Patent Publication Number: US-2009221559-A1

Title: Benzodiazepines as hcv inhibitors

Description:
This application claims priority of the benefits of the filing of PCT/EP2006/065938 filed Sep. 1, 2006; EP 05108058.8 filed Sep. 2, 2005; and EP 05110606 filed Nov. 10, 2005. The complete disclosures of the aforementioned related patent applications are hereby incorporated herein by reference for all purposes. 
    
    
     The present invention relates to the use of benzodiazepines as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections. In addition, the present invention relates to compounds per se. The present invention also concerns processes for the preparation of such compounds, pharmaceutical compositions comprising them, and combinations of said compounds with other anti-HCV agents. 
     Following its discovery in 1989 as the agent implicated in the majority of viral non-A, non-B hepatitis (Choo et al.,  Science  244, 359-362, 1989), hepatitis C virus (HCV) has become a focus of considerable medical research (Lauer, G. M and Walker, B. D.,  New Eng. J. Med.  345, 41-52, 2001). HCV is a member of the Flaviviridae family of viruses in the hepacivirus genus, and is closely related to the flavivirus genus, which includes a number of viruses implicated in human disease, such as dengue virus and yellow fever virus, and to the animal pestivirus family, which includes bovine viral diarrhea virus (BVDV). HCV is a positive-sense, single-stranded RNA virus, with a genome of around 9,600 bases. The genome comprises both 5′ and 3′ untranslated regions which adopt RNA secondary structures, and a central open reading frame that encodes a single polyprotein of around 3,010-3,030 amino acids. The polyprotein encodes ten gene products which are generated from the precursor polyprotein by an orchestrated series of co- and posttranslational endoproteolytic cleavages mediated by both host and viral proteases. The viral structural proteins include the core nucleocapsid protein, and two envelope glycoproteins E1 and E2. The non-structural (NS) proteins encode some essential viral enzymatic functions (helicase, polymerase, protease), as well as proteins of unknown function. Replication of the viral genome is mediated by an RNA-dependent RNA polymerase, encoded by non-structural protein 5b (NS5b). In addition to the polymerase, the viral helicase and protease functions, both encoded in the bifunctional NS3 protein, have been shown to be essential for replication of HCV RNA in chimpanzee models of infection (Kolykhalov, A. A., Mihalik, K., Feinstone, S. M., and Rice, C. M.  J. Virol.  74, 2046-2051, 2000). In addition to the NS3 serine protease, HCV also encodes a metalloproteinase in the NS2 region. 
     HCV replicates preferentially in hepatocytes but is not directly cytopathic, leading to persistent infection. In particular, the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection. There are 6 major HCV genotypes and more than 50 subtypes, which are differently distributed geographically. HCV type 1 is the predominant genotype in the US and Europe. For instance, HCV type 1 accounts for 70 to 75 percent of all HCV infections in the United States. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response to therapy. An estimated 170 million persons worldwide are infected with hepatitis C virus (HCV). Following the initial acute infection, a majority of infected individuals develop chronic hepatitis, which can progress to liver fibrosis leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma) (National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C.  Hepatology,  36, 5 Suppl. S3-S20, 2002). Liver cirrhosis due to HCV infection is responsible for about 10,000 deaths per year in the U.S.A. alone, and is the leading cause for liver transplantations. Transmission of HCV can occur through contact with contaminated blood or blood products, for example following blood transfusion or intravenous drug use. The introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence. However, given the slow progression to the end-stage liver disease, the existing infections will continue to present a serious medical and economic burden for decades (Kim, W. R.  Hepatology,  36, 5 Suppl. S30-S34, 2002). 
     The treatment of this chronic disease is an unmet clinical need, since current therapy is only partially effective and limited by undesirable side effects. 
     Current HCV therapies are based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. This combination therapy yields a sustained virologic response in more than 40% of patients infected by genotype 1 viruses and about 80% of those infected by genotypes 2 and 3. Beside the limited efficacy on HCV type 1, combination therapy has significant side effects and is poorly tolerated in many patients. For instance, in registration trials of pegylated interferon and ribavirin, significant side effects resulted in discontinuation of treatment in approximately 10 to 14 percent of patients. Major side effects of combination therapy include influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. The development of more effective, convenient and tolerated treatments is a major public health objective. 
     One area of particular focus has been the search for inhibitors of the NS5b RNA-dependent RNA polymerase referred to above as close structural homologs of this polymerase do not exist within the uninfected host cell and such inhibitors will provide a more specific mode of action. Inhibitors which are currently under investigation can be classified as either nucleoside inhibitors (NIs) or non-nucleoside inhibitors (NNIs). NIs directly compete with nucleotide substrates for binding to highly conserved active sites. Greater specificity may be achieved by NNIs, which may interact outside of the highly conserved active site at a unique allosteric site common only to structurally related polymerases. Preliminary clinical trials have resulted in a high failure rate, thereby highlighting the need to pursue the search for novel NS5b inhibitors. 
     Thus, there is a high medical need for low molecular weight compounds that lead to an inhibition of HCV replication. 
     It has been surprisingly found that certain benzodiazepine derivatives exhibit antiviral activity in mammals infected with HCV. These compounds are therefore useful in treating or combating HCV infections. 
     WO00/66106 discloses 1,4-benzodiazepine-2-one and 1,4-benzodiazepine-2,5-dione compounds, enantiomers, pharmaceutically acceptable salts, prodrugs or derivatives of the benzodiazepine compounds. These benzodiazepine compounds can be used to treat a variety of dysregulatory disorders related to cellular death, such as autoimmune disorders, inflammatory conditions, hyperproliferative conditions, viral infections, and atherosclerosis. 
     WO99/58117 relates to the use of compounds for reducing apoptosis. Said compounds are ligands of benzodiazepine peripheral receptor. 
     WO00/12547 relates to 1,4-benzodiazepines or 1,4-benzothiazepines derivatized with a peptide that can inhibit the interaction between annexin and annexin binding proteins, in particular, the interaction between annexin and viral proteins that bind annexins such as the HBsAg protein of HBV, glycoprotein B of the cytomegalovirus or any annexin binding protein from the influenza virus. These 1,4-benzodiazepines or 1,4-benzo-thiazepines derivatives can be used to prevent or treat diseases in which interactions between annexin family members and annexin binding proteins are involved such as HBV and/or HDV infections, cytomegalovirus infections or influenza virus infections. 
     EP0574781 discloses 2-amino-5-heterocyclic-substituted-1,4-benzodiazepines and their use in the treatment of AIDS and AIDS-related diseases. 
     Cortés E C et al.: “Efficient synthesis and spectral determination of 11-[(o-; m-; and p-substituted)-phenyl]-8-chloro-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones”. Journal of Heterocyclic Chemistry 2004, 41(2), 277-280. This publication discloses the synthesis of 11-aryl-8-chloro-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones, with possible pharmacological activity in the central nervous system. 
     Cortés Cortés E et al.: “Synthesis and spectral properties of 11-[(o-; and p-substituted)-phenyl]-8-[(o-; m-; p-methoxy)phenylthio]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones”. Journal of Heterocyclic Chemistry 2002, 39(1), 55-59. This publication discloses the preparation of twelve 2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones which have potentially useful pharmacological properties; by condensation and cyclization between 3-{[4-(o-; m-; p-methoxy)-phenylthio]-1,2-phenylenediamine}-5,5-dimethyl-2-cyclohexenone with (o-; and p-substituted)benzaldehyde. 
     Matsuo K et al.: “Synthesis and reactions of 11-substituted 3,3-dimethyl-2,3,4,5-tetra-hydro-1H-dibenzo[b,e][1,4]diazepin-1-ones”. Chemical &amp; Pharmaceutical Bulletin 1985, 33(9), 4057-62. This publication discloses 11-substituted 3,3-dimethyl-2,3,4,5-tetrahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones which are prepared by dehydrative cyclization of 3-(2-acylaminoanilino)-5,5-dimethyl-2-cyclohexen-1-ones with polyphosphoric acid, showing moderate analgesic activity in mice at 50 mg/kg. 
     WO 04/001058 describes certain 2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo-[b,e][1,4]diazepin-1-one derivatives as transcription modulating agents useful as anti-infective agents. 
     US 2005/123906 describes certain 2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]-diazepin-1-one derivatives as protein modulating agents. 
     WO 05/007141 describes certain 2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo-[b,e][1,4]diazepin-1-one derivatives as inhibitors of RING domain ubiquitin ligases. 
     US 2003/229065 describes certain 2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo-[b,e][1,4]diazepin-1-one derivatives as transcription modulating agents useful as anti-infective agents. 
     Other 2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one derivatives are described in the following references, generally without reference to any specific pharmaceutical utility:
     Chemistry of Heterocyclic Compounds (New York, N.Y., United States)(Translation of Khimiya Geterotsiklicheskikh Soedinenii) (2004), 40(7), 949-955;   Journal of Heterocyclic Chemistry (2004), 41(2), 277-280; Rigas Tehniskas Universitates Zinatniskie Raksti, Serija 1:   Materialzinatne un Lietiska Kimija (2002), 4, 84-88; Rigas Tehniskas Universitates Zinatniskie Raksti, Serija 1:   Materialzinatne un Lietiska Kimija (2001), (3), 24-27;   Journal of Heterocyclic Chemistry (2002), 39(1), 55-59;   THEOCHEM (1999), 489(1), 7-17;   Heterocyclic Communications (1996), 2(1), 47-50;   Alexandria Journal of Pharmaceutical Sciences (1993), 7(2), 137-9;   Journal of the Chinese Chemical Society (Taipei, Taiwan) (1993), 40(2), 189-94   Journal of the Indian Chemical Society (1992), 69(9), 596-8;   Bulletin des Societes Chimiques Belges (1992), 101(9), 801-6;   Chemistry Express (1992), 7(2), 133-6;   Journal of the Indian Chemical Society (1990), 67(7), 609-10;   Acta Crystallographica, Section C: Crystal Structure Communications (1987), C43(6), 1161-3;   Chemical &amp; Pharmaceutical Bulletin (1985), 33(9), 4057-62;   Journal of Heterocyclic Chemistry (1982), 19(2), 321-6;   JP 47029385; and   Chemical &amp; Pharmaceutical Bulletin (1972), 20(7), 1588-9.   

     The present invention thus relates to the use of the compounds of the formula (I) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV, said compounds being benzodiazepines of the formula (I): 
     
       
         
         
             
             
         
       
     
     and the salts, stereoisomeric forms, and racemic mixtures thereof in which
     R 1a  and R 1b  are independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 2  is hydrogen;
       C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 3-7 cycloalkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl,   C 3-7 cycloalkylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 2-6 alkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-7 cycloalkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-8 cycloalkenylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   aryl 2 ; or   Het 2 ;   
       R 6  is hydrogen;
       C 1-6 alkyl optionally substituted with carboxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy-carbonyl, Het-C 1-6 alkylaminocarbonyl;   —C(═O)—C 1-7 alkyl, the C 1-7 alkyl being optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl, and carboxyl;   —C(═O)—C 2-6 alkenyl;   —C(═O)—C 3-7 cycloalkyl, the C 3-7 cycloalkyl being optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;   —C(═O)-aryl;   —C(═O)-Het;   —C(═O)—NR 12a R 12b ,   in which each R 12a  and R 12b  is, independently, hydrogen, C 3-7 cycloalkyl, aryl, Het, or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;   —C(═O)—OR 13a ,   in which R 13  is hydrogen, C 2-6 alkenyl, C 3-7 cycloalkyl, Het, or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   —C(═O)—C 1-6 alkyloxycarbonylC 1-6 alkyl;   —C(═O)—Het-thioC 1-6 alkyl; or   —C(═O)-Het-oxyC 1-6 alkyl; or   
       R 2  and R 6 , together with the intervening grouping in formula (I) of sub-formula:   

     
       
         
         
             
             
         
       
         
         
           
             form a ring of formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         R 4a  and R 4b  are independently hydrogen; halo; cyano; C 1-6 alkyl optionally substituted with halo, hydroxy, Het, —OR 14a , or —NR 14a R 14b ; C 1-6 alkoxy optionally substituted with amino, hydroxy, C 1-6 alkoxy, hydroxycarbonyl, aryl, or Het; aryloxy; Het-oxy; carboxyl; C 1-6 alkylcarbonyloxy; C 1-6 alkoxycarbonyl; arylcarbonyl; —NR 14a R 14b ; or —C(═O)—NR 14a R 14b ;
       in which each R 14a  and R 14b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, mono- or diC 1-6 alkylamino, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;   
     
         R 5  is hydrogen; C 3-7 cycloalkyl; or C 1-6 alkyl optionally substituted with a C 3-7 cyclo-alkyl, aryl, Het, —C(═O)NR 15a R 15b , —NR 15a R 15b , —C(═O)R 17 , —NR 15a C(═O)R 17 , —NR 15a SO p R 18 , —SO p R 18 , —SO p NR 15a R 15b , —C(═O)OR 16 , or —NR 15a C(═O)OR 16a  in which
       p is 0, 1 or 2;   each R 15a  and R 15b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 16  is hydrogen; C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 16a  is C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 17  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or aryl;   R 18  is hydrogen; polyhaloC 1-6 alkyl; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl, aryl or Het;
 
aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally independently substituted with
   
     
         (a) one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, C 1-6 alkylthio, polyhalo-C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, cyanoC 1-6 alkyl, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl; or 
         (b) phenyl- or naphthyl-alkoxy optionally substituted with one, two or three substituents defined for (a) above; or 
         (c) phenyl- or naphthyl-carbonyloxy optionally substituted with one, two or three substituents defined for (a) above; and
 
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, aminocarbonyl, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl;
 
aryl 2  as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally independently substituted with one, two or three substituents selected from
       (a) halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, C 1-6 alkylthio, polyhalo-C 1-6 alkoxy, C 1-6 alkylcarbonyloxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkyl-carbonyl-piperazinyl, morpholinyl; phenyl- or napthyl-alkoxy optionally substituted with halogen; phenyl- or naphthyl-carbonyloxy optionally substituted with halogen, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkyl-carbonyl-piperazinyl, morpholinyl; or   (b) a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 20 —, —NR 20 —C 1-6 alkanediyl-, —NR 20 —CO—C 1-6 alkanediyl-, —CO—NR 20 —C 1-6 alkanediyl-, —O—, —CO—NR 20 —, —NR 20 —CO—, —NR 20 —SO 2 —, —SO 2 —NR 20 —, —O—C 1-6 alkanediyl-, —O—CO—, —CO—, —O—CO—C 1-6 alkanediyl-, —S— or —S—C 1-6 alkanediyl-
 
in which R 20  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;
 
Het 2  as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, oxo, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, morpholinyl; or Het 2  is substituted with a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 21 —, —NR 21 —C 1-6 alkanediyl-, —NR 21 —CO—C 1-6 alkanediyl-, —CO—NR 21 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S—, or —S—C 1-6 alkanediyl-
   in which R 21  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxyaryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl.   
     
       
    
     In one embodiment, the invention relates to the use of the compounds of formula (I) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV, said compounds being benzodiazepines of the formula (I): 
     
       
         
         
             
             
         
       
     
     and the salts, stereoisomeric forms, and racemic mixtures thereof in which
     R 1a  and R 1b  are independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 2  is hydrogen;
       C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 3-7 cycloalkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl,   C 3-7 cycloalkylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 2-6 alkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-7 cycloalkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-8 cycloalkenylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   aryl 2 ; or   Het 2 ;   
       R 6  is hydrogen;
       C 1-6 alkyl;   —C(═O)—C 1-7 alkyl, the C 1-7 alkyl being optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl, and carboxyl;   —C(═O)—C 3-7 cycloalkyl, the C 3-7 cycloalkyl being optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;   —C(═O)-aryl;   —C(═O)—Het;   —C(═O)—NR 12a R 12b ,
           in which each R 12a  and R 12b  is, independently, hydrogen, C 3-7 cycloalkyl, aryl, Het, or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   
           —C(═O)—OR 13a ,
           in which R 13  is hydrogen, C 2-6 alkenyl, C 3-7 cycloalkyl, Het, or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   
           —C(═O)—C 1-6 alkyloxycarbonylC 1-6 alkyl;   —C(═O)—Het-thioC 1-6 alkyl; or   —C(═O)—Het-oxyC 1-6 alkyl; or   
       R 2  and R 6 , together with the intervening grouping in formula (I) of sub-formula:   

     
       
         
         
             
             
         
       
         
         
           
             form a ring of formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         R 4a  and R 4b  are independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, arylcarbonyl or —NR 14a R 4b ;
       in which each R 14a  and R 14b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhalo-C 1-6 alkoxy, and C 3-7 cycloalkyl;   
     
         R 5  is hydrogen; C 3-7 cycloalkyl; or C 1-6 alkyl optionally substituted with a C 3-7 cyclo-alkyl, aryl, Het, —C(═O)NR 15a R 15b , —NR 15a R 15b , —C(═O)R 17 , —NR 15a C(═O)R 17 , —NR 15a SO p R 18 , is —SO p R 18 , —SO p NR 15a R 15b , —C(═O)OR 16 , or —NR 15a C(═O)OR 16a  in which
       p is 0, 1 or 2;   each R 15a  and R 15b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 16  is hydrogen; C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 16a  is C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 17  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or aryl;   R 18  is hydrogen; polyhaloC 1-6 alkyl; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl, aryl or Het;
 
aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally independently substituted with
   
     
         (a) one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, C 1-6 alkylthio, polyhalo-C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl; or 
         (b) phenyl- or naphthyl-alkoxy optionally substituted with one, two or three substituents defined for (a) above; or 
         (c) phenyl- or naphthyl-carbonyloxy optionally substituted with one, two or three substituents defined for (a) above; and
 
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl;
 
aryl 2  as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally independently substituted with
       (c) one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, C 1-6 alkylthio, polyhalo-C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkyl-carbonyl-piperazinyl, morpholinyl; phenyl- or napthyl-alkoxy optionally substituted with halogen; phenyl- or naphthyl-carbonyloxy optionally substituted with halogen, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, morpholinyl; or   (d) a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 20 —, —NR 20 —C 1-6 alkanediyl-, —NR 20 —CO—C 1-6 alkanediyl-, —CO—NR 20 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S— or —S—C 1-6 alkanediyl-
 
in which R 20  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;
 
Het 2  as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, oxo, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, morpholinyl; or Het 2  is substituted with a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 21 —, —NR 21 —C 1-6 alkanediyl-, —NR 21 —CO—C 1-6 alkanediyl-, —CO—NR 21 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S—, or —S—C 1-6 alkanediyl-
   in which R 21  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxyaryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl.   
     
       
    
     In a further embodiment, the present invention relates to the following novel compounds of formula (I) per se, 
     
       
         
         
             
             
         
       
     
     and the salts, stereoisomeric forms, and racemic mixtures thereof in which
     R 1a  and R 1b  are independently, hydrogen, aryl, Het, or C 1-6 alkyl;   R 2  is C 2-6 alkenyl optionally substituted independently with one or two substituents selected from halo, and aryl;
       aryl 2 ; or   Het 2 ;   
       R 6  is hydrogen;
       C 1-6 alkyl optionally substituted with carboxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy-carbonyl, Het-C 1-6 alkylaminocarbonyl;   —C(═O)—C 1-7 alkyl, the C 1-7 alkyl being optionally substituted independently with one, two or three substituents selected from halo, aryl, and cyano;   —C(═O)—C 2-6 alkenyl;   —C(═O)-aryl;   —C(═O)-Het;   —C(═O)—NR 12a R 12b ;   in which each R 12a  and R 12b  is, independently, hydrogen, aryl, or C 1-6 alkyl optionally substituted independently with one or two substituents selected from aryl and Het;   
       R 4a  and R 4b  are independently hydrogen; halo; cyano; C 1-6 alkyl optionally substituted with halo, hydroxy, Het, —OR 14a , or —NR 14a R 14b ; C 1-6 alkoxy optionally substituted with amino, hydroxy, C 1-6 alkoxy, hydroxycarbonyl, aryl, or Het; aryloxy; Het-oxy; carboxyl; C 1-6 alkylcarbonyloxy; C 1-6 alkoxycarbonyl; —NR 14a R 14b ; or
       —C(═O)—NR 14a R 14b ;
           in which each R 14a  and R 14b  is, independently, hydrogen; or C 1-6 alkyl optionally substituted independently with one or two substituents selected from mono- or diC 1-6 alkylamino, and Het;   
           
       R 5  is hydrogen; or C 1-6 alkyl optionally substituted with aryl;
 
aryl as a group or part of a group is phenyl or naphthyl, each of which may be optionally independently substituted with
   (a) one, two or three substituents selected from halo, C 1-6 alkyl, trifluoromethyl, C 1-6 alkoxy, carboxyl, C 1-6 alkylcarbonyl, cyano, cyanoC 1-6 alkyl, nitro, mono- or diC 1-6 alkylamino; or   (b) phenyl-alkoxy optionally substituted with one, two or three substituents defined for (a) above;
 
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of C 1-6 alkyl, and aminocarbonyl;
 
aryl 2  as a group or part of a group is phenyl or naphthyl, each of which may be optionally independently substituted with one, two or three substituents selected from
   (a) halo, C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkylcarbonyloxy, carboxyl, nitro, mono- or diC 1-6 alkylamino; or   (b) a radical of formula —(X) n -aryl or —(X) n -Het in which n is 1 and X is —O—, —CO—NH—, —NH—CO—, —NH—SO 2 —, —SO 2 —NH—, —O—C 1-6 alkanediyl-, —O—CO—, —CO—;
 
Het 2  as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, aryl, and nitro.
   

     In one embodiment, the invention relates to the use of the compounds of formula (Ia) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV, said compounds being acylated benzodiazepines of the formula (Ia): 
     
       
         
         
             
             
         
       
     
     and the salts, stereoisomeric forms, and racemic mixtures thereof in which
     R 1a  and R 1b  are independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 2  is hydrogen;
       C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 3-7 cycloalkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl,   C 3-7 cycloalkylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 2-6 alkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-7 cycloalkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-8 cycloalkenylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   aryl 2 ; or   Het 2 ;   
       R 3  is C 1-7 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, and Het; or with a cyano, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl or carboxyl;
       —C(═O)—C 2-6 alkenyl;   C 3-7 cycloalkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl,   aryl;   Het;   —NR 12a R 12b , OR 13a ;
           in which each R 12a  and R 12b  is, independently, hydrogen, C 3-7 cycloalkyl, aryl, Het, or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 13  is hydrogen, C 2-6 alkenyl, C 3-7 cycloalkyl, Het, or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   
           C 1-6 alkyloxycarbonylC 1-6 alkyl;   Het-thioC 1-6 alkyl; or   Het-oxyC 1-6 alkyl; or   
       R 2  and R 3 , together with the intervening grouping in formula (I) of sub-formula:   

     
       
         
         
             
             
         
       
         
         
           
             form a ring of formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         R 4a  and R 4b  are independently hydrogen; halo; cyano; C 1-6 alkyl optionally substituted with halo, hydroxy, Het, —OR 14a , or —NR 14a R 14b ; C 1-6 alkoxy optionally substituted with amino, hydroxy, C 1-6 alkoxy, hydroxycarbonyl, aryl, or Het; aryloxy; Het-oxy; carboxyl; C 1-6 alkylcarbonyloxy; C 1-6 alkoxycarbonyl; arylcarbonyl;
       —NR 14a R 14b ; or —C(═O)—NR 14a R 14b ;
           in which each R 14a  and R 14b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, mono- or diC 1-6 alkylamino, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;   
           
     
         R 5  is hydrogen; C 3-7 cycloalkyl; or C 1-6 alkyl optionally substituted with a C 3-7 cyclo-alkyl, aryl, Het, —C(═O)NR 15a R 15b , —NR 15a R 15b , —C(═O)R 17 , —NR 15a C(═O)R 17 , —NR 15a SO p R 18 , —SO p R 18 , —SO p NR 15a R 15b , —C(═O)R 16 , or —NR 15a C(═O)OR 16a  in which
       p is 0, 1 or 2;   each R 15a  and R 15b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 16  is hydrogen; C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 16a  is C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 17  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or aryl;   R 18  is hydrogen; polyhaloC 1-6 alkyl; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl, aryl or Het;
 
aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally independently substituted with
   
     
         (a) one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, cyanoC 1-6 alkyl, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl; or 
         (b) phenyl- or naphthyl-alkoxy optionally substituted with one, two or three substituents defined for (a) above; or 
         (c) phenyl- or naphthyl-carbonyloxy optionally substituted with one, two or three substituents defined for (a) above; and
 
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, aminocarbonyl, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl;
 
aryl 2  as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally substituted with one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, phenyl- or napthyl-alkoxy optionally substituted with halogen; mono- or di-alkylamino; C 1-6 alkylcarbonyloxy; nitro; polyhaloC 1-6 alkoxy; phenyl- or naphthyl-carbonyloxy optionally substituted with halogen, polyhalo-C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, mono or dialkylamino, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, morpholinyl; or aryl 2  is substituted with a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and
 
X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 20 —, —NR 20 —C 1-6 alkanediyl-, —NR 20 —CO—C 1-6 alkanediyl-, —CO—NR 20 —C 1-6 alkanediyl-, —O—, —CO—NR 20 —, —NR 20 —CO—, —NR 20 —SO 2 —, —SO 2 —NR 20 —, —O—C 1-6 alkanediyl-, —O—CO—, —CO—, —O—CO—C 1-6 alkanediyl-, —S— or —S—C 1-6 alkanediyl-
       in which R 20  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;
 
Het 2  as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, morpholinyl; or Het 2  is substituted with a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 21 —, —NR 21 —C 1-6 alkanediyl-, —NR 21 —CO—C 1-6 alkanediyl-, —CO—NR 21 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S—, —S—C 1-6 alkanediyl-
   in which R 21  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxyaryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl.   
     
