MXPA06009815A - 3,4-(cyclopentyl)-fused proline compounds as inhibitors of hepatitis c virus ns3 serine protease - Google Patents

Abstract

The present invention discloses novel compounds according to formula (I) which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease. Wherein:R1 is H, OR8, NR9R10, wherein R8, R9 and R10 can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, and heteroarylalkyl, or alternately R9 and R10 in NR9R10 are connected to each other such that NR9R10 forms a four to eight-membered heterocyclyl, and likewise independently alternately R9 and R10 in CHR9R10 are connected to each other such that CHR9R10 forms a four to eight-membered cycloalkyl;Y represents a group G-R wherein G is NH or O.

Description

PROLIN COMPOUNDS 3,4- (CICLOPENTIL) -FUSIONADOS, AS INHIBITORS OF SERINE PROTEASA NS3 OF HEPATITIS VIRUS FIELD OF THE INVENTION The present invention relates to hepatitis C virus protease inhibitors ("HCV"), to pharmaceutical compositions comprising one or more of said inhibitors, to the methods of preparing said inhibitors and to methods of using said inhibitors. inhibitors to treat hepatitis C and related disorders. This invention additionally discloses novel compounds containing bicyclic P2 portions as inhibitors of HCV serine protease NS3 / NS4a. This application claims priority of the Provisional North American Application No. 60 / 548-655, filed on February 27, 2004.

BACKGROUND OF THE INVENTION The hepatitis C virus (HCV) is an RNA virus of double-chain structure of (+) - sense that has been implicated as the main causative agent of non-A, non-B hepatitis (NANBH), particularly in NANBH (BB-NANBH) associated with blood (see, Publication of the Application of International Patent WO 89/04669 and Publication of European Patent Application No. EP 381, 216). NANBH should be distinguished from other types of liver diseases induced by viruses, such as hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis delta virus (HDV), cytomegalovirus (CMV) ) and the Epstein-Barr virus (EBV), as well as other forms of liver diseases such as alcoholism, and primary biliary cirrhosis. Recently, an HCV protease necessary for the processing of the polypeptides and for viral replication has been identified, cloned and expressed. (See, for example, U.S. Patent No. 5,712,145). This polyprotein of approximately 3000 amino acids contains, from the amino terminus to the carboxy terminus, a nucleocapsid protein (C), envelope proteins (E1 and E2) and several non-structural proteins (NS1, 2, 3, 4a, 5a and 5b) . NS3 is a protein of approximately 68 kda, encoded by approximately 1893 nucleotides of the HCV genome, and has two distinct domains: (a) a serine protease domain consisting of approximately 200 of the N-terminal amino acids; and (b) an ATPase domain that depends on RNA in the C-terminus of the protein. The NS3 protease is considered a member of the chymotrypsin family, due to the sequence similarities of the proteins, the general three-dimensional structure and the mechanism of catalysis. Other enzymes of the chymotrypsin type are elastase, factor Xa, thrombin, trypsin, plasmin, urokinase, tPA and PSA. HSV serine protease NS3 is responsible for the proteolysis of the polypeptide (polyprotein) in the junctions NS3 / NS4a, NS4a / NS4b, NS4b / NS5a and NS5a / NS5b and therefore is responsible for generating four viral proteins during viral replication. This has made HCV serine protease NS3 an attractive target for anti-viral chemotherapy. The compounds of the invention can inhibit said protease. They can also modulate the processing of the hepatitis C virus (HCV) polypeptide. It has been determined that the NS4a protein, a polypeptide of about 6 kda, is a co-factor for the serine protease activity of NS3. The autodisocytion of the NS3 / NS4a binding by serine protease NS3 / NS4a occurs intramolecularly (i.e., cis) while the other dissociation sites are processed thermolabularly (i.e., trans). The analysis of the natural dissociation sites for the HCV protease revealed the presence of cysteine in P1 and serine in P1 'and revealed that these residues are strictly conserved in the NS4a / NS4b, NS4b / NS5a and NS5a / NS5b junctions. The NS3 / NS4a junction contains a threonine in P1 and a serine in P1 '. It has been postulated that the Cys substitution? hr in NS3 / NS4a concerns the requirement of cis processing rather than that of trans, in this union. See, for example, Pizzi et al. (1994) Proc. Nati Acad. Sci (USA) 91: 888-892, Failla et al. (1996) Foldinq & Design 1: 35-42. The NS3 / NS4a cleavage site is also more tolerant to mutagenesis than the other sites. See, for example, Kollykhaiov et al. (1994) J. Virol. 68: 7525-7533. It has been also demonstrated that acid residues in the region upstream of the dissociation site are necessary for efficient dissociation. See, for example, Komoda et al. (1994) J. Virol. 68: 7351-7357. The aforementioned HCV protease inhibitors include antioxidants (see, International Patent Application Publication No. WO 98/14181), some peptides and peptide analogs (see, International Patent Application Publication No. WO 98/17679, Landro et al. (1997) Biochem. 36: 9340-9348, Ingallinella et al. (1998) Biochem. 37: 8906-8914, Llinás-Brunet et al. (1998) Bioorq. Med. Chem. Lett. 8: 1713- 1718), inhibitors that are based on the 70 amino acid eglin c polypeptide (Martin et al (1998) Biochem 37: 11459-11468, selected affinity inhibitors of the human pancreatic trypsin secretory inhibitor (hPSTI-C3) and repertoires of minibody (MBip) (Dimas-i et al. (1997) J. Virol. 71: 7461-7469), cVHE2 (a "camelized" variable domain antibody fragment (Martin et al. (1997) Protein Eng. 10: 607-614), and a1-antichymotrypsin (ACT) (Elzouki et al.) (1997) J. Hepat.27: 42-28) A ribozyme has recently been designed to selectively destroy A RN of the hepatitis C virus (see, BioWorld Today 9 (217): 4 (November 10, 1998)). Reference is also made to PCT publications, No. WO 98/17679, published April 30, 1998, (Vértex Pharmaceuticals Incorporated); WO 98/22496, published May 28, 1998 (F. Hoffmann-La Roche AG); and WO 99/07734, published February 18, 1999 (Boehringer Ingelheim Canada Ltd.).

