Substituted prolines as inhibitors of hepatitis c virus ns3 serine protease

Prolins substituted as inhibitors of hepatitis C NS3 virus serine protease.

Field of the Invention

The present invention relates to inhibitors of novel hepatitis C virus ("HCV") protease, pharmaceutical compositions containing one or more such inhibitors, methods for preparing such inhibitors and methods of use of such inhibitors to treat hepatitis C and related disorders This invention further describes compounds containing novel proline radicals in the position P2 as inhibitors of HCV NS3 / NS4a serine protease. This application claims priority of provisional patent application of the United States with Serial No. 60 / 573,191 filed on May 20, 2004.

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Background of the invention

Hepatitis C virus (HCV) is a virus with Single-stranded sense RNA (+) that has been implicated as an agent main cause of hepatitis A, no B (HNANB), particularly Blood-associated HNANB (HNANB-AS) (<i>see</i>, Publication of the Patent Application International No. WO 89/04669 and the Publication of the Application for European Patent No. EP 381 216). The HNANB must be distinguished from other types of virus-induced liver diseases, such such as hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis delta virus (VHD), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as other forms of liver diseases such as alcoholism and Primary biliary cirrhosis

Recently, it has been identified, cloned and expressed a HCV protease necessary for the processing of polypeptides and viral replication. (<i>See</i>, p. eg, the U.S. Patent No. 5,712,145). This polyprotein of approximately 3000 amino acids contain, from the amino end to carboxy terminus, a nucleocapsid protein (C), the envelope proteins (E1 and E2) and various proteins not structural (NS1, 2, 3, 4a, 5a and 5b). NS3 is a protein of approximately 68 kda, encoded by approximately 1893 HCV genome nucleotides, and has two distinct domains: (a) a serine protease domain consisting of approximately 200 of N-terminal amino acids; and (b) a domain RNA-dependent ATPase at the C-terminus of the protein. He considers that the NS3 protease is a member of the family of the chymotrypsin due to similarities in the protein sequence, the Global three-dimensional structure and the mechanism of catalysis. Other Chymotrypsin type enzymes are elastase, factor Xa, the thrombin, trypsin, plasmin, urokinase, tPA and PSA. HCV NS3 serine protease is responsible for the proteolysis of polypeptide (polyprotein) at NS3 / NS4a, NS4a / NS4b junctions, NS4b / NS5a and NS5a / NS5b and thus is responsible for the generation of four viral proteins during viral replication. This has made of HCV NS3 serine protease an attractive target for antiviral chemotherapy The compounds of the invention can inhibit such protease. They can also modulate the processing of hepatitis C virus (HCV) polypeptide.

It has been determined that the NS4a protein, a polypeptide of approximately 6 kda, is a cofactor for the NS3 serine protease activity. The self-splitting of the joint NS3 / NS4a by serine protease NS3 / NS4a is produced intramolecularly (i.e. <i>cis</i>) while the others cleavage sites are processed intermolecularly (i.e.<i>trans</i>).

The analysis of natural cleavage sites for HCV protease revealed the presence of cysteine ​​in P1 and serine in P1 'and that these residues are strictly conserved in the NS4a / NS4b, NS4b / NS5a and NS5a / NS5b splices. NS3 / NS4a splice It contains a threonine in P1 and a serine in P1 '. It is postulated that the replacement Cis \ rightarrowThr in NS3 / NS4a has the requirement for cis processing instead of <i>trans</i> in This joint. <i>See</i>, p. eg, Pizzi<i>et al</i>. (1994) Proc. Natl. Acad. Sci (USA) 91: 888-892, Failla<i>et to the</i>. (1996) Folding &amp; Design 1: 35-42. He NS3 / NS4a cleavage site is also more tolerant to mutagenesis than the other sites. <i>See</i>, p. eg Kollykhalov<i>et to the</i>. (1994) J. Virol. 68: 7525-7533. It has also found that acidic waste is required in the waters region above the cleavage site for effective cleavage. <i>See</i> p. eg, Komoda<i>et al</i>. (1994) J. Virol. 68: 7351-7357.

HCV protease inhibitors that have been referred include antioxidants (<i>see</i>, the Publication of International Patent Application No. WO 98/14181), some peptides and peptide analogs (<i>see</i>, Publication of the International Patent Application No. WO 98/17679, Landro <i>et to the</i>. (1997) Biochem. 36: 9340-9348, Ingallinella<i>et al</i>. (1998) Biochem. 37: 8906-8914, Llinàs-Brunet <i>et al</i>. (1998) Bioorg. Med. Chem. Lett. 8: 1713-1718), inhibitors based on 70 amino acid polypeptide eglin c (Martin <i>et al</i>. (1998) Biochem 37: 11459-11468, affinity inhibitors selected from the pancreatic secretor inhibitor of trypsin (hPSTI-C3) and repertoires of minibodies (MBip) (Dimasi <i>et al</i>. (1997) J. Virol. 71: 7461-7469), cV_H2 (a fragment of "camelid" variable domain antibody (Martin <i>et to the</i>. (1997) Protein Eng. 10: 607-614), and α1-anti-chymotrypsin (ACT) (Elzouki <i>et to the</i>.) (1997) J. Hepat. 27: 42-28). Recently a ribozyme designed to selectively destroy has been described hepatitis C virus RNA (<i>see</i> BioWorld Today 9 (217): 4 (November 10, 1998)).

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Reference is also made to the Publications PCT, No. WO 98/17679, published April 30, 1998 (Vertex Pharmaceuticals Incorporated); WO 98/22496, published May 28 1998 (F. Hoffmann-La Roche AG); and WO 99/07734, published on February 18, 1999 (Boehringer Ingelheim Canada Ltd.).

HCV has been implicated in liver cirrhosis and in the induction of hepatocellular carcinoma. The prognosis of Patients suffering from HCV infection is currently bad. The HCV infection is more difficult to treat than other forms of hepatitis due to lack of immunity or remission associated with HCV infection. Current data indicate a rate of Survival of less than 50% at four years of diagnosis of cirrhosis. Patients diagnosed with hepatocellular carcinoma Removable localized have a survival rate at five 10-30% years, while those with carcinoma localized non-removable hepatocellular have a rate of Five-year survival less than 1%.

Reference is made to WO 00/59929 (US 6,608,027, Assignee: Boehringer Ingelheim (Canada) Ltd .; Published on October 12, 2000) describing derivatives formula peptides:

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<figref>1</figref>

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Reference is made to A. Marchetti <i>et al</i>, Sinlett, S1, 1000-1002 (1999) describing the synthesis of bicyclic analogs of an NS3 protease inhibitor HCV A compound described there has the formula:

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<figref>2</figref>

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Reference is also made to W. Han <i>et to the</i>, Bioorganics &amp; Medicinal Chem. Lett, (2000) 10, 711-713, which describes the preparation of certain α-ketoamides, α-ketoesters and α-diketones containing functionalities allyl and ethyl.

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Reference is also made to WO document 00/09558 (Assignee: Boehringer Ingelheim Limited; Posted on 24 February 2000) describing peptide derivatives of formula:

<figref>3</figref>

where the different elements are define there. An illustrative compound of that series is:

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<figref>4</figref>

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Reference is also made to WO document 00/09543 (Assignee: Boehringer Ingelheim Limited; Posted on 24 February 2000) describing peptide derivatives of formula:

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<figref>5</figref>

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where the different elements are define there. An illustrative compound of this series is:

<figref>6</figref>

Reference is also made to the US document 6,608,027 (Boehringer Ingelheim, Canada) describing inhibitors of NS3 protease type:

<figref>7</figref>

where the different radicals are define there.

Current therapies for hepatitis C include interferon? (INF?) and combination therapy with ribavirin and interferon. <i>See</i>, p. eg, Beremguer<i>et to the</i>. (1998) Proc. Assoc. Am. Physicians 110 (2): 98-112. These therapies suffer from a low sustained response rate and frequent effects secondary. <i>See</i>, p. eg Hoofnagle<i>et al</i>. (1997) N. Engl. J. Med. 336: 347. Currently, a vaccine is not available. for HCV infection.

Reference is made further to the document WO 01/74768 (Assignee: Vertex Pharmaceuticals Inc) published on October 11, 2001, which describes some compounds of the following general formula (R is defined there) as inhibitors of NS3 serine protease from hepatitis C virus:

<figref>8</figref>

A specific compound described in the document WO 01/74768 mentioned above has the following formula:

<figref>9</figref>

PCT Publications WO 01/77113; WO 01/081325; WO 02/08198; WO 02/08256; WO 02/08187; WO 02/08244; WO 02/48172; WO 02/08251; and the patent application of the States United with Serial No. 10 / 052,386, filed on January 18 from 2002, describe different types of peptides and / or other compounds as NS-3 serine protease inhibitors of hepatitis C virus.

There is a need for new treatments and therapies for HCV infection. There is a need for compounds useful in the treatment or prevention or improvement of one or more symptoms of hepatitis C.

There is a need for treatment methods or prevention or improvement of one or more symptoms of hepatitis C.

There is a need for methods to modulate the activity of serine proteases, particularly serine HCV NS3 / NS4a protease, using the compounds provided In the present memory.

There is a need for methods to modulate the HCV polypeptide processing using the compounds provided herein.

Compendium of the invention

In its many embodiments, the present invention provides a novel class of inhibitors of the HCV protease, pharmaceutical compositions containing one or more of the compounds, methods for preparing formulations Pharmaceuticals comprising one or more such compounds, and HCV treatment or prevention methods or improvement of one or more of Hepatitis C symptoms using one or more such compounds or one or more such formulations. The compounds provided herein may be used in methods to modulate the interaction of an HCV polypeptide with the protease HCV Among the compounds provided herein, Compounds that inhibit protease activity are preferred of serine NS3 / NS4a of HCV. The present invention describes compounds that have the general structure shown in the Formula structural 1:

<figref>10</figref>

where:

<dl><dt>quad</dt><dd>Z is selected from the group consisting of a radical heterocyclyl, -N (H) (alkyl), -N (alkyl) 2, -N (H) (cycloal- chyl), -N (cycloalkyl) 2, -N (H) (aryl, -N (aryl) 2, -N (H) (heterocyclyl), -N (heterocyclyl) 2, -N (H) (heteroaryl), and -N (heteroaryl) 2;</dd></dl>

<dl><dt>quad</dt><dd>R 1 is H, OR 8, NR 9 R 10, or CHR 9 R 10, where R 8, R 9 and R 10 can be same or different, each independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, and heteroarylalkyl, or alternatively R9 and R 10 in NR 9 R 10 are connected to each other so that NR 9 R 10 forms a four to eight membered heterocyclyl, and similarly independently alternatively R 9 and R 10 in CHR 9 R 10 are connected to each other so that CHR 9 R 10 forms a cycloalkyl of four to eight members;</dd></dl>

<dl><dt>quad</dt><dd>R 2 and R 3 can be the same or different, selecting each one independently of the group that consists in H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;</dd></dl>

<dl><dt>quad</dt><dd>And it is selected among the radicals following:</dd></dl>

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<figref>11</figref>

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<figref>12</figref>

where G is NH or O; and R 15, R 16, R 17, R 18, R 19, R 20 and R 21 can be the same or different, selecting each one regardless of the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternatively (i) R 17 and R 18 connect independently of each other to form a cycloalkyl or heterocyclyl of three to eight members; (ii) thereof mode independently R 15 and R 19 connect to each other to form a four to eight membered heterocyclyl; (iii) of same mode independently R 15 and R 16 are connected between yes to form a four to eight member heterocyclyl; and (iv) similarly independently R 15 and R 20 are connected each other to form a four to eight heterocyclyl members;

where each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl may be unsubstituted or optionally independently substituted with one or more radicals selected from the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carboalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro, and where said aryl, heteroaryl, cycloalkyl and heterocyclyl they may be substituted with one or more system substituents cancel defined below.