       
    
     In one embodiment, the invention relates to the use of the compounds of formula (Ia) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV, said compounds being acylated benzodiazepines of the formula (Ia): 
     
       
         
         
             
             
         
       
     
     and the salts, stereoisomeric forms, and racemic mixtures thereof in which
     R 1a  and R 1b  are independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 2  is hydrogen;
       C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 3-7 cycloalkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl,   C 3-7 cycloalkylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 2-6 alkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-7 cycloalkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-8 cycloalkenylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   aryl 2 ; or   Het 2 ;   
       R 3  is C 1-7 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, and Het; or with a cyano, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl or carboxyl;
       C 3-7 cycloalkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy, C 3-7 cycloalkyl,   aryl;   Het;   NR 12a R 12b , OR 13a ;
           in which each R 12a  and R 12b  is, independently, hydrogen, C 3-7 cycloalkyl, aryl, Het, or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 13  is hydrogen, C 2-6 alkenyl, C 3-7 cycloalkyl, Het, or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   
           C 1-6 alkyloxycarbonylC 1-6 alkyl;   Het-thioC 1-6 alkyl; or   Het-oxyC 1-6 alkyl; or   
       R 2  and R 3 , together with the intervening grouping in formula (I) of sub-formula:   

     
       
         
         
             
             
         
       
         
         
           
             form a ring of formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         R 4a  and R 4b  are independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, arylcarbonyl or —NR 14a R 14b ;
       in which each R 14a  and R 14b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhalo-C 1-6 alkoxy, and C 3-7 cycloalkyl;   
     
         R 5  is hydrogen; C 3-7 cycloalkyl; or C 1-6 alkyl optionally substituted with a C 3-7 cyclo-alkyl, aryl, Het, —C(═O)NR 15a R 15b , NR 15a R 15b , —C(═O)R 17 , —NR 15a C(═O)R 17 , —NR 15a SO p R 18 , —SO p R 18 , —SO p NR 15a R 15b , —C(═O)OR 16 , or —NR 15a C(═O)OR 16  in which
       p is 0, 1 or 2;   each R 15a  and R 15b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 16  is hydrogen; C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 16a  is C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 17  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or aryl;   R 18  is hydrogen; polyhaloC 1-6 alkyl; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl, aryl or Het;
 
aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally independently substituted with
   
     
         (a) one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl; or 
         (b) phenyl- or naphthyl-alkoxy optionally substituted with one, two or three substituents defined for (a) above; or 
         (c) phenyl- or naphthyl-carbonyloxy optionally substituted with one, two or three substituents defined for (a) above; and
 
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl;
 
aryl 2  as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally substituted with one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, phenyl- or napthyl-alkoxy optionally substituted with halogen; mono- or di-alkylamino; phenyl- or naphthyl-carbonyloxy optionally substituted with halogen, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, mono or dialkylamino, cyano, nitro, amino, mono- or diC 1-6 alkyl-amino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, morpholinyl; or aryl 2  is substituted with a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 20 —, —NR 20 —C 1-6 alkanediyl-, —NR 20 —CO—C 1-6 alkanediyl-, —CO—NR 1e —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S— or —S—C 1-6 alkanediyl-
       in which R 20  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;
 
Het 2  as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, morpholinyl; or Het 2  is substituted with a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 20 —, —NR 20 —C 1-6 alkanediyl-, —NR 21 —CO—C 1-6 alkanediyl-, —CO—NR 21 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S—, —S—C 1-6 alkanediyl-
   in which R 21  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxyaryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl.   
     
       
    
     In a further embodiment, the present invention relates to the following novel compounds of formula (Ia) per se, 
     
       
         
         
             
             
         
       
     
     and the salts, stereoisomeric forms, and racemic mixtures thereof in which
     R 1a  and R 1b  are independently, hydrogen, aryl, Het, or C 1-6 alkyl;   R 2  is C 2-6 alkenyl optionally substituted independently with one or two substituents selected from halo, and aryl;
       aryl 2 ; or   Het 2 ;   
       R 3  is C 1-7 alkyl optionally substituted independently with one, two or three substituents selected from halo, aryl, and cyano;
       C 2-6 alkenyl;   aryl;   Het;   —NR 12a R 12b ,   in which each R 12a  and R 12b  is, independently, hydrogen, aryl, or C 1-6 alkyl optionally substituted independently with one or two substituents selected from aryl and Het;   
       R 4a  and R 4b  are independently hydrogen; halo; cyano; C 1-6 alkyl optionally substituted with halo, hydroxy, Het, —OR 14a , or —NR 14a R 14b ; C 1-6 alkoxy optionally substituted with amino, hydroxy, C 1-6 alkoxy, hydroxycarbonyl, aryl, or Het; aryloxy; Het-oxy; carboxyl; C 1-6 alkylcarbonyloxy; C 1-6 alkoxycarbonyl; —NR 14a R 14b ; or —C(═O)—NR 14a R 14b ;
       in which each R 14a  and R 14b  is, independently, hydrogen; or C 1-6 alkyl optionally substituted independently with one or two substituents selected from mono- or diC 1-6 alkylamino, and Het;   
       R 5  is hydrogen; or C 1-6 alkyl optionally substituted with aryl; aryl as a group or part of a group is phenyl or naphthyl, each of which may be optionally independently substituted with   (a) one, two or three substituents selected from halo, C 1-6 alkyl, trifluoromethyl, C 1-6 alkoxy, carboxyl, C 1-6 alkylcarbonyl, cyano, cyanoC 1-6 alkyl, nitro, mono- or diC 1-6 alkylamino; or   (b) phenyl-alkoxy optionally substituted with one, two or three substituents defined for (a) above;
 
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of C 1-6 alkyl, and aminocarbonyl;
 
aryl 2  as a group or part of a group is phenyl or naphthyl, each of which may be optionally independently substituted with one, two or three substituents selected from
   (c) halo, C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-6 alkoxy, C 1-6 alkylcarbonyloxy, polyhaloC 1-6 alkoxy, nitro, mono- or diC 1-6 alkylamino; or   (d) a radical of formula —(X) n -aryl or —(X) n -Het in which n is 1 and X is —O—, —CO—NH—, —NH—CO—, —NH—SO 2 —, —SO 2 —NH—, —O—C 1-6 alkanediyl-, —O—CO—, —CO—;
 
Het 2  as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, aryl, and nitro.
   

     In a further embodiment, the present invention relates to the following novel compounds of formula (Ia) per se, namely Compound Nos. 101, 128, 129, 131, 132, 134, 210, 223 and 224, referred to in the Tables below, and the salts, stereoisomeric forms, and racemic mixtures thereof. 
     In one embodiment, the invention relates to the use of the compounds of formula (Ib) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV, said compounds being benzodiazepines of the formula (Ib): 
     
       
         
         
             
             
         
       
     
     and the salts, stereoisomeric forms, and racemic mixtures thereof in which
     R 1a  and R 1b  are independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 2  is hydrogen;
       C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 3-7 cycloalkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl,   C 3-7 cycloalkylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 2-6 alkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-7 cycloalkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-8 cycloalkenylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   aryl 2 ; or   Het 2 ;   
       R 3  is hydrogen; or C 1-6 alkyl optionally substituted with carboxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, or Het-C 1-6 alkylaminocarbonyl;   R 4a  and R 4b  are independently hydrogen; halo; cyano; C 1-6 alkyl optionally substituted with halo, hydroxy or —NR 14a R 14b ; C 1-6 alkoxy; carboxyl; C 1-6 alkoxycarbonyl; arylcarbonyl; or —NR 14a R 14b ;
       in which each R 14a  and R 14b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhalo-C 1-6 alkoxy, and C 3-7 cycloalkyl;   
       R 5  is hydrogen; C 3-7 cycloalkyl; or C 1-6 alkyl optionally substituted with a C 3-7 cyclo-alkyl, aryl, Het, —C(═O)NR 15a R 15b , —NR 15a R 15b , —C(═O)R 17 , —NR 15a C(═O)R 17 , —NR 15a SO p R 18 , —SO p R 18 , —SO p NR 15a R 15b , —C(═O)OR 16 , or —NR 15a C(═O)OR 16a  in which
       p is 0, 1 or 2;   each R 15a  and R 15b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 16  is hydrogen; C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 16a  is C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 17  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or aryl;   R 18  is hydrogen; polyhaloC 1-6 alkyl; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl, aryl or Het;
 
aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally independently substituted with
   
       (a) one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, C 1-6 alkylthio, polyhalo-C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl; or   (b) phenyl- or naphthyl-alkoxy optionally substituted with one, two or three substituents defined for (a) above; or   (c) phenyl- or naphthyl-carbonyloxy optionally substituted with one, two or three substituents defined for (a) above; and
 
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl;
 
aryl 2  as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally independently substituted with one, two or three substituents selected from
   (e) halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, C 1-6 alkylthio, polyhalo-C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl and morpholinyl; or   (f) a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 20 —, —NR 20 —C 1-6 alkanediyl-, —NR 20 —CO—C 1-6 alkanediyl-, —CO—NR 20 —C 1-6 alkanediyl-, —O—, —CO—NR 20 —, —SO 2 —NR 20 —, —O—C 1-6 alkanediyl-, —O—CO—, —CO—, —O—CO—C 1-6 alkanediyl-, —S— or —S—C 1-6 alkanediyl-
       in which R 20  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;
 
Het 2  as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, oxo, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, morpholinyl; or Het 2  is substituted with a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 21 —, —NR 21 —C 1-6 alkanediyl-, —NR 21 —CO—C 1-6 alkanediyl-, —CO—NR 21 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S—, or —S—C 1-6 alkanediyl-
   in which R 21  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxyaryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl.   
       

     In one embodiment, the invention relates to the use of the compounds of formula (Ib) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV, said compounds being benzodiazepines of the formula (Ib): 
     
       
         
         
             
             
         
       
     
     and the salts, stereoisomeric forms, and racemic mixtures thereof in which
     R 1a  and R 1b  are independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 2  is hydrogen;
       C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 3-7 cycloalkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl,   C 3-7 cycloalkylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 2-6 alkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-7 cycloalkenyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   C 4-8 cycloalkenylC 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   aryl 2 ; or   Het 2 ;   
       R 3  is hydrogen or C 1-6 alkyl;   R 4a  and R 4b  are independently hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, arylcarbonyl or —NR 14a R 14b ;
       in which each R 14a  and R 14b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhalo-C 1-6 alkoxy, and C 3-7 cycloalkyl;   
       R 5  is hydrogen; C 3-7 cycloalkyl; or C 1-6 alkyl optionally substituted with a C 3-7 cyclo-alkyl, aryl, Het, —C(═O)NR 15a R 15b , —NR 15a R 15b , —C(═O)R 17 , —NR 15a C(O)R 17 , —NR 15a SO p R 18 , —SO p R 18 , —SO p NR 15a R 15b , —C(═O)OR 16 , or —NR 15a C(═O)OR 16a  in which
       p is 0, 1 or 2;   each R 15a  and R 15b  is, independently, hydrogen; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl;   R 16  is hydrogen; C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 16a  is C 2-6 alkenyl; C 3-7 cycloalkyl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl or Het;   R 17  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or aryl;   R 18  is hydrogen; polyhaloC 1-6 alkyl; C 3-7 cycloalkyl; aryl; Het; or C 1-6 alkyl optionally substituted with a C 3-7 cycloalkyl, aryl or Het;
 
aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally independently substituted with
   
       (a) one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, C 1-6 alkylthio, polyhalo-C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl; or   (b) phenyl- or naphthyl-alkoxy optionally substituted with one, two or three substituents defined for (a) above; or   (c) phenyl- or naphthyl-carbonyloxy optionally substituted with one, two or three substituents defined for (a) above; and
 
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl;
 
aryl 2  as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally independently substituted with
   (g) one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, trifluoromethyl, alkylenedioxy, C 1-6 alkoxy, C 1-6 alkylthio, polyhalo-C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, azido, mercapto, C 3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkyl-carbonyl-piperazinyl and morpholinyl; or   (h) a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 20 —, —NR 20 —C 1-6 alkanediyl-, —NR 20 —CO—C 1-6 alkanediyl-, —CO—NR 20 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S— or —S—C 1-6 alkanediyl-
       in which R 20  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxy, aryl, Het, cyano, polyhaloC 1-6 alkoxy, and C 3-7 cycloalkyl;
 
Het 2  as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, hydroxy, oxo, aryl, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6 alkylcarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, morpholinyl; or Het 2  is substituted with a radical of formula —(X) n -aryl or —(X) n -Het in which n is 0 or 1 and X is —C 1-6 alkanediyl-, C 1-6 alkenediyl-, —NR 21 —, —NR 21 —C 1-6 alkanediyl-, —NR 21 —CO—C 1-6 alkanediyl-, —CO—NR 21 —C 1-6 alkanediyl-, —O—, —O—C 1-6 alkanediyl-, —O—CO—, —O—CO—C 1-6 alkanediyl-, —S—, or —S—C 1-6 alkanediyl-
   in which R 21  is hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted independently with one, two or three substituents selected from halo, C 1-6 alkoxyaryl and Het; or with a cyano, polyhaloC 1-6 alkoxy or C 3-7 cycloalkyl.   
       

     In a further embodiment, the present invention relates to the following novel compounds of formula (Ib) per se, 
     
       
         
         
             
             
         
       
     
     and the salts, stereoisomeric forms, and racemic mixtures thereof in which
     R 1a  and R 1b  are independently, hydrogen, aryl, or C 1-6 alkyl;   R 2  is C 2-6 alkenyl optionally substituted independently with one or two substituents selected from halo, and aryl;
       aryl 2 ; or   Het 2 ;   
       R 3  is hydrogen;
       C 1-6 alkyl optionally substituted with carboxyl, C 1-6 alkylcarbonyl,   C 1-6 alkoxycarbonyl, Het-C 1-6 alkylaminocarbonyl;   
       R 4a  and R 4b  are independently hydrogen; halo; cyano; C 1-6 alkyl optionally substituted with halo, hydroxy, or —NR 14a R 14b ; C 1-6 alkoxy optionally substituted with C 1-6 alkoxy; carboxyl; or —NR 14a R 14b ;
       in which each R 14a  and R 14b  is, independently, hydrogen; or C 1-6 alkyl;   
       R 5  is hydrogen;
 
aryl as a group or part of a group is phenyl or naphthyl, each of which may be optionally independently substituted with
   (a) one, two or three substituents selected from halo, and C 1-6 alkoxy; or   (b) phenyl-alkoxy optionally substituted with one, two or three substituents defined for (a) above;
 
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings;
 
aryl 2  as a group or part of a group is phenyl or naphthyl, each of which may be optionally independently substituted with one, two or three substituents selected from
   a) halo, hydroxy, polyhalo-C 1-6 alkoxy, carboxyl, nitro; or   b) a radical of formula —(X) n -aryl in which n is 1 and
       X is —O—, —CO—NH—, —SO 2 —NH—, —O—C 1-6 alkanediyl-, —O—CO—, —CO—;
 
Het 2  as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one or two benzene rings, and wherein the group Het as a whole may be optionally substituted with one, two or three halo.
   
       

     In a further embodiment, the present invention relates to the following novel compounds of formula (Ib) per se, namely Compound Nos. 94, 95, 96, 97, 98, 124, 154, 156, 157, 158 and 159, referred to in the Tables below, and the salts, stereoisomeric forms, and racemic mixtures thereof. 
     The term “C 1-6 alkyl” as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example methyl, ethyl, propyl, butyl, 2-methyl-propyl, pentyl, 2-methylbutyl, hexyl, 3-methylpentyl and the like. 
     The term “C 1-7 alkyl” as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 7 carbon atoms, such as, for example methyl, ethyl, propyl, butyl, 2-methyl-propyl, pentyl, 2-methylbutyl, hexyl, 3-methylpentyl, heptyl and the like. 
     The term “C 1-6 alkoxy” means C 1-6 alkyloxy wherein C 1-6 alkyl is as defined above. 
     The term “C 3-7 cycloalkyl” as a group or part of a group defines cyclic saturated hydrocarbon radicals having from 3 to 7 carbon atoms, such as, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 
     The term “C 2-6 alkenyl” as a group or part of a group defines straight and branched chained hydrocarbon radicals having at least one double bond, and from 2 to 6 carbon atoms, such as, for example, ethenyl, prop-1-enyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, 1-methyl-pent-2-enyl and the like. Preferred are C 2-6 alkenyls having one double bond. 
     The term “C 4-8 cycloalkenyl” as a group or part of a group defines cyclic hydrocarbon radicals having at least one double bond, and from 4 to 8 carbon atoms, such as, for example cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl and the like, and including alkyl substitution on the ring, such as for example 2,2-dimethyl-3-methyl-cyclopent-3-enyl. Preferred are C 4-8 cycloalkenyls having one double bond. 
     The term “C 1-6 alkanediyl” as a group or part of a group defines bivalent straight and branched chained hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methanediyl, 1,2-ethanediyl, or 1,1-ethanediyl, 1,3-propanediyl, 1,3-butanediyl, 1,4-butanediyl, 1,3-pentanediyl, 1,5-pentanediyl, 1,4-hexanediyl, 1,6-hexanediyl, and the like. 
     The term “halo” is generic to fluoro, chloro, bromo or iodo. 
     As used in the foregoing and hereinafter “polyhaloC 1-6 alkyl” as a group or part of a group is defined as mono- or polyhalosubstituted C 1-6 alkyl, for example, 1,1,1-trifluoroethyl, 1,1-difluoro-ethyl, the polyhalomethyl groups mentioned hereinafter, and the like. A preferred subgroup of polyhaloC 1-6 alkyl is polyhalomethyl, wherein the latter as a group or part of a group is defined as mono- or polyhalo-substituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl. In case more than one halogen atom is attached to an alkyl group within the definition of polyhalomethyl or polyhaloC 1-4 alkyl, they may be the same or different. 
     It should also be noted that the radical positions on any molecular moiety used in the definitions, unless indicated otherwise, may be anywhere on such moiety as long as it is chemically stable. For instance pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl. 
     When any variable (e.g. halogen or C 1-4 alkyl) occurs more than one time in any constituent, each definition is independent. 
     The N-oxide forms of the present compounds are meant to comprise any one of the compounds of the present invention wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. 
     For therapeutic use, the salts of the compounds of the present invention are those wherein the counter-ion is pharmaceutically or physiologically acceptable. However, salts having a pharmaceutically unacceptable counter-ion may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound of formula (I). All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention. 
     The pharmaceutically acceptable or physiologically tolerable addition salt forms which the compounds of the present invention are able to form can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, hemisulphuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, aspartic, dodecyl-sulphuric, heptanoic, hexanoic, benzoic, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methane-sulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids. 
     Conversely said acid addition salt forms can be converted by treatment with an appropriate base into the free base form. 
     The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition base salt form by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Alternatively, when a carboxyl moiety is present on the compound of formula (I), the compound may also be supplied as a salt with a pharmaceutically acceptable cation. 
     Conversely said base addition salt forms can be converted by treatment with an appropriate acid into the free acid form. 
     The term “salts” also comprises the hydrates and the solvent addition forms that the compounds of the present invention are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like. 
     In the event that any of the substituents of formula (I) contain chiral centers, as some, indeed, do, the compounds of formulas (I) include all stereoisomeric forms thereof, both as isolated stereoisomers and mixtures of these stereoisomeric forms. 
     The term stereochemically isomeric forms of compounds of the present invention, as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention. 
     Pure stereoisomeric forms of the compounds as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term ‘stereoisomerically pure’ concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms ‘enantiomerically pure’ and ‘diastereomerically pure’ should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question. 
     Pure stereoisomeric forms of the compounds of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyl-tartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. 
     The diastereomeric racemates of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography. 
     The present compounds may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. For example, within the definition of Het, for example an 1,2,4-oxadiazole may be substituted with a hydroxy group in the 5-position, thus being in equilibrium with its respective tautomeric form as depicted below. 
     
       
         
         
             
             
         
       
     
     The term “prodrug” as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8 th  ed, McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p 13-15) describing prodrugs generally is hereby incorporated. Prodrugs of a compound of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. For example, a substituent containing sulfhydryl could be coupled to a carrier which renders the compound biologically inactive until removed by endogenous enzymes or, for example, by enzymes targeted to a particular receptor or location in the subject. 
     Prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. 
     The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14. 
     Whenever used hereinafter, the term “compounds of formula (I)”, or similar term is meant to include the compounds of general formula (I), (Ia), (Ib), their N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs and esters. An interesting subgroup of the compounds of the present invention or any subgroup thereof are the N-oxides, salts and all the stereoisomeric forms thereof. 
     Examples of compounds of formula (J) include those wherein the aryl or aryl 2  group is phenyl or naphthyl optionally substituted with halogen; alkoxy; phenyl- or naphthyl-oxy optionally substituted with halo; mono- or di C 1-6 alkylamino; nitro; hydroxy; or phenyl- or naphthyl-carbonyloxy optionally substituted with halo. Especially preferred substituents include halo such as fluoro, chloro, bromo; alkoxy such as methoxy, ethoxy, isopropoxy, n-butoxy or n-pentoxy; and mono- or di C 1-6 alkylamino such as dimethylamino or diethylamino. 
     Examples of compounds of formula (J) include those wherein the Het or Het 2  group is a 5 or 6 membered heterocyclic ring containing 1, 2 or 3, preferably 1 or 2 heteroatoms selected from nitrogen, oxygen and sulphur, for example, furanyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl, and the like. Such Het or Het 2  groups may be optionally substituted with halogen, C 1-6 alkyl, nitro or aryl optionally substituted with halo. In the compounds of formula (Ib), such heterocyclic groups may be optionally condensed with one or two benzene rings to form for example a carbazolyl, indolyl or cromenyl group. 
     The above groups which may be optionally substituted with one, two or three substituents are generally preferably either unsubstituted or substituted with one or two substituents. 
     Further embodiments of the present invention include compounds of formula (I) or any subgroup thereof, wherein at least one of R 1a  and R 1b  is hydrogen, halo, C 1-6 alkyl, aryl or Het. In a preferred embodiment, both R 1a  and R 1b  are methyl. In another preferred embodiment, R 1a  is hydrogen and R 1b  is aryl substituted with one or two substituents selected from C 1-6 alkoxy and phenylC 1-6 alkoxy. In particular, R 1a  is hydrogen and R 1b  is phenyl substituted with one or two substituents selected from methoxy, ethoxy, and phenylmethoxy. 
     Further embodiments of the present invention include compounds of formula (I) or any subgroup thereof, wherein R 2  is hydrogen; C 2-6 alkenyl optionally substituted with aryl or halo; C 4-8 cycloalkenylC 1-6 alkyl; aryl 2 ; or Het 2 . In a preferred embodiment, R 2  is aryl 2  substituted with one or two substituents selected from halo, C 1-6 alkoxy, and —(X) n -aryl, wherein n is 1 and X is —O—C 1-6 alkanediyl. In particular, R 2  is phenyl substituted with two substituents selected from halo, methoxy, 1-methyl-propoxy, and —(X) n -phenyl, wherein n is 1 and X is —O-methanediyl. In another preferred embodiment, R 2  is C 2-6 alkenyl substituted with aryl and halo, in particular ethenyl substituted with halo and phenyl. 
     Further embodiments of the present invention include compounds of formula (Ia) or any subgroup thereof, wherein R 3  is C 1-7 alkyl optionally substituted with halo, aryl or carboxyl; C 3-7 cycloalkyl; aryl; Het; Het-thioC 1-6 alkyl; or —NR 12a R 12b . In a preferred embodiment of the compounds of formula (Ia) or any subgroup thereof, R 3  is C 1-6 alkyl or polyhaloC 1-6 alkyl, in particular methyl, pentyl, or trifluoromethyl. 
     Further embodiments of the present invention include compounds of formula (Ib) or any subgroup thereof, wherein R 3  is hydrogen. In a preferred embodiment of the compounds of formula (Ib) or any subgroup thereof, R 3  is hydrogen or C 1-6 alkyl, in particular propyl. 
     Further embodiments of the present invention include compounds of formula (Ia) or any subgroup thereof, wherein at least one of R 4a  and R 4b  is hydrogen or arylcarbonyl. 
     Further embodiments of the present invention include compounds of formula (Ib) or any subgroup thereof, wherein at least one of R 4a  and R 4b  is hydrogen, halo, C 1-6 alkyl or arylcarbonyl. In a preferred embodiment, both R 4a  and R 4b  are hydrogen. 
     Further embodiments of the present invention include compounds of formula (I) or any subgroup thereof, wherein R 5  is hydrogen. 
     Further embodiments of the present invention include compounds of formula (Ia) or any subgroup thereof, wherein at least one of R 1a  and R 1b  is hydrogen, chloro; methyl; phenyl optionally substituted with halo, C 1-6 alkoxy (for example methoxy, ethoxy or n-propoxy), nitro or mono- or di-C 1-6 alkylamino; or at least one of R 1a  and R 1b  is furanyl or thienyl. 
     Further embodiments of the present invention include compounds of formula (Ib) or any subgroup thereof, wherein at least one of R 1a  and R 1b  is hydrogen, chloro; methyl; phenyl optionally substituted with halo, alkylenedioxy, C 1-6 alkoxy (for example methoxy, ethoxy or n-propoxy), nitro, mono- or di-C 1-6 alkylamino or benzyloxy; or at least one of R 1a  and R 1b  is furanyl or thienyl. 
     Further embodiments of the present invention include compounds of formula (Ia) or any subgroup thereof, wherein both of R 1a  and R 1b  are hydrogen. 
     Further embodiments of the present invention include compounds of formula (Ib) or any subgroup thereof, wherein both of R 1a  and R 1b  are hydrogen or both are methyl. 
     Further embodiments of the present invention include compounds of formula (Ia) or any subgroup thereof, wherein R 2  is hydrogen, phenyl optionally substituted with halo, C 1-6 alkyl, polyhalo-C 1-6 alkyl, C 1-6 alkoxy, alkylenedioxy, nitro, hydroxy, mono- or di C 1-6 alkylamino or with benzyloxy optionally substituted with halo (for example fluoro), or R 2  is phenyl optionally substituted with benzoyloxy optionally substituted with halo (for example chloro), or R 2  is furanyl, thienyl or pyrrolyl optionally substituted with halo, C 1-6 alkyl, nitro, or R 2  is C 2-6 alkenyl optionally substituted with aryl especially phenyl, or with aryl, especially phenyl, and halogen, especially bromo; or R 2  is cyclopentenylmethyl optionally substituted on the cyclopentenyl ring with C 1-6  alkyl for example methyl, especially cyclopent-3-enyl, substituted for example with 1, 2 or 3 methyl groups especially 2,2,3-trimethyl. 
     Further embodiments of the present invention include compounds of formula (Ib) or any subgroup thereof, wherein R 2  is hydrogen, phenyl optionally substituted with halo, C 1-6 alkyl, polyhaloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, alkylenedioxy, nitro, hydroxy, mono- or di-C 1-6 alkylamino or with benzyloxy optionally substituted with halo (for example fluoro), or R 2  is phenyl or naphthyl, each optionally substituted with benzoyloxy optionally substituted with halo (for example chloro), or R 2  is pyridyl, thienyl, carbazoyl, indolyl or cromenyl, each optionally substituted with C 1-6 alkyl; or R 2  is C 2-6 alkenyl optionally substituted with aryl especially phenyl, or with aryl, especially phenyl, and halogen, especially bromo. 
     Further embodiments of the present invention include compounds of formula (Ia) or any subgroup thereof, wherein R 3  is methyl, ethyl, isopropyl, n-butyl, sec-butyl, pentyl, heptyl; polyhalomethyl; cyclopropyl; phenyl optionally substituted with halo for example fluoro or with carboxy; benzyl optionally substituted with halo for example fluoro; or R 3  is arylamino for example dichlorophenylamino; or benzothiazolylthio-alkyl (for example -methyl) optionally substituted with C 1-6 alkoxy for example methoxy. 
     Further embodiments of the present invention include compounds of formula (J) or any subgroup thereof, wherein at least one of R 4a  and R 4b  is hydrogen, for example wherein R 4a  and R 4b  are both hydrogen. 
     Further embodiments of the invention include compounds of formula (Ia) or any subgroup thereof, containing one of more of the following groups: 
     R 1a  and R 1b  are both methyl;
 