HCV has been implicated in cirrhosis of the liver and in the induction of hepatocellular carcinoma. The prognosis for patients suffering from HCV infection is usually bad. HCV infection is more difficult to treat than other forms of hepatitis due to the lack of immunity or remission associated with HCV infection. Current data indicate a survival rate of less than 50% in the four years following the diagnosis of cirrhosis. Patients who have been diagnosed with a localized operable hepatocellular carcinoma have a 10-30% survival rate in the following five years, while those with unresectable localized hepatocellular carcinoma have a survival rate of less than 1% in five years. Reference is made to WO 00/59929 (US 6,608,027, entitled: Boehringer Ingelheim (Canada) Ltd .. Published on October 12, 2000) which describes peptide derivatives of the formula reference is made to A. Marchetti ef al, Synlett, SI, 1000-1002 (1999) which describes the synthesis of bicyclic analogs of a HCV NS3 protease inhibitor. A compound described here has the formula: reference is also made to W. Han ef al, Bioorganic & Medicinal Chem. Lett, (2000) 1_0, 711-713, which describes the preparation of certain α-ketoamides, α-keto esters and α-diketones containing allyl and ethyl functionalities. Reference is also made to WO 00/09558 (Titular: Boehringer Ingelheim Limited, Published February 24, 2000) which describes peptide derivatives of the formula: in which the various elements are defined here. An illustrative compound of this series is: reference is also made to WO 00/09543 (Titular: Boehringer Ingelheim Limited, Published on February 24, 2000) which describes peptide derivatives of the formula: where the various elements are defined here. An illustrative compound of this sene is: reference is also made to US Patent No. 6,608,027 (Boehringer Ingelheim, Canada) which describes NS3 protease inhibitors of the type: where the various portions are defined here. Current therapies for hepatitis C include interferon-a (INFa) and combination therapy with ribavirin and interferon. See for example, Beremguer et al. (1998) Proc. Assoc. Am. Phvsicians 110 (2): 98-112. These therapies suffer from a low sustained response rate and frequent side effects. See, for example, Hoofnagle et al. (1997) N. Engl. J. Med. 336: 347. Currently, there is no vaccine available for HCV infection. Reference is further made to WO 01/74768 (Titular: Vértex Pharmaceuticals Inc) published on October 11, 2001, which discloses certain compounds of the following general formula (R is as defined herein), as inhibitors of serine protease NS3 of the hepatitis C virus: a specific compound described in WO 01/74768 mentioned above has the following formula: 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 U.S. Patent Application Laid-Open No. 10 / 052,386 filed January 18, 2002, describe various types of peptides and / or compounds as serine protease inhibitors NS-3 of hepatitis C virus. Descriptions of these applications they are incorporated here as a reference to them.

There is a need to have new treatments and therapies for HCV infection. Useful compounds are needed in the treatment or prevention or improvement of one or more symptoms of hepatitis O There is a need for methods to modulate the activity of serine proteases particularly of the serine protease HCV NS3 / NS4a using the compounds provided herein. There is a need for methods to modulate HCV polypeptide processing using the compounds provided herein.