In the definitions indicated above, the alkyl preferred is formed by one to ten carbon atoms, the preferred alkenyl or alkynyl is formed by two to ten atoms carbon, the preferred cycloalkyl consists of three to eight carbon atoms, and heteroalkyl, heteroaryl or Preferred heterocycloalkyl (heterocyclyl) has one to six oxygen, nitrogen, sulfur, or phosphorus atoms.

The compounds represented by Formula I, by themselves or in combination with one or more other suitable agents described herein, may be useful for treating diseases such as, for example, HCV, HIV, AIDS ( Acquired Immune Deficiency), and related disorders, as well as to modulate hepatitis virus protease activity C (HCV), prevent HCV, or improve one or more symptoms of hepatitis C. Such modulation, treatment, prevention or improvement is can perform with the compounds of the invention as well as with pharmaceutical compositions or formulations comprising such compounds. Without being limited by theory, it is believed that the HCV protease may be NS3 or NS4a protease. The compounds of The invention can inhibit such protease. They can also modulate the Hepatitis C virus polypeptide processing (HCV).

Detailed description

In one embodiment, the present invention describes compounds that are represented by the Formula structural 1 or one of its pharmaceutically active salts or solvates acceptable, where different radicals are defined as before.

In another embodiment, the compound of Formula 1 It exists in the following stereomeric form:

<figref>13</figref>

where the different radicals are define as for the Formula I.

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In another embodiment, Z is selected from the group which consists of the following radicals:

<figref>14</figref>

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<figref>15</figref>

where k = 0-4, m = 0-4, kym may be the same or different, R 26 and R27 may be the same or different, each being selected one independently of the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carboalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro

In another embodiment, R1 is NR 9 R 10, and R 9 is H, R 10 is H, or R 14

where R 14 is alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl heteroaryl, aryl alkyl, alkenyl, alkynyl or heteroaryl-alkyl.

In another embodiment, R 14 is selected from group consisting of:

<figref>16</figref>

<figref>17</figref>

In another embodiment, R2 is selected from group consisting of the following radicals:

<figref>18</figref>

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<figref>19</figref>

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In a further embodiment, R 3 is select from the group consisting of:

<figref>20</figref>

<figref>21</figref>

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where R 31 is OH u O-alkyl; and

R 32 is H, C (O) CH 3, C (O) OtBu or C (O) N (H) tBu. In an additional embodiment, R 3 is selected from the group that It consists of the following radicals:

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<figref>22</figref>

<figref>23</figref>

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In yet another embodiment, G is NH.

In a further embodiment, Y is selected between the following radicals:

<figref>24</figref>

where R 15, R 16, R 17, R 18, R 19, R 20 and R 21 are each selected regardless of the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternatively (i) R 17 and R 18 connect independently of each other to form a cycloalkyl or heterocyclyl of three to eight members; (ii) of same mode independently R 15 and R 19 are connected between yes to form a four to eight member heterocyclyl; (iii) similarly independently R 15 and R 16 are connected each other to form a four to eight member heterocyclyl; and (iv) similarly independently R 15 and R 20 are connect with each other to form a four to eight heterocyclyl members;

where each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl may be unsubstituted or optionally independently substituted with one or more radicals selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carboalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro

In another additional embodiment, the radical:

<figref>25</figref>

is selected among the following:

<figref>26</figref>

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<figref>27</figref>

where Y 32 is selected from group consisting in:

<figref>28</figref>

In one more embodiment, Y is selected between:

<figref>29</figref>

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<figref>30</figref>

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<figref>31</figref>

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In a further embodiment, Z is selected of the group consisting of the following structures:

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<figref>32</figref>

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where k = 0-4, m = 0-4, kym may be the same or different, R 26 and R27 may be the same or different, each being selected one independently of the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carboalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro

In another additional embodiment, Z is selected of the group consisting of radicals:

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<figref>33</figref>

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In another additional embodiment, Z is selected between the following radicals:

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<figref>34</figref>

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In another additional embodiment, R1 is NH 2 or NHR 14, where R 14 is selected from the group that consists in:

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<figref>35</figref>

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R2 is selected from the group consisting of the following radicals:

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<figref>36</figref>

<figref>37</figref>

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R3 is selected from the group consisting of the following radicals:

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<figref>38</figref>

Z is selected from

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<figref>39</figref>

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e Y is selected between:

<figref>40</figref>

<figref>41</figref>

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In yet another embodiment of the invention describes the compounds shown in Table 1.

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TABLE 1

<figref>42</figref>

<figref>43</figref>

<figref>44</figref>

<figref>45</figref>

<figref>46</figref>

<figref>47</figref>

<figref>48</figref>

<figref>49</figref>

As they have been used before, and throughout this description, it should be understood that the following terms, to unless otherwise indicated, they have the following meanings:

<dl><dt>quad</dt><dd>"Patient" includes both human beings and animals.</dd></dl>

<dl><dt>quad</dt><dd>"Mammal" means human beings and others mammals.</dd></dl>

<dl><dt>quad</dt><dd>"Alkyl" means a hydrocarbon group aliphatic which can be linear or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. The groups more preferred alkyl contain from about 1 to approximately 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to an alkyl chain linear. "Lower alkyl" means a group that has about 1 to about 6 carbon atoms in the chain that can be linear or branched. The term "alkyl substituted "means that the alkyl group may be substituted with one or more substituents that may be the same or different, independently selecting each substituent from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH (alkyl), -NH (cycloalkyl), -N (alkyl) 2, carboxy and -C (O) O-alkyl. The examples do not Limitations of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl</dd></dl>

<dl><dt>quad</dt><dd>"Alkenyl" means a hydrocarbon group aliphatic containing at least one double bond carbon-carbon and that can be linear or branched and comprising from about 2 to about 15 atoms of carbon in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably from about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, They are attached to a linear alkenyl chain. "Alkenyl lower "means from about 2 to about 6 carbon atoms in the chain that can be linear or branched. The term "substituted alkenyl" means that the group alkenyl may be substituted with one or more substituents that they can be the same or different, independently selected each substituent of the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and -S (alkyl). The examples do not Limitations of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.</dd></dl>

<dl><dt>quad</dt><dd>"Alkynyl" means a hydrocarbon group aliphatic containing at least one triple bond carbon-carbon and that can be linear or branched and comprising from about 2 to about 15 atoms of carbon in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably from about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, They are attached to a linear alkynyl chain. "Alkynyl lower "means from about 2 to about 6 carbon atoms in the chain that can be linear or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutinyl. The term "alkynyl substituted "means that the alkynyl group may be substituted with one or more substituents that may be the same or different, independently selecting each substituent from the group consisting of alkyl, aryl and cycloalkyl.</dd></dl>

<dl><dt>quad</dt><dd>"Aryl" means a monocyclic ring system or aromatic multicyclic comprising from about 6 to about 14 carbon atoms, preferably of about 6 to about 10 carbon atoms. The group aryl may be optionally substituted with one or more "ring system substituents" that may be the same or different, and are defined as herein. The examples Non-limiting suitable aryl groups include phenyl and Naphthyl</dd></dl>

<dl><dt>quad</dt><dd>"Heteroaryl" means an annular system monocyclic or multicyclic aromatic comprising of about 5 to about 14 ring atoms, preferably from about 5 to about 10 atoms annular, where one or more of the annular atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, only or combined. Preferred heteroaryls contain about 5 to about 6 ring atoms. He "heteroaryl" may be optionally substituted with one or more "ring system substituents" that may be the same or different, and are defined as herein. The prefix aza, oxa or aunt before the root name of the heteroaryl means that at least one nitrogen, oxygen or sulfur atom respectively, It is present as an annular atom. A nitrogen atom of a heteroaryl can be optionally oxidized by Corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including pyridones N-substituted), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxoindolyl, imidazo [1,2-a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" is also refers to partially saturated heteroaryl radicals such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and Similar.</dd></dl>

<dl><dt>quad</dt><dd>"Aralkyl" or "arylalkyl" means a aryl-alkyl group where aryl and alkyl are Describe as before. Preferred aralkyls comprise a group lower alkyl. Non-limiting examples of groups Suitable aralkyl include benzyl, 2-phenethyl and naphthalenylmethyl. The link to the origin radical is through of the alkyl.</dd></dl>

<dl><dt>quad</dt><dd>"Alkylaryl" means a group alkyl-aryl where alkyl and aryl are Describe as before. Preferred alkylaryls comprise a lower alkyl group. A non-limiting example of a group Suitable alkylaryl is tolyl. The link to the radical of Origin is through the aryl.</dd></dl>

<dl><dt>quad</dt><dd>"Cycloalkyl" means a non-ring system mono- or multicyclic aromatic comprising from about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms. The Preferred cycloalkyl rings contain about 5 to approximately 7 ring atoms. The cycloalkyl may be optionally substituted with one or more "system substituents void "that may be the same or different, and are defined as before. Non-limiting examples of monocyclic cycloalkyl Suitable include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of Suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like.</dd></dl>

<dl><dt>quad</dt><dd>"Halogen" or "halo" means fluoro, Chlorine, bromine, or iodine. Fluorine, chlorine and bromine are preferred.</dd></dl>

<dl><dt>quad</dt><dd>"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces a hydrogen available in the system cancel. The ring system substituents may be the same or different, each independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkyl, heteroarylalkyl, alkyl heteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C (= N-CN) -NH2, -C (= NH) -NH2, -C (= NH) -NH (alkyl), Y 1 Y 2 N-, Y 1 Y 2 N-alkyl-, Y_ {1} Y_ {2} NC (O) -, Y_ {1} Y_ {2} NSO_ {2} - y -SO_ {2} NY_ {1} Y_ {2}, where Y_ {1} and Y_ {2} can be the same or different and are independently selected from the group that It consists of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Replacement of the annular system" may also mean a single radical that simultaneously replaces two hydrogens available in two adjacent carbon atoms (one H in each carbon) in an annular system. Examples of such a radical are methylenedioxy, ethylenedioxy, -C (CH 3) 2 - and similar ones that form radicals such as, for example:</dd></dl>

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

<figref>50</figref>

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

<dl><dt>quad</dt><dd>"Heterocyclyl" means an annular system monocyclic or multicyclic saturated non-aromatic comprising about 3 to about 10 ring atoms, preferably from about 5 to about 10 atoms annular, where one or more of the atoms in the annular system is a non-carbon element, for example nitrogen, oxygen or Sulfur, alone or combined. There are no oxygen and / or sulfur atoms adjacent in the annular system. Heterocyclyls Preferred contain from about 5 to about 6 ring atoms The prefix aza, oxa or aunt after the root name of the heterocyclyl means that at least one atom of nitrogen, oxygen or sulfur respectively as an annular atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, a group -N (Boc), -N (CBz), -N (Cough) and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted with one or more "system substituents void "that may be the same or different, and are defined as In the present memory. The nitrogen or sulfur atom of heterocyclyl can be optionally oxidized by N-oxide, S-oxide or S, corresponding S-dioxide. The examples do not Limitations of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and Similar.</dd></dl>

It should be noted that in annular systems containing hetero atoms of this invention, there are no groups hydroxyl in carbon atoms adjacent to N, O or S, as well as not there are N or S groups in carbons adjacent to other heteroatoms. A) Yes, for example, in the ring:

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

<figref>51</figref>

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

there is no -OH anchored directly to the carbons indicated as 2 and 5.