R 2  is 2,4-dichlorophenyl, 3-methoxy-4-benzyloxy-phenyl or 1-bromo-2-phenylethenyl;
 
R 3  is methyl, phenyl, trifluoromethyl or cyclopropyl;
 
R 4a  and R 4b  are both hydrogen; and
 
R 5  is hydrogen.
 
     Further embodiments of the invention include compounds of formula (Ib) or any subgroup thereof, containing one of more of the following groups: 
     R 1a  and R 1b  are both methyl or one of R 1a  and R 1b  is hydrogen and the other is phenyl substituted with one or two C 1-6 alkoxy substituents or by a benzyloxy substituent;
 
R 2  is phenyl substituted with one or two halo or C 1-6 alkoxy substituents or with a nitro or benzyloxy substituent;
 
R 3  is hydrogen;
 
R 4a  and R 4b  are both hydrogen or one of R 4a  and R 4b  is hydrogen and the other is benzoyl; and
 
R 5  is hydrogen.
 
     Examples of specific compounds of formula (Ia) in accordance with the invention include Compound Nos. 35, 38, 42, 45, 48, 51, 53 and 193, referred to in the Tables below, and the salts, stereoisomeric forms, and racemic mixtures thereof. 
     Examples of specific compounds of formula (Ib) in accordance with the invention include Compound Nos. 78, 97, 108, 116, 156 and 157 referred to in the Tables below, and the salts, stereoisomeric forms, and racemic mixtures thereof. 
     Pharmacology 
     Due to their favorable antiviral properties, as will be apparent from the examples, the compounds of the present invention are useful in the treatment of individuals infected by HCV and for the prophylaxis of these individuals. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with flaviviruses. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HCV and other pathogenic flaviviruses, such as Yellow fever, Dengue fever (types 1-4), St. Louis encephalitis, Japanese encephalitis, Murray valley encephalitis, West Nile virus and Kunjin virus. The conditions associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and HCC; and for the other pathogenic flaviruses the conditions include yellow fever, dengue fever, hemorrhagic fever and encephalitis. 
     The compounds of the present invention or any subgroup thereof may therefore be used as medicines against the above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HCV-infected subjects of an amount effective to combat the conditions associated with HCV and other pathogenic flaviviruses. Consequently, the compounds of the present invention can be used in the manufacture of a medicament useful for treating conditions associated with HCV and other pathogenic flaviviruses. 
     In an embodiment, the invention relates to the use of a compound of formula (I) or any subgroup thereof as defined herein in the manufacture of a medicament for treating or combating infection or disease associated with HCV infection in a mammal. The invention also relates to a method of treating a flaviviral infection, in particular an HCV infection, or a disease associated with flavivirus infection comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or a subgroup thereof as defined herein. 
     In another embodiment, the present invention relates to the use of formula (I) or any subgroup thereof as defined herein for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with flaviviruses, in particular HCV. 
     In another embodiment, the present invention relates to the use of formula (I) or any subgroup thereof as defined herein for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with flaviviruses, wherein said HCV is inhibited in its replication. 
     In a further aspect, the present invention concerns a pharmaceutical composition comprising a therapeutically effective amount of a novel compound of formula (I) as specified herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount in this context is an amount sufficient to prophylactically act against, to stabilize or to reduce viral infection, and in particular HCV viral infection, in infected subjects or subjects being at risk of being infected. In still a further aspect, this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a said compound of formula (I), as specified herein. 
     Therefore, the compounds of the present invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. 
     The compounds of the present invention may also be administered via oral inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation are suitable for the administration of the present compounds. 
     Thus, the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Preferably, the compounds of the present invention are administered via inhalation of a solution in nebulized or aerosolized doses. 
     It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. 
     Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof. 
     The dosages of the compounds of the invention will depend on a number of factors which will vary from patient to patient. However, it is believed that generally, the daily oral dosage will utilize 0.001-100 mg/kg total body weight, preferably from 0.01-50 mg/kg and more preferably about 0.01 mg/kg-10 mg/kg. The dose regimen will vary, however, depending on the conditions being treated and the judgment of the practitioner. 
     It should be noted that the compounds of the invention can be administered as individual active ingredients, or as mixtures of several embodiments of this formula. In addition, the compounds of the invention may be used as single therapeutic agents or in combination with other therapeutic agents. 
     Also, the combination of previously known anti-HCV compound, such as, for instance, interferon-α (IFN-α), pegylated interferon-α and/or ribavirin, and a compound of the present invention can be used as a medicine in a combination therapy. The term “combination therapy” relates to a product containing mandatory (a) a compound of the present invention, and (b) optionally another anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV infections, in particular, in the treatment of infections with HCV type 1. Thus, to combat or treat HCV infections, the compounds of this invention may be co-administered in combination with for instance, interferon-α (IFN-α), pegylated interferon-α and/or ribavirin, as well as therapeutics based on antibodies targeted against HCV epitopes, small interfering RNA (Si RNA), ribozymes, DNAzymes, antisense RNA, small molecule antagonists of for instance NS3 protease, NS3 helicase and NS5B polymerase. 
     Accordingly, the present invention relates to the use of a compound of formula (I) or any subgroup thereof as defined above for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV viruses, wherein said medicament is used in a combination therapy, said combination therapy preferably comprising a compound of formula (I) and (pegylated) IFN-α and/or ribavirin. 
     Preparation 
     The compounds according to the invention are either commercially available or can be prepared in accordance with conventional procedures for example as described in the patent and literature references identified above or in accordance with the synthetic routes described below. 
     Compounds of formulae (Ia) and (Ib) in which R 5  is hydrogen, represented by formulae (Ia′) and (Ib′) below, can be prepared in accordance with the synthetic route set out in Scheme 1 below: 
     
       
         
         
             
             
         
       
     
     Step (a) a cyclohexane-1,3-dione of formula (JJ) is reacted with an o-phenylene-diamine of formula (III), to give an adduct of formula (IV); the reaction being generally effected in an organic solvent for example toluene for example at reflux. 
     Step (b): an adduct of formula (IV) is reacted with an aldehyde of formula (V) for example in an anhydrous organic solvent such as ethanol under acid conditions for example in the presence of acetic acid, advantageously at an elevated temperature for example 40° C. to 130° C. preferably at 75° C. for about 5 hours. 
     Step (c): a compound of formula (Ib′) is reacted with an acylating agent of formula (VI), namely R 3 —C(═O)-LG, in which LG represent a leaving group; examples of such acylating agents include acyl halides for example acyl chlorides and acyl anhydrides, the acylating reaction being effected in a basic organic solvent such as pyridine for example at a temperature of −20° C. to 50° C. preferably about 0° C. 
     Compounds of formula (Ia′) in which R 5  is other than hydrogen can be prepared by reacting a corresponding compound of formula (Ia′) in which R 5  is hydrogen with a compound of formula R 5a -LG 1  in which R 5a  is as defined for R 5  other than hydrogen and LG 1  is a leaving group, such as an halogen atom, the reaction being generally effected in the presence of a base such sodium hydride, and in an appropriate organic solvent for example tetrahydrofuran or dimethylformamide. 
     Compounds of formula (Ib) in which R 3  is C 1-6 alkyl may be prepared from a corresponding compound of formula (Ib) in which R 3  is hydrogen by treatment with an alkylating agent for example a C 1-6 alkyl halide for example an iodide, generally in the presence of a base such as potassium carbonate, and in an appropriate solvent such as acetone, conveniently at room temperature. 
     Compounds of formula (J) in which R 5  is other than hydrogen can be prepared by reacting a corresponding compound of formula (I), (Ia) or (Ib) in which R 5  is hydrogen with a compound of formula R 5a -LG 1  in which R 5a  is as defined for R 5  other than hydrogen and LG 1  is a leaving group, such as an halogen atom, the reaction being generally effected in the presence of a base such sodium hydride, and in an appropriate organic solvent for example tetrahydrofuran or dimethylformamide. 
     The starting materials of formula (JJ) are either commercially available or can be prepared in accordance with conventional procedures. For example compounds of Formula (II) in which R 1b  is H, represented by formula (IIa) below can be prepared in accordance with the synthetic route set out in Scheme 2 below: 
     
       
         
         
             
             
         
       
     
     Step a): an aldehyde of formula (VII) is reacted with acetone, in presence of a base such as aqueous sodium hydroxide, to give a ketone of formula (VIII); 
     Step b): a ketone of formula (VIII) is cyclized to the corresponding cyclohexane-1,3-dione of formula (Ia) by reaction with diethyl malonate in presence of a base, such as potassium tert-butoxide in an appropriate solvent such as ethanol. 
     Other starting materials of formula (II) are commercially available for example the compound of formula (II) in which R 1a  and R 1b  are both methyl is widely available under the name of dimedone. 
     Alternatively compounds of formula (II) can be prepared from an alpha alkene ketone of Formula (IX) by condensation with diethyl malonate in accordance with Scheme 3 below: 
     
       
         
         
             
             
         
       
     
     Accordingly, a ketone of Formula (IX) can react with one equivalent or an excess of diethylmalonate, optionally in presence of a solvent such as ethanol or isopropanol. 
     The present invention further includes the novel compounds of formula (IV) and (Ib′) for example for use as intermediates in the preparation of the compounds of formula (Ia). The present invention further includes the novel compounds of formula (IV) for example for use as intermediates in the preparation of the compounds of formula (Ib). 
    
    
     EXAMPLES 
     The following Examples are intended to illustrate, but not to limit, the present invention. 
     Some of the compounds prepared in the Examples have been analysed by LC/MS on one of the following equipments:
         LCT: method XterragradPOS@V1002V1003.olp   electrospray ionisation in positive mode, scanning mode from 100 to 900 amu   Xterra MS C18 (Waters, Milford, Mass.) 5 μm, 3.9×150 mm); Flow rate 1 ml/min. Two mobile phases (mobile phase A: 85% 6.5 mM ammonium acetate+15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate+80% acetonitrile) were employed to run a gradient from 100% A for 3 min to 100% B in 5 min., 100% B for 6 min to 100% A in 3 min, and equilibrate again with 100% A for 3 min).   ZQ: method Xterra — 15 cm@V2001V2001.olp   electrospray ionisation in both positive and negative (pulsed) mode scanning from 100 to 1000 amu   Xterra RP C18 (Waters, Milford, Mass.) 5 μm, 3.9×150 mm); Flow rate 1 ml/min. Two mobile phases (mobile phase A: 85% 6.5 mM ammonium acetate+15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate+80% acetonitrile) were employed to run a gradient condition from 100% A for 3 min to 100% B in 5 min., 100% B for 6 min to 100% A in 3 min, and equilibrate again with 100% A for 3 min).       

     In the Examples the following abbreviations are used: 
     (M+H) + : molecular ion: Å: Angstrom (10 −10  m); Ac 2 O: acetic acid anhydride; AcOH: acetic acid; Et 2 O: diethyl ether; EtOAc: ethyl acetate; EtOH: ethanol; i-Pr 2 O: diisopropyl ether; M: molar; mol·L −1 ; m/z: mass to charge ratio; MeOH: methanol; N: normal; TLC: Thin Layer Chromatography; DIPE: diisopropyl ether; THF: tetrahydrofuran; DMAP: 4-dimethylamino pyridine; DMF: dimethylformamide; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT: 1-hydroxy-benzotriazole; DMA: N,N-dimethylaniline. 
     Example 1 
     10-Acetyl-3-(2-benzyloxyphenyl)-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 186 diastereomer A 
     Step A 
     
       
         
         
             
             
         
       
     
     2-Benzyloxybenzaldehyde (30 g, 141.3 mmol) (Intermediate (1-1)) was stirred for 1 week in a mixture of 80 mL acetone and 500 mL of an aqueous NaOH 5% solution. The white precipitate was filtered off, thoroughly washed with water and dried, yielding 35.2 gram (98.9%) of Intermediate (1-2): m/z=253 (M+H) + . 
     Step B 
     
       
         
         
             
             
         
       
     
     Potassium tert-butoxide (2.22 g, 19.8 mmol) and diethyl malonate (3.01 mL, 19.8 mmol) were added to 50 mL EtOH (dried on 3 Å molecular sieves). To this mixture, Intermediate (1-2) (5 g, 19.8 mmol) and another 10 mL of dry EtOH was added. The reaction mixture was refluxed overnight. The EtOH was evaporated, and the residue was refluxed in 100 mL 2M NaOH for 2 h. The solution was cooled in an ice-bath, 100 mL 5M H 2 SO 4  were added, and the mixture was refluxed for 4 h. Two layers were formed, and the aqueous layer was decanted from the oily layer. The oil solidified after cooling to room temperature and was extracted with Et 2 O. The Et 2 O layer was dried (Na 2 SO 4 ) and evaporated to give 4.21 g (72.2%) of Intermediate (1-3): m/z=295 (M+H) + . 
     Step C 
     
       
         
         
             
             
         
       
     
     A mixture of Intermediate (1-3) (3.47 g, 11.78 mmol) and o-phenylenediamine (1.27 g, 11.74 mmol) in 100 mL of dry toluene was reacted in a Dean-Stark apparatus overnight. The reaction was cooled to room temperature and the toluene was evaporated. The residue was stirred in i-Pr 2 O and filtered off to yield 4.26 g (77.6%) of Intermediate (1-4). 
     Step D 
     
       
         
         
             
             
         
       
     
     A solution of Intermediate (1-4) (200 mg, 0.520 mmol) and 2,4-dichlorobenzaldehyde (91 mg, 0.520 mmol) in 10 mL dry EtOH and 1 mL AcOH was heated at 75° C. for 5 h. Solvents were evaporated. The residue was dissolved in EtOAc and stirred for 1.5 h with saturated aqueous NaHCO 3 , and dried (Na 2 SO 4 ). Two diastereomers were obtained, and purified by silica flash column chromatography (gradient elution from heptane/EtOAc 4:1 to 2:1) to give Intermediate (1-5) diastereomer A, (yield: 118 mg, 41.1%): m/z=542 (M+H) + , and Intermediate (1-5) diastereomer B (yield: 57 mg, 20.2%): m/z=542 (M+H) + . 
     Step E 
     
       
         
         
             
             
         
       
     
     Acetic anhydride (211 μL) was added at 0° C. to a solution of Intermediate (1-5) diastereomer A (52 mg, 0.096 mmol) in pyridine (3 mL). The mixture was stirred at 0° C. during 3 days. Then, water was added to the reaction mixture and the solid was filtered off and washed with water. Purification by preparative TLC (Gradient EtOAc/Heptane 2:1 to 3:1; followed by CH 2 Cl 2 /MeOH 9:1) provided 41 mg (73.2%) of the final Compound No. 186: m/z=583 (M+H) + . 
     Example 2 
     10-Acetyl-3-(2-benzyloxyphenyl)-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 187 diastereomer B 
     The title product was prepared from Intermediate (1-5) diastereomer B (52 mg, 0.096 mmol) following the procedure described in Example 1. 
     Example 3 
     10-Acetyl-3,11-bis-(2-benzyloxyphenyl)-1-(3-benzyloxyphenyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 189 diastereomer A 
     
       
         
         
             
             
         
       
     
     The title product was prepared from Intermediate (1-4) (300 mg, 0.780 mmol) and 3-benzyloxybenzaldehyde (199 mg, 0.938 mmol) following the procedure described in Example 1. 
     Example 4 
     10-Acetyl-3,11-bis-(2-benzyloxyphenyl)-11-(3-benzyloxyphenyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound 190 diastereomer B 
     The title product was prepared from Intermediate (1-4) and 3-benzyloxybenzaldehyde following the procedure described in Example 1. 
     Example 5 
     10-Acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 38 and enantiomer A Compound No. 36 and enantiomer B Compound No. 35 
     Step A 
     
       
         
         
             
             
         
       
     
     A solution of dimedone (Intermediate (5-1)), 5.0 g, 35.67 mmol) and o-phenylene-diamine (3.86 g, 35.69 mmol) in 150 mL dry toluene were refluxed overnight in a Dean-Stark trap. After 24 h, the solvent was evaporated to give Intermediate (5-2) as an orange foam which was used without further purification in the next step. 
     Step B 
     
       
         
         
             
             
         
       
     
     A solution of Intermediate (5-2) (35.7 mmol) and 2,4-dichlorobenzaldehyde (6.24 g, 35.65 mmol) in a mixture of 100 mL dry EtOH and 10 mL AcOH was heated at 75° C. overnight. The reaction mixture was cooled to room temperature and the solvents evaporated. The residue was dissolved in EtOAc and stirred with saturated aqueous NaHCO 3  for 1.5 h. Then, the water layer was removed in a separating funnel and the organic layer was filtered off, the filtrate was washed twice with EtOAc. Organic layers were dried (Na 2 SO 4 ), evaporated and the residue dried under high vacuum, yielding 9.45 g (68.4%) of Intermediate (5-3): m/z=387 (M+H) + . 
     Step C 
     
       
         
         
             
             
         
       
     
     Intermediate (5-3) (1.0 g, 2.582 mmol) was dissolved in 25 mL Pyridine, cooled to 0° C., and 1 mL acetic anhydride was added. The temperature was allowed to warm to room temperature. After 12 h, the reaction mixture was cooled to 0° C., and another 1 mL of acetic anhydride was added. After 12 h, the reaction mixture was filtered off, washed with water and dried overnight at 40° C. under high vacuum. Then, the material was stirred for 1 h in 0.5 N KHSO 4  and extracted with CH 2 Cl 2 . The organic layer was washed with 0.5 N KHSO 4 , dried (Na 2 SO 4 ) and evaporated. The product was finally sonicated in i-Pr 2 O, filtered off and dried to give 834 mg (75.2%) of Compound No. 38 as mixture of Compound No. 36 enantiomer A and Compound No. 35 enantiomer B. 
     Step D: Separation of Compound No. 36 Enantiomer A and Compound No. 35 Enantiomer B. 
     Compound No. 36 enantiomer A and Compound No. 35 enantiomer B obtained above in admixture were separated by chiral HPLC using a Berger Minigram SFC, Knauer K2501 UV detector apparatus equipped with a Daicel AD-H 4.6×250 mm column. The mobile phase was 80% CO 2 /20% MeOH, the flow of 5 mL/min and the pressure 100 bars. Detection was performed at 220 nm. Several 100 microL injections of a 5 mg/mL solution were performed. Compound No. 36 enantiomer A or the “front enantiomer” is the enantiomer which was eluted from the column first followed by Compound No. 35 enantiomer B or the “back enantiomer”, which was the enantiomer which was eluted from the column second: m/z=430 (M+H) + . 
     Example 6 
     10-Acetyl-11-(1-bromo-2-phenylvinyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No 274 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from Intermediate (5-2) and 2-bromo-3-phenyl-acroleine following the procedure described in Example 5m/z=466 (M+H) + . 
     Example 7 
     10-Acetyl-11-(1-chloro-2-phenylvinyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 273 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from Intermediate (5-2) and 2-chloro-3-phenyl-acroleine following the procedure described in Example 5m/z=421 (M+H) + . 
     Example 8 
     10-Acetyl-3,3-dimethyl-11-[3-(4-chlorobenzoyloxy)phenyl]-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 101 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from Intermediate (5-2) and 3-[(4-chlorobenzoyl)-oxy]benzaldehyde following the described in Example 5: m/z=515 (M+H) + . 
     Example 9 
     10-Acetyl-11-(2,4-dichlorophenyl)-3,3,7,8-tetramethyl-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 308 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from 4,5-dimethyl-o-phenylenediamine and 2,4-dichlorobenzaldehyde following the procedure described in Example 5m/z=457 (M+H) + . 
     Example 10 
     10-Acetyl-3-(2-benzyloxyphenyl)-11-[3-(4-chlorobenzoyloxy)phenyl]-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 192 diastereomer A 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from Intermediate (1-4) and 3-[(4-chlorobenzoyl)-oxy]benzaldehyde following the procedure described in Example 1: m/z=669 (M+H)+. 
     Example 11 
     10-Acetyl-3-(2-benzyloxyphenyl)-11-[3-(4-chlorobenzoyloxy)phenyl]-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one—Compound No. 191 diastereomer B 
     The title compound was prepared from Intermediate (1-4) and 3-[(4-chlorobenzoyl)oxy]benzaldehyde following the procedure described in Example 2m/z=669 (M+H) + . 
     Example 12 
     10-Acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]-diazepin-1-one Compound No. 291. 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from cyclohexan-1,3-dianone, o-phenylenediamine and 2,4-dichlorobenzaldehyde following the procedure described in Example 5: m/z=401 (M+H) + . 
     Example 13 
     10-Acetyl-7,8-dichloro-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 307. 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from 4,5-dichloro-o-phenylenediamine and 2,4-dichlorobenzaldehyde following the procedure described in Example 5m/z=497 (M+H) + . 
     Example 14 
     3,3-dimethyl-11-(4-hydroxyphenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 440 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from intermediate 5-2 and 4-hydroxybenzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexa-hydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=335 (M+H) + . 
     Example 15 
     11-(4-acetoxyphenyl)-10-acetyl-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 1001 
     
       
         
         
             
             
         
       
     
     Ac 2 O (5 mL) was added at 0° C. to a solution of 3,3-dimethyl-11-(4-hydroxyphenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 440 in pyridine (50 mL). After 7 days, the reaction mixture was quenched with water (250 mL). Then, the solid was filtered off and washed with water. The solid was successively re-dissolved in CH 2 Cl 2 , washed with 0.5 N KHSO 4  (twice), dried (Na 2 SO 4 ) and evaporated. The residue was sonicated in Et 2 O and filtered off to give 4.36 g (71%) of the target compound 1001: m/z=419 (M+H)+. 
     Example 16 
     10-acetyl-11-(4-hydroxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound N o. 137 
     
       
         
         
             
             
         
       
     
     A solution of lithium hydroxide hydrate (672 mg) in water (5 mL) was added to a stirred suspension of 11-(4-acetoxyphenyl)-10-acetyl-3,3-dimethyl-2,3,4,5,10,11-hexa-hydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1001 (4.26 g, 10.2 mmol) in MeOH/THF/H 2 O 2.5:0.5:1 (70 mL). After 30 minutes, 1N HCl (20 mL) was added. Then, the reaction mixture was diluted with water (100 mL) and concentrated under reduced pressure. The precipitate was successively filtered off, washed with water and dried to give 3.70 g (97%) of the title product 137 as a white powder: m/z=377 (M+H) + . 
     Example 17 
     10-acetyl-3,3-dimethyl-11-[4-(2-pyridylmethoxy)phenyl]-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 141 
     
       
         
         
             
             
         
       
     
     A mixture of 10-acetyl-3,3-dimethyl-11-(4-hydroxyphenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 137 (250 mg, 0.664 mmol), 2-picolylchloride hydrochloride (109 mg, 1 eq.), cesium carbonate (476 mg, 2.2 eq.) in dry DMF (10 mL) were stirred at room temperature for 78 h. Then, the reaction mixture was diluted with water (300 mL) and the precipitate was successively filtered off, washed with water, dried and triturated in isopropylether to give 79 mg of the target product 141: m/z=468 (M+H) + . 
     Example 18 
     10-acetyl-11-[4-(2-chlorobenzyloxy)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 148. 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from 10-acetyl-11-(4-hydroxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 137 and 2-chlorobenzyl-bromide following the procedure described for example 17: m/z=501 (M+H) + . 
     Example 19 
     10-acetyl-3,3-dimethyl-11-[4-(4-pyridylmethoxy)phenyl]-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 145 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from 10-acetyl-11-(4-hydroxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 137 and 4-picolyl-chloride hydrochloride following the procedure described for example 17: m/z=468 (M+H) + . 
     Example 20 
     10-acetyl-3,3-dimethyl-11-[4-(3-pyridylmethoxy)phenyl]-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 140. 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from 10-acetyl-11-(4-hydroxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 137 and 3-picolyl-chloride hydrochloride following the procedure described for example 17: m/z=468 (M+H) + . 
     Example 21 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid methyl ester Compound no. 520 
     Step A. 
     
