product VIIa was purified by preparative HPLC.
    [579] TABLE 15
    [580]
    [581]
    [582] General Process for the Preparation of Examples 57-64
    [583]
    [584] To indole glyoxamide VI (1 equiv) in DCE was added chloroformate R 2 OCOCl (3 equiv) followed by i-Pr 2 NEt (4 equiv). The reaction mixture was stirred at rt for 16 h and then carbamate VIIb was purified by preparative HPLC.
    [585] TABLE 16
    [586]
    [587] General Process for Preparation of Examples 65-69
    [588]
    [589] To indole glyoxamide VIe (1 equiv) in NMP was added carbamoyl chloride R 1 R 2 NCOCl (2 equiv) followed by i-Pr 2 NET (4 equiv). The reaction mixture was stirred at rt for 16 h and then urea VIIe was purified by preparative HPLC.
    [590] General Process for Preparation of Examples 65-69
    [591] A step
    [592]
    [593] To indole glyoxamide VIIe (1 equiv) in DCE was added p-nitrophenylchloroformate (1.1 equiv) followed by i-Pr 2 NET (3 equiv). The reaction mixture was stirred at room temperature for 3 hours and then the crude product was used as such in the next step without further work-up or purification.
    [594] Step B
    [595]
    [596] Secondary amine R 1 R 2 NH was added to the crude p-nitrophenylcarbamate VIIIe. The reaction mixture was added 16 hours at room temperature and urea IXe was purified by preparative HPLC.
    [597] Preparation of Examples 65-69 in Table 17
    [598]
    [599] To indole glyoxamide VIIe (1 equiv) in CH 2 Cl 2 was added isocyanate (R 1 NCO) (2 equiv) followed by i-Pr 2 NEt (3 equiv). The reaction mixture was stirred at rt for 18 h and then the crude product was purified by preparative HPLC.
    [600] TABLE 17
    [601]
    [602] Preparation of Examples 77-71 in Table 18
    [603]
    [604] To indole groxamide XIf (1 equiv) in DCE was added sulfonyl chloride (2 equiv) followed by i-Pr 2 NEt (3 equiv). The reaction mixture was stirred for 3 hours at room temperature and then the crude product XIIf was purified by preparative HPLC.
    [605] TABLE 18
    [606]
    [607] Additional Analytical Data for Selected Compounds
    [608]
    [609]
    [610]
    [611]
    [612] The compounds of the present invention may be administered orally, parenterally (subcutaneously, intravenously, intramuscularly, intratranal injections or infusions) in the form of unit dosage compositions containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles ( infusion), inhalation nebulization, or rectal administration.
    [613] Thus, further provided are pharmaceutical compositions and methods of treatment for treating viral infections such as HIV infection and AIDS in accordance with the present invention. Such treatment consists of administering to a patient in need thereof a pharmaceutical composition containing a therapeutically effective amount of a compound of the invention and a pharmaceutical carrier.
    [614] Pharmaceutical compositions may be orally administrable suspensions or tablets; Nasal sprays, sterile injectable preparations, such as sterile injectable aqueous or oily suspensions or suppositories.
    [615] When administered orally as a suspension, these compositions are prepared according to techniques well known in the art of pharmacy, including microcrystalline cellulose to impart bulkiness, alginic acid or sodium alginate as suspending agent, methylcellulose as viscosity enhancer, as known in the art Sweeteners / flavours may be added. As instant release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants. .
    [616] Injectable solutions or suspensions are suitable non-toxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersions or wetting and suspending agents, It can be formulated according to the known art using fatty acids including, for example, sterile, blended, nonvolatile oils such as mono- or diglycerides, and oleic acid.
    [617] Compounds of the invention can be administered orally to humans in several doses ranging from 1 to 100 mg / kg body weight. One preferred dosage range is divided oral doses of 1 to 10 mg / kg body weight. Another preferred dosage range is divided orally administered at 1-20 mg / kg body weight. However, specific dosage levels and frequency of administration suitable for a particular patient can be altered and include the activity, metabolic stability and duration of action of the specific compound used, age, weight, general health, sex, diet, It may change at the time and manner of administration, the rate of excretion, the combination of the drug and the severity of the particular disease, and at the discretion of the practitioner.