It should also be noted that the shape tautomeric such as, for example, radicals:

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

<figref>52</figref>

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

they are considered equivalent in certain embodiments of this invention.

"Alkylalkyl" means a group alkynyl-alkyl- where alkynyl and alkyl are Describe as before. Preferred alkylalkyls contain a lower alkynyl and a lower alkyl group. The link to the Origin radical is through alkyl. The examples do not Limitations of suitable alkylalkyl groups include Propargylmethyl

"Heteroaralkyl" means a group heteroaryl-alkyl- where heteroaryl and alkyl are described as before. Preferred heteroaralkyl They contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The link to The radical of origin is through alkyl.

"Hydroxyalkyl" means a group HO-alkyl- where the alkyl is defined as before. Preferred hydroxyalkyl contain lower alkyl. The non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Acyl" means a group HC (O) -, C-alkyl (O) - or cycloalkyl-C (O) -, where the different Groups are described as before. The link to the radical of Origin is through carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of acyl groups Suitable include formyl, acetyl and propanoyl.

"Aroilo" means a group aryl-C (O) - where the aryl group is described like before. The link to the radical of origin is through carbonyl Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl.

"Alcoxi" means a group alkyl-O- where the alkyl group is described as before. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The link to the origin radical is a through the oxygen of the ether.

"Aryloxy" means a group aryl-O- where the aryl group is described as before. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The link to the origin radical is through of the oxygen of the ether.

"Aralkyloxy" means a group aralkyl-O- where the aralkyl group is described like before. Non-limiting examples of aralkyloxy groups Suitable include benzyloxy and 1- or 2-naphthalenemethoxy. The link to the radical of Origin is through the oxygen of the ether.

"Alkylthio" means a group alkyl-S- where the alkyl group is described as before. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The link to the radical of origin is through sulfur.

"Ariltio" means a group aril-S- where the aryl group is described as before. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The link to the origin radical is a through the sulfur.

"Aralkylthio" means a group aralkyl-S- where the aralkyl group is described like before. A non-limiting example of an aralkylthio group suitable is benzylium. The link to the origin radical is a through the sulfur.

"Alkoxycarbonyl" means a group alkyl-O-CO-. The examples do not Limitations of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The link to the radical of Origin is through carbonyl.

"Aryloxycarbonyl" means a group aril-OC (O) -. The examples do not Limitations of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The link to the radical of Origin is through carbonyl.

"Aralkoxycarbonyl" means a group aralquil-OC (O) -. The example Non-limiting of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The link to the origin radical is through of carbonyl.

"Alkylsulfonyl" means a group alkyl-S (O2) -. Preferred groups are those where the alkyl group is lower alkyl. The link towards the radical of origin it is through sulfonyl.

"Arylsulfonyl" means a group aril-S (O2) -. The link to the radical of origin is through sulfonyl.

The term "substituted" means that one or more hydrogens in the designated atom are replaced by a selection of the indicated group, provided that the normal valence of the atoms designated in the existing circumstances, and that the substitution of as a result a stable compound. Are permissible combinations of substituents and / or variables only if such combinations result in stable compounds. By "stable compound" or "stable structure" means a compound that is robust enough to survive the insulation to a useful degree of purity from a mixture of reaction, and formulation in an effective therapeutic agent.

The term "one or more" or "at least one ", when indicating the number of substituents, the compounds, the combined agents and the like refers to at least one, and up to the maximum number of substituents, compounds, agents combined and similar chemically and physically permissible, which they are present or added, depending on the context. Such techniques and knowledge are well known to experts in the technique involved.

The term "optionally substituted" means optional substitution with groups, radicals or specified portions.

The term "isolated" or "in form isolated "for a compound refers to the physical state of said compound after being isolated from a synthetic procedure or A natural source or its combinations. The term "purified" or "in purified form" for a compound is refers to the physical state of said compound after being obtained of a procedure or several purification procedures described herein or well known to experts in the art, with sufficient purity to be characterizable by the conventional analytical techniques described in the present report or well known by experts in the technique.

It should also be noted that it is also assumed that any carbon or heteroatom with valences not satisfied in text, schematics, examples and Tables in this memory has the atom or hydrogen atoms to satisfy the valences

When a functional group in a compound is called "protected", this means that the group is fit modified to exclude unwanted side reactions in the protected site when the compound is subjected to a reaction. The Appropriate protective groups will be recognized by experts normal in the art as well as by reference to books of conventional text such as, for example, TW Greene <i>et to the</i>, Protective Groups in Organic Synthesis (1991), Wiley, New York

When any variable (e.g., aryl, heterocycle, R2, etc.) appears more than once in each element or in Formula 1, its definition in each occurrence is independent of its definition in each of the other appearances.

As used herein, it is it is intended that the term "composition" encompasses a product that includes the ingredients specified in the quantities specified, as well as any product that results, directly or indirectly, from the combination of the ingredients specified in the specified quantities.

The solvates of the compounds of the invention They are also contemplated herein.

"Solvato" means a physical association of a compound of this invention with one or more molecules of solvent This physical association implies varying degrees of ionic and covalent bonding, including hydrogen bonds. In some cases the solvate will be susceptible to isolation, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvato" encompasses Solvates in solution phase and insulated. The examples do not Limitations of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate where the Solvent molecule is H2O.

It is intended that "effective amount" or "therapeutically effective amount" describe an amount of compound or a composition of the present invention effective for inhibit serine protease and thus produce the effect therapeutic, improver, inhibitor or preventive desired.

Compounds of Formula 1 may form salts which are also within the scope of this invention. It is understood that the reference to a compound of Formula 1 herein It includes the reference to its salts, unless indicated contrary. The term "salt or salts", as used in the This report indicates acid salts formed with acids inorganic and / or organic, as well as alkaline salts formed with inorganic and / or organic bases. In addition, when a compound of Formula 1 contains both an alkaline radical, such as, but not limited to pyridine or imidazole, and an acid radical, such as, but not limited to a carboxylic acid, may form zwitterions ( "Inner salts") and are included within the term "salt or Salts "as used herein. Preferred are pharmaceutically acceptable salts (i.e. physiologically acceptable, non-toxic), although other salts are also useful. The salts of the compounds of Formula 1 can be formed, for example, by reacting a compound of Formula 1 with an amount of acid or base, such as an equivalent amount, in such a medium as one in which the salt precipitates or in an aqueous medium followed by lyophilization

Illustrative acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, canforates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids that are considered generally suitable for the formation of pharmaceutically useful salts from alkaline pharmaceutical compounds, for example, are commented by P. Stahl <i>et al</i>, Camille G. (eds.) Handbook of Pharmaceutical Salts Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge <i>et al</i>, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson<i>et al</i>, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food &amp; Drug Administration, Washington, DC in its website).

Illustrative alkaline salts include salts of ammonium, alkali metal salts such as salts of sodium, lithium, and potassium, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butylamines, and salts with amino acids such as arginine, lysine and the like. The nitrogen containing groups alkaline can be quaternized with agents such as halides of lower alkyl (eg chlorides, bromides and methyl iodides, ethyl, and butyl), dialkyl sulfates (eg sulfates of dimethyl, diethyl, and dibutyl), long chain halides (e.g. chlorides, bromides and iodides of decyl, lauryl, and stearyl), aralkyl halides (eg benzyl and phenethyl bromides), and others.

It is intended that all these acid salts and base salts are pharmaceutically acceptable salts within the scope of the invention and all salts of acids and bases are considered equivalent to the free form of the compounds corresponding for the purposes of the invention.

The compounds of Formula 1, and their salts, solvates, they can exist in their tautomeric form (for example, in form of an amide or iminoether). All these tautomeric forms are contemplated herein as part of this invention.

All stereoisomers (for example, isomers geometric, optical isomers and the like) of the present compounds (including those of salts, solvates of compounds), such as those that may exist due to carbons asymmetric in different substituents, including the form enantiomeric (which may exist even in the absence of carbons asymmetric), the rotamerican form, the atropisomers, and the form diastereomeric, are contemplated within the scope of this invention, since they are positional isomers (such as, by example, 4-pyridyl and 3-pyridyl). The individual stereoisomers of the compounds of the invention they may be, for example, essentially free of other isomers, or they can be mixed, for example, in the form of racemates or with all others, or other selected stereoisomers. The centers chiral of the present invention may have the configuration S or R as defined in <i>IUPAC</i> 1974 Recommendations. The intention is to that the use of the terms "salt", "solvate" and the like, apply equally to salt, enantiomer solvate, stereoisomers, rotamers, tautomers, positional isomers, racemates of the compounds of the invention.

It should be understood that the usefulness of compounds of Formula 1 for therapeutic applications commented herein is applicable to each compound by itself or the combination or combinations of one or more compounds of Formula 1 as illustrated, for example, in the following paragraph righ now. The same interpretation also applies to the composition or pharmaceutical compositions comprising such compound or such compounds and to the method or methods of treatment involving such compound or such compounds.

The compounds according to the invention they can have pharmacological properties; in particular the Compounds of Formula 1 may be protease inhibitors of HCV, each compound by itself or one or more compounds of Formula 1 can be combined with one or more compounds selected from those of Formula 1. The compound or compounds may be useful. to treat diseases such as, for example, HCV, HIV, (AIDS, Acquired Immune Deficiency Syndrome), and disorders related, as well as to modulate the protease activity of the hepatitis C virus (HCV), prevent HCV, or improve one or more hepatitis C symptoms

The compounds of Formula 1 can be used for the manufacture of a medicine to treat disorders associated with HCV protease, for example, comprising the method of intimately contacting a compound of Formula 1 and a pharmaceutically acceptable carrier.