       
         
         
             
             
         
       
     
     Thionyl chloride (16.0 mL, 220 mmol) was added to a suspension of 3,4-diamino-benzoic acid (16.8 g, 110 mmol) in dry MeOH (200 mL). The resulting mixture was heated at reflux. After 12 h, the solution was successively cooled down to room temperature and concentrated under reduced pressure. The residue was triturated in diluted NaHCO 3 . Then, the precipitate was filtered off and dried to give 10.1 g (55%) of the target compound 1007. 
     Step B. 
     
       
         
         
             
             
         
       
     
     The intermediates 1008 and 1009 were prepared from 3,4-diaminobenzoic acid methyl ester 1007 and dimedone 1000 following the procedure (Step A) described for the synthesis of 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38). 
     Step C. 
     
       
         
         
             
             
         
       
     
     The title compound 520 was prepared from 1008 and 2,4-dichlorobenzaldehyde following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=487 (M+H) + . 
     Example 22 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-8-carboxylic acid methyl ester Compound no. 521 
     
       
         
         
             
             
         
       
     
     The title compound 521 was prepared from 1009 and 2,4-dichlorobenzaldehyde following the procedure described for 10-acetyl-1-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=487 (M+H) + . 
     Example 23 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid Compound no. 1012 
     
       
         
         
             
             
         
       
     
     A solution of lithium hydroxide hydrate (354 mg, 8.2 mmol) was added to a suspension of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid methyl ester 520 (2.0 g, 4.10 mmol) in water (25 mL) and THF (25 mL). After 12 h, the pH of the reaction mixture was adjusted to 3 with 1 N HCl. The precipitate was collected by filtration, the washed with water and dried to afford 1.87 g (96.4%) of the title product 1012: m/z=473 (M+H) + . 
     Example 24 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-8-carboxylic acid Compound no. 522. 
     
       
         
         
             
             
         
       
     
     The title compound 522 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-8-carboxylic acid methyl ester 521 following the procedure described for the preparation of 10 acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid 1012: m/z=473 (M+H) + . 
     Example 25 
     10-acetyl-N-(morpholin-4-ylethyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide Compound no. 321 
     
       
         
         
             
             
         
       
     
     A solution of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid 1012 (250 mg, 0.53 mmol), 4-(2-aminoethyl)morpholine, EDCI.HCl (203 mg, 1.06 mmol), HOAT (144 mg, 1.06 mmol), and DIPEA (185 μL, 1.06 mmol) in dry DMF (5 mL) was stirred overnight at room temperature. Then, the reaction mixture was diluted with water (75 mL), and the precipitate formed was collected by filtration, then washed with water and dried to give 120 mg (39%) of the title product 321: m/z=585 (M+H) + . 
     Example 26 
     10-acetyl-N—(N,N-dimethylaminopropyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide Compound no. 1015 
     
       
         
         
             
             
         
       
     
     The title compound 1015 was prepared in 73% yield from 10-acetyl-11-(2,4-dichloro-phenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid 1012 and 3-(N,N-dimethylamino)propylamine following the procedure reported for the preparation of N-(morpholin-4-ylethyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide 321: m/z=557 (M+H) + . 
     Example 27 
     10-acetyl-N-(4-pyridylethyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide Compound no. 1016. 
     
       
         
         
             
             
         
       
     
     The title compound 1016 was prepared in 53% yield from 10-acetyl-11-(2,4-dichloro-phenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid 1012 and 4-pyridylethylamine following the procedure reported for the preparation of 10-acetyl-N-(morpholin-4-ylethyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide 321: m/z=577 (M+H) + . 
     Example 28 
     10-acetyl-N—(N,N-dimethylaminoethyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide Compound no. 1018 
     
       
         
         
             
             
         
       
     
     The title compound 1018 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid 1012 and 2-(N,N-dimethylamino)ethylamine following the procedure reported for the preparation of 10-acetyl-N-(morpholin-4-ylethyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide 321: m/z=543 (M+H) + . 
     Example 29 
     10-acetyl-N-(2-piperidin-1-ylethyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide Compound no. 1019. 
     
       
         
         
             
             
         
       
     
     The title compound 1019 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid 1012 and 2-(piperidin-1-yl)ethylamine following the procedure reported for the preparation of 10-acetyl-N-(morpholin-4-ylethyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide 321: m/z=583 (M+H) + . 
     Example 30 
     10-acetyl-N-(2-cyanoethyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide Compound no. 1020. 
     
       
         
         
             
             
         
       
     
     The title compound 1020 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid 1012 and 2-cyanoethylamine following the procedure reported for the preparation of 10-acetyl-N-(morpholin-4-ylethyl)-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxamide 321: m/z=525 (M+H) + . 
     Example 31 
     10-acetyl-11-(2,4-dichlorophenyl)-7-hydroxymethyl-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 523 
     
       
         
         
             
             
         
       
     
     Sodium borohydride (824 mg, 21.8 mmol) was added portion wise to a solution of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxylic acid methyl ester 520 (5.3 g, 10.9 mmol) in absolute ethanol (100 mL). After 24 h, sodium borohydride (824 mg, 21.8 mmol) was added to the reaction mixture. This operation was repeated 3 times (total: 14 eq. of NaBH 4  were used). The reaction mixture was added dropwise to a solution of 2N HCl (500 mL). The precipitate was collected by filtration, washed with water and dried to give 3.83 g (77%) of the title product 523 as a white powder: m/z=459 (M+H) + . 
     Example 32 
     10-acetyl-7-bromomethyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1022 
     
       
         
         
             
             
         
       
     
     Phosphorous tribromide (118 μL, 1.25 mmol) was gradually added under nitrogen at 0° C. to a stirred solution of 10-acetyl-11-(2,4-dichlorophenyl)-7-hydroxymethyl-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 523 in DCE (2 mL). The resulting solution was stirred at room temperature for 1 h. Then, a diluted aqueous solution of sodium bicarbonate was added. The reaction mixture was extracted with AcOEt, dried (Na 2 SO 4 ) and evaporated to give 157 mg (68%) of the title product 1022: m/z=522 (M+H) + . 
     Example 33 
     10-acetyl-7-chloromethyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1023. 
     
       
         
         
             
             
         
       
     
     Thionylchloride (238 μL, 3.26 mmol) was added dropwise under nitrogen at 0° C. to a stirred solution of 10-acetyl-11-(2,4-dichlorophenyl)-7-hydroxymethyl-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 523 (500 mg, 1.09 mmol) in DCE (10 mL). The resulting solution was stirred at room temperature for 2 h. Then, ice-cold water was added. The reaction mixture was extracted with DCM, dried (Na 2 SO 4 ) and evaporated to give 410 mg (79%) of the title product 1023: m/z=477 (M+H) + . 
     Example 34 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde Compound no. 1024. 
     
       
         
         
             
             
         
       
     
     Manganese (IV) oxide was added to a stirred solution of 10-acetyl-11-(2,4-dichloro-phenyl)-7-hydroxymethyl-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 523 in acetone (10 mL). The resulting solution was heated to reflux. After 2 days, the reaction mixture was cooled down to room temperature, filtered over kieselguhr, and evaporated to give 400 mg (40%) of the title product 1024: m/z=457 (M+H) + . 
     Example 35 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1025. 
     
       
         
         
             
             
         
       
     
     A solution of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 (200 mg, 0.44 mmol) and 4-(2-aminoethyl)morpholine (53 μL, 0.40 mmol) in DCM (5 mL) was stirred at room temperature for 30 minutes. Then, NaBH(OAc) 3  (122 mg, 0.57 mmol) and acetic acid (26.3 μL, 1.2 eq.) were added. The resulting reaction mixture was stirred overnight at room temperature, then quenched with a saturated solution of sodiumbicarbonate, extracted with AcOEt, dried (Na 2 SO 4 ) and evaporated to give 190 mg (87%) of the title product 1025: m/z=571 (M+H) + . 
     Example 36 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-[3-(N,N-dimethyl-amino)propylaminomethyl]-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1026. 
     
       
         
         
             
             
         
       
     
     The title compound 1026 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and 3-(N,N-dimethylaminopropylamine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1025: m/z=543 (M+H) + . 
     Example 37 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-[2-(4-pyridyl)ethyl-aminomethyl]-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1027. 
     
       
         
         
             
             
         
       
     
     The title compound 1027 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and 4-pyridylethylamine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-yl-ethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1025: m/z=563 (M+H) + . 
     Example 38 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-[2-(N,N-dimethyl-amino)ethylaminomethyl]-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1028. 
     
       
         
         
             
             
         
       
     
     The title compound 1028 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and 2-(N,N-dimethylamino)ethylamine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1025: m/z=529 (M+H) + . 
     Example 39 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-[2-(piperidin-1-yl)-ethylaminomethyl]-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1030 
     
       
         
         
             
             
         
       
     
     The title compound 1030 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and 2-(piperidin-1-yl)ethylamine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1025: m/z=569 (M+H) + . 
     Example 40 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-cyanoethylamino-methyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1031. 
     
       
         
         
             
             
         
       
     
     The title compound 1031 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and 2-cyanoethylamine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1025: m/z=511 (M+H) + . 
     Example 41 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(morpholin-4-ylmethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1032. 
     
       
         
         
             
             
         
       
     
     The title compound 1032 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and morpholine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1025: m/z=528 (M+H) + . 
     Example 42 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(N-methyl-N-propyl-aminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1033 
     
       
         
         
             
             
         
       
     
     The title compound 1033 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and N-methylpropylamine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1025: m/z=514 (M+H) + . 
     Example 43 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-[4-(aminocarbonyl)-piperidin-1-ylmethyl]-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1034. 
     
       
         
         
             
             
         
       
     
     The title compound 1034 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and 4-(aminocarbonyl)piperidine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]-diazepin-1-one 1025: m/z=569 (M+H) + . 
     Example 44 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(4-methylpiperazin-1-ylmethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1035. 
     
       
         
         
             
             
         
       
     
     The title compound 1035 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and 4-methylpiperazine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1025: m/z=541 (M+H) + . 
     Example 45 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(piperidin-1-ylmethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1037 
     
       
         
         
             
             
         
       
     
     The title compound 1037 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and piperidine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1025: m/z=526 (M+H) + . 
     Example 46 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(pyrrolidin-1-yl-methyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1038 
     
       
         
         
             
             
         
       
     
     The title compound 1038 was prepared from 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepine-7-carboxaldehyde 1024 and pyrrolidine following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-(2-morpholin-4-ylethylaminomethyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1025: m/z=512 (M+H) + . 
     Example 47 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-[2-(piperidin-1-yl)-ethoxymethyl]-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1039. 
     
       
         
         
             
             
         
       
     
     Sodium hydride (17 mg, 60% in mineral oil, 0.42 mmol) was added at 0° C. under argon to a solution of N-piperidineethanol (53 μL, 0.4 mmol) in dry DMF (4 mL). The resulting solution was added at 0° C. under argon to a solution of 10-acetyl-7-bromo-methyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo-[b,e][1,4]diazepin-1-one 1022 (200 mg, 0.38 mmol) in dry DMF (2 mL). After 2 h, the reaction mixture was diluted with ice-cold water (70 mL). The pH of the resulting solution was adjusted to 7 with 2N aqueous NaOH. Then, the reaction mixture was successively extracted with AcOEt (3 times), THF (3 times). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and evaporated. The residue was triturated in toluene, the evaporated. The residue was triturated in DCM and methanol, filtered and concentrated under vacuum. The residue was purified by column chromatography on alumina (CH 2 Cl 2 /MeOH, gradient 1:0 to 92:8) to give 85 mg (39%) of the target compound 1039: m/z=570 (M+H) + . 
     Example 48 
     10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-[3-(N,N-dimethyl-amino)propoxymethyl]-2,3,45,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1040. 
     
       
         
         
             
             
         
       
     
     The title compound 1040 was prepared from 10-acetyl-7-bromomethyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1022 and 3-(N,N-dimethylamino)propanol following the procedure reported for the preparation of 10-acetyl-11-(2,4-dichlorophenyl)-3,3-dimethyl-7-[2-(piperidin-1-yl)ethoxymethyl]-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1039: m/z=544 (M+H) + . 
     Example 49 
     10-acetyl-11-[4-(phenalaminocarbonyl)phenyl]-33-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1041. 
     
       
         
         
             
             
         
       
     
     The title compound 1041 was prepared from 4-(phenylaminocarbonyl)benzaldehyde following the procedure reported for the synthesis of 10-acetyl-11-(2,4-dichloro-phenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=480 (M+H) + . 
     Example 50 
     10-acetyl-11-[4-(N-acetyl-N-phenalaminosulfonyl)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1042. 
     
       
         
         
             
             
         
       
     
     The title compound 1042 was prepared from 4-(N-phenylaminosulfonyl)benzaldehyde following the procedure reported for the synthesis of 10-acetyl-11-(2,4-dichloro-phenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=558 (M+H) + . 
     Example 51 
     10-acetyl-11-[4-(N-phenylaminosulfonyl)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1043 
     
       
         
         
             
             
         
       
     
     A solution of lithium hydroxide hydrate (11 mg, 0.26 mmol) in water (0.5 mL) was added at 0° C. to a stirred solution of 10-acetyl-11-[4-(N-acetyl-N-phenylamino-sulfonyl)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1042 (133 mg, 0.26 mmol). After 12 h at room temperature, the reaction mixture was diluted with a saturated solution of ammonium chloride, extracted twice with AcOEt, washed with brine, dried (Na 2 SO 4 ) and evaporated to give 100 mg of the title product: m/z=516 (M+H) + . 
     Example 52 
     10-acetyl-11-(4-nitrophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1044 
     
       
         
         
             
             
         
       
     
     The title compound 1044 was prepared from intermediate 5-2 and 4-nitrobenzaldehyde following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=406 (M+H) + . 
     Example 53 
     10-acetyl-11-(4-aminophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1045 
     
       
         
         
             
             
         
       
     
     A solution of 10-acetyl-11-(4-nitrophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1044 (862 mg, 2.13 mmol) in MeOH (3 mL) and THF (3 mL) was added to a suspension of iron (476 mg, 8.52 mmol) and ammonium chloride (460 mg, 8.52 mmol) in water (3 mL). The resulting mixture was heated at 70° C. After 2 h, the reaction mixture was filtered on kieselguhr and extensively washed with AcOEt. The combine organic extracts were washed with brine, the dried (Na 2 SO 4 ) and evaporated to give 272 mg (35%) of the title product 1045: m/z=376 (M+H) + . 
     Example 54 
     10-acetyl-11-[4-(phenylsulfonylamino)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1046. 
     
       
         
         
             
             
         
       
     
     A solution of 10-acetyl-11-(4-aminophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1045 (127 mg, 0.34 mmol), benzensulfonyl chloride (45.5 μL, 0.36 mmol) in pyridine (2 mL) was stirred at room temperature for 12 h. The reaction mixture was successively added dropwise to 10 mL of water, extracted with AcOEt, washed with brine, dried (Na 2 SO 4 ) and evaporated to afford 78 mg of the title product 1046: m/z=516 (M+H) + . 
     Example 55 
     10-acetyl-11-[4-(phenylcarbonylamino)henyl]-33-dimethyl-2,3,4,5,1011-hexahydro-1H-dibenzo[b,e][1,4]diazenin-1-one Compound no. 1047. 
     
       
         
         
             
             
         
       
     
     The title compound 1047 was prepared from 10-acetyl-11-(4-aminophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1045 and benzoyl chloride following the procedure described for 10-acetyl-11-[4-(phenyl-sulfonylamino)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]-diazepin-1-one 1046: m/z=480 (M+H) + . 
     Example 56 
     11-[4-(phenylcarbonyl)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1048. 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from intermediate 5-2 and 4-(phenylcarbonyl)-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=423 (M+H) + . 
     Example 57 
     10-acetyl-11-[4-(phenylcarbonyl)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1049. 
     
       
         
         
             
             
         
       
     
     The title compound 1049 was prepared from 11-[4-(phenylcarbonyl)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 1048 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexa-hydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=465 (M+H) + . 
     Example 58 
     11-[4-benzyloxycarbonyl-2-chlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 443. 
     
       
         
         
             
             
         
       
     
     The title compound 443 was prepared from intermediate 5-2 and 4-benzyloxy-2-chlorobenzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=459 (M+H) + . 
     Example 59 
     10-acetyl-11-[4-benzyloxycarbonyl-2-chlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 142. 
     
       
         
         
             
             
         
       
     
     The title compound 142 was prepared from 11-[4-benzyloxycarbonyl-2-chlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 443 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=501 (M+H) + . 
     Example 60 
     11-[3,5-dichlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 436. 
     
       
         
         
             
             
         
       
     
     The title compound 436 was prepared from intermediate 5-2 and 2,5-dichloro-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=387 (M+H) + . 
     Example 61 
     10-acetyl-11-[3,5-dichlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 133. 
     
       
         
         
             
             
         
       
     
     The title compound 133 was prepared from 11-[3,5-dichlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 436 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=429 (M+H) + . 
     Example 62 
     11-[4-benzyloxy-3-chlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 439. 
     
       
         
         
             
             
         
       
     
     The title compound 439 was prepared from intermediate 5-2 and 3-chloro-4-benzyloxy-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=459 (M+H) + . 
     Example 63 
     10-acetyl-11-[4-benzyloxy-3-chlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 139 
     
       
         
         
             
             
         
       
     
     The title compound 139 was prepared from 11-[4-benzyloxy-3-chlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 439 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=501 (M+H) + . 
     Example 64 
     11-[4-benzyloxy-3,5-dichlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 444. 
     
       
         
         
             
             
         
       
     
     The title compound 444 was prepared from intermediate 5-2 and 3,5-dichloro-4-benzyloxybenzaldehyde following the procedure described for 11-(2,4-dichloro-phenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=493 (M+H) + . 
     Example 65 
     10-acetyl-11-[4-benzyloxy-3,5-dichlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 143 
     
       
         
         
             
             
         
       
     
     The title compound 143 was prepared from 11-[4-benzyloxy-3,5-dichlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 444 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=535 (M+H) + . 
     Example 66 
     11-[2,5-dichlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 438 
     
       
         
         
             
             
         
       
     
     The title compound 438 was prepared from intermediate 5-2 and 2,5-dichloro-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=387 (M+H) + . 
     Example 67 
     10-acetyl-11-[2,5-dichlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 138 
     
       
         
         
             
             
         
       
     
     The title compound 138 was prepared from 11-[2,5-dichlorophenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 438 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=429 (M+H) + . 
     Example 68 
     11-[2,4-dibenzyloxyphenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 445. 
     
       
         
         
             
             
         
       
     
     The title compound 445 was prepared from intermediate 5-2 and 2,4-dibenzyloxy-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=531 (M+H) + . 
     Example 69 
     10-acetyl-11-[2,4-dibenzyloxyphenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 144. 
     
       
         
         
             
             
         
       
     
     The title compound 144 was prepared from 11-[2,4-dibenzyloxyphenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 445 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=573 (M+H) + . 
     Example 70 
     11-(2,4-difluorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 441 
     
       
         
         
             
             
         
       
     
     The title compound 441 was prepared from intermediate 5-2 and 2,4-difluoro-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=355 (M+H) + . 
     Example 71 
     10-acetyl-11-(2,4-difluorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 146 
     
       
         
         
             
             
         
       
     
     The title compound 146 was prepared from 11-(2,4-difluorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 441 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=397 (M+H) + . 
     Example 72 
     11-(4-trifluoromethyloxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 434 
     
       
         
         
             
             
         
       
     
     The title compound 434 was prepared from intermediate 5-2 and 4-trifluoromethyloxy-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=403 (M+H) + . 
     Example 73 
     10-acetyl-11-(4-trifluoromethyloxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 1064. 
     
       
         
         
             
             
         
       
     
     The title compound 1064 was prepared from 11-(4-trifluoromethyloxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 434 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=445 (M+H) + . 
     Example 74 
     11-(4-benzyloxy-2,6-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 447. 
     
       
         
         
             
             
         
       
     
     The title compound 447 was prepared from intermediate 5-2 and 4-benzyloxy-2,6-dichlorobenzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=493 (M+H) + . 
     Example 75 
     10-acetyl-11-(4-benzyloxy-2,6-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 150. 
     
       
         
         
             
             
         
       
     
     The title compound 150 was prepared from 11-(4-benzyloxy-2,6-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 447 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=535 (M+H) + . 
     Example 76 
     11-(3-benzyloxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 437 
     
       
         
         
             
             
         
       
     
     The title compound 437 was prepared from intermediate 5-2 and 3-benzyloxy-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=425 (M+H) + . 
     Example 77 
     10-acetyl-11-(3-benzyloxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 136. 
     