BRIEF DESCRIPTION OF THE INVENTION In its many embodiments, the present invention provides a new class of HCV protease inhibitors, pharmaceutical compositions containing one or more of the compounds, methods of preparing the pharmaceutical formulations comprising one or more of said compounds, and methods of treatment. or prevention of HCV or improvement of one or more of the symptoms of hepatitis C using one or more of said compounds or one or more of said formulations. Methods are also provided to modulate the interaction of the HCV polypeptide with the HCV protease. Among the compounds provided herein, compounds that inhibit the activity of HCV serine protease NS3 / NS4a are preferred. The present invention describes a compound or enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates of said compound, or a pharmaceutically acceptable salt, solvate or ester of said compound, wherein said compound has the general structure shown in the structural Formula 1 : Formula 1 wherein: R1 is H, OR8, NR9R10, or CHR9R10, where R8, R9 and R10 may be the same or different, and each is independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, aryl -, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, and heteroarylalkyl, or alternatively R9 and R10 in NR9R10 are connected together so that NR9R10 forms a heterocyclyl of four to eight members, and likewise, independently, alternatively R9 and R10 in CHR9R10 are connected together so that CHR9R10 forms a cycloalkyl of four to eight members; R2 and R3 may be identical or different, and each is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl or arylalkyl, heteroaryl, and heteroarylalkyl; And it is selected from the following portions: R18 R «Laughs R15 R1? or R « R19 R? VN R -ó? xGo. ? V R ~ «- -y., R, 1lße 00 RRl1ß6 • ^ O O "O R19 O R17OR'8 R I1.0" A "" »Ov O wherein G is NH or O; and R15, R16, R7, R18, R19, R20, R21, R22, R23, R24 and R25 may be the same or different, and each is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl , heteroalkynyl, cycloalkyl, heterocyclyl, aryl or arylalkyl, heteroaryl, and heteroarylalkyl; or alternatively, (i) R17 and R8 they are independently connected to each other to form a cycloalkyl or heterocyclyl of three to eight members; (ii) likewise, independently R15 and R19 are connected together to form a heterocyclyl of four to eight members; (iii) likewise independently R15 and R16 are connected to each other to form a heterocyclyl of four to eight members; (iv) likewise independently R15 and R20 are connected to each other to form a heterocyclyl of four to eight members; (v) likewise independently R22 and R23 are connected together to form a cycloalkyl of three to eight members or a heterocyclyl of four to eight members; and (vi) likewise independently R24 and R25 are connected together to form a cycloalkyl of three to eight members or a heterocyclyl of four to eight members; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl can be unsubstituted or can be independently optionally substituted with one or more portions selected from the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, aicylamine, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carboalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro. In the previously mentioned definitions, alkyl is preferred which is constituted by one to three carbon atoms, preferably alkyl or alkynyl of two to ten carbon atoms, and the preferred cycloalkyl it is three to eight carbon atoms, and the heteroalkyl, heteroaryl or heterocycloalkyl (heterocyclyl) preferred have from 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 appropriate agents described herein may be useful for the treatment of diseases such as, for example, HCV, HIV, AIDS (Acquired Immunodeficiency Syndrome), and related disorders, as well as to modulate the activity of the hepatitis C virus protease (HCV), to prevent HCV, to improve one or more symptoms of hepatitis C. Said modulation, treatment, prevention or improvement can be carried out with the compounds of the invention, as well as with pharmaceutical compositions or formulations comprising said compounds. Without limiting ourselves to any theory, we believe that the HCV protease can be the NS3 or NS4a protease. The compounds of the invention can inhibit said protease. They can also modulate the processing of the hepatitis C virus (HCV) polypeptide.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the present invention describes compounds that are represented by structural formula 1 or by a salt pharmaceutically acceptable, a solvate or an ester thereof where the various portions are as defined above.

In one embodiment, R1 is NR9R10, and R9 is H, R10 is H, or R14 where R14 is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaryl-alkyl.

In another embodiment, R14 is selected from the group consisting of: OH /. OH V \ - \ 1 -3 ? -OSH, -OMe. O OMe OH - J 1-3 in another embodiment, R2 is selected from the group consisting of the following portions: modality, R3 is selected from the group consisting of: wherein R 31 is OH or O-alkyl; and R32 is H, C (0) CH3, C (0) OtBu or C (0) N (H) tBu. In an additional embodiment, R3 is selected from the group consisting of the following portions: in another mode G is NH. In an additional mode, Y is selected from the following portions: wherein R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each independently selected from the group consisting of: H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl , heterocyclyl, aryl or arylalkyl, heteroaryl, and heteroarylalkyl; or alternatively, (i) R17 and R18 are independently connected to each other to form a cycloalkyl of three to eight members or a heterocyclyl; (ii) likewise, independently R15 and R19 are connected together to form a heterocyclyl of four to eight members; (iii) likewise independently R15 and R16 are connected to each other to form a heterocyclyl of four to eight members; and (v) likewise independently R15 and R20 are connected to each other to form a four to eight member heterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl can be unsubstituted or can be independently optionally substituted with one or more portions 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 a further embodiment, the portion: It is selected from the following: in which Y32 is selected from the group consisting of: in another additional mode, Y is selected from: in an additional mode, the portion: It is selected from the following structures: in a further embodiment, R1 is NHR14, where R14 is selected from the group consisting of: -OH, l-OMe, OMe 1-3 AQOH V V V SMe and \ QY \ Y.N R is selected from the group consisting of the following portions: R3 is selected from the group consisting of the following portions: Serving: is selected from and Y is selected from: Another embodiment of the invention describes compounds shown in Table 1.