In another embodiment, this invention provides pharmaceutical compositions comprising the compound or the compounds of the invention as active ingredient. The pharmaceutical compositions generally further comprise at least one carrier diluent, excipient or carrier pharmaceutically acceptable (collectively referred to herein memory as carrier substances). Due to its activity HCV inhibitor, such pharmaceutical compositions possess utility to treat hepatitis C and disorders related.

In yet another embodiment, the present invention describes methods for preparing pharmaceutical compositions that they comprise the compounds of the invention as active ingredient. In the pharmaceutical compositions and methods herein invention, the active ingredients will typically be administered mixed with suitable carrier substances selected properly with respect to the desired form of administration, it is say oral tablets, capsules (loaded with solid, loaded as semi-solid or filled with liquid), powders for reconstitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with the practices conventional pharmaceuticals. For example, for administration oral in the form of tablets or capsules, the component Active pharmacological can be combined with any inert carrier Pharmaceutically acceptable non-toxic oral, such as lactose, starch, sucrose, cellulose, magnesium stearate, phosphate dicalcium, calcium sulfate, talc, mannitol, ethyl alcohol (form liquid) and the like. On the other hand, when desired or needed, binders, lubricants, can also be incorporated into the mixture disintegrating agents and suitable coloring agents. Dusts and the tablets may comprise about 5 to approximately 95 percent of the composition of the invention.

Suitable binders include starch, jelly, natural sugars, corn sweeteners, natural gums and synthetics such as acacia, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. Between the lubricants can be mentioned for use in these forms of Dosage, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum and the like.

Sweetening agents and flavorings and preservatives when appropriate. Some of the terms indicated above, for example disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.

Additionally, the compositions herein invention can be formulated in a sustained release form to provide controlled speed release of one or more any of the active components or ingredients for optimize therapeutic effects, i.e. inhibitory activity of HCV and the like. Dosage forms suitable for Sustained release include stratified tablets that contain layers with variable disintegration rates or polymeric controlled release matrices impregnated with the active and molded components in tablet or capsule form containing such impregnated porous polymeric matrices or encapsulated

Liquid form preparations include solutions, suspensions and emulsions. As an example you can mention the water or the solutions of water-propylene glycol for parenteral injections or the addition of sweeteners and opacifiers to the solutions, oral suspensions and emulsions. Liquid form preparations may also include solutions for administration intranasal

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which can be combined with a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. ex. nitrogen.

To prepare suppositories, a low melting wax such as a mixture of glycerides of fatty acids such as cocoa butter, and the active ingredient it disperses there homogeneously by stirring or mixing in one way Similary. The softened homogeneous mixture is then poured into molds of the appropriate size, allowed to cool and thereby solidifies.

Preparations are also included in solid form that is intended to be converted, immediately after its use, preparations in liquid form for administration oral or parenteral Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention can be also transdermally releasable. The compositions transdermal can take the form of creams, lotions, aerosols and / or emulsions and may be included in a patch transdermal matrix or reservoir type as is conventional in the technique for this purpose.

The compounds of the invention can be also administer orally, intravenously, intrathecally, intranasally or subcutaneously.

The compounds of the invention may comprise also preparations that are in a dosage form unitary. In this way, the preparation is subdivided into doses. units of the appropriate size containing appropriate amounts of the active components, p. eg, an effective amount to achieve the desired purpose

The amount of active composition of the invention in a unit dose of preparation can be varied or generally fit approximately 1.0 milligrams to about 1,000 milligrams, preferably about 1.0 to about 950 milligrams, more preferably of about 1.0 to about 500 milligrams, and typically from about 1 to about 250 milligrams, according With the concrete application. The actual dosage used can vary depending on age, sex, patient weight and the severity of the condition being treated. Such Mechanisms are well known to those skilled in the art.

Generally, the oral dosage form for humans that contains the active ingredients can be administered 1 or 2 times a day. The amount and frequency of the administration will be regulated according to the criteria of the attending clinical doctor. A daily dosing regimen Generally recommended for oral administration may vary from about 1.0 milligrams to about 1,000 milligrams daily, in single or divided doses. Below are described some useful terms:

<dl><dt>quad</dt><dd>Capsule - refers to a container or special receptacle made of methylcellulose, polyvinyl alcohols, or jellies or starch denatured to house or contain compositions that They understand the active ingredients. Hardcover capsules they are typically made from combinations of bone jellies and Pigskin with relatively high gel strength. Own capsules may contain small amounts of dyes, agents opacifiers, plasticizers and preservatives.</dd></dl>

<dl><dt>quad</dt><dd>Compressed - refers to a form of Compressed or molded solid dosage containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.</dd></dl>

<dl><dt>quad</dt><dd>Oral gel - refers to the ingredients dispersed or solubilized assets in a semi-solid matrix hydrophilic</dd></dl>

<dl><dt>quad</dt><dd>Powder for reconstitution refers to combinations of powders containing the active ingredients and suitable diluents that can be suspended in water or juices</dd></dl>

<dl><dt>quad</dt><dd>Diluent - refers to substances that usually they constitute the main portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches wheat, corn, rice and potato derivatives; and cellulose such as microcrystalline cellulose. The amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably of about 25 to about 75%, more preferably of about 30 to about 60% by weight, even more preferably from about 12 to about 60%</dd></dl>

<dl><dt>quad</dt><dd>Disintegrant - refers to added substances to the composition to help it break (disintegrate) and release the drugs. Suitable disintegrants include starches; modified "cold water soluble" starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean gum, karaya, guar, tragacanth and agar; derivatives of cellulose such as methyl cellulose and sodium carboxymethyl cellulose; microcrystalline celluloses and crosslinked microcrystalline celluloses such as croscarmellose sodium; alginates such as acid alginic and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition it can range from about 2 to about 15% by weight of the composition, more preferably about 4 to approximately 10% by weight.</dd></dl>

<dl><dt>quad</dt><dd>Binder - refers to substances that bind or "stick" the powders together and make them cohesive forming granules, serving as "adhesive" in the formulation. The binders add cohesive strength already available in the diluent or the agent to confer volume. Suitable binders include sugars such as sucrose; starches derived from wheat, corn, rice and potato; natural gums such as acacia, jelly and tragacanth; algae derivatives such as alginic acid, alginate sodium and calcium ammonium alginate; cellulosic materials such as methyl cellulose and sodium carboxymethyl cellulose and hydroxypropyl methylcellulose; polyvinylpyrrolidone; and inorganic such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% in weight.</dd></dl>

<dl><dt>quad</dt><dd>Lubricant - refers to an added substance to the dosage form to enable the tablet, the granules, etc. after they have been compressed, they are released from mold or die reducing friction or wear. The Suitable lubricants include metal stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; low melting waxes; and lubricants Water soluble such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d, l-leucine. Lubricants are usually added in the last stage before compression, since they must be present on the surfaces of the granules and between them and the pieces of the press for tablets. The amount of lubricant in The composition can range from about 0.2 to about 5% by weight of the composition, preferably of about 0.5 to about 2%, more preferably of about 0.3 to about 1.5% by weight.</dd></dl>

<dl><dt>quad</dt><dd>Anti-caking - material that prevents agglutination and improves the flow characteristics of granulations, so that the flow is smooth and uniform. The Suitable anti-caking agents include silicon dioxide and talc. The Amount of anti-caking in the composition may range from about 0.1% to about 5% by weight of the composition total, preferably from about 0.5 to about 2% in weigh.</dd></dl>

<dl><dt>quad</dt><dd>Coloring agents - excipients that provide coloration to the composition or dosage form. Such excipients may include food grade dyes and food grade dyes adsorbed on an adsorbent suitable such as clay or aluminum oxide. The amount of coloring agent may vary from about 0.1 to about 5% by weight of the composition, preferably of about 0.1 to about 1%.</dd></dl>

<dl><dt>quad</dt><dd>Bioavailability - refers to speed and to the extent to which the active or radical pharmacological ingredient therapeutic is absorbed in the general circulation from a form of dosing administered compared to a standard or control.</dd></dl>

<dl><dt>quad</dt><dd>Conventional methods to prepare tablets They are known. Such methods include dry methods such as direct compression and granulation compression produced by compaction, or wet methods or other procedures special. Conventional methods are also well known. to develop another form for administration such as, by example, capsules, suppositories and the like.</dd></dl>

The compounds of the invention can be use for the treatment of HCV in humans in mode of monotherapy or in a combination therapy mode (e.g., combination dual, triple combination etc.) such as, for example, combined with antiviral agents and / or immunomodulators. Examples of such Antiviral agents and / or immunomodulators include Ribavirin (from Schering-Plow Corporation, Madison, New Jersey) and Levovirin® (from ICN Pharmaceuticals, Costa Mesa, California), VP 50406® (from Viropharma, Incorporated, Exton, Pennsylvania), ISIS 14803 ™ (from ISIS Pharmaceuticals, Carlsbad, California), Heptazyme® (from Ribozyme Pharmaceuticals, Boulder, Colorado), VX 497® (from Vertex Pharmaceuticals, Cambridge, Massachusetts), Thimosin® (from SciClone Pharmaceuticals, San Mateo, California), Maxamine® (Maxim Pharmaceuticals, San Diego, California), Mycophenolate mofetil (from Hoffman-LaRoche, Nutley, New Jersey), interferon (such as, for example, interferon alpha, conjugated products of PEG-interferon alfa) and the like The "conjugate products of PEG-interferon alfa "are interferon molecules alpha covalently linked to a PEG molecule. The products Illustrative PEG-interferon alpha conjugates include interferon alfa-2a (Roferon®, from Hoffman La-Roche, Nutley, New Jersey) in the form of pegylated interferon alfa-2a (e.g., marketed with the factory name Pegasys®), interferon alpha-2b (Intron®, by Schering-Plow Corporation) in the form of pegylated interferon alfa-2b (p. e.g., marketed under the factory name PEG-Intron®), interferon alfa-2c (Berofor Alpha®, from Boehringer Ingelheim, Ingelheim, Germany) or consensus interferon as defined by determining a consensus sequence of naturally occurring alpha interferons (Infergen®, from Amgen, Thousand Oaks, California).

As stated above, the invention It also includes tautomers, rotamers, enantiomers and others stereoisomers of the compounds of the invention. In this way, as one skilled in the art appreciates, some of the compounds of The invention may exist in suitable isomeric forms. Such variations are contemplated within the scope of the invention.

Another embodiment of the invention describes a method for making the compounds described herein memory. The compounds can be prepared by various mechanisms known in the art. The illustrative procedures they are outlined in the following reaction schemes. The illustrations they should not be considered limiting the scope of the invention which is defined in the appended claims. The routes alternative mechanics and alternative analog structures they will be apparent to those skilled in the art.