       
         
         
             
             
         
       
     
     The title compound 136 was prepared from 11-(3-benzyloxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 437 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=467 (M+H) + . 
     Example 78 
     11-(4-phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 435 
     
       
         
         
             
             
         
       
     
     The title compound 435 was prepared from intermediate 5-2 and 4-phenoxy-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=411 (M+H) + . 
     Example 79 
     10-acetyl-11-(4-phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 134 
     
       
         
         
             
             
         
       
     
     The title compound 134 was prepared from 11-(4-phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 435 following the procedure described for 10-acetyl-1-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=453 (M+H) + . 
     Example 80 
     11-[4-(2-bromophenoxy)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 442 
     
       
         
         
             
             
         
       
     
     The title compound 442 was prepared from intermediate 5-2 and 4-(2-bromophenoxy)-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=490 (M+H) + . 
     Example 81 
     10-acetyl-11-[4-(2-bromophenoxy)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 147 
     
       
         
         
             
             
         
       
     
     The title compound 147 was prepared from 11-[4-(2-bromophenoxy)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 442 following the procedure described for 10-acetyl-1-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=532 (M+H) + . 
     Example 82 
     11-(3-phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 433 
     
       
         
         
             
             
         
       
     
     The title compound 433 was prepared from intermediate 5-2 and 3-phenoxy-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=411 (M+H) + . 
     Example 83 
     11-(3-phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 135 
     
       
         
         
             
             
         
       
     
     The title compound 135 was prepared from 11-(3-phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 433 following the procedure described for 10-acetyl-1-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=453 (M+H) + . 
     Example 84 
     11-[3-(2-bromophenoxy)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 446 
     
       
         
         
             
             
         
       
     
     The title compound 446 was prepared from intermediate 5-2 and 3-(2-bromophenoxy)-benzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=490 (M+H) + . 
     Example 85 
     10-acetyl-11-[3-(2-bromophenoxy)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 149 
     
       
         
         
             
             
         
       
     
     The title compound 149 was prepared from 11-[3-(2-bromophenoxy)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 446 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=532 (M+H) + . 
     Example 86 
     7,8-dimethoxy-11-(2,4-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 467 
     
       
         
         
             
             
         
       
     
     The title compound 467 was prepared from 2,4-dichlorobenzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=447 (M+H) + . 
     Example 87 
     10-acetyl-7,8-dimethoxy-11-(2,4-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 309 
     
       
         
         
             
             
         
       
     
     The title compound 309 was prepared from 7,8-dimethoxy-11-(2,4-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 467 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=489 (M+H) + . 
     Example 88 
     7,8-difluoro-11-(2,4-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 466 
     
       
         
         
             
             
         
       
     
     The title compound 466 was prepared from 2,4-dichlorobenzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=423 (M+H) + . 
     Example 89 
     10-acetyl-7,8-difluoro-11-(2,4-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 310 
     
       
         
         
             
             
         
       
     
     The title compound 310 was prepared from 7,8-difluoro-11-(2,4-dichlorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 466 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=465 (M+H) + . 
     Example 90 
     11-(2,4-dichlorophenyl)-3-methyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 422 
     
       
         
         
             
             
         
       
     
     The title compound 422 was prepared from 2,4-dichlorobenzaldehyde following the procedure described for 11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one 5-3: m/z=373 (M+H) + . 
     Example 91 
     10-acetyl-11-(2,4-dichlorophenyl)-3-methyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one Compound no. 294 
     
       
         
         
             
             
         
       
     
     The title compound 294 was prepared from 11-(2,4-dichlorophenyl)-3-methyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one 442 following the procedure described for 10-acetyl-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one (compound no. 38): m/z=415 (M+H) + . 
     Example 92 
     
       
         
         
             
             
         
       
     
     A mixture of a-1 (0.0022 mol) in Ac 2 O (10 ml) was stirred and refluxed for 1 hour. A tip spat of DMAP was added. The mixture was stirred for 1 hour. H 2 O was added. The mixture was extracted with CH 2 Cl 2 . The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 99/1/0.05). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone (few)/diethyl ether/EtOH. The precipitate was filtered off and dried, yielding: 0.352 g of Compound no. 48 (melting point: 216° C.). 
     
       
         
         
             
             
         
       
     
     b-2 (0.024 mol, 0.54 g) was added at 0° C. to a solution of b-1 (0.0006 mol) in pyridine (6 ml). The mixture was stirred at room temperature for 12 h. b-2 (0.0024 mol, 0.54 g) was added again at 0° C. The mixture was stirred for 24 h, then evaporated until dryness. The residue was taken up in CH 2 Cl 2 . The organic layer was washed with H 2 O, dried (over MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding: 0.089 g of compound no. 45 (melting point &gt;250° C.). 
     
       
         
         
             
             
         
       
     
     A mixture of c-1 (0.0003 mol) in c-2 (5 ml) was stirred at room temperature for 12 h, then cooled with an ice bath. H 2 O was added drop wise. The mixture was taken up in CH 2 Cl 2 . The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (0.165 g) was crystallized from CH 3 CN. The precipitate was filtered off and dried, yielding: 0.089 g of Compound no. 107 (74%) (melting point &gt;260° C.). 
     
       
         
         
             
             
         
       
     
     Ac 2 O (2 ml) was added drop wise at 0° C. to a solution of d-1 (0.0052 mol) in Pyridine (50 ml). The mixture was stirred at room temperature for 12 h. Ac 2 O (2 ml) was added again at 0° C. The mixture was stirred at room temperature for 12 h. The precipitate was filtered, washed with H 2 O and dried, yielding: 1.67 g of Compound no. 38 (75%) (melting point &gt;260° C.). 
     
       
         
         
             
             
         
       
     
     A mixture of e-1 (0.0004 mol) and NaH (0.0004 mol) in DMF (2 ml) was stirred for 10 minutes. CH 3 I (0.0004 mol) was then added. The mixture was stirred at room temperature for 12 h and evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH 99/1; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding: 0.037 g of Compound no. 322 (20%) (melting point: 145° C.). 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     A mixture of f-1 (0.0057 mol) and f-2 (0.0057 mol) in toluene (20 ml) was stirred and refluxed for 12 h, then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 96/4/0.2). Two fractions were collected and the solvent was evaporated until dryness, yielding a mixture of f-3 and f-4 (71%). 
     A mixture of f-3+f-4 (0.004 mol) and f-5 (0.004 mol) in EtOH (10 ml) and AcOH (10 ml) was stirred at 75° C. for 12 h, then evaporated until dryness. The residue was taken up in EtOAc. Saturated NaHCO 3  was added. The mixture was stirred for 1 hour and 30 minutes, then filtered and extracted with EtOAc. The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH 99.5/0.5). Three fractions were collected and the solvent was evaporated, yielding: 0.2 g of f-7, 1 g of a mixture f-6+f-7 and 0.1 g of f-6 (melting point: 170° C.). 
     A mixture of f-6+f-7 (0.0004 mol) in Ac 2 O (5 ml) was stirred and refluxed for 4 hours, then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 97/3/0.1). Two fractions were collected and the solvent was evaporated, yielding: 0.065 g of f-9 and 0.09 g of f-8. A part of f-8 was crystallized from diethyl ether/2-propanone. The precipitate was filtered off and dried, yielding: 0.03 g (melting point &gt;260° C.). 
     
       
         
         
             
             
         
       
     
     The title compound no. 139 was prepared from Intermediate (5-2) and 4-benzyloxy-3-chlorobenzaldehyde following the procedure described in Example 5: m/z=501 (M+H) + . 
     Separation of the (R)- and (S)-enantiomers of compound no. 139. 
     
       
         
         
             
             
         
       
     
     The two enantiomers were separated by SFC with a chiral column (eluent: CO 2 /CH 3 OH 40/60). Two fractions were collected and the solvent was evaporated, yielding: 0.085 g of enantiomer A and 0.085 g of enantiomer B. Both fractions were crystallized from DIPE/2-propanone. The precipitate was filtered off and dried, yielding: 0.042 g of Compound no. 303 (enantiomer A) (melting point: 130° C.) and 0.055 g of Compound no. 304 (enantiomer B) (melting point: 130° C.). 
     
       
         
         
             
             
         
       
     
     A mixture of h-1 (0.0004 mol), Zn(CN) 2  (0.0007 mol), Pd 2  dba 3  (0.022 g), dppf (0.033 g), Zn (0.0002 mol) and Zn(OAc) 2  (0.0002 mol) in DMA (2 ml) was stirred at 130° C. in a microwave oven for 30 minutes, then poured into H 2 O and extracted with EtOAc. The organic layer was washed with H 2 O, dried (over MgSO 4 ), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /EtOAc 95/5). The pure fractions were collected and the solvent was evaporated. The residue (0.14 g) was crystallized from CH 3 CN. The precipitate was filtered off and dried, yielding: 0.06 g of h-2 (melting point: 225° C.). 
     A mixture of h-2 (0.0002 mol) in Ac 2 O (4 ml) was stirred and refluxed for 12 hours and then evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue (0.07 g) was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried. Yielding: 0.025 g of Compound no. 313 (melting point: 248° C.). 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     A mixture of i-1 (0.0094 mol) and i-2 (0.0094 mol) in toluene (50 ml) was stirred and refluxed for 12 h in a Dean Stark apparatus, then cooled down to room temperature. The precipitate was filtered off and dried, yielding: 2.3 g of i-3 (76%). 
     A mixture of i-3 (0.0044 mol) and i-4 (0.0044 mol) in EtOH (12.44 ml) and AcOH (1.23 ml) was stirred at 75° C. for 12 h, then evaporated until dryness. The residue was taken up in EtOAc/NaHCO3 10% aq. The mixture was stirred at room temperature for 1 hour and 30 minutes, then filtered off and dried. The residue (0.4 g) was washed with EtOAc, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (1.77 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 98.5/1.5/0.1). The pure fractions were collected and the solvent was evaporated, yielding: 1 g of I-5 (52%). A small fraction was crystallized from CH3CN/DIPE (melting point: 208° C.). The remaining fraction of i-5 was used in the next reaction step. 
     A mixture of i-5 (0.0008 mol) in Ac 2 O (60 ml) was stirred and refluxed for 4 hours, then evaporated until dryness, yielding: 0.46 g of i-6 (100%). 
     i-6 (0.0059 mol) was added at 0° C. to a suspension of LiAlH 4  (0.0018 mol) in THF (4 ml) under N 2  flow. The mixture was stirred at 0° C. for 3 hours. EtOAc then ice were added. The mixture was extracted with EtOAc. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (0.175 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 95/5/0.5 to 93/7/0.7). The pure fractions were collected and the solvent was evaporated, yielding: 0.032 g of i-7 (12%) (melting point 200° C.). 
     A mixture of i-7 (0.0005 mol) and MnO 2  (1.5 g) in CH 2 Cl 2  (10 ml) was stirred at room temperature for 3 hours, then filtered over celite and washed with CH 2 Cl 2 . The filtrate was evaporated until dryness. The residue was crystallized from CH 3 CN/DIPE. The precipitate was filtered off and dried, yielding: 0.12 g of i-8 (48%). 
     A mixture of i-8 (0.0001 mol), i-9 (0.0001 mol), BH 3 CN— on solid support (0.0001 mol) and AcOH (5 drops) in CH 3 OH (5 ml) was stirred at room temperature for 5 hours. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 94/6/0.6 to 82/18/1.8). The pure fractions were collected and the solvent was evaporated. The residue (0.035 g) was crystallized from CH 3 CN. The precipitate was filtered off and dried. Yielding: 0.022 g of Compound no. 514 (31%) (melting point: 258° C.). 
     
       
         
         
             
             
         
       
     
     A mixture of j-1 (0.0004 mol) and LiOH (0.0009 mol) in THF (20 ml) and H 2 O (20 ml) was stirred at 50° C. for 36 hours. THF was evaporated. The mixture was acidified with HCl 1N until pH was set to 7. The precipitate was filtered. The filtrate was basified with K 2 CO 3  10%. The aqueous layer was acidified with HCl 1N. The precipitate was filtered off and dried, yielding: 0.092 g of j-2 (60%). 
     A mixture of j-2 (0.0001 mol), j-3 (0.0003 mol), EDCI (0.0003 mol) and HOBT (0.0003 mol) in CH 2 Cl 2  (4 ml) and THF (2 ml) was stirred at room temperature for 6 hours, poured into H 2 O and extracted with CH 2 Cl 2 . The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated until dryness. The residue (0.1 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 92/8/0.8 to 78/20/2). The pure fractions were collected and the solvent was evaporated. The residue (0.054 g) was crystallized from CH 3 CN/DIPE. The precipitate was filtered off and dried, yielding: 0.048 g of Compound no. 515 (melting point: 226° C.). 
     
       
         
         
             
             
         
       
     
     NaH (0.0001 mol) was added to a solution of k−1 (0.0005 mol) in DMF (2.5 ml). The mixture was stirred for 10 minutes. k-2 (0.0001 mol) was added. The mixture was stirred at room temperature for 12 h, then evaporated until dryness. The residue (0.45 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue (0.2 g) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding: 0.043 g of Compound no. 323 (melting point: 235° C.). 
     
       
         
         
             
             
         
       
     
     A mixture of l-1 (0.0003 mol), l-2 (0.0004 mol) and NEt 3  (0.065 ml) in CH 2 Cl 2  (4 ml) was stirred at room temperature for 48 hours. The mixture was stirred at room temperature for 12 h, then poured into H 2 O/CH 2 Cl 2 . The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated. The residue (0.13 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 99/1/0.1 to 94/6/0.6). The pure fractions were collected and the solvent was evaporated. The residue (0.05 g) was crystallized from CH 3 CN/DIPE. The precipitate was filtered off and dried, yielding: 0.041 g of Compound no. 151 (23%) (melting point &gt;260° C.). 
     
       
         
         
             
             
         
       
     
     A mixture of m-1 (0.0002 mol) and m-2 (0.0003 mol) in THF (5 ml) was stirred and refluxed for 1 hour and 30 minutes, then taken up in H 2 O/CH 2 Cl 2  and extracted with CH 2 Cl 2 . The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated until dryness. The residue was crystallized from CH 3 CN/DIPE (few). The precipitate was filtered off and dried, yielding: 0.064 g of Compound no. 156 (53%) (melting point &gt;260° C.). 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     A mixture of n-1 (0.01 mol) and n-2 (0.01 mol) in toluene (20 ml) was stirred and 5 refluxed in a Dean Stark apparatus for 12 h, then evaporated until dryness, yielding: 3 g of n-3+n-4. This mixture of product was used directly in the next reaction step. 
     A mixture of n-3+n-4 (0.01 mol) and n-5 (0.01 mol) in EtOH (25 ml) and AcOH (25 ml) was stirred at 75° C. for 12 h, then evaporated until dryness. The residue was taken up in EtOAc and saturated solution of NaHCO 3 . The mixture was stirred for 1 hour and 30 minutes, and then filtered. The aqueous layer was extracted with EtOAc. The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2  100). The pure fractions were collected and the solvent was evaporated, yielding: 1.25 g of n-6+n-7. 
     Ac 2 O (1 ml) was added to a solution of n-6+n-7 (0.0012 mol) in pyridine (10 ml). The mixture was stirred at room temperature for 12 h, then evaporated until dryness. The residue (0.54 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 98/2/0.2 to 92/8/0.8). Two fractions were collected and the solvent was evaporated, yielding: 0.14 g F1 (24%) and 0.15 g F2 (25%). Each fraction was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried. Yielding: n-8 (melting point &gt;250° C.) and n-9 (melting point &gt;250° C.). 
     
       
         
         
             
             
         
       
     
     A mixture of o-1 (0.003 mol) and LiAlH 4  (0.012 mol) in THF (60 ml) was stirred at room temperature for 2 hours. H 2 O and NaOH 3M were the added carefully. The mixture was stirred for 1 h. The mixture was extracted with CH 2 Cl 2 /CH 3 OH (few). The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated until dryness. The residue was washed with H2O and dried, yielding: 1.54 g o-2 (100%). A small part (0.07 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 98/2/0.2 to 92/8/0.8). The pure fractions were collected and the solvent was evaporated, yielding: 0.022 g. The remaining product was used in the next reaction step. 
     Dess Martin reagent (13.34 ml) was added at room temperature of o-2 (0.0031 mol) in CH 2 Cl 2  (11.6 ml). The mixture was stirred at room temperature for 1 hour. Saturated NaHCO 3  and Na 2 S 2 O 4  were added. The mixture was extracted with CH 2 Cl 2 . The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated until dryness. The residue was crystallized from CH 3 CN. The precipitate was filtered off and dried, yielding: 1.3 g of o-3. 
     A mixture of o-3 (0.0002 mol), dimethylamine (0.0006 mol), BH 3 CN— on solid support (0.0006 mol) and AcOH (4 drops) in CH 3 OH (5 ml) was stirred at room temperature for 12 h. Dimethylamine (0.5 eq) and BH 3 CN— on solid support (0.5 eq) were added again. The mixture was stirred at room temperature for 12 h, then filtered. The filtrate was evaporated. The mixture was taken up in CH 2 Cl 2 /H 2 O. The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 97/3/0.5). The pure fractions were collected and the solvent was evaporated. The residue (0.085 g) was crystallized from CH 3 CN/DIPE. The precipitate was filtered off and dried, yielding: 0.056 g of Compound no. 516 (52%) (melting point &gt;260° C.). 
     
       
         
         
             
             
         
       
     
     A mixture of p-1 (0.0001 mol) and LiOH/H 2 O (0.0004 mol) in THF/H 2 O (1/1) (10 ml) was stirred at room temperature for 12 h, and then concentrated under reduced pressure. The aqueous layer was washed with diethyl ether, made acidic with HCl 1N and filtered. The precipitate was dried, yielding: 0.045 g of Compound no. 517 (melting point &gt;250° C.). 
     
       
         
         
             
             
         
       
     
     q-2 (0.0012 mol) was added drop wise to a mixture of q-1 (0.001 mol) and NEt 3  (0.0012 mol) in THF (5 ml). The mixture was stirred and refluxed for 12 h, then cooled down to room temperature. The precipitate was filtered, washed with THF. The filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 98/2/0.2, 93/7/0.7 then 94/6/0.6). The pure fractions were collected and the solvent was evaporated. The residue (0.09 g, 18%) was crystallized from 2-propanone. The precipitate was filtered off and dried. Yielding: q-3 (melting point: 190° C.). 
     A mixture of q-3 (0.0001 mol) and LiOH/H 2 O (0.0002 mol) in THF (5 ml) and H 2 O (5 ml) was stirred at room temperature for 3 hours. THF was evaporated. The residue was extracted with CH 2 Cl 2 . The aqueous layer was made acidic with HCl 3N. The mixture was filtered off and dried, yielding: 0.055 g of Compound no. 518 (83%) (melting point: 200° C.). 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     A mixture of r-1 (0.02 mol) and r-2 (0.02 mol) in toluene (100 ml) was stirred and refluxed for 12 h in a Dean Stark apparatus. The solution was concentrated under reduced pressure and the residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 95/5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 2.04 g of the mixture r-3+r-4. 
     A mixture of r-3+r-4 (0.0063 mol) and r-5 (0.0035 mol) in EtOH (30 ml) and AcOH (3 ml) was stirred at 75° C. for 12 h, then evaporated until dryness. The residue was taken up in EtOAc and saturated solution of NaHCO 3 . The mixture was stirred for 1 hour and 30 minutes, filtered and extracted with EtOAc. The organic layer was separated, dried (over MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 98.5/1.5/0.1). The pure fractions were collected and the solvent was evaporated, yielding 0.072 g of the mixture r-6+r-7. 
     A mixture of r-6+r-7 (0.0004 mol) in C (5 ml) was stirred and refluxed for 2 hours, then evaporated until dryness. The residue (0.2 g) was purified by column chromatography over silica gel (eluent: toluene/iPrOH/NH 4 OH 90/10/0.5). Two fractions were collected and the solvent was evaporated. Yielding: 0.125 g F1 and 0.037 g F2. Each fraction was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding: 0.034 g of Compound no. 319 (r-8) (melting point &gt;250° C.) and 0.008 g of Compound no. 318 (r-9) (melting point &gt;250° C.). 
     
       
         
         
             
             
         
       
     
     s-1 (0.0001 mol) was purified by SFC with a chiral column (eluent: CO 2 /iPrOH 65/35). Two fractions were collected and the solvent was evaporated, yielding: 0.02 g of Compound no. 306 (enantiomer A) and 0.018 g of Compound no. 305 (enantiomer B). 
     
       
         
         
             
             
         
       
     
     t-1 (0.1 g) was purified by column chromatography over Chiracel pack OD (eluent: EtOH/2-propanol 50/50), yielding 0.054 g of Compound no. 302 (enantiomer A) and 0.044 g of Compound no. 301 (enantiomer B). 
     
       
         
         
             
             
         
       
     
     tBuOK (0.00044 mol) was added portion wise to a solution of u-2 (0.00044 mol) in THF (5 ml) at 0° C. The mixture was stirred at this temperature for 15 min and u-1 (0.00022 mol) was then added. The reaction was stirred at room temperature for 2 h and poured into water. The solution was acidified using HCl 3N and extracted with CH 2 Cl 2 . The organic layer was dried (over MgSO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 95/5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 0.1 g of u-3 (95%). 
     A mixture of u-3 (0.1 g), Raney Nickel (0.1 g) in a solution of NH 3 /MeOH 7 N (10 ml) was hydrogenated under a 3 bars pressure at room temperature for 8 h. The solution was then filtered through a pad of celite using MeOH and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 85/15/1). The pure fractions were collected and the solvent was evaporated, yielding 0.024 g. The residue was crystallized from CH 3 CN/DIPE, yielding 0.013 g of Compound no. 519 (TMC533774) (13%) (melting point 242° C.). 
     Example 93 
     3-(2-Benzyloxyphenyl)-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one: Compound 417 (diastereomer A) and Compound 419 (diastereomer B) 
     
       
         
         
             
             
         
       
     
     A solution of Intermediate (1-4) (200 mg, 0.520 mmol) and 2,4-dichlorobenzaldehyde (91 mg, 0.520 mmol) in 10 mL dry EtOH and 1 mL AcOH was heated at 75° C. for 5 h. Solvents were evaporated. The residue was dissolved in EtOAc and stirred for 1.5 h with saturated aqueous NaHCO 3 , and dried (Na 2 SO 4 ). Two diastereomers were obtained, and purified by silica flash column chromatography (gradient elution from heptane/EtOAc 4:1 to 2:1) to give final Compound No. 417 diastereomer A, (yield: 118 mg, 41.1%): m/z=542 (M+H) + , and final Compound No. 419 diastereomer B (yield: 57 mg, 20.2%): m/z=542 (M+H) + . 
     Example 94 
     3-(2-Benzyloxyphenyl)-11-(3-benzyloxyphenyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 418 (diastereomer A) and Compound No. 420 (diastereomer B. 
     
       
         
         
             
             
         
       
     
     The title compounds were prepared and separated from Intermediate (1-4) and 3-benzyloxybenzaldehyde following the procedure reported for Compounds Nos. 417 and 419: m/z=580 (M+H) + . 
     Example 95 
     11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 423. 
     Step A. 
     
       
         
         
             
             
         
       
     
     A solution of dimedone (95-7, 5.0 g, 35.67 mmol) and o-phenylenediamine (3.86 g, 35.69 mmol) in 150 mL dry toluene were refluxed overnight in a Dean-Stark trap. After 24 h, the solvent was evaporated to give Intermediate (95-8) as an orange foam which was used without further purification in the next step. 
     Step B. 
     
       
         
         
             
             
         
       
     
     A solution of Intermediate (95-8) (35.7 mmol) and 2,4-dichlorobenzaldehyde (6.24 g, 35.65 mmol) in a mixture of 100 mL dry EtOH and 10 mL AcOH was heated at 75° C. overnight. The reaction mixture was cooled to room temperature and the solvents evaporated. The residue was dissolved in EtOAc and stirred with saturated aqueous NaHCO 3  for 1.5 h. Then, the water layer was removed in a separating funnel and the organic layer was filtered off, the filtrate was washed twice with EtOAc. Organic layers were dried (Na 2 SO 4 ), evaporated and the residue dried under high vacuum, yielding 9.45 g (68.4%) of the final Compound No. 423: m/z=387 (M+H) + . 
     Example 96 
     11-(2,4-Dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3,10-trimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 507 
     
       
         
         
             
             
         
       
     
     Methyl iodide (97 μL, 1.555 mmol) was added to a solution of Compound No. 423 (0.50 g, 1.291 mmol) and K 2 CO 3  (214 mg, 1.55 mmol) in acetone. The tube was sealed and stirred at room temperature overnight. Additional methyl iodide (146 μL, 2.34 mmol) was added and the sealed tube was stirred for 2 days. The reaction mixture was dropped onto water and the solid was filtered off and dried. Purification by preparative TLC (EtOAc/heptane 1:1) followed by sonication in i-Pr 2 O and filtration afforded final Compound No. 507: m/z=401 (M+H) + . 
     Example 97 
     11-(2,4-dichlorophenyl)-10-ethyl-2,3,4,5,10,11-hexahydro-3,3-dimethyl1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 508. 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from Compound No. 423 and ethyl iodide (1 mL, 12.5 mmol) following the procedure reported for Compound No. 507 m/z=415 (M+H) + . 
     Example 98 
     11-(2,4-Dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-10-propyl-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 509 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from Compound No. 423 and propyl iodide (1.26 mL, 12.9 mmol) following the procedure reported for Compound No. 507 m/z=429 (M+H) + . 
     Example 99 
     11-(1-Bromo-2-phenylvinyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 500 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from Intermediate (95-8) (11.9 mmol) and 2-bromo-3-phenylacroleine (2.51 g, 11.9 mmol) following the procedure reported for Compound No. 423: m/z=424 (M+H) + . 
     Example 100 
     11-(1-Chloro-2-phenylvinyl)-3,3-dimethyl-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 506 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from Intermediate (95-8) (11.9 mmol) and 2-chloro-3-phenylacroleine (1.98 g, 11.88 mmol) following the procedure reported for Compound No. 423: m/z=380 (M+H) + . 
     Example 101 
     11-[3-(4-Chlorobenzoyloxy)phenyl]-3,3-dimethyl-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 431 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from Intermediate (95-8) (3.9 mmol) and 3-[(4-chlorobenzoyl)oxy]benzaldehyde (1.03 g, 3.95 mmol) following the procedure reported for Compound No. 423: m/z=474 (M+H) + . 
     Example 102 
     11-(2,4-Dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3,7,8-tetramethyl-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 464 
     
       
         
         
             
             
         
       
     
     The title compound was prepared from 4,5-dimethyl-o-phenylenediamine (2.48 g, 18.21 mmol), and 2,4-dichlorobenzaldehyde (3.19 g, 18.23 mmol) following the procedure reported for Compound No. 423: m/z=416 (M+H) + . 
     Example 103 
     11-[3-(4-Chlorobenzoyloxy)phenyl]-3-(2-benzyloxyphenyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one Compound No. 512 diastereomer A 
     
       
         
         
             
             
         
       
     
     The compound was prepared from Intermediate (93-4) (300 mg, 0.780 mmol) and 3-[(4-chlorobenzoyl)oxy]benzaldehyde (244 mg, 0.936 mmol) following the procedure reported for Compound No. 417: m/z=628 (M+H) + . 
     Example 104 
     3-(2-benzyloxyphenyl)-11-[3-(4-chlorobenzoyloxy)phenyl]-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one—Compound No. 513 diastereomer B 
     The compound was prepared from Intermediate (93-4) (300 mg, 0.780 mmol) and 3-[(4-chlorobenzoyl)oxy]benzaldehyde (244 mg, 0.936 mmol) following the procedure reported for Compound No. 419: m/z=628 (M+H) + . 
     Example 105 
     7,8-Dichloro-11-(2,4-dichlorophenyl)-2,3,4,5,10,11-hexahydro-3,3-dimethyl-1H-dibenzo[b,e][1,4]diazepin-1-one Compound No. 465 
     The title compound was prepared from 4,5-dichloro-o-phenylenediamine, and 2,4-dichlorobenzaldehyde following the procedure reported for Compound No. 423: m/z=455 (M+H)+. 
     Example 106 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     A mixture of v-1 (0.0089 mol) and v-2 (0.0089 mol) in toluene (50 ml) was stirred and refluxed for 12 h in a Dean Starck apparatus, then cooled to room temperature. The precipitate was filtered, washed with diethyl ether and dried, yielding: 2 g of v-3 (100%). 
     A mixture of v-3 (0.0106 mol) and v-4 (0.0106 mol) in AcOH (2.6 ml) and EtOH (50 ml) was stirred at 75° C. for 24 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH 2 Cl 2 . The organic layer was washed with K 2 CO 3  10%, dried (over MgSO 4 ), filtered and the solvent was evaporated. The residue (5.7 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 100/0/0 to 99/1/0.1). Three fractions were collected and the solvent was evaporated, yielding: 0.27 g of v-5 (4.5%) (melting point &gt;260° C.), 0.4 g of v-6 (6.7%) and 0.34 g of v-7 (5.7%) (melting point &gt;260° C.). 
     A mixture of v-6 (0.0006 mol) and NH 2 —NH 2 /H 2 O (0.003 mol) in EtOH (20 ml) was stirred and refluxed for 6 hours, then concentrated under reduced pressure. The residue was crystallized from CH 3 CN. The precipitate was filtered off and dried, yielding: 0.12 g (50%). Part of this fraction (0.04 g) was crystallized from CH 3 CN. The precipitate was filtered off and dried, yielding: 0.03 g of v-8 (melting point: 248° C.). 
     