    [618] Abbreviation
    [619] TFA trifluoroacetic acid
    [620] P-EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide reinforced polymer
    [621] EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
    [622] DCE 1,2-dichloroethane
    [623] DMF N, N-dimethylformamide
    [624] THF tetrahydrofuran
    [625] NMP N-methylpyrrolidone
    [626] BEMP 2-3 tert-Butylmino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-
    [627] Diazaphosphorin
    权利要求:
    Claims (13)
    [1" claim-type="Currently amended] Compounds having Formula I and pharmaceutically acceptable salts thereof
    Formula I

    During the formula:
    R 1 , R 2 , R 3 , R 4 and R 5 are H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 Alkynyl, halogen, CN, nitro, COOR 6 or XR 7 , wherein said alkyl and cycloalkyl are each optionally substituted with one to three identical or different halogens, amino, OH, CN or NO 2 ;
    R 6 is H, C 1-6 alkyl, or C 3-6 cycloalkyl, benzyl and each of said alkyl, cycloalkyl and benzyl is selected from 1 to 3 same or different halogen, amino, OH, CN or NO 2 Optionally substituted;
    X is O, S or NR 6 R 7 ;
    R 7 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl or C (O) R 8 , said alkyl And cycloalkyl is optionally substituted with 1 to 3 same or different halogens, OH, amino, CN or NO 2 , respectively;
    R 8 is H, C 1-6 alkyl or C 3-6 cycloalkyl;
    -W-

    And R9,R10, R11, R12,R13, R14, R15,R16, R17, R18,R19, R20,R21,R22Are each independently H, C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C3-6Cycloalkenyl, C2-6 Alkynyl, CR23R24OR25, COR26, COOR27Or C (O) NR28R29Wherein each of said alkyl and cycloalkyl is one to three same or different halogen, amino, OH, CN or NO2Optionally substituted by;
    R 23, R 24 , R 25, R 26 , R 27 , R 28, R 29 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 Cycloalkenyl or C 2-6 alkynyl;
    Ar is a 4-7 membered aromatic ring which may contain 1 to 5 heteroatoms independently selected from O, S, N or NR 6 , which aromatic ring may optionally be fused to Group B;
    B is a group selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; Or 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-tritianyl, indolinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolininyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, Heteroaryl group selected from 8-naphthyridinyl, putridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl;
    B and the 4-7 membered aromatic ring may each independently contain 1 to 5 substituents selected from R 30 , R 31 , R 32 , R 33 or R 34 ;
    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-dimethylisoxazolyl, isoxazolyl, 2-methylthiazolyl, thiazolyl , 2-thienyl, 3-thienyl, or pyrimidyl; p is 0-2;
    R 30 , R 31 , R 32 , R 33 and R 34 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, halogen, CN, nitro, C (O) R 35 , COXR 36 , hydroxyl, COOR 6 , hydroxymethyl, trifluoromethyl, trifluoromethoxy, O-[(C 1-4 )-Straight chain or branched alkyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, OC (O) C 1-6 alkyl, SC (O) C 1-6 alkyl, S (O) m C 1-6 alkyl, S (O) 2 NR a R b , amino, carboxyl, OZ, CH 2- (CH 2 ) p -Z, O- (CH 2 ) p -Z, (CH 2 ) p- OZ, CH = CH-Z, or XR 37 , wherein said alkyl and cycloalkyl may each be optionally substituted with 1 to 3 same or different halogen, amino, OH, CN or NO 2 ;
    m is 0-2;
    R 35 and R 36 are each independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
    R 37 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, C (O) R 38 or C (O OR 39 , wherein each of the alkyl and cycloalkyl may be optionally substituted by one to three same or different halogen, amino, OH, CN or NO 2 ;
    R 38 , R 39 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, said alkyl and cycloalkyl being each of 1 to 3 same or different halogens, amino, OH, CN or NO 2 . Optionally substituted by; Provided that R 39 is not H;
    R 40 is (CH 2 ) n -Y and n = 0-6;
    Y is selected from:
    (1) H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, halogen, CN, nitro, Ar, COOR 6 , COOAr, -CONR a R b , TR 6 , NR a R b , -NC (O) R a R b , -OC (O) R 6 , -C [N (R a ) 2 ] = NTR b , XR 6 , C (O) R 6 , -C (O) Ar, -S (O) R a or -S (O) 2 R a , provided that Y is -S (O) 2 R a, then R a is H Not);
    (2) a 4-7 membered heterocyclic ring which may be optionally substituted by R 6 and may contain 1-3 heteroatoms selected from O, S, SO, SO 2 , N, and NR 41 , wherein R 41 is selected from hydrogen, (C 1-4 )-straight chain or branched alkyl, (C 2-4 )-straight chain or branched alkenyl or alkynyl;
    T is S or O;
    Provided that R 1-5 , R 9-16 , and R 30-34 are not all H at the same time and Ar is phenyl;
    Provided that R 1-5 , R 9-16 and R 30-34 are not all H at the same time and Ar is 2-furyl).