<pre listing-type="other">\ vskip1.000000 \ baselineskip</pre>

Abbreviations

Abbreviations used in descriptions of the schemes, preparations and examples that follow are:

THF: Tetrahydrofuran

DMF: N, N-Dimethylformamide

EtOAc: Ethyl Acetate

AcOH: Acetic Acid

HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4 (3H) -one

EDCI: Hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

NMM: N-Methylmorpholine

ADDP: 1,1 '- (Azodicarbonyl) dipiperidine

DEAD: Diethyl Azodicarboxylate

MeOH: Methanol

EtOH: Ethanol

Et2O: Diethyl Ether

DMSO: Dimethylsulfoxide

HOBt: N-Hydroxybenzotriazole

PyBrOP: Hexafluorophosphate bromo-tris-pyrrolidinophosphonium

DCM: Dichloromethane

DCC: 1,3-Dicyclohexylcarbodiimide

TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy

Phg: Phenylglycine

Chg: Cyclohexylglycine

Bn: Benzyl

Bzl: Benzyl

Et: ethyl

Ph: Phenyl

iBoc: isobutoxycarbonyl

iPr: Isopropyl

t Bu or Bu t: tert-Butyl

Boc: tert-Butyloxycarbonyl

Cbz: Benzyloxycarbonyl

Cp: ​​Cyclopentyldienyl

Ts: p-toluenesulfonyl

Me: Methyl

HATU: Hexafluorophosphate O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium

DMAP: 4-N, N-Dimethylaminopyridine

BOP: Benzotriazol-1-yl-oxy-tris (dimethylamino) hexafluorophosphate

PCC: Pyridinium Chlorochromate

KHMDS: Potassium hexamethyldisilazide or potassium bis (trimethylsilylamide)

NaHMDS: Sodium hexamethyldisilazide or sodium bis (trimethylsilylamide)

LiHMDS: Lithium hexamethyldisilazide or lithium bis (trimethylsilylamide)

10% Pd / C: 10% palladium on carbon (in weight).

TG: Thioglycerol

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Examples

Preparation of intermediates

Intermediate Preparation 1.01

Stage 1

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<figref>53</figref>

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To a solution of the derivative of 4-hydroxyproline 1.02 (1.0 g, 4.1 mmol) in dichloromethane (50 mL) at 0 ° C was added chloroformate 4-nitrophenyl (2.46 g, 12.2 mmol) followed by pyridine (0.987 mL, 12.2 mmol). After 15 minutes at that temperature, the reaction flask was stored in the freezer (-20 ° C), overnight (16 hr). The reaction mixture was diluted. with dichloromethane (100 mL) and washed with a saturated solution of ammonium chloride (2 x 100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated. The gross substance is purified by chromatography on silica using EtOAc / hexanes 20/80 to 50/50 to provide 1.03 (1.5 g).

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Stage two

<figref>54</figref>

To a stirred solution of proline derivative 1.03 (1.5 g, 3.66 mmol) in dichloromethane (30 mL) at 0 ° C added 1,2,3,4-tetrahydroisoquinoline (0.55 mL, 4.39 mmol) and DIPEA (2.02 mL, 10.98 mmol). After 15 minutes at that temperature, the reaction flask was stored in the freezer (-20 ° C), overnight (16 hr). The reaction mixture was diluted. with dichloromethane (70 mL) and washed with a saturated solution of ammonium chloride (100 mL), a saturated solution of bicarbonate of sodium (3 x 100 mL), brine (100 mL), dried (Na2SO4), It was filtered and concentrated. The crude substance was purified by chromatography on silica using EtOAc / dichloromethane 5/95 a 25/75 to provide 1.4 g of the required substance, 1.04, LC-MS: 405.1 (M + H) +.

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Stage 3

<figref>55</figref>

To the substance obtained from before, 1.04 (1.4 g) 4M HCl in dioxane (25 mL) was added. The reaction was maintained at RT for 1 h and then concentrated to provide the intermediate required 1.01 with a quantitative yield that was used without purification.

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Preparation of Intermediates 10.11 and 10.12

Stage 1

<figref>56</figref>

A stirred solution of ketimine 10.01 (50 g, 187.1 mmol) in N 2 in dry THF (400 mL) was cooled to -78 ° C and It was treated with a 1M solution of K-t BuO (220 mL, 1.15 equiv.) in THF. The reaction mixture was warmed to 0 ° C and was stirred for 1 h and treated with bromomethylcyclobutane (28 mL, 249 mmoles). The reaction mixture was stirred at room temperature. for 48 h and concentrated in vacuo. The residue was dissolved in Et 2 O (300 mL) and treated with ac HCl. (2 M, 300 mL). The resulting solution was stirred at room temperature for 5 h It was extracted with Et2O (1 L). The aqueous layer was alkalized at pH. ~ 12-14 with NaOH (50% aq) and extracted with CH 2 Cl 2 (3x300 mL). The combined organic layers are dried (MgSO 4), filtered, and concentrated to produce pure amine (10.02, 18 g) in the form of a colorless oil.

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Stage two

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<figref>57</figref>

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A solution of the amine 10.02 (18 g, 105.2 mmol) at 0 ° C in CH 2 Cl 2 (350 mL) was treated with dicarbonate of di-<i>tert</i>butyl (23 g, 105.4 mmol) and stirred at rt. for 12 h. After completion of the reaction (TLC), the mixture of reaction was concentrated in vacuo and the residue was dissolved in THF / H 2 O (200 ml, 1: 1) and treated with LiOH • 2 O (6.5 g, 158.5 mmol) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the alkaline aqueous layer was extracted with Et2O. The aqueous layer was acidified with conc. HCl. at pH sim1-2 and extracted with CH2Cl2. The Combined organic layers were dried (MgSO4), filtered, and they were concentrated in vacuo to yield 10.03 as an oil colorless viscous that was used for the next stage without any additional purification

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Stage 3

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<figref>58</figref>

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A solution of 10.03 acid (15.0 g, 62 mmol) in CH 2 Cl 2 (250 mL) it was treated with BOP reagent (41.1 g, 93 mmoles), N-methylmorpholine (27 mL), hydrochloride N, O-dimethylhydroxylamine (9.07 g, 93 mmol) and se He stirred overnight at rt. The reaction mixture was diluted with HCl ac. 1 N (250 mL), and the layers were separated and the aqueous layer was extracted with CH2Cl2 (3x300 ml). Organic layers combined were dried (MgSO4), filtered and concentrated under vacuum and purified by chromatography (SiO2, EtOAc / Hex 2: 3) to produce the amide 10.04 (15.0 g) in the form of a colorless solid.

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Stage 4

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<figref>59</figref>

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A solution of the amide 10.04 (15 g, 52.1 mmol) in dry THF (200 mL) was treated dropwise with a solution of LiAIH4 (1 M, 93 mL, 93 mmol) at 0 ° C. Reaction mixture stirred at room temperature for 1 h and suffocated carefully at 0 ° C with a solution of KHSO4 (10% aq.) and stirred for 0.5 h. The reaction mixture was diluted with aq HCl. (1 M, 150 mL) and extracted with CH2Cl2 (3x200 mL). Layers combined organics were washed with ac HCl. (1 M), NaHCO 3 saturated, brine, and dried (MgSO4). The mixture was filtered. and concentrated in vacuo to yield 10.05 as an oil colorless viscous (14 g).

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Stage 5

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<figref>60</figref>

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A solution of aldehyde 10.05 (14 g, 61.6 mmol) in CH 2 Cl 2 (50 mL), treated with Et 3 N (10.73 mL, 74.4 mmol), and acetone-cyanohydrin (10.86 g, 127.57 mmol) and stirred at room temperature for 24 hrs. The reaction mixture was concentrated in vacuo and diluted with aq HCl. (1 M, 200 mL) and extracted in CH2Cl2 (3x200 mL). Layers The combined organics were washed with H2O, brine, dried (MgSO 4), filtered, concentrated in vacuo and purified by chromatography (SiO2, EtOAc / Hex 1: 4) to produce 10.06 (10.3 g) in the form of a colorless liquid.

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Stage 6

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<figref>61</figref>

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Methanol saturated with HCl *, prepared by making bubble HCl gas through CH 3 OH (700 ml) at 0 ° C, treated with cyanohydrin 10.06 and heated at reflux for 24 h. The reaction was concentrated in vacuo to yield 10.07, which was used in the next stage without purification.

* Alternatively you can also use HCl 6M prepared by adding AcCl to dry methanol.

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Stage 7

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<figref>62</figref>

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A solution of amine hydrochloride 10.07 in CH 2 Cl 2 (200 mL) was treated with Et 3 N (45.0 mL, 315 mmol) and Boc2O (45.7 g, 209 mmol) at -78 ° C. The mixture of reaction was then stirred at room temperature overnight and it was diluted with HCl (2M, 200 mL) and extracted in CH2Cl2. The combined organic layers were dried (MgSO4) dried filtered, concentrated in vacuo and purified by chromatography (EtOAc / Hex 1: 4) to produce the hydroxy ester 10.08.

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Stage 8

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<figref>63</figref>

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A solution of methyl ester 10.08 (3 g, 10.5 mmol) in THF / H2O (1: 1) was treated with LiOH · H2O (645 mg, 15.75 mmol) and stirred at rt for 2 h. Reaction mixture was acidified with ac HCl. (1 M, 15 mL) and concentrated in vacuo. He residue was dried under vacuum to provide 10.09 with a yield quantitative.

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Stage 9

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<figref>64</figref>

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A solution of acid 10.09 (from before) in CH 2 Cl 2 (50 mL) and DMF (25 mL) was treated with NH 4 Cl (2.94 g, 55.5 mmol), EDCl (3.15 g, 16.5 mmol), HOOBt (2.69 g, 16.5 mmol), and NMM (4.4 g, 44 mmol). The reaction mixture is stirred at room temperature for 3 d. The solvents are removed in vacuo and the residue was diluted with aq HCl. (250 mL) and it extracted with CH 2 Cl 2. The combined organic layers are washed with NaHCO3 aq. saturated, dried (MgSO 4), dried filtered, concentrated in vacuo to obtain 10.10, which used as is in the following stages. (Alternatively 10.10 it can also be obtained directly by reaction of 10.06 (4.5 g, 17.7 mmol) with H 2 O 2 aq. (10 mL), LiOH • H 2 O (820 mg, 20.8 mmol) at 0 ° C in 50 mL of CH 3 OH for 0.5 h).

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Stage 10

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<figref>65</figref>

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A solution of 10.10 obtained in the stage It was previously dissolved in 4N HCl in dioxane and stirred at rt. during 2 h. The reaction mixture was concentrated in vacuo to yield the intermediate 10.11 in the form of a solid, which was used without additional purification

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Stage eleven

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<figref>66</figref>

The required intermediate 10.12 was obtained from of compound 10.09 using essentially the procedures described above in Steps 9.10 with the appropriate reagents.