TABLE 1 Also presented in Table 1a are additional compounds found with the present invention: TABLE 1A As used above, and throughout this description, the following terms, unless otherwise indicated, will be construed as having the following meanings: "Patient" includes both human beings and animals. "Mammals" refers to humans and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched chain 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. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkyl" means a group having from about 1 to about 6 carbon atoms in the chain which may be straight or branched. The term "substituted alkyl" means that the alkyl group may be substituted with one or more substituents which may be the same or different, wherein each substituent is independently selected 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) 0 -alkyl. Non-limiting examples of the appropriate alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-to-carbon double bond and which may be straight or branched chain and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably 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 are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain, which may be straight or branched. The term "substituted alkenylene" means that the alkenyl group may be substituted with one or more substituents which may be the same or different, and each substituent is independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and - S (alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-to-carbon triple bond and which may be straight or branched chain and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably about 2 up about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain, which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted with one or more substituents which may be identical or different, wherein each substituent is independently selected from the group consisting of alkyl, aryl and cycloalkyl. "Aryl" means a monocyclic or multicyclic aromatic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more "ring system substituents" which may be the same or different, and which are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means a monocyclic or multicyclic aromatic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which, one or more of the ring atoms is an element other than the ring atom. carbon, for example, nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 up to about 6 atoms in the ring. The "heteroaryl" may be optionally substituted with one or more "ring system substituents" which may be identical or different, and which are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least one nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4- thiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-a] pyridinyl, imidazo [2.1-b] thiazoliol, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as for example tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl group in which, the aryl and the alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of the appropriate aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The link with the main portion was made through the alkyl.

"Alkylaryl" means an alkyl-aryl group in which the alkyl and the aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. A non-limiting example of an appropriate alkylaryl group is tolyl. The link with the main portion is made through the aril. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and which are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls 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. "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are preferred. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system that, for example, replaces a hydrogen available in the ring system. System substituents of the ring may be the same or different, each independently selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy , acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroalkylthio, cycloalkyl, heterocyclyl, -C (= N-CN) -NH2, -C (= NH) -NH2, -C (= NH) -NH (alkyl), Y1Y2N-, Y1Y2N-alkyl-, YOsNCyO) -, YO2NS02- and -SO2NY., Y2, where Y-, and Y2 can be same or different and are independently selected from the group consisting of hydrogen, alkyl aryl, cycloalkyl and aralkyl. "Substituent of the ring system" may also mean a simple portion that simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) in a ring system. Examples of said portions are methylene dioxy, ethylenedioxy, -C (CH3) 2- and the like forming portions such as for example: "Heterocyclyl" refers to a monocyclic or multicyclic saturated non-aromatic ring system comprising approximately 3 to about 10 atoms in the ring, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen, or sulfur, alone or in combination. No oxygen and / or adjacent sulfur atom is present in the ring system. Preferred heterocycls contain about 5 to about 6 ring atoms. The prefix aza, oxa, or tia before the heterocyclic root name means that at least one nitrogen, oxygen or sulfur atom is respectively present as a ring atom. Any -NH in a heterocyclyl ring can exist protected as such, for example, as a group -N (Boc), -N (CBz), -N (Tos) and the like; such protections are also considered part of this invention. The heterocyclyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and which are as defined herein. The nitrogen or sulfur atom of the heterocyclyl may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone and the like. It should also be noted that in the ring systems of this If there are no heteroatoms, there is no hydroxyl group on the carbon atoms adjacent to N, O or S, nor is there any group N or S on the carbon adjacent to the other heteroatom. Therefore, for example, in the ring: there is no -OH attached directly to the carbons marked 2 and 5. It should also be noted that the tautomeric forms, such as for example the portions: they are considered equivalent in certain embodiments of this invention. "Alkynylalkyl" means an alkynyl-alkyl group in which the alkynyl and the alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The link with the main portion is made through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl group in which heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Examples not Limitations of appropriate aralkyl groups include pyridylmethyl and quinolin-3-ylmethyl. The link with the main portion is made through the alkyl. "Hydroxyalkyl" means an HO-alkyl- group in which the alkyl is as previously defined. Preferred hydroxyalkyl contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl" means a group H-C (O) -, alkyl-C (O) - or cycloalkyl-C (O) -, in which the various groups are as previously described.

The bond with the main portion is made through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C (O) - group in which the aryl group is as previously described. The bond with the main portion is made through the carbonyl. Non-limiting examples of appropriate groups include benzoyl and 1-naphtholyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond with the main portion is effected through the oxygen of the ether. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond with the main portion is effected through the oxygen of the ether.