    [2" claim-type="Currently amended] A compound according to claim 1, wherein Ar is phenyl, furyl, isoxazolyl, thiophenyl, pyrazolyl, pyridyl, benzofuryl, benzothiophenyl, indolyl, pyrazinyl, thiazolyl, imidazolyl, or thiazolyl .
    [3" claim-type="Currently amended] The compound of claim 1 wherein W is

    Phosphorus Compound:
    Wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each H;
    R 16 is methyl.
    [4" claim-type="Currently amended] The compound of claim 1, wherein R 2 is H, fluoro, or methoxy.
    [5" claim-type="Currently amended] The compound of claim 1 , wherein R 1 , R 3 and R 4 are each H. 7.
    [6" claim-type="Currently amended] A pharmaceutical composition containing an antiviral effective amount of a compound of any one of claims 1 to 6.
    [7" claim-type="Currently amended] The method of claim 6,
    (a) AIDS antiviral agents;
    (b) anti-infective agents;
    (c) immunomodulators; And
    (d) HIV influx inhibitors
    A pharmaceutical composition useful for the treatment of infection by HIV, which additionally contains an antiviral effective amount of an AIDS therapeutic agent selected from among.
    [8" claim-type="Currently amended] A method of treating a mammal infected with a virus comprising administering to the mammal infected the virus an antiviral effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof:
    Formula II

    During the formula:
    R 1 , R 2 , R 3 , R 4 and R 5 are H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 Alkynyl, halogen, CN, nitro, COOR 6 or XR 7 , wherein said alkyl and cycloalkyl are each optionally substituted with one to three identical or different halogens, amino, OH, CN or NO 2 ;
    R 6 is H, C 1-6 alkyl, or C 3-6 cycloalkyl, benzyl and each of said alkyl, cycloalkyl and benzyl is selected from 1 to 3 same or different halogen, amino, OH, CN or NO 2 Optionally substituted;
    X is O, S or NR 6 R 7 ;
    R 7 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl or C (O) R 8 , said alkyl And cycloalkyl is optionally substituted with 1 to 3 same or different halogens, OH, amino, CN or NO 2 , respectively;
    R 8 is H, C 1-6 alkyl or C 3-6 cycloalkyl;
    -W-

    And R9,R10, R11, R12,R13, R14, R15,R16, R17, R18,R19, R20,R21,R22Are each independently H, C1-6Alkyl, C3-6Cycloalkyl, C2-6Alkenyl, C3-6Cycloalkenyl, C2-6 Alkynyl, CR23R24OR25, COR26, COOR27Or C (O) NR28R29Wherein each of said alkyl and cycloalkyl is one to three same or different halogen, amino, OH, CN or NO2Optionally substituted by;
    R 23, R 24 , R 25, R 26 , R 27 , R 28, R 29 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 Cycloalkenyl or C 2-6 alkynyl;
    Ar is a 4-7 membered aromatic ring which may contain 1 to 5 heteroatoms independently selected from O, S, N or NR 6 , which aromatic ring may optionally be fused to Group B;
    B is a group selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; Or 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-tritianyl, indolinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolininyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, Heteroaryl group selected from 8-naphthyridinyl, putridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl;
    B and the 4-7 membered aromatic ring may each independently contain 1 to 5 substituents selected from R 30 , R 31 , R 32 , R 33 or R 34 ;
    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-dimethylisoxazolyl, isoxazolyl, 2-methylthiazolyl, thiazolyl , 2-thienyl, 3-thienyl, or pyrimidyl; p is 0-2;