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Intermediate Preparation 11.01

Stage 1

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<figref>67</figref>

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To a solution of 4-pentin-1-ol, 11.02 (4.15 g; Aldrich) Peryodinano of Dess-Martin (30.25 g; Aldrich) and the mixture resulting was stirred for 45 min. after the addition of (tert-Butoxycarbonylmethylene) triphenylphosphorane (26.75 g; Aldrich). The resulting dark reaction was stirred. overnight, diluted with EtOAc), washed with sodium sulphite aqueous, NaHCO3 aq. sat., water, brine and dried. The volatile substances were removed under reduced pressure and the residue It was purified by silica gel column chromatography using 1% EtOAc in hexanes as eluent to produce the desired compound, 11.03 (3.92 g). Some were also obtained impure fractions but withdrew at this time.

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Stage two

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<figref>68</figref>

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Using alkene 11.03 (1.9 g) in n-propanol (20 ml; Aldrich)), benzyl carbamate (4.95 g; Aldrich) in n-propanol (40 ml), NaOH (1.29 g) in water (79 ml), tert-butyl hypochlorite (3.7 ml), (DHQ) 2 PHAL (0.423 g; Aldrich)) in n-propanol (37.5 ml), and osmiato potassium: dehydrated (0.1544 g; Aldrich) and the procedure Exposed in Angew. Chem. Int. Ed. Engl (1998), 35, (23/24), p. 2813-7, a crude product was provided that purified by silica gel column chromatography using EtOAc: Hexanes (1: 5) to produce amino alcohol 11.04 (1.37 g, 37%) desired in the form of a solid.

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Stage 3

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<figref>69</figref>

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To the 11.04 ester (0.700 g) 4M HCl was added in dioxane (20 ml; Aldrich) and the resulting mixture was allowed to stand at room temperature overnight. Volatile substances are removed under reduced pressure to produce acid 11.05 (0.621 g) as a solid.

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Stage 4

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<figref>70</figref>

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BOP reagent (3.65 g; Sigma) was added followed of triethylamine (3.45 ml) to a solution in dichloromethane (20 ml) of carboxylic acid 11.05 (2.00 g) and allylamine (0.616 ml) at room temperature and the resulting mixture was stirred during night. The reaction mixture was partitioned between EtOAc and aq. HCl. to the 10% The organic phase was separated, washed with sodium bicarbonate. saturated aqueous, water, dried (magnesium sulfate). The product of crude reaction was purified by column chromatography of silica gel using (EtOAc: Hexanes; 70:30) as eluent for provide the desired 11.01 (1.73 g) amide in the form of an oil yellow viscous.

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Preparation of Intermediates 12.03 and 12.04

Stage 1

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<figref>71</figref>

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Compound 12.01 became the substance required 12.02 using essentially the procedures described for Intermediate 10.11, Stages 3-8.

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Stage two

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<figref>72</figref>

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Compound 12.02 became the intermediate required 12.03 using essentially the procedures described for Intermediate 10.11, Stages 9, 10.

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Stage 3

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<figref>73</figref>

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Compound 12.02 became the intermediate required 12.03 using essentially the procedures described for Intermediate 10.12, Stage 11.

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Preparation of Intermediates 13.01 and 13.06

Stage 1

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<figref>74</figref>

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To a stirred solution of 1-nitrobutane, 13.02 (16.5 g, 0.16 mol) and acid glyoxylic in H2O (28.1 g, 0.305 mol) and MeOH (122 mL) at 0 ° C-5 ° C, triethylamine (93) was added dropwise mL, 0.667 moles) over 2 hrs. The solution was tempered to room temperature, stirred overnight and concentrated to dryness to produce an oil. The oil was then dissolved in H2O and acidified to pH = 1 with 10% HCl, followed by extraction with EtOAc. The combined organic solution was washed with brine, dried over Na2SO4, filtered and concentrated to dryness to produce the product 13.03 (28.1 g, yield 99%)

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Stage two

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<figref>75</figref>

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To a stirred solution of compound 13.03 (240 g, 1.35 mol) in acetic acid (1.25 L) was added 10% Pd / C (37 g). The resulting solution was hydrogenated at 4.15 kg / cm2 for 3 hrs and then at 4.22 kg / cm2 overnight. He Acetic acid was then evaporated and the azeotrope formed 3 times with toluene, then triturated with MeOH and ether. The solution was filtered. then and the azeotrope was formed twice with toluene to provide 13.04 in the form of an off-white solid (131 g, 0.891 mol, 66%).

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Stage 3

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<figref>76</figref>

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To a stirred solution of amino acid 13.04 (2.0 g, 13.6 mmol) in dioxane (10 mL) and H2O (5 mL) at 0 ° C, it is added a solution of 1N NaOH (4.3 mL, 14.0 mmol). The solution resulting was stirred for 10 minutes, followed by the addition of di- dicarbonate<i>t</i>-butyl (0.110 g, 14.0 mmol) and stirred at 0 ° C for 15 minutes. The solution was then tempered to room temperature, stirred for 45 minutes and kept at a refrigerator overnight and concentrated to dryness to produce a raw substance To the solution of this raw substance in EtOAc (100 mL) and ice, KHSO4 (3.36 g) was added and H2O (32 mL) and stirred for 4-6 minutes. The organic layer was then separated and the aqueous layer was extracted two times with EtOAc and the combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated until dry to provide the product 13.05 in the form of a clear gum (3.0 g, 89% yield).

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Stage 4

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<figref>77</figref>

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Compound 13.05 became the intermediate required 13.01 using essentially the procedures described for Intermediate 10.12, Stage 11.

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Stage 5

<figref>78</figref>

Compound 13.05 became the intermediate required 13.06 essentially following the procedures described for Intermediate 10.12, Stage 11, using cyclopropylamine (instead of allylamine) in the reaction of coupling

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Intermediate Preparation 14.01

Stage 1

<figref>79</figref>

Compound 14.02 became the substance required 14.03 using essentially the procedures described for Intermediate 13.01, Stages 1-3.

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Stage two

<figref>80</figref>

Compound 14.03 became the intermediate required 14.01 using essentially the procedures described for Intermediate 10.12, Stage 11.

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Intermediate Preparation 15.01

Stage 1

<figref>81</figref>

To a suspension of silver nitrite (9 g, 58.5 mmol) in diethyl ether (25 mL) at 0 ° C a solution was added from 4-iodine-1,1,1-trifluorobutane, 15.02 (10 g, 42.0 mmol) in diethyl ether (25 mL) slowly at through an addition funnel (approx. 15 min). Mix resulting was vigorously stirred at 0 ° C and warmed to rt. After after 50 h, the solid substance was filtered off from a bed of celite. The resulting diethyl ether solution is concentrated in vacuo to produce 15.03 as an oil colorless, which was used without further purification.

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Stage two

<figref>82</figref>

Compound 15.03 became the substance required 15.04 essentially using the procedures described for Intermediate 13.01, Stages 1-3.

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Stage 3

<figref>83</figref>

Compound 15.04 became the intermediate required 15.01 using essentially the procedures described for Intermediate 10.12, Stage 11.

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Intermediate Preparation 16.01

<figref>84</figref>

Acid 16.02 (Winkler, D .; Burger, K., Synthesis, 1996, 1419) is treated as described before (preparation of Intermediate 10.12) to produce the intermediate expected 16.01.

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Intermediate Preparation 50.01

Stage 1

<figref>85</figref>

To a solution of 50.02 (15 g) in MeOH (150 mL) HCl conc. (3-4, mL) and the mixture is refluxed for 16 h. The reaction mixture was cooled to tem peratura ambient and concentrated. The residue was taken up in ether diethyl (250 mL) and washed with a saturated cold solution of baking soda, and brine. The organic layer was dried (Na 2 SO 4) and concentrated to provide the ester methyl 50.03 (12.98 g) that was continued without purification additional.

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Stage two

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<figref>86</figref>

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The above 50.03 methyl ester was dissolved in methylene chloride (100 mL) and cooled to -78 ° C, in an atmosphere of nitrogen. DIBAL was added dropwise (1.0 M solution in methylene, 200 mL) over a period of 2 h. The mixture of reaction was warmed at room temperature over 16 h. The reaction mixture was cooled to 0 ° C and MeOH was added dropwise (5-8 mL). An aqueous solution was added slowly of 10% sodium potassium tartrate (200 mL) with stirring. It was diluted with methylene chloride (100 mL) and the organic layer was separated (along with some white precipitate). The organic layer is washed with 1 N HCl (250 mL), brine (200 mL), dried (Na 2 SO 4) and concentrated to provide 50.04 alcohol (11.00 g) in the form of a clear oil.

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Stage 3

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<figref>87</figref>

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The alcohol 50.04 above was dissolved in chloride of methylene (400 mL) and cooled to 0 ° C under a nitrogen atmosphere. PCC (22.2 g) was added portionwise and the reaction mixture was slowly warmed at room temperature over 16 h. The reaction mixture was diluted with diethyl ether (500 mL) and filtered through a bed of celite. The filtrate was concentrated and The residue was taken up in diethyl ether (500 mL). This was done pass through a bed of silica gel and the filtrate concentrated to provide the 50.05 aldehyde that was made proceed without further purification.

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Stage 4

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<figref>88</figref>

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The above 50.05 aldehyde became the desired substance 50.01 using essentially the method of Chakraborty <i>et. to the</i> (Tetrahedron, 1995, 51 (33), 9179-90).

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Intermediate Preparation 51.01

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<figref>89</figref>

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The required intermediate 51.01 was obtained from of aldehyde 51.02 using the procedure described in publications (TK Chakraborty <i>et al</i>., Tetrahedron, 1995, 51 (33), 9179-90).

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Intermediate Preparation 60.01

Stage 1

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<figref>90</figref>

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To a solution of phthalimide (1.01 g) in 50 mL of Dry THF was added triphenylphosphine (3 eq) and Nt-boc-tert-leucineol 60.02 (1 eq). The mixture was cooled in an ice water bath and was added diisopropyl azodicarboxylate (2.5 eq) dropwise. The resulting mixture was stirred at 0 ° C for 10 min and warmed to room temperature and stirred for about 2.5 h until that no more starting substance was detected by TLC (acetate ethyl / hexanes; 3: 7). The mixture was concentrated under reduced pressure. He residue was suspended in 80 mL of dichloromethane. The solids are separated by filtration. The filtrate was concentrated. to half its volume and hexanes (30 mL) were added. The solids were separated by filtration. The filtered product is concentrated under reduced pressure and the residue was subjected to silica gel chromatography (gradient: acetate ethyl / hexanes; 1: 9 to 4: 6) to provide the product 60.03.