       
         
         
             
             
         
       
     
     w-2 (0.0024 mol) was added at 5° C. to a solution of w-1 (0.0021 mol) and NEt 3  (0.0032 mol) in CH 2 Cl 2  (15 ml). The mixture was stirred at 5° C. for 2 hours, then stirred at room temperature for 2 hours. The precipitate was filtered, washed with CH 2 Cl 2  and dried, yielding: 0.15 g of w-3 (17%) (melting point: 240° C.). 
     A mixture of w-3 (0.0001 mol) and PPA (1.4 g) was stirred at 130° C. for 3 hours, then cooled to room temperature and taken up in K 2 CO 3  10%. The precipitate was filtered, washed with H 2 O and taken up in CH 2 Cl 2 . The organic layer was separated, dried (over MgSO 4 ), filtered, washed with H 2 O and the solvent was evaporated until dryness. The residue was crystallized from CH 3 CN/DIPE. The precipitate was filtered off and dried, yielding: 0.032 g of w-4 (44%) (melting point: 252° C.). 
     Compounds according to the invention are listed in the Tables below including the compounds that were prepared in accordance with Examples 1-106 above. The remaining compounds listed in the Table may be prepared in an analogous manner to that described in the Examples. In these Tables the suffix A against a compound number denotes a diastereomer A, namely the diastereomer which was eluted first from the chromatography system; the suffix B against a compound number denotes a diastereomer B, namely the diastereomer which was eluted second from the chromatography system. Otherwise the compounds are mixtures of stereoisomeric forms. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Comp. 
                   
                   
                   
                   
               
               
                 No. 
                 R 3   
                 R 4   
                 R 5   
                 L 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1 
                 2-OCH 3   
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2 
                 4 O—CH 2 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3 
                 2-OCH 3   
                 5-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4 
                 4-F 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 5 
                 4-CF 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 7 
                 4-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 8 
                 4-[N((CH 3 ) 2 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 9 
                 4-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 10 
                 4-F 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 12 
                 4-OCH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 13 
                 4-NO 2   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 14 
                 4 O—(CH 2 ) 3 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 15 
                 2-OCH 3   
                 3-Cl 
                 5-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 16 
                 2-Cl 
                 6-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 17 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 20 
                 4-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 21 
                 4-OCH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 22 
                 2-OCH 3   
                 5-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 23 
                 2-F 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 24 
                 2-Cl 
                 6-F 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 25 
                 2-Cl 
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 26 
                 2-OCH 3   
                 3-Cl 
                 5-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 28 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 29 
                 2-Cl 
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 30 
                 2-OCH 3   
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 31 
                 3-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 32 
                 4-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 33 
                 4-OCH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 34 
                 3-OCH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 36 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 35 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 37 
                 2-Cl 
                 6-F 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 38 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 39 
                 3-OH 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 40 
                 2-Cl 
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 41 
                 4-OCH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 43 
                 2-Cl 
                 6-F 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 45 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 46 
                 2-Cl 
                 6-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 47 
                 3-NO 2   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 49 
                 4-F 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 50 
                 2-Cl 
                 6-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 53 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 54 
                 4-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 55 
                 4-CF 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 56 
                 4-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 57 
                 4 O—CH 2 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 58 
                 2-OCH 3   
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 60 
                 2-OCH 3   
                 5-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 62 
                 2-OCH 3   
                 3-Cl 
                 5-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 63 
                 2 O—(CH 2 ) 2 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 64 
                 3 O—CH 2 —CH 3 ] 
                 4-OH 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 65 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 66 
                 2-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 67 
                 4 O—(CH 2 ) 4 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 68 
                 3-OCH 3   
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 69 
                 2-Cl 
                 6-F 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 70 
                 2-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 71 
                 2-OCH 3   
                 5-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 72 
                 2-OCH 3   
                 5-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 73 
                 3-Cl 
                 5-Cl 
                 6-OCH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 74 
                 4-Br 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 75 
                 2-OCH 3   
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 76 
                 4 N(CH 3 ) 2 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 77 
                 4-F 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 78 
                 3-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 79 
                 3 O—(CH 2 ) 3 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 80 
                 3-OCH 3   
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 81 
                 2-OCH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 82 
                 3-OCH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 83 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 84 
                 3-OCH 3   
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 85 
                 4 O—CH 2 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 86 
                 4 O—CH 2 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 87 
                 2-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 88 
                 4-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 89 
                 4-NO 2   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 90 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 91 
                 4 O—(CH 2 ) 3 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 92 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 93 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 94 
                 2-F 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 95 
                 4-Br 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 96 
                 2-Br 
                 3-OCH 3   
                 6-OCH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 98 
                 4 O—(CH 2 ) 2 —CH 3 ] 
                 3-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 99 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 100 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 101 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 102 
                 4 O—(CH 2 ) 4 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 103 
                 3-NO 2   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 104 
                 3-F 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 105 
                 3-O—CH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 106 
                 3-O—CH 3   
                 4-O—CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 107 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 108 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 109 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 110 
                 4-O—CH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 111 
                 4-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 112 
                 2-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 113 
                 4-Br 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 114 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 115 
                 4 O—(CH 2 ) 3 —CH 3 ] 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 116 
                 2-O—CH 3   
                 3-Cl 
                 5-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 117 
                 3-OH 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 118 
                 2-O—CH 3   
                 5-O—CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 119 
                 3-O—CH 3   
                 4-O—CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 120 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 121 
                 3-O—CH 2 —CH 3   
                 4-OH 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 122 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 123 
                 3-O—(CH 2 ) 2 —CH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 124 
                 3-O—CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 125 
                 2-O—CH 2 —CH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 126 
                 3-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 127 
                 4-O—(CH 2 ) 3 —CH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 128 
                 2-O—CH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 129 
                 3-O—CH 3   
                 4-O—(CH 2 ) 2 —CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 130 
                 2-O—(CH 2 ) 2 —CH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 131 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 132 
                 2-O—CH 3   
                 4-O—CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 133 
                 3-Cl 
                 5-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 134 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 135 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 136 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 137 
                 4-OH 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 138 
                 2-Cl 
                 5-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 139 
                 3-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 140 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 141 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 142 
                 2-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 143 
                 3-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 5-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 144 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 145 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 146 
                 2-F 
                 4-F 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 147 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 148 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 149 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 150 
                 2-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 151 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 152 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 153 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 154 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 155 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 156 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 157 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 158 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 159 
                 2-Cl 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Comp 
                   
                   
                   
                   
                   
               
               
                 .No. 
                 Z 1   
                 Z 2   
                 R 3   
                 R 4   
                 L 
               
               
                   
               
               
                 160 
                 4-Cl 
                 H 
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 161 
                 4-CH 3   
                 H 
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 162 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 163 
                 2-[—O—(CH 2 ) 2 —CH 3 ] 
                   
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 164 
                 4-Cl 
                 H 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 165 
                 4-OCH 3   
                 H 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 166 
                 2-F 
                 H 
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 167 
                 4-[—O—(CH 2 ) 3 —CH 3 ] 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 168 
                 3-NO 2   
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 169 
                 4-CH 3   
                 H 
                 2-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 170 
                 3-OCH 3   
                 4-OCH 3   
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 171 
                 4-[—O—(CH 2 ) 3 —CH 3 ] 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 172 
                 3-OCH 3   
                 4-OCH 3   
                 3-NO 2   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 173 
                 2-[—O—CH 2 —CH 3 ] 
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 174 
                 3-NO 2   
                 H 
                 3-OCH 3   
                 4-OCH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 175 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 176 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 177 
                 3-OCH 3   
                 4-OCH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 178 
                 3-OCH 3   
                 4-OCH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 179 
                 4-OCH 3   
                 H 
                 2-[—O—CH 2 —CH 3 ] 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 180 
                 3-NO 2   
                 H 
                 3-OCH 3   
                 4-OCH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 181 
                 3-OCH 3   
                 4-OCH 3   
                 3-NO 2   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 182 
                 4-CH 3   
                 H 
                 2-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 183 
                 3-OCH 3   
                 4-OCH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 184 
                 4-OCH 3   
                 5-OCH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 185 
                 3-OCH 3   
                 4-OCH 3   
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 186 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2-Cl 
                 4-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 187 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2-Cl 
                 4-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 188 
                 4-CH 3   
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 189 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 190 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 191 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 192 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 193 
                 4-OCH 3   
                 5-OCH 3   
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 194 
                 4-CH 3   
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 195 
                 4-CH 3   
                 H 
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 196 
                 4-OCH 3   
                 H 
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 197 
                 4-CH 3   
                 H 
                 3-OCH 3   
                 4-OCH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 198 
                 3-OCH 3   
                 4-OCH 3   
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 199 
                 H 
                 H 
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 200 
                 4-Cl 
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 201 
                 4-CH 3   
                 H 
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 202 
                 4-Cl 
                 H 
                 3-NO 2   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 203 
                 4-Cl 
                 H 
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 204 
                 4-CH 3   
                 H 
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 205 
                 3-OCH 3   
                 4-OCH 3   
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 206 
                 4-OCH 3   
                 H 
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 207 
                 3-NO 2   
                 H 
                 3-OCH 3   
                 4-OCH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 208 
                 4-Cl 
                 H 
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 209 
                 4-CH 3   
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 210 
                 4-OCH 3   
                 H 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 211 
                 3-NO 2   
                 H 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 212 
                 3-NO 2   
                 H 
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 213 
                 4-F 
                 H 
                 3-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 214 
                 3-NO 2   
                 H 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 215 
                 4-Cl 
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 216 
                 4-OCH 3   
                 H 
                 2-[—O—CH 2 —CH 3 ] 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 217 
                 4-[—O—(CH 2 ) 3 —CH 3 ] 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 218 
                 3-OCH 3   
                 4-OCH 3   
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 219 
                 2-[—O—CH 2 —CH 3 ] 
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 220 
                 2-[—O—(CH 2 ) 2 —CH 3 ] 
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 221 
                 3-NO 2   
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 222 
                 2-[—O—(CH 2 ) 2 —CH 3 ] 
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 223 
                 4-OCH 3   
                 H 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 224 
                 H 
                 H 
                 2-F 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 225 
                 3-Cl 
                 H 
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 226 
                 3-OCH 3   
                 4-OCH 3   
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 227 
                 4-OCH 3   
                 H 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 228 
                 3-OCH 3   
                 4-OCH 3   
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 229 
                 2-Cl 
                 H 
                 4-CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 230 
                 4-CH 3   
                 H 
                 3-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 231 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 232 
                 4-OCH 3   
                 H 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 233 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 4-O—CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 234 
                 3-NO 2   
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 235 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 236 
                 2-F 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 237 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                 M 
                 L 
                 Z 
               
               
                   
               
               
                 238 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 239 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 240 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 241 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 242 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 243 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 244 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 245 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 246 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 247 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 248 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 249 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 250 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 251 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 252 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 253 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 254 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 255 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 256 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 257 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 258 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 259 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 260 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 261 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 262 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 263 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 264 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 265 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 266 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 267 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 268 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 269 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 270 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 271 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 272 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 273 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 274 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 275 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 276 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 277 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 278 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 279 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 280 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 281 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 282 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 283 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 284 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Comp. No. 
                 R 1   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Z 
               
               
                   
               
               
                 285 
                 phenyl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Comp. 
                   
                   
                   
                   
                   
               
               
                 No. 
                 R 1   
                 R 3   
                 R 4   
                 L 
                 Z 
               
               
                   
               
               
                 286 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-NO 2   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 287 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-OCH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 288 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-NO 2   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 289 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-Cl 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 290 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-NO 2   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 291 
                 H 
                 2-Cl 
                 4-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 292 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 293 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 3   
                 4-O—CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 294 
                 CH 3   
                 2-Cl 
                 4-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Comp 
                   
                   
                   
                   
               
               
                 .No. 
                 R 1   
                 R 2   
                 R 3   
                 L 
               
               
                   
               
               
                 295 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 296 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 297 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 298 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 299 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 300 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 302 
                 CH 3   
                 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 301 
                 CH 3   
                 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 304 
                 CH 3   
                 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 303 
                 CH 3   
                 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 306 
                 CH 3   
                 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 305 
                 CH 3   
                 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Comp. 
                   
                   
               
               
                 No. 
                 Z 1   
                 Z 2   
               
               
                   
               
               
                 307 
                 2-Cl 
                 3-Cl 
               
               
                 308 
                 2-CH 3   
                 3-CH 3   
               
               
                 309 
                 2-O—CH 3   
                 3-O—CH 3   
               
               
                 310 
                 2-F 
                 3-F 
               
               
                 311 
                 1-Br 
                 H 
               
               
                 312 
                 4-Br 
                 H 
               
               
                 313 
                 1-CN 
                 H 
               
               
                 314 
                 1-CH 3   
                 H 
               
               
                 315 
                 4-CH 3   
                 H 
               
               
                 316 
                 4-CN 
                 H 
               
               
                 317 
                 4-O—(CH 2 ) 3 —CH 3   
                 H 
               
               
                 318 
                 2-CN 
                 H 
               
               
                 319 
                 2-N 
                 H 
               
               
                 320 
                 4-O—CH 3   
                 H 
               
               
                   
               
               
                 321 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                 Z 1   
                 Z 2   
                 R 1   
               
               
                   
               
               
                 322 
                 H 
                 H 
                 CH 3   
               
               
                   
               
               
                 323 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Comp. 
                   
                   
                   
                   
               
               
                 No 
                 R 
                 R 1   
                 R 2   
                 R 3   
               
               
                   
               
               
                 324 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-CF 3   
                 H 
                 H 
               
               
                   
               
               
                 325 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-Cl 
                 H 
                 H 
               
               
                   
               
               
                 326 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 327 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-F 
                 H 
                 H 
               
               
                   
               
               
                 328 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 329 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-CF 3   
                 H 
                 H 
               
               
                   
               
               
                 330 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 3   
                 H 
                 H 
               
               
                   
               
               
                 331 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 332 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-O—CH 2 —CH 3   
                 H 
                 H 
               
               
                   
               
               
                 333 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 334 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Cl 
                 6-F 
                 H 
               
               
                   
               
               
                 335 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 5-Br 
                 H 
               
               
                   
               
               
                 336 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 5-O—CH 3   
                 H 
               
               
                   
               
               
                 337 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-NO 2   
                 H 
                 H 
               
               
                   
               
               
                 338 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—(CH 2 ) 3 —CH 3   
                 H 
                 H 
               
               
                   
               
               
                 339 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 3   
                 4-O—CH 3   
                 5-O—CH 3   
               
               
                   
               
               
                 340 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Cl 
                 H 
                 H 
               
               
                   
               
               
                 341 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 342 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-Br 
                 4-OH 
                 5-O—CH 3   
               
               
                   
               
               
                 343 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-CF 3   
                 H 
                 H 
               
               
                   
               
               
                 344 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-CH 3   
                 H 
                 H 
               
               
                   
               
               
                 345 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Br 
                 H 
                 H 
               
               
                   
               
               
                 346 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Cl 
                 3-Cl 
                 H 
               
               
                   
               
               
                 347 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 3-O—CH 3   
                 H 
               
               
                   
               
               
                 348 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 3-O—CH 3   
                 H 
               
               
                   
               
               
                 349 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-CF 3   
                 H 
                 H 
               
               
                   
               
               
                 350 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-Cl 
                 H 
                 H 
               
               
                   
               
               
                 351 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 5-O—CH 3   
                 H 
               
               
                   
               
               
                 352 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 3   
                 4-O—CH 3   
                 H 
               
               
                   
               
               
                 353 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-Br 
                 4-OH 
                 5-O—CH 2 —CH 3   
               
               
                   
               
               
                 354 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-CH 3   
                 H 
                 H 
               
               
                   
               
               
                 355 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-Cl 
                 4-Cl 
                 H 
               
               
                   
               
               
                 356 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 5-O—CH 3   
                 H 
               
               
                   
               
               
                 357 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Cl 
                 3-Cl 
                 H 
               
               
                   
               
               
                 358 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-NO 2   
                 4-CH 3   
                 H 
               
               
                   
               
               
                 359 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-NO 2   
                 4-CH 3   
                 H 
               
               
                   
               
               
                 360 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 3   
                 H 
                 H 
               
               
                   
               
               
                 361 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 362 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-S—CH 3   
                 H 
                 H 
               
               
                   
               
               
                 363 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 364 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 365 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 366 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 367 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 368 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-S—CH 3   
                 H 
                 H 
               
               
                   
               
               
                 369 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 H 
                 H 
               
               
                   
               
               
                 370 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 371 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 5-O—CH 3   
                 H 
               
               
                   
               
               
                 372 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 4-O—CH 3   
                 H 
               
               
                   
               
               
                 373 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 374 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 375 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Cl 
                 5-NO 2   
                 H 
               
               
                   
               
               
                 376 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
               
               
                   
               
               
                 377 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-CF 3   
                 H 
                 H 
               
               
                   
               
               
                 378 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-Br 
                 4-OH 
                 5-O—CH 2 —CH 3   
               
               
                   
               
               
                 379 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 2 —CH 3   
                 H 
                 H 
               
               
                   
               
               
                 380 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-F 
                 H 
                 H 
               
               
                   
               
               
                 381 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-CH 3   
                 H 
                 H 
               
               
                   
               
               
                 382 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-S—CH 3   
                 H 
                 H 
               
               
                   
               
               
                 383 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Cl 
                 H 
                 H 
               
               
                   
               
               
                 384 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-CH 3   
                 H 
                 H 
               
               
                   
               
               
                 385 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 3   
                 H 
               
               
                   
               
               
                 386 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 2 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 387 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-NO 2   
                 H 
                 H 
               
               
                   
               
               
                 388 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 389 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-NO 2   
                 4-Cl 
                 H 
               
               
                   
               
               
                 390 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Br 
                 H 
                 H 
               
               
                   
               
               
                 391 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-CH 3   
                 H 
                 H 
               
               
                   
               
               
                 392 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-OH 
                 H 
                 H 
               
               
                   
               
               
                 393 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 2 —CH 3   
                 H 
                 H 
               
               
                   
               
               
                 394 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 3   
                 4-O—(CH 2 ) 2 —CH 3   
                 H 
               
               
                   
               
               
                 395 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-CH 3   
                 H 
                 H 
               
               
                   
               
               
                 396 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-NO 2   
                 H 
                 H 
               
               
                   
               
               
                 397 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-Br 
                 4-OH 
                 5-O—CH 3   
               
               
                   
               
               
                 398 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 4-O—CH 3   
                 5-O—CH 3   
               
               
                   
               
               
                 399 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-Br 
                 4-OH 
                 5-O—CH 2 —CH 3   
               
               
                   
               
               
                 400 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Br 
                 4-O—CH 3   
                 5-O—CH 3   
               
               
                   
               
               
                 401 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 3-O—CH 3   
                 H 
               
               
                   
               
               
                 402 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-Br 
                 4-O—CH 3   
                 5-O—CH 3   
               
               
                   
               
               
                 403 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 4-O—CH 3   
                 5-O—CH 3   
               
               
                   
               
               
                 404  
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-O—CH 3   
                 5-Br 
                 H 
               
               
                   
               
               
                 405 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 3   
                 H 
               
               
                   
               
               
                 406 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-Br 
                 4-O—CH 3   
                 5-O—CH 2 —CH 3   
               
               
                   
               
               
                 407 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-CF 3   
                 H 
                 H 
               
               
                   
               
               
                 408 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-CH 3   
                 H 
                 H 
               
               
                   
               
               
                 409 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-CH 3   
                 H 
                 H 
               
               
                   
               
               
                 410 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-O—CH 2 CH 3   
                 H 
                 H 
               
               
                   
               
               
                 411 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Cl 
                 H 
                 H 
               
               
                   
               
               
                 412 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-F 
                 H 
                 H 
               
               
                   
               
               
                 413 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-Cl 
                 H 
                 H 
               
               
                   
               
               
                 414 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
               
               
                   
               
               
                 415 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-Cl 
                 H 
                 H 
               
               
                   
               
               
                 416 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-Cl 
                 H 
                 H 
               
               
                   
               
               
                 417 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Cl 
                 4-Cl 
                 H 
               
               
                   
               
               
                 418 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 419 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-Cl  
                 4-Cl 
                 H 
               
               
                   
               
               
                 420 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 421 
                 H 
                 2-Cl 
                 4-Cl 
                 H 
               
               
                   
               
               
                 422 
                 CH 3   
                 2-Cl 
                 4-Cl 
                 H 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Comp. 
                   
                   
                   
               
               
                 No 
                 R 1   
                 R 2   
                 R 3   
               
               
                   
               
               
                 423 
                 2-Cl 
                 4-Cl 
                 H 
               
               
                   
               
               
                 424 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-O—CH 3   
                 H 
               
               
                   
               
               
                 425 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 426 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 427 
                 2-Cl 
                 3-Cl 
                 H 
               
               
                 428 
                 2-Cl 
                 6-F 
                 H 
               
               
                 429 
                 4-CF 3   
                 H 
                 H 
               
               
                   
               
               
                 430 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-O—CH 3   
                 H 
               
               
                   
               
               
                 431 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 432 
                 2-COOH 
                 H 
                 H 
               
               
                   
               
               
                 433 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 434 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 435 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 436 
                 3-Cl 
                 5-Cl 
                 H 
               
               
                   
               
               
                 437 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 438 
                 2-Cl 
                 5-Cl 
                 H 
               
               
                   
               
               
                 439 
                 3-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 440 
                 4-OH 
                 H 
                 H 
               
               
                   
               
               
                 441 
                 2-F 
                 4-F 
                 H 
               
               
                   
               
               
                 442 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 443 
                 2-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 444 
                 3-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 5-Cl 
               
               
                   
               
               
                 445 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 446 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 447 
                 2-Cl 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-Cl 
               
               
                   
               
               
                 448 
                 4-NO 2   
                 H 
                 H 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Comp. 
                   
                   
                   
                   
                   
                   
               
               
                 No 
                 R 
                 R 1   
                 R 2   
                 R 3   
                 Z 1   
                 Z 2   
               
               
                   
               
               
                 449 
                 H 
                 3-NO 2   
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 450 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 451 
                 H 
                 2-O—CH 3   
                 5-O—CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Comp. 
                   