    R 30 , R 31 , R 32 , R 33 and R 34 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, halogen, CN, nitro, C (O) R 35 , COXR 36 , hydroxyl, COOR 6 , hydroxymethyl, trifluoromethyl, trifluoromethoxy, O-[(C 1-4 )-Straight chain or branched alkyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, OC (O) C 1-6 alkyl, SC (O) C 1-6 alkyl, S (O) m C 1-6 alkyl, S (O) 2 NR a R b , amino, carboxyl, OZ, CH 2- (CH 2 ) p -Z, O- (CH 2 ) p -Z, (CH 2 ) p- OZ, CH = CH-Z, or XR 37 , wherein said alkyl and XR 37 , said alkyl and cycloalkyl, may each be optionally substituted with 1 to 3 same or different halogen, amino, OH, CN or NO 2 ;
    m is 0-2;
    R 35 and R 36 are each independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
    R 37 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, C (O) R 38 or C (O OR 39 , wherein each of the alkyl and cycloalkyl may be optionally substituted by one to three same or different halogen, amino, OH, CN or NO 2 ;
    R 38 , R 39 are each independently H, C 1-6 alkyl, C 3-6 cycloalkyl, said alkyl and cycloalkyl being each of 1 to 3 same or different halogens, amino, OH, CN or NO 2 . Optionally substituted by; Provided that R 39 is not H;
    R 40 is (CH 2 ) n -Y and n = 0-6;
    Y is selected from:
    (1) H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, C 2-6 alkynyl, halogen, CN, nitro, Ar, COOR 6 , COOAr, -CONR a R b , TR 6 , NR a R b , -NC (O) R a R b , -OC (O) R 6 , -C [N (R a ) 2 ] = NTR b , XR 6 , C (O) R 6 , -C (O) Ar, -S (O) R a or -S (O) 2 R a , provided that Y is -S (O) 2 R a, then R a is H Not);
    (2) a 4-7 membered heterocyclic ring which may be optionally substituted by R 6 and may contain 1-3 heteroatoms selected from O, S, SO, SO 2 , N, and NR 41 , wherein R 41 is selected from hydrogen, (C 1-4 )-straight chain or branched alkyl, (C 2-4 )-straight chain or branched alkenyl or alkynyl;
    T is S or O.
    [9" claim-type="Currently amended] The method of claim 8, wherein the virus is HIV.
    [10" claim-type="Currently amended] The method of claim 8, wherein Ar is phenyl, furyl, isoxazolyl, thiophenyl, pyrazolyl, pyridyl, benzofuryl, benzothiophenyl, indolyl, pyrazinyl, thiazolyl, imidazolyl or thiadiazolyl. .
    [11" claim-type="Currently amended] 9. The compound of claim 8 wherein W is
    How to be:
    In the formula,
    R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each H;
    R 16 is methyl.
    [12" claim-type="Currently amended] The method of claim 8, wherein R 2 is H, fluoro or methoxy
    [13" claim-type="Currently amended] The method of claim 8, wherein R 1 , R 3 and R 4 are each H. 10.
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    同族专利:
    公开号 | 公开日
    CA2340663A1|2000-12-21|
    BR0006675A|2002-01-22|
    HU0200734A2|2002-10-28|
    IL141224D0|2002-03-10|
    NO20010743D0|2001-02-14|
    EP1105135A4|2001-12-12|
    NO20010743L|2001-04-05|
    WO2000076521A1|2000-12-21|
    AU761719B2|2003-06-05|
    CZ2001559A3|2002-03-13|
    PL346117A1|2002-01-28|
    UY26205A1|2001-01-31|
    PE20010286A1|2001-05-20|
    HU0200734A3|2002-11-28|
    JP2003501476A|2003-01-14|
    AU5044500A|2001-01-02|
    CN1320037A|2001-10-31|
    TR200100671T1|2001-07-23|
    ID28033A|2001-05-03|
    EP1105135A1|2001-06-13|
    US6469006B1|2002-10-22|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-06-15|Priority to US13921399P
    1999-06-15|Priority to US60/139,213
    2000-05-24|Application filed by 말라테스티닉 니콜라스 피., 브리스톨-마이어즈 스퀴브 컴페니
    2000-05-24|Priority to PCT/US2000/014359
    2001-07-31|Publication of KR20010072471A
    优先权:
    申请号 | 申请日 | 专利标题
    US13921399P| true| 1999-06-15|1999-06-15|
    US60/139,213|1999-06-15|
    PCT/US2000/014359|WO2000076521A1|1999-06-15|2000-05-24|Antiviral indoleoxoacetyl piperazine derivatives|
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