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Stage two

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<figref>91</figref>

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The amine protected with N-Boc 60.03 (1.4 g) was dissolved in 20 mL of a 4M solution of HCl in dioxane The mixture was stirred for 2 h. All substances Volatiles were removed in vacuo. No purification was performed additional and the required product 60.04 was used as is.

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Stage 3

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<figref>92</figref>

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A mixture of amine hydrochloride 60.04 (1.14 g) in 20 mL of dichloromethane and 20 mL of a saturated aqueous solution of NaHCO3 at 0 ° C was treated with phosgene (10 mL, 15% solution in toluene) and stirred for 2 h. The reaction mixture was diluted. with 100 mL of dichloromethane and washed with 30 mL of aqueous solution saturated with cold NaHCO3. The organic layer was dried over magnesium sulfate, filtered, and diluted further with 10 mL of toluene. The mixture was concentrated and the product 60.01 was maintained. in the form of a 0.2M solution in toluene.

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Intermediate Preparation 61.01

Stage 1

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<figref>93</figref>

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The required product 61.01 was obtained from of 60.02 and 4,4-dimethylglutarimide using the procedures described above for intermediate 60.01.

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Summary of Intermediate 62.01

Stage 1

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<figref>94</figref>

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Amide 62.02 (0.5 g, 1 eq) in THF is given added cyclopropylmagnesium bromide (4 eq, 7.68 mmol) at 0 ° C. The reaction was quenched at RT after 15 min and the reaction was stirred at RT for 5 hrs, then quenched by the addition of 1 N HCl. The reaction was diluted with EtOAc and washed with brine. The layer The organic was dried over MgSO4, purified by column chromatography with 10% EtOAc in hexane to obtain 0.2 g of product 62.03, Yield 43.1%.

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Stage two

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<figref>95</figref>

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To the amine protected with N-Boc 62.03 (0.2 g) 4M HCl (in Dioxane) was added. The reaction was stirred. at RT for 50 min whose TLC indicated that the reaction. The mixture was concentrated to dryness to yield 0.162 g of product 62.04 required.

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Stage 3

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<figref>96</figref>

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To a phosgene mixture in CH2Cl2 (2 eq, 1.65 mmol), NaHCO3 (5 mL of sat. aq. solution) is given added 62.04 at 0 ° C. The mixture was stirred at RT for 2.5 h. Separated the organic layer and dried over Na2SO4 (anhydrous). He Concentrate to half its volume with a cooling bath. He diluted to 10 mL to obtain the desired isocyanate 62.01 in form of a 0.083M solution in dichloromethane.

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Summary of Intermediate 63.01

Stage 1

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<figref>97</figref>

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KHMDS (200 ml of a 0.5M solution in toluene), drop by drop to a stirred solution of methyl cyclohexanecarboxylate 63.02 (11.1 g; 78 mmol) in THF anhydrous (200 ml), at -78 ° C under a nitrogen atmosphere. Once the addition completed the reaction was maintained at this temperature for an additional 0.5 h. After the addition of ether Benzylchloromethyl (18.6 ml; 134 mmol). The reaction was left tempering at room temperature overnight and water was added (100 ml) The aqueous treatment provided a residue that was purified by silica gel column chromatography using EtOAc: hexanes (1:10) as eluent to produce the ether intermediate, impure, desired (14.98 g) in the form of an oil colorless.

A black suspension of 10% Pd / C (0.5 g) and the above-mentioned crude ether (4.1 g) in MeOH (80 ml) was exposed to a nitrogen atmosphere (balloon) at temp. atmosphere, during the night. The reaction was filtered through a Celite bed and the solid was washed thoroughly with methanol. He Combined filtrate was concentrated under reduced pressure and the crude product was purified by gel column chromatography of silica using EtOAc: hexanes (1: 5) to produce alcohol primary (63.03; 0.62 g), a colorless oil.

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Stage two

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<figref>98</figref>

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Methanesulfonyl Chloride (0.31 were added ml) followed by triethylamine (0.75 ml) to a stirred solution of the primary alcohol (63.03, 0.62 g) at 0 ° C, in an atmosphere of nitrogen. The resulting mixture was stirred at this temperature for 0.5 h. The reaction mixture was extracted in EtOAc and washed with HCl 1 M, NaHCO 3 ac. sat., water, dried (MgSO4) and concentrated. The residue (mesylate 63.04, 0.74 g), was obtained in the form of a yellow oil, which was used in subsequent stages without purification.

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Stage 3

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<figref>99</figref>

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Dimethylformamide (20 ml; anhydrous; Aldrich) to sodium hydride (0.56 g; Aldrich) and added tert-butylmercaptane to the suspension while it cooled in an ice bath in a nitrogen atmosphere. Once when the addition was complete, the mesylate was added (63.04; prepared as before from 2.00 g of alcohol; 63.03) and the resulting mixture It was stirred overnight at room temperature. The reaction is partitioned between EtOAc and water and the organic phase separated, dried (MgSO 4). Column chromatography on silica gel using EtOAc-Hexanes (2:98) provided the methyl sulphide ester (63.05; 1.75 g).

EtOAc was added to the aqueous phase and HCl was added ac. at 10% until the pH of the aqueous layer was equal to 1. The layer Organic was separated, washed with water, dried and concentrated to reduced pressure to produce the sulfide-carboxylic acid (63.06; 0.747 g) in the form of a solid.

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Stage 4

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<figref>100</figref>

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To sulfide (63.06; 2.287 g) in methanol (75 ml) an oxone solution (18.00 g; Aldrich) was added and the resulting white suspension was stirred overnight to room temperature. Volatile substances were removed at reduced pressure and the white solid was partitioned between EtOAc and water. The organic phase was separated, dried and concentrated to provide sulfone (63.07; 2.52 g; contains some solvent).

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Stage 5

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<figref>101</figref>

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A solution of acid 63.07 (1.61 g) in 50 mL of toluene was treated with DPPA (1 eq, 1.33 mL, d 1,270) and triethylamine (1 eq, 0.85 mL, d 0.726). The mixture was heated at 100 ° C for 2 h. The reaction mixture was diluted with NaHCO3 aq. sat. and extracted with dichloromethane (2 x 100 mL). Organic layers combined were washed with NaHCO3 aq. sat. and brine. The layer The organic was dried over MgSO4, filtered and concentrated to reduced pressure until approximately 20 mL of solvent The product solution 63.01 was adjusted to a 0.2 M concentration of isocyanate using toluene.

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Summary of Intermediate 64.01

Stage 1

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<figref>102</figref>

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To a solution of phthalimide 60.03 (7 g) in 100 mL of MeOH was added hydrazine (0.9 mL, 28.68 mmol, 1.4 eq) and the The mixture was refluxed (in N2) for 6 h. The FTA showed that some starting substance was present and more was added hydrazine (0.45 mL) and stirring was continued at room temperature overnight. A white precipitate formed. The solids were filtered off and the filtrate was concentrated to provide product 64.02 (4.48 g) as a solid.

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Stage two

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<figref>103</figref>

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A solution of the amine 64.02 (2.16 g, 10 mmol) in 100 mL of dichloromethane was cooled to 0 ° C and treated with triethylamine (2 eq, 2.8 mL). Chloride chloride was added dropwise methanesulfonyl (1.2 eq, 0.93 mL). The heterogeneous mixture stirred overnight (temp. 0 to 25 ° C). The solids separated by filtration and the filtrate was washed with a solution saturated aqueous ammonium chloride (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was collected in a minimum amount of dichloromethane / ethyl acetate (approx. 10 mL) and insoluble solid White color was separated by filtration. The filtered product it was purified by silica gel column chromatography to provide the product 64.03 (2.7 g) in the form of a semi-solid dense.

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Stage 3

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<figref>104</figref>

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A solution of sulfonamide 64.03 (2.2 g, 7.5 mmol) in 50 mL of dry DMF was cooled to 0 ° C and treated with cesium carbonate (3 eq, 7.34 g). Iodomethane was added dropwise (5 eq, 2.34 mL) and the mixture was stirred for 45 min. Bathroom refrigerant was removed and the mixture was stirred for an additional 4 h. The reaction was quenched by the addition of an aqueous solution. saturated with ammonium chloride (100 mL) and extracted with acetate ethyl (2 x 100 mL). The combined organic layers were washed with water (200 mL), brine (200 mL) and dried over sulfate sodium. The organic layer was filtered and concentrated. The residue is chromatographed on silica gel to provide the product 64.04 (2.16 g).

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Stage 4

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<figref>105</figref>

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The amine protected with N-Boc 64.04 (2.1 g, 6.82 mmol) was dissolved in 20 mL of 4M HCl in dioxane at room temperature. The reaction mixture was stirred for 1 h. and then all volatile substances were removed under pressure reduced to provide product 64.05 with performance quantitative.

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Stage 5

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<figref>106</figref>

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A mixture of amine hydrochloride 64.05 in dichloromethane and a saturated aqueous solution of NaHCO3 solution at 0 ° C it was treated with phosgene (15% solution in toluene) and stirred for 2 h. The reaction mixture was diluted with dichloromethane and was washed with a cold saturated aqueous solution of NaHCO3. The layer Organic was dried over magnesium sulfate, filtered, and diluted additionally with toluene. The mixture was concentrated and the product 64.01 was adjusted and maintained in the form of a 0.2 M solution in toluene

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Summary of Intermediate 65.01

Stage 1

<figref>107</figref>

Isocyanate 65.01 was prepared according to the procedure described for isocyanate 64.01 using chloride of 2-thiophenesulfonyl instead of methanesulfonyl in the stage of synthesis of sulfonamide.

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Synthesis of the preparative examples

Synthesis of Example 101

Stage 1

<figref>108</figref>

To a stirred solution of proline derivative 1.01 (3.66 mmol, prepared as described above) in dichloromethane (20 mL) and DMF (15 mL) at 0 ° C were added L-boc-tert-leucine (930 mg, 4.03 mmol), DIPEA (2.02 mL, 10.98 mmol) and HATU (1.8 g, 4.76 mmol). After 15 minutes at that temperature, the flask of reaction was stored in the freezer (-20ºC), overnight (16 hr). The reaction mixture was diluted with dichloromethane (80 mL) and was washed with a saturated solution of sodium bicarbonate (80 mL), a 10% aqueous solution of citric acid (80 mL), brine (80 mL), dried (Na2SO4), filtered and concentrated. The substance crude was purified by chromatography on silica using EtOAc / hexanes from 25/75 to 50/50 to provide 1.77 g of the required substance, 101a. LC-MS: 518.1 (M + H) +.

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Stage two

<figref>109</figref>

To a solution of the methyl ester 101a (1.21 g, 2.34 mmol) in THF (10 mL) and MeOH (5 mL) a solution was added 1 M aqueous LiOH (5 mL). The reaction mixture was stirred at RT for 4 h. It was then concentrated, diluted with water (50 mL) and acidified with solid citric acid (pH of about 3) when the solid white substance disintegrated. This solid separated by filtration, washed with water and dried under vacuum to provide 970 mg of 101b. LC-MS: 504.1 (M + H) +.