"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond with the main portion is effected through the oxygen of the ether. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The connection with the main portion is made through sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The connection with the main portion is made through sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. A non-limiting example of an appropriate aralkylthio group is benzylthio. The connection with the main portion is made through sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond with the main portion is made through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C (O) - group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond with the main portion is made through the carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C (O) - group. A non-limiting example of an appropriate aralkoxycarbonyl group is benzyloxycarbonyl. The bond with the main portion is made through the carbonyl. "Alkylsulfonyl" means an alkyl-S- (O 2) - group. Preferred groups are those in which the alkyl group is lower alkyl. The link with the main portion is effected through the sulfonyl. "Arylsulfonyl" means an aryl-S- (O2) group. The link with the main portion is effected through the sulfonyl. The term "substituted" means that one or more hydrogens in the designated atom are replaced with a selection of the indicated group, with the proviso that the normal valence of the designated atom under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently strong to survive isolation to a degree of useful purity from a reaction mixture, and its formulation into an effective therapeutic agent. The term "one or more" or "at least one", when the amount of substituents, compounds, combination agents and the like is indicated, refers to at least one, and up to a maximum amount of chemically and physically permissible substituents of compounds, combination agents and the like, which are present or added, depending on the context. Said techniques and knowledge are known to those skilled in the corresponding art. The term "optionally substituted" means an optional substitution with the radical groups or specified portions. The term "isolated" or in "isolated form" for a compound refers to the physical state of said compound after having been isolated by a synthesis process or from natural sources or combinations thereof. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after it has been obtained by a purification process or procedures such as those described herein or others well known to the person skilled in the art, with sufficient purity so that it can be characterized by conventional analytical techniques such as those described herein or well known to those skilled in the art. It should also be noted that any carbon or heteroatom with valences not satisfied in the text, schemes, examples and tables present is assumed to have the hydrogen atoms that satisfy the valences. When a functional group in a compound is called "protected", this means that the group is in a modified form for avoid any undesirable secondary reaction at the protected site, when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art as well as by references in conventional textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York. When any variable (for example aryl, heterocycle, R2, etc.) occurs more than once in any constituent or in Formula 1, its definition each time it occurs is independent of its definition when it occurs any other time. As used herein, the term "composition" encompasses a product that comprises the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified amounts. The prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug" as used herein, denotes a compound that is a precursor of a drug, which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to provide a compound of Formula 1 of a salt and / or a solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, which are incorporated herein by reference. "Solvate" refers to a physical association of a compound of this invention with one or more solvent molecules. This physical association involves several degrees of ionic and covalent binding, including the binding of hydrogen. In some cases the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystalline lattice of the crystalline solid. "Solvate" covers both solution phase solvates and insulable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecule is H2O. "Effective amount" or "therapeutically effective amount" is provided to describe an amount of compound or composition of the present invention that is effective to inhibit CDK (s) and therefore to produce the desired therapeutic, enhancer, inhibitor or preventive effect . The compounds of Formula 1 can form salts, which are also within the scope of the invention. Reference is made to a compound of Formula 1 which is considered to refer to the salts thereof unless otherwise indicated. The term "salt (s)" as used herein, denotes the acid salts formed with inorganic and / or organic acids, as well as the basic salts formed with inorganic and / or organic bases. Also, when a compound of Formula 1 contains both a basic portion and such, but not limited to a pyridine or imidazole, and an acid portion, such as but not limited to a carboxylic acid, zwitterions can be formed ("internal salts") and are included within the the) term (s) "salt (s)" that is used here. Pharmaceutically acceptable salts (ie, non-toxic, physiologically acceptable) are preferred, although other salts are also useful. Salts of the compounds of Formula 1 can be formed for example, by reaction with a compound of Formula 1 respectively with an amount of acid or base, such as an equivalent amount, in a medium such as that in which the salt precipitates or in an aqueous medium followed by lyophilization. Examples of acid addition salts include acetate, ascorbate, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphor sulfonates, fumarates, hydrochlorides, hydrobromides, iodides, lactates, maleates, methanesulfonates, naphthalenesulphonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds have been discussed, for example, in P. Stahl ef a /, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food &Drug Administration, Washington, D.C. on its website). These descriptions are incorporated herein by reference. Examples of basic salts include the ammonium salts, the alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic groups containing nitrogen can be quaternized with agents such as lower alkyl halides (for example, methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (for example dimethyl, diethyl and dibutyl sulphates), long chain (for example decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (for example benzyl and phenethyl bromides), and others. All said acid salts and basic salts are pharmaceutically acceptable salts which are within the scope of the invention and all acidic and basic salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. The pharmaceutically acceptable esters of the compounds herein include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl portion of the carboxylic acid moiety of the ester group is selected from straight or branched chain alkyl (for example acetyl, n-propyl, t-butyl, or n-butyl) alkoxyalkyl (for example, methoxymethyl), aralkyl (for example benzyl), aryloxyalkyl (for example phenoxymethyl), aryl (for example phenyl optionally substituted with for example halogen, alkyl C? -, or C -? - or amino alkoxy); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphate esters and (5) esters of mono-, di- or triphosphate. The phosphate esters can be further esterified, for example by a C?-20 alcohol or a reactive derivative thereof, or by a 2,3-di-acyl of C6-24 glycerol. The compounds of Formula 1 and the salts, solvates, esters and prodrugs thereof may exist in their tautomeric form, (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. All stereoisomers, for example geometric isomers, optical isomers, and the like of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as may exist the asymmetric carbons on various substituents, including the enantiomeric forms (which may exist even in the absence of asymmetric carbons), the rotamer forms, the atropisomers, and the diastereomeric forms, are contemplated within the scope of the invention, as well as the positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). The individual stereoisomers of the compounds of the invention can be, for example, substantially free of other isomers, or can be mixed, for example, as racemates, or with all others, or with other selected stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvates", "prodrugs" and the like will also apply to salt. , solvate and prodrug of the enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the compounds of the invention. The polymorphic forms of the compounds of Formula 1, and the salts, solvates and prodrugs of the compounds of Formula 1 are included in the present invention. It should be understood that the utility of the compounds of Formula 1 for the therapeutic applications discussed herein, is applicable to each of the compounds by themselves or to the combination or combinations of one or more compounds of Formula 1 as illustrated, for example in the next immediate paragraph. The same interpretation can also be applied to pharmaceutical compositions comprising said compound or compounds and methods of treatment involving said compound or compounds. The compounds according to the invention may have pharmacological properties. In particular, the compounds of Formula 1 can be inhibitors of the HCV protease and each compound by itself or one or more compounds of Formula 1 may be combined with one or more compounds selected from Formula 1. The compounds may be useful for treating diseases such as, for example, HCV, HIV, (AIDS, Acquired Immune Deficiency Syndrome) and related disorders, as well as to modulate the activity of the hepatitis C virus protease (HCV), prevent HCV, or improve one or more symptoms of hepatitis C. The compounds of Formula 1 can be used for the manufacture of a medicament for treating disorders associated with the HCV protease, for example, the method comprising intimately contacting a compound of Formula 1 and a pharmaceutically acceptable carrier. In another embodiment, this invention provides pharmaceutical compositions comprising the compound or compounds of the invention, as an active ingredient. The pharmaceutical compositions generally additionally comprise at least one pharmaceutically acceptable diluent, excipient, or carrier (collectively referred to herein as carrier materials). Due to their HCV inhibitory activity, these pharmaceutical compositions are useful in the treatment of hepatitis C and related disorders. In a further embodiment, the present invention describes methods for preparing pharmaceutical compositions comprising the compounds of the invention as an active ingredient. In the pharmaceutical compositions and methods of the present invention, the active ingredients they will typically be administered in admixture with appropriate carrier materials selected conveniently with respect to the proposed form of administration, i.e., oral tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for reconstitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and in accordance with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with any inert non-toxic pharmaceutically acceptable carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate. , talc, mannitol, ethyl alcohol (liquid forms) and the like. In addition, when desired or necessary, binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. The powders and tablets may constitute from about 5 to about 95% of the composition of the invention. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums, such as acacia gum, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned to be used in these dosage forms boric acid, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include starch, methylcellulose, guar gum and the like.