                   
                   
                   
                   
               
               
                 No 
                 R 1   
                 R 2   
                 R 3   
                 Z 1   
                 Z 2   
               
               
                   
               
               
                 452 
                 3-NO 2   
                 4-Cl 
                 H 
                 2-CH 3   
                 3-CH 3   
               
               
                   
               
               
                 453 
                 3-O—CH 3   
                 4-O—CH 3   
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 454 
                 2-F 
                 6-F 
                 H 
                 2-CH 3   
                 3-CH 3   
               
               
                   
               
               
                 455 
                 3-NO 2   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 456 
                 3-O—CH 3   
                 4-O—CH 3   
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 457 
                 2-Cl 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 458 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 459 
                 4-Cl 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 460 
                 3-Cl 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 461 
                 4-F 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 462 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 463 
                 2-Cl 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 464 
                 2-Cl 
                 4-Cl 
                 H 
                 2-CH 3   
                 3-CH 3   
               
               
                 465 
                 2-Cl 
                 4-Cl 
                 H 
                 2-Cl 
                 3-Cl 
               
               
                 466 
                 2-Cl 
                 4-Cl 
                 H 
                 2-F 
                 3-F 
               
               
                 467 
                 2-Cl 
                 4-Cl 
                 H 
                 2-O—CH 3   
                 3-O—CH 3   
               
               
                 468 
                 2-Cl 
                 4-Cl 
                 H 
                 4-Br 
                 H 
               
               
                 469 
                 2-Cl 
                 4-Cl 
                 H 
                 4-CH 3   
                 H 
               
               
                 470 
                 2-Cl 
                 4-Cl 
                 H 
                 4-CN 
                 H 
               
               
                 471 
                 2-Cl 
                 4-Cl 
                 H 
                 1-CH 3   
                 H 
               
               
                 472 
                 2-Cl 
                 4-Cl 
                 H 
                 2-CN 
                 H 
               
               
                 473 
                 2-Cl 
                 4-Cl 
                 H 
                 3-CN 
                 H 
               
               
                 474 
                 2-Cl 
                 4-Cl 
                 H 
                 1-NH 2   
                 H 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Comp. 
                   
                   
                   
                   
               
               
                 No 
                 R 
                 R 4   
                 Z 1   
                 Z 2   
               
               
                   
               
               
                 475 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 476 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 477 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 478 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 479 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 480 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 481 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 482 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 483 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 484 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 485 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 486 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 487 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 488 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 489 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 490 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 491 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 492 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 493 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 494 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 495 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 496 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 497 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 498 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Comp. 
                   
                   
                   
               
               
                 No 
                 R 4   
                 Z 1   
                 Z 2   
               
               
                   
               
               
                 499 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 500 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 501 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 502 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 503 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
               
               
                   
               
               
                 504 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 505 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
               
                 506 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Comp. 
                   
               
               
                   
                 No 
                 R 5   
               
               
                   
                   
               
               
                   
                 507 
                 CH 3   
               
               
                   
                 508 
                 CH 2 —CH 3   
               
               
                   
                 509 
                 CH 2 —CH 2 —CH 3   
               
               
                   
                   
               
               
                   
                 510 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 511 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Comp. 
                   
               
               
                   
                 No 
                 R 
               
               
                   
                   
               
               
                   
                 512 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 513 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
             
               
                 TABLE 17 
               
               
                   
               
               
                 Comp. 
                   
               
               
                 No 
                 Structure 
               
               
                   
               
             
            
               
                 514 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 515 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 516 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 517 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 518 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 519 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 520 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 521 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 522 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 523 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 524 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 525 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 526 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 527 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 528 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 529 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 530 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 531 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 532 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 533 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 534 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 535 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 536 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 537 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 538 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 539 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 540 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 541 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     Antiviral Testing 
     The compounds of formula (I) were tested for anti-HCV activity in an assay determining their activity against NS5b polymerase and in an HCV replicon assay 
     A) NS5b Polymerase Assay 
     a) Protein Purification 
     The cDNA encoding NS5B amino acid 1-570 (HC-J4, genotype 1b, pCV-J4L6S, genebank accession number AF054247) was subcloned into the Nhe I and Xho I restriction sites of pET-21b. Expression of the subsequent His-tagged C-terminal 21 amino acid deleted NS5B was performed as follows: 
     Following transformation in BL21 (DE3) competent cells, bacterial cells were grown in 22 liter LB/Amp media until to reach OD 600 =0.4-0.6. Protein expression was induced by addition of IPTG 0.4 mM, supplemented with 10 μM MgCl 2 , and incubated for 14-16 hrs at 20° C. Cells were harvested, resuspended in lysis buffer (20 mM Tris-HCl pH=7.5, 0.3 M NaCl, 10% glycerol, 0.1% NP40, 4 mM MgCl 2 , 14 mM beta-mercaptoethanol, with tablet of EDTA-free protease cocktail inhibitors) and lysed by sonification. The cell lysate was cleared by high-speed centrifugation (20K×g for 30 min), captured on Ni-NTA beads for 70 min at 4° C., and eluted with 25 mM Hepes pH 7.5, 0.5 M NaCl, 10% glycerol, 14 mM BME, 500 mM imidazole. The eluent was dialysed against 25 mM Hepes pH 7.5, 10% glycerol, 50 mM NaCl, 14 mM BME, after which the protein was further purified by heparin chromatography using the same buffer with 1 M NaCl for elution. Fractions containing pure protein were collected, dialyzed against storage buffer 25 mM Hepes pH=7.5, 300 mM NaCl, 10% glycerol, 14 mM BME), and flash-freezed in liquid nitrogen. This procedure yielded approximately 40 mg of protein. The protein was judged to be at least 90% pure by SDS PAGE Coomassie staining. 
     
       
         
           
               
               
            
               
                 b) Protein Sequence 
                   
               
               
                 PDB: 1nb4, Apo form 
               
               
                 M A S S M S Y T W T G A L I T P C A A E E S K L P I N P L S N S L L R H H N M 
               
               
                   
               
               
                 V Y A T T S R S A S L R Q K K V T F D R L Q V L D D H Y R D V L K E M K A K 
               
               
                   
               
               
                 A S T V K A K L L S I E E A C K L T P P H S A K S K F G Y G A K D V R N L S S 
               
               
                   
               
               
                 R A V N H I R S V W E D L L E D T E T P I D T T I M A K S E V F C V Q P E K G 
               
               
                   
               
               
                 G R K P A R L I V F P D L G V R V C E K M A L Y D V V S T L P Q A V M G S S 
               
               
                   
               
               
                 Y G F Q Y S P K Q R V E F L V N T W K S K K C P M G F S Y D T R C F D S T V 
               
               
                   
               
               
                 T E S D I R V E E S I Y Q C C D L A P E A R Q A I R S L T E R L Y I G G P L T N 
               
               
                   
               
               
                 S K G Q N C G Y R R C R A S G V L T T S C G N T L T C Y L K A T A A C R A A 
               
               
                   
               
               
                 K L Q D C T M L V N G D D L V V I C E S A G T Q E D A A A L R A F T E A M T 
               
               
                   
               
               
                 R Y S A P P G D P P Q P E Y D L E L I T S C S S N V S V A H D A S G K R V Y Y 
               
               
                   
               
               
                 L T R D P T T P L A R A A W E T A R H T P I N S W L G N I I M Y A P T L W A R 
               
               
                   
               
               
                 M I L M T H F F S I L L A Q E Q L E K A L D C Q I Y G A C Y S I E P L D L P Q I 
               
               
                   
               
               
                 I E R L H G L S A F T L H S Y S P G E I N R V A S C L R K L G V P P L R T W R 
               
               
                   
               
               
                 H R A R S V R A K L L S Q G G R A A T C G R Y L F N W A V R T K L K L T P I 
               
               
                   
               
               
                 P A A S Q L D L S G W F V A G Y S G G D I Y H S L S R A R P R A A A L E H H 
               
               
                   
               
               
                 H H H H 
               
               
                   
               
               
                 Calc. Mol. Properties 64941.4 g/mol 
               
            
           
         
       
     
     c) Biochemical RdRp Assay 
     Measurement of HCV NS5B polymerization activity was performed by evaluating the amount of radiolabeled GTP incorporated by the enzyme in a newly synthesized RNA using heteropolymeric RNA template/primer. The highthroughput RdRp assay was carried out in 384-well plates using 200 nM enzyme, 0.1 μCi of  3 H GTP, 5 mM MgCl 2 , 600 nM GTP, 30 nM PolyC, 300 nM 5′-biotinylated oligo(rG13)/poly(rC) in 20 mM Tris pH 7.5, 21 mM KCl, 2.5 mM DTT, 16.7 mM NaCl and 0.17 mM EDTA. Test compounds were dissolved in dimethylsulfoxide. The test compounds were added to the preformed polymerase-template complex, and incubated at room temperature (RT) for 15 min before the addition of NTPs. The 30-μl reaction was terminated after 2 h at 25° C. upon addition of 30-μl PVT-SPA beads (Amersham Biosciences RPNQ0009, 5 mg/ml in 0.5 M EDTA). After incubation at 25° C. for 30 min, the plate was counted using a Packard TopCount microplate reader (30 sec/well, 1 min count delay) and EC50 values were calculated. 
     B) Replicon Assay 
     a) Stable Replicon Cell Reporter Assays: 
     The compounds of the present invention were examined for activity in the inhibition of HCV RNA replication in a cellular assay. The assay demonstrated that the present compounds exhibit activity against HCV replicons functional in a cell culture. The cellular assay was based on a bicistronic expression construct, as described by Lohmann et al. (1999) Science vol. 285 pp. 110-113 with modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, in a multi-target screening strategy. In essence, the method was as follows. 
     The assay utilized the stably transfected cell line Huh-7 luc/neo (hereafter referred to as Huh-Luc). This cell line harbored an RNA encoding a bicistronic expression construct comprising the wild type NS3-NS5B regions of HCV type 1b translated from an Internal Ribosome Entry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by a reporter portion (FfL-luciferase), and a selectable marker portion (neo R , neomycine phosphotransferase). The construct was bordered by 5′ and 3′ NTRs (non-translated regions) from HCV type 1b. Continued culture of the replicon cells in the presence of G418 (neo R ) was dependent on the replication of the HCV RNA. The stably transfected replicon cells that expressed HCV RNA, which replicated autonomously and to high levels, encoding inter alia luciferase, were used for screening the antiviral compounds. 
     b) Cellular Assay Experimental Method: 
     The replicon cells were plated in 384 well plates in the presence of the test and control compounds which were added in various concentrations. Following an incubation of three days, HCV replication was measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLux™ ultraHTS microplate imager). Replicon cells in the control cultures had high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compound on luciferase activity was monitored on the Huh-Luc cells, enabling a dose-response curve for each test compound. IC50 values were then calculated, which value represents the amount of the compound required to decrease by 50% the level of detected luciferase activity, or more specifically, the ability of the genetically linked HCV replicon RNA to replicate. 
     The activities of the compounds tested in the above assays are given below. A strip, i.e., indicates that no result is available. 
     
       
         
           
               
               
               
             
               
                 TABLE 18 
               
               
                   
               
               
                 Compound 
                 NS5B Polymerase Assay 
                 Replicon Assay 
               
               
                 No. 
                 IC 50  (μM) 
                 EC 50  (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 245 
                 &gt;42.612 
                 =3.506 
               
               
                 33 
                 &gt;42.612 
                 =24.740 
               
               
                 254 
                 &gt;42.612 
                 =15.302 
               
               
                 251 
                 &gt;42.612 
                 =9.884 
               
               
                 250 
                 &gt;42.612 
                 =7.950 
               
               
                 22 
                 &gt;42.612 
                 =10.824 
               
               
                 40 
                 &gt;42.667 
                 &gt;24.713 
               
               
                 26 
                 &gt;42.612 
                 =17.830 
               
               
                 48 
                 =15.915 
                 =16.717 
               
               
                 30 
                 &gt;42.612 
                 =23.008 
               
               
                 13 
                 &gt;42.660 
                 =20.373 
               
               
                 88 
                 =18.467 
                 =6.096 
               
               
                 45 
                 =4.826 
                 =6.794 
               
               
                 74 
                 &gt;42.656 
                 &gt;26.654 
               
               
                 20 
                 &gt;42.612 
                 =6.576 
               
               
                 248 
                 &gt;42.612 
                 =7.236 
               
               
                 95 
                 &gt;33.333 
                 — 
               
               
                 275 
                 &gt;42.658 
                 =10.085 
               
               
                 84 
                 &gt;42.677 
                 =20.852 
               
               
                 259 
                 =29.507 
                 &gt;33.046 
               
               
                 8 
                 &gt;42.666 
                 =5.652 
               
               
                 263 
                 &gt;42.670 
                 =10.392 
               
               
                 1 
                 &gt;42.659 
                 =8.527 
               
               
                 85 
                 &gt;42.671 
                 =21.418 
               
               
                 5 
                 &gt;42.661 
                 =19.866 
               
               
                 262 
                 &gt;42.667 
                 =5.538 
               
               
                 29 
                 &gt;42.662 
                 =6.795 
               
               
                 50 
                 &gt;42.662 
                 &gt;31.996 
               
               
                 82 
                 &gt;42.675 
                 =6.804 
               
               
                 52 
                 &gt;42.667 
                 =7.444 
               
               
                 25 
                 &gt;42.674 
                 =24.634 
               
               
                 100 
                 &gt;42.663 
                 =3.595 
               
               
                 56 
                 &gt;42.663 
                 =25.337 
               
               
                 266 
                 &gt;42.663 
                 =23.975 
               
               
                 58 
                 &gt;42.661 
                 =8.783 
               
               
                 87 
                 &gt;42.663 
                 &gt;31.997 
               
               
                 89 
                 &gt;42.662 
                 =5.323 
               
               
                 47 
                 &gt;42.662 
                 =16.405 
               
               
                 268 
                 &gt;42.660 
                 =9.041 
               
               
                 243 
                 &gt;33.333 
                 =25.540 
               
               
                 257 
                 &gt;42.659 
                 =22.403 
               
               
                 55 
                 =33.253 
                 &gt;32.007 
               
               
                 75 
                 &gt;42.677 
                 =20.485 
               
               
                 54 
                 &gt;42.659 
                 =22.348 
               
               
                 10 
                 &gt;33.333 
                 =19.511 
               
               
                 265 
                 &gt;42.674 
                 =11.344 
               
               
                 83 
                 &gt;42.676 
                 =4.161 
               
               
                 19 
                 &gt;42.669 
                 &gt;32.001 
               
               
                 11 
                 &gt;42.672 
                 =14.661 
               
               
                 6 
                 &gt;42.664 
                 =7.321 
               
               
                 267 
                 &gt;42.678 
                 =9.391 
               
               
                 2 
                 &gt;42.659 
                 =26.500 
               
               
                 66 
                 &gt;42.667 
                 =23.012 
               
               
                 86 
                 &gt;42.678 
                 =9.693 
               
               
                 255 
                 &gt;42.663 
                 =21.784 
               
               
                 73 
                 &gt;42.667 
                 =19.936 
               
               
                 81 
                 &gt;42.675 
                 =6.720 
               
               
                 64 
                 &gt;42.664 
                 =22.852 
               
               
                 3 
                 &gt;42.661 
                 &gt;31.996 
               
               
                 99 
                 &gt;42.658 
                 =3.690 
               
               
                 90 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 98 
                 &gt;42.674 
                 =7.333 
               
               
                 264 
                 &gt;42.673 
                 =8.865 
               
               
                 9 
                 &gt;42.667 
                 =3.614 
               
               
                 15 
                 &gt;42.667 
                 =3.094 
               
               
                 31 
                 &gt;42.667 
                 =6.364 
               
               
                 247 
                 &gt;33.333 
                 =17.296 
               
               
                 28 
                 &gt;42.667 
                 =5.524 
               
               
                 23 
                 &gt;42.667 
                 =20.314 
               
               
                 240 
                 &gt;42.667 
                 =7.729 
               
               
                 94 
                 &gt;42.667 
                 =3.395 
               
               
                 49 
                 &gt;42.667 
                 =11.194 
               
               
                 21 
                 &gt;42.667 
                 =14.234 
               
               
                 38 
                 =2.844 
                 =23.797 
               
               
                 253 
                 &gt;42.667 
                 =8.698 
               
               
                 68 
                 &gt;42.667 
                 =23.134 
               
               
                 260 
                 &gt;42.667 
                 =22.501 
               
               
                 72 
                 &gt;42.667 
                 =23.610 
               
               
                 91 
                 &gt;42.667 
                 =8.139 
               
               
                 46 
                 &gt;42.667 
                 =11.148 
               
               
                 16 
                 &gt;42.667 
                 =10.570 
               
               
                 24 
                 &gt;42.667 
                 =12.961 
               
               
                 60 
                 &gt;42.667 
                 =17.884 
               
               
                 14 
                 &gt;33.333 
                 =10.584 
               
               
                 62 
                 &gt;42.667 
                 =22.629 
               
               
                 34 
                 &gt;42.667 
                 =6.810 
               
               
                 246 
                 &gt;42.667 
                 =1.876 
               
               
                 242 
                 &gt;42.667 
                 =1.766 
               
               
                 41 
                 &gt;42.667 
                 =8.444 
               
               
                 92 
                 &gt;42.667 
                 =17.569 
               
               
                 17 
                 &gt;42.667 
                 =6.595 
               
               
                 39 
                 &gt;42.667 
                 =7.420 
               
               
                 7 
                 &gt;42.667 
                 =8.310 
               
               
                 37 
                 &gt;42.667 
                 =6.928 
               
               
                 12 
                 &gt;42.667 
                 =3.110 
               
               
                 170 
                 &gt;42.667 
                 =3.748 
               
               
                 252 
                 &gt;42.667 
                 =4.759 
               
               
                 271 
                 &gt;33.333 
                 =22.883 
               
               
                 258 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 239 
                 &gt;42.667 
                 — 
               
               
                 69 
                 &gt;42.667 
                 =4.585 
               
               
                 241 
                 &gt;42.667 
                 =17.066 
               
               
                 290 
                 &gt;42.667 
                 — 
               
               
                 288 
                 &gt;42.667 
                 =24.997 
               
               
                 172 
                 &gt;42.667 
                 =11.320 
               
               
                 176 
                 =30.838 
                 =10.320 
               
               
                 163 
                 &gt;42.667 
                 =1.763 
               
               
                 212 
                 &gt;42.667 
                 =23.885 
               
               
                 167 
                 &gt;42.667 
                 =3.246 
               
               
                 295 
                 &gt;42.667 
                 =21.566 
               
               
                 219 
                 &gt;42.667 
                 =2.264 
               
               
                 211 
                 &gt;42.667 
                 — 
               
               
                 214 
                 &gt;42.667 
                 — 
               
               
                 231 
                 &gt;42.667 
                 — 
               
               
                 217 
                 &gt;42.667 
                 =20.287 
               
               
                 296 
                 &gt;42.667 
                 =18.259 
               
               
                 168 
                 &gt;42.667 
                 =3.611 
               
               
                 175 
                 &gt;36.173 
                 =3.894 
               
               
                 173 
                 &gt;42.667 
                 =0.208 
               
               
                 221 
                 &gt;42.667 
                 =23.217 
               
               
                 174 
                 &gt;42.667 
                 =1.854 
               
               
                 222 
                 &gt;42.667 
                 =7.730 
               
               
                 199 
                 &gt;42.667 
                 =11.460 
               
               
                 171 
                 &gt;42.667 
                 =4.541 
               
               
                 162 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 220 
                 &gt;42.667 
                 =3.082 
               
               
                 244 
                 &gt;33.333 
                 =15.928 
               
               
                 77 
                 &gt;42.667 
                 =21.246 
               
               
                 249 
                 &gt;42.667 
                 =3.663 
               
               
                 166 
                 &gt;42.667 
                 =3.983 
               
               
                 43 
                 &gt;42.667 
                 =9.171 
               
               
                 53 
                 =19.720 
                 &gt;32.000 
               
               
                 57 
                 &gt;42.667 
                 =4.473 
               
               
                 42 
                 =5.679 
                 =6.393 
               
               
                 79 
                 &gt;42.667 
                 =31.261 
               
               
                 59 
                 &gt;42.667 
                 =5.740 
               
               
                 61 
                 &gt;42.667 
                 =9.452 
               
               
                 63 
                 &gt;42.667 
                 =4.996 
               
               
                 223 
                 &gt;42.667 
                 =25.025 
               
               
                 297 
                 &gt;42.667 
                 =23.598 
               
               
                 179 
                 &gt;42.667 
                 =8.544 
               
               
                 65 
                 &gt;42.667 
                 =2.480 
               
               
                 44 
                 &gt;42.667 
                 =9.544 
               
               
                 67 
                 &gt;42.667 
                 =5.672 
               
               
                 93 
                 &gt;42.667 
                 =4.050 
               
               
                 286 
                 &gt;42.667 
                 =19.241 
               
               
                 229 
                 &gt;42.667 
                 =10.947 
               
               
                 225 
                 &gt;42.667 
                 — 
               
               
                 261 
                 &gt;42.667 
                 =9.304 
               
               
                 70 
                 &gt;42.667 
                 =14.626 
               
               
                 96 
                 &gt;42.667 
                 =11.418 
               
               
                 238 
                 &gt;42.667 
                 — 
               
               
                 272 
                 &gt;42.667 
                 — 
               
               
                 27 
                 &gt;42.667 
                 =20.667 
               
               
                 216 
                 &gt;42.667 
                 =25.257 
               
               
                 180 
                 &gt;42.667 
                 =11.778 
               
               
                 4 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 76 
                 &gt;33.333 
                 =6.266 
               
               
                 270 
                 &gt;33.333 
                 =25.531 
               
               
                 161 
                 =29.915 
                 &gt;25.000 
               
               
                 160 
                 &gt;33.333 
                 &gt;25.000 
               
               
                 165 
                 &gt;33.333 
                 =18.632 
               
               
                 177 
                 &gt;33.333 
                 =0.767 
               
               
                 164 
                 &gt;33.333 
                 =18.510 
               
               
                 285 
                 &gt;33.333 
                 =10.996 
               
               
                 80 
                 &gt;33.333 
                 =9.532 
               
               
                 195 
                 &gt;33.333 
                 =6.900 
               
               
                 287 
                 &gt;33.333 
                 =5.013 
               
               
                 205 
                 &gt;33.333 
                 =9.962 
               
               
                 181 
                 &gt;33.333 
                 =2.405 
               
               
                 269 
                 &gt;33.333 
                 =19.617 
               
               
                 227 
                 &gt;33.333 
                 =17.008 
               
               
                 178 
                 &gt;42.667 
                 =0.599 
               
               
                 215 
                 &gt;33.333 
                 =14.135 
               
               
                 185 
                 &gt;33.333 
                 =4.787 
               
               
                 232 
                 &gt;33.333 
                 =22.568 
               
               
                 188 
                 &gt;33.333 
                 =5.161 
               
               
                 182 
                 &gt;42.667 
                 =1.817 
               
               
                 197 
                 &gt;33.333 
                 =8.971 
               
               
                 256 
                 — 
                 =3.982 
               
               
                 202 
                 &gt;33.333 
                 =9.684 
               
               
                 218 
                 &gt;33.333 
                 =14.826 
               
               
                 200 
                 &gt;33.333 
                 =9.573 
               
               
                 169 
                 &gt;33.333 
                 =17.687 
               
               
                 224 
                 &gt;33.333 
                 =16.077 
               
               
                 213 
                 &gt;33.333 
                 =12.842 
               
               
                 184 
                 &gt;33.333 
                 =4.780 
               
               
                 210 
                 &gt;33.333 
                 =12.148 
               
               
                 201 
                 &gt;33.333 
                 =9.618 
               
               
                 183 
                 &gt;42.667 
                 =1.319 
               
               
                 289 
                 &gt;33.333 
                 =15.375 
               
               
                 193 
                 &gt;33.333 
                 =5.917 
               
               
                 203 
                 &gt;33.333 
                 =9.939 
               
               
                 196 
                 &gt;33.333 
                 =7.322 
               
               
                 208 
                 &gt;33.333 
                 =11.148 
               
               
                 206 
                 &gt;33.333 
                 =10.917 
               
               
                 228 
                 &gt;33.333 
                 =17.242 
               
               
                 198 
                 &gt;33.333 
                 =9.223 
               
               
                 209 
                 &gt;33.333 
                 =11.802 
               
               
                 204 
                 &gt;33.333 
                 =9.959 
               
               
                 230 
                 &gt;33.333 
                 =19.583 
               
               
                 194 
                 &gt;33.333 
                 =5.222 
               
               
                 51 
                 — 
                 =7.658 
               
               
                 78 
                 &gt;33.333 
                 =22.168 
               
               
                 226 
                 &gt;33.333 
                 =16.342 
               
               
                 186 
                 =40.853 
                 =2.027 
               
               
                 36 
                 &gt;41.341 
                 =17.039 
               
               
                 35 
                 =1.283 
                 =20.495 
               
               
                 189 
                 &gt;42.667 
                 =3.991 
               
               
                 191 
                 &gt;42.667 
                 =2.875 
               
               
                 190 
                 &gt;42.667 
                 =1.094 
               
               
                 192 
                 &gt;42.667 
                 =4.869 
               
               
                 102 
                 &gt;42.676 
                 &gt;32.007 
               
               
                 103 
                 &gt;42.668 
                 &gt;32.001 
               
               
                 104 
                 &gt;42.675 
                 &gt;32.006 
               
               
                 105 
                 &gt;42.661 
                 &gt;31.996 
               
               
                 106 
                 &gt;42.661 
                 &gt;31.996 
               
               
                 107 
                 &gt;133.334 
                 =11.546 
               
               
                 108 
                 &gt;42.660 
                 &gt;31.995 
               
               
                 109 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 110 
                 &gt;42.674 
                 =8.112 
               