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Stage 3

<figref>110</figref>

Acid 101b (503 mg, 1 mmol) was coupled to the intermediate 13.06 (334 mg, 1.5 mmol) using essentially the procedure described above (Stage 1, preparation of 101a) for provide 101c that was used without purification. MS: 672.37 (M + H) +.

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Stage 4

<figref>111</figref>

To a solution of the hydroxylated compound 101c above in dichloromethane (15 mL) was added periodynan of Dess-Martin (848 mg, 2 mmol) and the mixture of reaction was stirred at RT for 5 h. At this time, the mix of reaction was diluted with dichloromethane (30 mL) and washed with a 1: 1 mixture of an ac solution. of 10% sodium thiosulfate and a saturated sodium bicarbonate solution (2 x 25 mL of each), brine (50 mL), dried (Na2SO4), filtered and concentrated. The crude substance was purified by chromatography. on silica using acetone / hexanes 15/85 to 50/50 to provide 410 mg of the required substance, 101d. LC-MS: 670.2 (M + H) +.

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Stage 5

<figref>112</figref>

Check out functionality 101d N-boc to provide the substance required 101e was carried out as described for the intermediate 1.01, Stage 3 (reaction time = 2 h). LC-MS: 570.1 (M + H) +.

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Stages 6

<figref>113</figref>

To a solution of the amine salt 101e (60 mg, 0.1 mmol) in dichloromethane (2 mL) at 0 ° C DIPEA (0.06) was added mL, 0.3 mmol) followed by intermediate isocyanate 65.01 (solution 0.25 M in toluene, 0.8 mL, 0.2 mmol). After 15 minutes at that temperature, the reaction flask was stored in the freezer (-20 ° C), overnight (16 hr). The reaction mixture was diluted. with dichloromethane (20 mL) and washed with a saturated solution of ammonium chloride (20 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated. The gross substance is purified by chromatography on silica using acetone / hexanes 15/85 to 50/50 to provide compound 101 (53 mg) required; LC-MS: 872.2 (M + H) +.

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Synthesis of Example 102

Stage 1

<figref>114</figref>

The required compound 102 was prepared from of 101e and intermediate 63.01 using the procedure described above for Example 101, Step 6, LC-MS of 102: 829.2 (M + H) +.

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Synthesis of Example 103

Stage 1

<figref>115</figref>

The required compound 103 was prepared from of 101e and intermediate 64.01 using described procedure before for Example 101, Step 6, LC-MS of 103: 804.2 (M + H) +.

In procedures similar to those described before, the other compounds of Table 2 were prepared. Additionally, the compounds of Table 1 can be prepared also similarly.

The present invention relates to inhibitors of novel HCV protease. This utility can be manifested in its ability to inhibit HCV NS3 / NS4a serine protease. A General procedure for such demonstration is illustrated by the following analysis <i>in vitro</i>.

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Analysis in search of the Protease Inhibitory Activity of HCV

<i>Spectrophotometric analysis</i>: The analysis Spectrophotometric looking for HCV serine protease can be perform on the compounds of the invention following the procedure described by R. Zhang <i>et al</i>, in Analytical Biochemistry, 270 (1999) 268-275, whose description It is incorporated herein by reference. The analysis based on the proteolysis of substrate chromogenic esters is suitable for continuous verification of the activity of the HCV NS3 protease. The substrates are derived from the P side of the NS5A-NS5B splice sequence (Ac-DTEDVVX (Nva), where X = A or P) whose C-terminal carboxyl groups are esterified with one of four different chromophoreic alcohols (3- or 4-nitrophenol, 7-hydroxy-4-methyl coumarin, or 4-phenylazophenol). Below are illustrated the synthesis, characterization and application of these esters Novel substrate spectrophotometric at high scrutiny performance and detailed kinetic evaluation of inhibitors of NS3 HCV protease.

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Materials and methods

Materials: Chemical reagents for Analysis of related buffers are obtained from Sigma Chemical Company (St. Louis, Missouri). Reagents for the synthesis of Peptides were from Aldrich Chemicals, Novabiochem (San Diego, California), Applied Biosystems (Foster City, California) and Perseptive Biosystems (Framingham, Massachusetts). The peptides are synthesized manually or in an ABI model 431A synthesizer automatic (from Applied Biosystems). The UV / VIS spectromer LAMBDA 12 model was from Perkin Elmer (Norwalk, Connecticut) and the 96-well UV plates were obtained from Corning (Corning, New York). The preheating block can be from USA Scientific (Ocala, Florida) and the vortex apparatus for 96-well plates is from Labline Instruments (Melrose Park, Illinois). The reader of Spectramax Plus se monochromator microtiter plates obtained from Molecular Devices (Sunnyvale, California).

<i>Enzyme Preparation</i>: The protease Recombinant heterodimeric HCV NS3 / NS4A (strain 1a) is prepared using previously published procedures (DL Sali<i>et al</i>, Biochemistry, 37 (1998) 3392-3401). Protein concentrations are determined by the method. Biorad dye using HCV protease standards recombinant previously quantified by analysis of amino acids. Before the start of the analysis, the buffer of Enzyme storage (50 mM sodium phosphate pH 8.0, NaCl 300 mM, glycerol 10%, laurilmaltósido to 0.05% and 10 mM DTT) is change to the analysis buffer (25 mM MOPS pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% laurilmaltósido to, EDTA 5 \ 5 uM DTT µM) using a Biorad Bio-Spin column P-6 preloaded.

<i>Synthesis of Substrate and Purification</i>: The Substrate synthesis is performed as reported by R. Zhang <i>et to the</i>, (<i>idem</i>) and starts anchoring Fmoc-Nva-OH to chloride resin 2-chlorotrityl using a conventional protocol (K. Barlos <i>et al</i>, Int. J. Pept. Protein Res., 37 (1991), 513-520). The peptides are assembled with later, using Fmoc chemistry, manually or in a ABI model 431 automatic peptide synthesizer. Fragments N-acetylated and fully protected peptides they are cleaved from the resin with 10% acetic acid (HOAc) and 10% trifluoroethanol (TFE) in dichloromethane (DCM) for 30 min, or with 2% trifluoroacetic acid (TFA) in DCM for 10 min. He combined filtrate and washing with DCM evaporates azeotropically (or extracted repeatedly with an aqueous solution of Na 2 CO 3) to separate the acid used in the cleavage. The DCM phase is dried over Na2SO4 and is evaporates

The substrate esters are assembled using acid-alcohol coupling procedures Conventional (K. Holmber <i>et al</i>, Act Chem. Scand., B33 (1979) 410-412). The peptide fragments are dissolved in anhydrous pyridine (30-60 mg / ml) at that 10 molar equivalents of chromophore and an amount were added catalytic (0.1 eq.) of para-toluenesulfonic acid (pTSA). Dicyclohexylcarbodiimide (DCC, 3 eq.) Is added to start coupling reactions. Product formation is verified using HPLC and you can find it is complete after 12-72 hours of reaction at room temperature. He Pyridine solvent is evaporated in vacuo and removed additionally by azeotropic evaporation with toluene. He peptide ester was deprotected with 95% TFA in DCM for two hours and extracted three times with anhydrous ethyl ether to remove the excess chromophore. The unprotected substrate is purified by reverse phase HPLC on a C3 or C8 column with a 30% to 60% acetonitrile gradient (using six volumes of the spine). The overall yield after purification by HPLC it can be about 20-30%. The molecular mass can be confirmed by spectroscopy of electrospray ionization masses. The substrates are stored in the form of dry powder by drying.

<i>Spectrum of Substrates and Products</i>: The spectra of substrates and chromophore products corresponding are obtained in the pH 6.5 buffer. He determine extinction coefficients at wavelength optimal outside the peak in 1-cm cuvettes (340 nm for 3-Np and HMC, 370 nm for PAP and 400 nm for 4-Np) using multiple dilutions. The length Optimal waveform outside the peak is defined as the wavelength which produces the maximum fractional difference in absorbance between the substrate and the product (DO product - DO substrate) / DO substratum).

<i>Protease Analysis</i>: the analyzes of HCV protease are performed at 30 ° C using a mixture of 200 µl reaction in a 96 microtiter plate wells. The conditions of the analysis buffer (MOPS 25 mM pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% laurylmaltoside, EDTA 5 µM and DTT 5) are optimized for the NS3 / NS4A heterodimer (DL Exited <i>et al, idem</i>.)). Typically, 150 are placed µl of the buffer, substrate and inhibitor mixtures in the wells (final concentration of DMSO? 4% v / v) and left pre-incubating at 30 ° C for approximately 3 minutes. Later use 50 µl of preheated protease (12 nM, 30 ° C) in buffer of analysis to start the reaction (final volume of 200 µl). Plates are monitored throughout the analysis (60 minutes) in Search for absorbance change at the appropriate wavelength (340 nm for 3-Np and HMC, 370 nm for PAP, and 400 nm for 4-Np) using a plate reader Spectromax Plus microtiter equipped with a monochromator (se they can get acceptable results with plate readers that use cutting filters). Proteolytic bond cleavage ester between Nva and the chromophore is controlled at the wavelength appropriate against a blank without enzyme as a control for non-enzymatic hydrolysis. The evaluation of kinetic parameters of the substrate is carried out over a concentration range 30-fold substrate (-6-200 µM). The initial speeds are determined using linear regression and Kinetic constants are obtained by adjusting the data to the Michaelis-Menten equation using analysis of nonlinear regression (Mac Curve Fit 1.1, K. Raner). The numbers of spare part (<i>k_ {cat}</i>) are calculated assuming that the enzyme is fully active

<i>Inhibitor Evaluation and Inactivators</i>: The inhibition constants (Ki) for the competitive inhibitors Ac-D- (D-Gla) -Ll- (Cha) -C-OH (27), Ac-DTEDVVA (Nva) -OH and Ac-DTEDVVP (Nva) -OH se experimentally determined at fixed concentrations of enzyme and substrate tracing v_ {o} / v_ {i} against the concentration of inhibitor ([I] o) according to the equation of Michaelis-Menten reordered for kinetics of competitive inhibition: v_ {o} / v_ {i} = 1 + [I] o / (K_ {(1 + [S] o / K_m)), where v_ {o} is the initial speed not inhibited, v_ {i} is the initial velocity in the presence of inhibitor at any given concentration of inhibitor ([I] o) and [S] o is the concentration of substrate used. The resulting data are adjusted using linear regression and the resulting slope, 1 / (K_ (([S] o / K_)), It is used to calculate the value of K_ {i}. Ki values ​​* obtained (in nanoMoles) for some of the compounds of the invention are shown below in Table 2.

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TABLE 2

<figref>116</figref>

<figref>117</figref>

<figref>118</figref>

<figref>119</figref>

<figref>120</figref>

<figref>121</figref>