Sweetening and flavoring agents and preservatives may also be included where appropriate. Some of the terms indicated above, that is, the disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below. Additionally, the compositions of the present invention can be formulated in sustained release form to provide a controlled release regimen of one or more of the components or active ingredients, to optimize the therapeutic effects, i.e., the HCV inhibitory activity and Similar. Suitable dosage forms for sustained release include layered tablets containing layers of various disintegration regimes or controlled release polymer matrices, impregnated with the active components and configured in the form of tablets or capsules containing said impregnated or encapsulated porous polymer matrices. . Liquid form preparations include solutions, suspensions and emulsions. As an example, water or water-propylene glycol solutions for parenteral injection or for addition of sweeteners and painkillers for solutions, suspensions and oral emulsions may be mentioned. The liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, eg, nitrogen. To prepare suppositories, a low-melting wax such as a mixture of fatty acid glycerides, such as cocoa butter, is first melted and the active ingredient is homogeneously dispersed there by agitation or similar mixture. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool and then solidified. Also included are solid form preparations which may be converted shortly before use into liquid form preparations for oral or parenteral administration. Said liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be distributed transdermally. The transdermal compositions may take the form of creams, lotions, aerosols, and / or emulsions and may be included in a transdermal patch of the matrix or reservoir type such as are conventional in the art for this purpose. The compounds of this invention can also be administered orally, intravenously, intranasally or subcutaneously. The compounds of the invention may also comprise preparations that are in unit dosage form. In this form the preparation is subdivided into unit doses of appropriate size that they contain the appropriate quantities of active components, for example, an effective amount to achieve the desired purpose. The amount of the active composition of the invention in a unitized form of preparation may generally vary or be adjusted to from about 1.0 milligrams to about 1000 milligrams, preferably from about 1.0 to about 950 milligrams, more preferably from about 1.0 to about 500 milligrams, and typically from about 1 to about 250 milligrams according to the particular application. The actual dose used may vary depending on the age of the patient, sex, weight and the severity of the disease being treated. Such techniques are well known to those skilled in the art. In general, the human oral dosage form containing the active ingredients can be administered once or twice a day. The amount and frequency of administration will be regulated according to the opinion of the attending physician. A daily dosage regimen generally recommended for oral administration, may be comprised between about 1.0 milligrams to about 1,000 milligrams per day, in single or divided doses. Some useful terms will be described below: Capsule- refers to a special container or capsule prepared with methylcellulose, polyvinyl alcohols or gelatins denatured or starch to hold or contain compositions comprising the active ingredients. Hard shell capsules are typically prepared with pig leather gelatin mixtures having a relatively high gel strength. The capsule itself may contain small amounts of dyes, opacifying agents, plasticizers and preservatives. Tablet- refers to a solid or molded dosage form containing the active ingredients with appropriate diluents. The tablet can be prepared by understanding mixtures or by granulations obtained by wet granulation, dry granulation or by compaction. Oral gel- refers to the active ingredients dispersed or solubilized in a hydrophilic semisolid matrix. Powder for reconstitution refers to powder mixtures containing the appropriate active ingredients and diluents that may be in suspension, in water, or in juice. Diluent- refers to substances that usually constitute the main portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potatoes; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition may be in a range of from about 10 to about 90% by weight of the total composition preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, and even more preferably from about 12 to about 60%. Disintegrant- refers to materials added to the composition to aid in the decomposition (disintegration) and to release the drugs. Suitable disintegrants include starches; "soluble in cold water", modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust, karaya, guar, tragacanth and agar flour; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as croscarmellose sodium; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can be in a range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight. Binder- refers to substances that agglutinate or "stick" powders together and give them cohesion through the formation of granules, and therefore serve as "adhesives" in the formulation. The binders add cohesive strength already available in the diluent or in the bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn, rice and potatoes; natural gums such as gum acacia, gelatin and tragacanth; algae derivatives such as acid alginic, sodium alginate and calcium and ammonium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinyl pyrrolidone; and inorganics such as aluminum and magnesium silicate. The amount of binder in the composition may be in the range of from about 2 to about 20% by weight of a composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight. weight. Lubricant- refers to a substance added to the dosage form to allow the tablet, granules, etc., after being compressed, to be removed from the mold or matrix reducing friction or wear. Suitable lubricants include metal stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants 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, because they must be present on the surfaces of the granules and between them and the pressed parts of the tablets. The amount of lubricant in the composition may be from about 0.2 to about 5% by weight of the composition, preferably from about 0.5. up to about 2%, and more preferably between from about 0.3 to about 1.5% by weight. Slipper - material that prevents the formation of hardening and improves the flow characteristics of the granulates, so that their fluidity is smooth and uniform. Useful glidants include silicon dioxide and talc. The amount of glidant in the composition should be in a range of from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight. Coloring agents - excipients that provide coloration to the composition or dosage form. Such excipients may include food grade dyes absorbed onto a suitable absorbent such as clay or aluminum oxide. The amount of coloring agent is from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%. Bioavailability- refers to the regimen and the degree to which the active drug ingredient or therapeutic portion is absorbed into the systemic circulation from a dosage form administered, as compared to a standard or control. Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and granulation compression produced by compaction, or methods wet or other special procedures. Special methods for preparing other forms of administration such as for example capsules, suppositories and the like are well known. Another embodiment of the invention describes the use of the compounds of the invention or of the pharmaceutical compositions described above for the treatment of diseases such as, for example, hepatitis C and the like. The method comprises administering a therapeutically effective amount of the compound of the invention or a pharmaceutical composition to a patient suffering from said disease or diseases and in need of such treatment. In a further embodiment, the compounds of the invention can be used for the treatment of HCV in humans in monotherapy mode or in a combination therapy mode (eg, dual combination, triple combination, etc.) a mode such as for example, in combination with antiviral agents and / or immunomodulators. Examples of such antiviral and / or immunomodulatory agents 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), Heptazima ™ (from Ribozyme Pharmaceuticals, Boulder, Colorado), VX 497 ™ (from Vertex Pharmaceuticals, Cambridge, Massachusetts), Timosina ™ (from SciClone Pharmaceuticals, San Mateo, California) ), Maxamina ™ (Maxim Pharmaceuticals, San Diego, California), mycophenolate mofetil (from Hoffman-LaRoche, Nutley, New Jersey), interferon (such as, for example, interferon-alpha, PEG-interferon alpha conjugates) and the like. "PEG-interferon alpha conjugates" represent interferon alpha molecules covalently linked to a PEG molecule. Illustrative interferon alpha-PEG conjugates include interferon alfa-2a (Roferon ™, from Hoffman La-Roche, Nutley, New Jersey) in the form of pegylated interferon alfa-2a, (ie, as sold under the commercial name Pegasys ™). interferon alfa-2b (Intron ™, from Schering-Plow Corporation) in the form of pegylated interferon alfa-2b (for example, the one sold under the trade name PEG-Intron ™), interferon alfa-2c (Berofor Alpha ™, from Boehringer Ingelheim, Ingelheim, Germany) or consensus interferon defined according to the determination of a natural interferon alpha consensus sequence (Infergen ™, from Amgen, Thousand Oaks, California). As stated above, the invention also includes tautomers, rotamers, enantiomers, and other stereoisomers of the compounds of the invention. Therefore, as one skilled in the art will appreciate, some of the compounds of the invention may exist in appropriate isomeric forms. Said variations are contemplated within the scope of the invention. Another embodiment of the invention describes a method for preparing the compounds described herein. The compounds can be prepared by various techniques known in the art. The procedures Illustrative are indicated in the following reaction schemes. The illustrations should not be considered as limiting the scope of the invention, which is defined in the appended claims. Alternative mechanical routes and analogous structures will be apparent to those skilled in the art. It should be understood that although the following illustrative schemes describe the preparation of a few representative compounds of the invention, the appropriate substitution of either of the two amino acids, natural and unnatural, will result in a formation of the desired compounds based on said substitution. . Said variations are contemplated within the scope of the invention.