               
                 111 
                 &gt;42.669 
                 &gt;32.001 
               
               
                 112 
                 &gt;42.669 
                 &gt;32.001 
               
               
                 113 
                 &gt;42.660 
                 &gt;31.996 
               
               
                 114 
                 &gt;42.669 
                 &gt;32.001 
               
               
                 115 
                 &gt;42.666 
                 =14.369 
               
               
                 116 
                 &gt;42.662 
                 &gt;31.996 
               
               
                 117 
                 &gt;42.657 
                 &gt;31.993 
               
               
                 118 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 119 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 120 
                 &gt;133.334 
                 =31.781 
               
               
                 121 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 122 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 123 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 124 
                 =8.563 
                 =28.867 
               
               
                 125 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 126 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 127 
                 &gt;42.667 
                 =11.472 
               
               
                 128 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 129 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 130 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 131 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 132 
                 &gt;42.667 
                 =12.754 
               
               
                 133 
                 &gt;133.334 
                 =10.960 
               
               
                 134 
                 =47.268 
                 =4.636 
               
               
                 135 
                 =54.699 
                 =2.470 
               
               
                 136 
                 &gt;133.334 
                 =9.505 
               
               
                 137 
                 &gt;133.334 
                 &gt;100 
               
               
                 138 
                 &gt;133.334 
                 =26.739 
               
               
                 139 
                 =1.013 
                 =2.902 
               
               
                 140 
                 =19.094 
                 =7.229 
               
               
                 141 
                 =7.906 
                 =16.310 
               
               
                 142 
                 =0.187 
                 =4.681 
               
               
                 143 
                 =16.033 
                 =6.300 
               
               
                 144 
                 =23.014 
                 =3.095 
               
               
                 145 
                 =23.123 
                 =5.921 
               
               
                 146 
                 =2.021 
                 =23.938 
               
               
                 147 
                 =1.971 
                 =4.219 
               
               
                 148 
                 =83.670 
                 =3.226 
               
               
                 149 
                 =30.388 
                 =1.777 
               
               
                 150 
                 &gt;133.334 
                 =1.686 
               
               
                 151 
                 =1.247 
                 =18.369 
               
               
                 152 
                 =24.121 
                 =2.505 
               
               
                 153 
                 =4.054 
                 =18.647 
               
               
                 154 
                 =122.580 
                 =5.461 
               
               
                 155 
                 &gt;133.334 
                 — 
               
               
                 156 
                 =5.153 
                 =6.688 
               
               
                 157 
                 =29.513 
                 =1.946 
               
               
                 158 
                 — 
                 =31.083 
               
               
                 159 
                 — 
                 =9.593 
               
               
                 233 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 234 
                 &gt;36.173 
                 =3.894 
               
               
                 235 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 236 
                 &gt;42.667 
                 =11.765 
               
               
                 237 
                 &gt;42.667 
                 =18.189 
               
               
                 276 
                 &gt;42.657 
                 &gt;31.993 
               
               
                 277 
                 &gt;42.670 
                 =13.631 
               
               
                 278 
                 &gt;42.666 
                 =13.300 
               
               
                 279 
                 &gt;42.675 
                 =9.266 
               
               
                 280 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 281 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 282 
                 &gt;42.667 
                 =17.042 
               
               
                 283 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 284 
                 &gt;42.667 
                 =30.898 
               
               
                 291 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 293 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 294 
                 =10.424 
                 =41.974 
               
               
                 298 
                 &gt;42.667 
                 &gt;32.000 
               
               
                 299 
                 &gt;133.334 
                 =2.362 
               
               
                 300 
                 &gt;133.334 
                 =0.706 
               
               
                 302 
                 =92.472 
                 =1.870 
               
               
                 301 
                 =1.517 
                 =15.257 
               
               
                 304 
                 =0.460 
                 =7.589 
               
               
                 303 
                 =31.530 
                 — 
               
               
                 306 
                 =83.119 
                 =3.921 
               
               
                 305 
                 =0.035 
                 =7.739 
               
               
                 309 
                 &gt;133.334 
                 =39.644 
               
               
                 310 
                 =14.520 
                 =16.441 
               
               
                 311 
                 =13.328 
                 =4.028 
               
               
                 312 
                 =6.115 
                 =7.809 
               
               
                 313 
                 =6.043 
                 =27.481 
               
               
                 314 
                 =4.432 
                 =3.004 
               
               
                 315 
                 =4.776 
                 =14.636 
               
               
                 316 
                 =6.973 
                 =15.385 
               
               
                 317 
                 &gt;133.334 
                 =5.752 
               
               
                 318 
                 =67.086 
                 — 
               
               
                 319 
                 =12.687 
                 =32.428 
               
               
                 320 
                 =6.767 
                 =33.022 
               
               
                 321 
                 &gt;133.334 
                 =72.172 
               
               
                 322 
                 — 
                 =44.085 
               
               
                 323 
                 =53.800 
                 =1.650 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
             
               
                 TABLE 19 
               
               
                   
               
               
                 Compound 
                 NS5B Polymerase Assay 
                 Replicon Assay 
               
               
                 No. 
                 IC 50  (μM) 
                 EC 50  (μM) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 324 
                 &gt;42.612 
                 =18.527 
               
               
                 325 
                 &gt;42.612 
                 =16.290 
               
               
                 326 
                 &gt;33.333 
                 =4.692 
               
               
                 327 
                 &gt;33.333 
                 =12.494 
               
               
                 328 
                 &gt;42.670 
                 =22.713 
               
               
                 329 
                 &gt;33.333 
                 =11.085 
               
               
                 330 
                 &gt;42.680 
                 =23.202 
               
               
                 331 
                 &gt;42.663 
                 =7.441 
               
               
                 332 
                 &gt;42.675 
                 =9.740 
               
               
                 333 
                 &gt;42.678 
                 — 
               
               
                 334 
                 &gt;42.670 
                 — 
               
               
                 335 
                 &gt;42.672 
                 =11.929 
               
               
                 336 
                 &gt;42.664 
                 =13.762 
               
               
                 337 
                 &gt;42.660 
                 =17.547 
               
               
                 338 
                 &gt;42.664 
                 =16.895 
               
               
                 339 
                 &gt;42.664 
                 =9.154 
               
               
                 340 
                 &gt;42.673 
                 =5.094 
               
               
                 341 
                 &gt;42.667 
                 =3.926 
               
               
                 342 
                 &gt;42.663 
                 =4.193 
               
               
                 343 
                 &gt;42.658 
                 =10.962 
               
               
                 344 
                 &gt;42.664 
                 =21.600 
               
               
                 345 
                 &gt;42.662 
                 =21.008 
               
               
                 346 
                 &gt;42.666 
                 =24.584 
               
               
                 347 
                 &gt;42.672 
                 =20.700 
               
               
                 348 
                 =29.574 
                 =4.476 
               
               
                 349 
                 &gt;42.677 
                 =2.863 
               
               
                 350 
                 =25.136 
                 =5.213 
               
               
                 351 
                 &gt;42.672 
                 — 
               
               
                 352 
                 &gt;42.665 
                 =9.608 
               
               
                 353 
                 &gt;42.667 
                 =5.304 
               
               
                 354 
                 &gt;42.664 
                 =20.534 
               
               
                 355 
                 &gt;42.666 
                 =5.483 
               
               
                 356 
                 &gt;42.665 
                 =16.095 
               
               
                 357 
                 &gt;42.666 
                 =7.006 
               
               
                 358 
                 &gt;42.670 
                 =20.435 
               
               
                 359 
                 &gt;42.663 
                 =7.332 
               
               
                 360 
                 &gt;42.667 
                 =11.225 
               
               
                 361 
                 &gt;42.667 
                 =6.650 
               
               
                 362 
                 =30.574 
                 =19.271 
               
               
                 363 
                 &gt;42.667 
                 =25.826 
               
               
                 364 
                 &gt;42.667 
                 =20.793 
               
               
                 365 
                 =27.340 
                 =5.240 
               
               
                 366 
                 &gt;42.667 
                 =5.308 
               
               
                 367 
                 &gt;42.667 
                 =24.606 
               
               
                 368 
                 &gt;42.667 
                 =14.940 
               
               
                 369 
                 &gt;42.667 
                 =10.001 
               
               
                 370 
                 &gt;42.667 
                 =3.425 
               
               
                 371 
                 &gt;42.667 
                 =3.737 
               
               
                 372 
                 &gt;42.667 
                 =1.944 
               
               
                 373 
                 &gt;42.667 
                 =9.415 
               
               
                 374 
                 &gt;42.667 
                 =10.106 
               
               
                 375 
                 &gt;42.667 
                 =19.933 
               
               
                 376 
                 &gt;42.667 
                 =9.450 
               
               
                 377 
                 &gt;42.667 
                 =4.463 
               
               
                 378 
                 &gt;42.667 
                 =5.944 
               
               
                 379 
                 &gt;42.667 
                 =6.789 
               
               
                 380 
                 &gt;42.667 
                 =8.626 
               
               
                 381 
                 &gt;42.667 
                 =4.766 
               
               
                 382 
                 &gt;42.667 
                 =16.660 
               
               
                 383 
                 &gt;42.667 
                 =17.252 
               
               
                 384 
                 =4.582 
                 =15.911 
               
               
                 385 
                 &gt;42.667 
                 =3.535 
               
               
                 386 
                 &gt;42.667 
                 &gt;29.590 
               
               
                 387 
                 &gt;42.667 
                 =5.558 
               
               
                 388 
                 &gt;42.667 
                 =6.350 
               
               
                 389 
                 &gt;42.667 
                 =5.577 
               
               
                 390 
                 &gt;42.667 
                 =9.067 
               
               
                 391 
                 &gt;42.667 
                 =18.488 
               
               
                 392 
                 &gt;42.667 
                 =22.649 
               
               
                 393 
                 &gt;33.333 
                 =6.844 
               
               
                 394 
                 &gt;42.667 
                 =14.075 
               
               
                 395 
                 &gt;42.667 
                 =9.906 
               
               
                 396 
                 &gt;42.667 
                 =11.306 
               
               
                 397 
                 &gt;42.667 
                 =6.131 
               
               
                 398 
                 &gt;42.667 
                 =10.911 
               
               
                 399 
                 &gt;42.667 
                 =19.434 
               
               
                 400 
                 &gt;42.667 
                 =3.278 
               
               
                 401 
                 &gt;42.667 
                 =2.880 
               
               
                 402 
                 &gt;42.667 
                 =8.593 
               
               
                 403 
                 &gt;42.667 
                 =7.115 
               
               
                 404 
                 &gt;42.667 
                 =3.242 
               
               
                 405 
                 &gt;42.667 
                 =5.344 
               
               
                 406 
                 &gt;42.667 
                 =7.290 
               
               
                 407 
                 &gt;33.333 
                 =15.646 
               
               
                 408 
                 &gt;33.333 
                 =14.159 
               
               
                 409 
                 &gt;33.333 
                 =14.892 
               
               
                 410 
                 &gt;33.333 
                 =22.575 
               
               
                 411 
                 &gt;33.333 
                 =17.869 
               
               
                 412 
                 &gt;33.333 
                 =16.678 
               
               
                 413 
                 &gt;33.333 
                 =12.031 
               
               
                 414 
                 &gt;33.333 
                 =13.640 
               
               
                 415 
                 &gt;33.333 
                 =14.666 
               
               
                 416 
                 &gt;33.333 
                 =11.166 
               
               
                 417 
                 &gt;42.667 
                 =8.328 
               
               
                 418 
                 &gt;42.667 
                 =2.162 
               
               
                 419 
                 &gt;42.667 
                 =4.815 
               
               
                 420 
                 &gt;42.667 
                 =3.235 
               
               
                 421 
                 &gt;133.334 
                 =51.929 
               
               
                 423 
                 =37.863 
                 =26.399 
               
               
                 424 
                 =11.606 
                 =12.534 
               
               
                 425 
                 &gt;42.674 
                 =13.245 
               
               
                 426 
                 =30.781 
                 =7.306 
               
               
                 427 
                 &gt;42.667 
                 =20.672 
               
               
                 428 
                 &gt;42.667 
                 =15.991 
               
               
                 429 
                 &gt;42.667 
                 &gt;30.966 
               
               
                 430 
                 &gt;33.333 
                 =10.832 
               
               
                 431 
                 =82.880 
                 &gt;100 
               
               
                 449 
                 &gt;42.667 
                 =1.211 
               
               
                 450 
                 &gt;42.667 
                 =4.517 
               
               
                 451 
                 &gt;33.333 
                 =11.324 
               
               
                 452 
                 &gt;42.680 
                 =19.688 
               
               
                 453 
                 &gt;42.664 
                 =19.174 
               
               
                 454 
                 &gt;42.667 
                 =3.435 
               
               
                 455 
                 &gt;42.667 
                 =5.070 
               
               
                 456 
                 &gt;42.667 
                 =17.759 
               
               
                 457 
                 &gt;42.667 
                 =2.636 
               
               
                 458 
                 &gt;42.667 
                 =22.916 
               
               
                 459 
                 &gt;42.667 
                 — 
               
               
                 460 
                 &gt;42.667 
                 =15.648 
               
               
                 461 
                 &gt;42.667 
                 =24.525 
               
               
                 462 
                 =30.855 
                 &gt;25.000 
               
               
                 463 
                 &gt;33.333 
                 =7.432 
               
               
                 464 
                 &gt;133.334 
                 =82.697 
               
               
                 475 
                 &gt;42.661 
                 — 
               
               
                 465 
                 =59.958 
                 =3.838 
               
               
                 476 
                 &gt;42.667 
                 =22.889 
               
               
                 477 
                 &gt;42.667 
                 =4.492 
               
               
                 478 
                 &gt;42.667 
                 =2.405 
               
               
                 479 
                 &gt;42.667 
                 — 
               
               
                 480 
                 &gt;42.667 
                 =5.695 
               
               
                 481 
                 &gt;42.667 
                 =1.609 
               
               
                 482 
                 &gt;42.667 
                 =27.029 
               
               
                 483 
                 &gt;42.667 
                 =15.517 
               
               
                 484 
                 &gt;42.667 
                 =6.647 
               
               
                 485 
                 &gt;42.667 
                 =3.388 
               
               
                 486 
                 &gt;42.667 
                 =3.305 
               
               
                 487 
                 &gt;42.667 
                 =3.149 
               
               
                 488 
                 &gt;42.667 
                 =17.821 
               
               
                 489 
                 &gt;42.667 
                 =5.905 
               
               
                 490 
                 &gt;42.667 
                 =24.862 
               
               
                 491 
                 &gt;42.667 
                 =12.070 
               
               
                 492 
                 &gt;42.667 
                 =11.024 
               
               
                 493 
                 &gt;42.667 
                 =1.302 
               
               
                 494 
                 &gt;42.667 
                 =21.678 
               
               
                 495 
                 &gt;42.667 
                 =3.692 
               
               
                 496 
                 &gt;42.667 
                 =22.875 
               
               
                 499 
                 &gt;42.667 
                 &gt;31.959 
               
               
                 500 
                 &gt;133.334 
                 =26.452 
               
               
                 501 
                 &gt;42.678 
                 =19.781 
               
               
                 502 
                 &gt;42.678 
                 =13.195 
               
               
                 503 
                 &gt;42.668 
                 =22.390 
               
               
                 504 
                 =39.062 
                 =17.106 
               
               
                 505 
                 &gt;42.667 
                 =13.457 
               
               
                 506 
                 &gt;42.667 
                 =56.654 
               
               
                 507 
                 &gt;42.667 
                 =4.632 
               
               
                 508 
                 &gt;42.667 
                 =1.366 
               
               
                 509 
                 &gt;42.667 
                 =0.894 
               
               
                 512 
                 =84.493 
                 =8.418 
               
               
                 513 
                 =70.082 
                 =3.672 
               
               
                 422 
                 &gt;133.334 
                 &gt;100 
               
               
                 432 
                 &gt;42.667 
                 =17.691 
               
               
                 433 
                 &gt;133.334 
                 =3.811 
               
               
                 434 
                 &gt;133.334 
                 =22.924 
               
               
                 435 
                 &gt;133.334 
                 =6.699 
               
               
                 436 
                 &gt;133.334 
                 =19.689 
               
               
                 437 
                 =32.922 
                 =6.350 
               
               
                 438 
                 &gt;133.334 
                 =15.402 
               
               
                 439 
                 =3.631 
                 =4.332 
               
               
                 440 
                 &gt;133.334 
                 &gt;100 
               
               
                 441 
                 &gt;133.334 
                 &gt;100 
               
               
                 442 
                 &gt;133.334 
                 =2.706 
               
               
                 443 
                 =0.312 
                 =1.778 
               
               
                 444 
                 =33.230 
                 =4.449 
               
               
                 445 
                 &gt;133.334 
                 =1.984 
               
               
                 446 
                 &gt;133.334 
                 =4.125 
               
               
                 447 
                 &gt;133.334 
                 =2.518 
               
               
                 448 
                 &gt;133.334 
                 &gt;100 
               
               
                 466 
                 =68.053 
                 =6.808 
               
               
                 467 
                 &gt;133.334 
                 =30.030 
               
               
                 468 
                 =25.627 
                 =5.175 
               
               
                 469 
                 =32.310 
                 =8.242 
               
               
                 470 
                 =23.314 
                 =16.518 
               
               
                 471 
                 &gt;133.334 
                 =14.691 
               
               
                 472 
                 =9.354 
                 =16.965 
               
               
                 473 
                 =49.962 
                 =19.998 
               
               
                 474 
                 =1.721 
                 =34.082 
               
               
                 497 
                 &gt;133.334 
                 =3.786 
               
               
                 498 
                 &gt;133.334 
                 =2.922 
               
               
                 510 
                 &gt;133.334 
                 =4.563 
               
               
                 511 
                 =1.902 
                 &gt;100 
               
               
                   
               
            
           
         
       
     
     In the following Table 20 there is listed the Mass spectroscopy (MH+) and melting point values for some of the compounds of the invention. An indication of the procedure employed for the preparation of these compounds is also provided. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 20 
               
               
                   
               
               
                 Comp. No. 
                 MH+ 
                 Melting point 
                 prepared according to 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 48 
                 497 
                 216 
                 Scheme A of Example 92 
               
               
                 45 
                 491-495 
                 &gt;250 
                 Scheme B of Example 92 
               
               
                 107 
                 483-487 
                 &gt;260 
                 Scheme C of Example 92 
               
               
                 38 
                 429-433 
                 &gt;250 
                 Scheme D of Example 92 
               
               
                 120 
                 429 
                 &gt;250 
                 Scheme D of Example 92 
               
               
                 124 
                 497 
                 215 
                 Scheme D of Example 92 
               
               
                 42 
                 467 
                 170 
                 Scheme D of Example 92 
               
               
                 273 
                 421-423 
                 258 
                 — 
               
               
                 322 
                 443-447 
                 145 
                 Scheme E of Example 92 
               
               
                 302 
                 467 
                 — 
                 Scheme T of Example 92 
               
               
                 301 
                 467 
                 — 
                 Scheme T of Example 92 
               
               
                 311 
                 507-513 
                 &gt;260 
                 Scheme F of Example 92 
               
               
                 312 
                 507-513 
                 — 
                 Scheme F of Example 92 
               
               
                 139 
                 501-503 
                 197 
                 Scheme G of Example 92 
               
               
                 313 
                 454-458 
                 248 
                 Scheme H of Example 92 
               
               
                 314 
                 443-447 
                 — 
                 Scheme F of Example 92 
               
               
                 315 
                 443-447 
                 &gt;260 
                 Scheme F of Example 92 
               
               
                 316 
                 454-458 
                 — 
                 Scheme H of Example 92 
               
               
                 520 
                 487-491 
                 &gt;250 
                 Scheme N of Example 92 
               
               
                 521 
                 487-491 
                 &gt;250 
                 Scheme N of Example 92 
               
               
                 517 
                 473-477 
                 &gt;250 
                 Scheme P of Example 92 
               
               
                 522 
                 473-477 
                 — 
                 Scheme P of Example 92 
               
               
                 523 
                 459-463 
                 — 
                 Scheme O of Example 92 
               
               
                 524 
                 459-463 
                 — 
                 Scheme O of Example 92 
               
               
                 518 
                 473-477 
                 200 
                 Scheme Q of Example 92 
               
               
                 525 
                 473-477 
                 &gt;260 
                 Scheme P of Example 92 
               
               
                 526 
                 459-463 
                 200 
                 Scheme O of Example 92 
               
               
                 304 
                 501-503 
                 130 
                 Scheme G of Example 92 
               
               
                 303 
                 501-503 
                 130 
                 Scheme G of Example 92 
               
               
                 318 
                 454-458 
                 &gt;250 
                 Scheme R of Example 92 
               
               
                 319 
                 454-458 
                 &gt;250 
                 Scheme R of Example 92 
               
               
                 527 
                 571-575 
                 236 
                 Scheme I of Example 92 
               
               
                 306 
                 501-503 
                 — 
                 Scheme S of Example 92 
               
               
                 305 
                 501-503 
                 — 
                 Scheme S of Example 92 
               
               
                 515 
                 557-561 
                 226 
                 Scheme J of Example 92 
               
               
                 321 
                 585-589 
                 &gt;260 
                 Scheme J of Example 92 
               
               
                 528 
                 577-581 
                 &gt;260 
                 Scheme J of Example 92 
               
               
                 514 
                 543-547 
                 258 
                 Scheme I of Example 92 
               
               
                 529 
                 563-567 
                 212 
                 Scheme I of Example 92 
               
               
                 323 
                 519-523 
                 235 
                 Scheme K of Example 92 
               
               
                 530 
                 514-518 
                 &gt;260 
                 Scheme I of Example 92 
               
               
                 531 
                 458-462 
                 &gt;260 
                 Scheme O of Example 92 
               
               
                 532 
                 528-532 
                 &gt;260 
                 Scheme I of Example 92 
               
               
                 151 
                 454-458 
                 &gt;260 
                 Scheme L of Example 92 
               
               
                 152 
                 519-523 
                 242 
                 Scheme L of Example 92 
               
               
                 153 
                 481-485 
                 &gt;260 
                 Scheme L of Example 92 
               
               
                 533 
                 469-473 
                 200 
                 Scheme L of Example 92 
               
               
                 154 
                 505-509 
                 &gt;260 
                 Scheme L of Example 92 
               
               
                 155 
                 498-502 
                 &gt;260 
                 Scheme L of Example 92 
               
               
                 156 
                 472-476 
                 &gt;260 
                 Scheme M of Example 92 
               
               
                 516 
                 486-490 
                 &gt;260 
                 Scheme O of Example 92 
               
               
                 534 
                 546-550 
                 220 
                 Scheme M of Example 92 
               
               
                 535 
                 472-476 
                 &gt;260 
                 Scheme O of Example 92 
               
               
                 157 
                 549-553 
                 238 
                 Scheme M of Example 92 
               
               
                 158 
                 510-514 
                 &gt;260 
                 Scheme M of Example 92 
               
               
                 159 
                 520-524 
                 &gt;260 
                 Scheme O of Example 92 
               
               
                 519 
                 486-490 
                 242 
                 Scheme U of Example 92 
               
               
                 468 
                 465-471 
                 170 
                 Scheme F of Example 92 
               
               
                 469 
                 401-405 
                 235 
                 Scheme F of Example 92 
               
               
                 470 
                 412-416 
                 225 
                 Scheme H of Example 92 
               
               
                 471 
                 401-405 
                 225 
                 Scheme F of Example 92 
               
               
                 536 
                 431-434 
                 &gt;250 
                 Scheme P of Example 92 
               
               
                 537 
                 444-448 
                 — 
                 Scheme I of Example 92 
               
               
                 538 
                 417-421 
                 160 
                 Scheme O of Example 92 
               
               
                 539 
                 417-421 
                 168 
                 Scheme O of Example 92 
               
               
                 472 
                 412-416 
                 &gt;250 
                 Scheme R of Example 92 
               
               
                 473 
                 412-416 
                 — 
                 Scheme R of Example 92 
               
               
                 474 
                 402-406 
                 248 
                 Scheme V of Example 106 
               
               
                 540 
                 459-463 
                 208 
                 Scheme I of Example 92 
               
               
                 541 
                 417-421 
                 &gt;260 
                 Scheme I of Example 92