Abbreviations The abbreviations used in the descriptions of the schemes, preparations, and the 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: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride NMM: N-methylmorpholine ADDP: 1.1 '- (Azodcarbonyl) dipperidine DEAD: Diethyl azodicarboxylate MeOH: Methanol EtOH: Ethanol Et2O: Diethyl ether DMSO: Dimethyl sulfoxide HOBt: N-Hydroxybenzotriazole PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate 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: Boc: Isobutoxycarbonyl iPr: isopropyl 'Bu or Bu': ter-Butyl Boc: ter-Butyloxycarbonyl Cbz: Benzyloxycarbonyl Cp: Cyclopentyldienyl Ts: p-toluenesulfonyl Me: Methyl HATU: O- (7-azabenzotriazol-1-iI) -1,1, 3,3-tetramethyluronium hexafluorophosphate DMAP: 4-N, N-Dimethylaminopyridine BOP: Benzotriazol-l-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 EXAMPLES Synthesis of intermediaries Synthesis of ethyl ester 1a: 1 a Ethyl ester 1a was synthesized according to the procedure described by Monn and Valli (J. Org. Chem. 1994, 59, 2773-2778).

Synthesis of broker 1: Stage A 1a 1 b Sodium borohydride (924.5 mg) was added in small portions to a heterogeneous mixture of bicyclic ketone 1a in ethanol (50 ml) at 0 ° C. The reaction was stirred for 30 minutes, and TLC analysis (ethyl acetate / hexanes: 1: 1) showed that all the starting material had been consumed. The reaction was quenched by the addition of AcOH (3 mL). The mixture was diluted with 250 ml of ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate (2 x 50 ml) and brine (1 x 40 ml). The layer organic was dried over magnesium sulfate and filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide the product in 92% yield.

Stage B I b 1 c A solution of cyclopentanol 1b in 130 ml of dry tetrahydrofuran at 0 ° C was treated with 1.08 g of a 60% suspension of NaH. The cooling bath was removed and the resulting yellow solution was stirred for 30 minutes. Carbon disulfide (16.2 ml) was added and the reaction was stirred for 45 minutes. Then iodomethane (16.8 ml) was added dropwise and the mixture was stirred for an additional hour. The reaction was quenched by careful addition of a saturated solution of ammonium chloride (30 ml). The mixture was extracted with 80 ml of ether and the layers were separated. The aqueous layer was extracted again with ether (2 x 80 ml). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: hexane to 30% acetone in hexane) to give the xanthate product as a yellow oil in 63% yield.

A solution of xanthate 1c in 90 ml of toluene was degassed with dry nitrogen. AIBN (150.4 mg) and tri-n-butyl tin hydride (3.7 ml) were added. The reaction mixture was degassed again and stirred at 95 ° C for 1 h. Analysis of TLC (acetone / hexanes: 1: 9) showed that all the starting material had been consumed. All volatiles were removed under reduced pressure and the residue was dissolved in 250 ml of ether and washed with a saturated aqueous solution of potassium fluoride (2 x 30 ml). The organic layer was dried over magnesium sulfate and filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: hexane to 20% ethyl acetate in hexanes) to provide the product in 98% yield.

Stage D I d The starting material N-Cbz 1d (2.5 g) was dissolved in 80 ml of trifluoroacetic acid at 0 ° C followed by the addition of 20 ml of dimethyl sulfide. The reaction mixture was stirred at 0 ° C for 5 minutes and then the cooling bath. The reaction was stirred for a further 5 hours. All volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane (250 ml) and 1 N aqueous NaOH (50 ml). The aqueous layer was extracted again with dichloromethane (2 x 80 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. No further purification was carried out for the product (1.46 g, 97% yield).

Step E A solution of N-Boc-t-butyl leucine (1.46 g) in 80 ml of dry dichloromethane and 60 ml of dry dimethylformamide was stirred at 0 ° C and treated with HATU (3.26 g). Racemic amine 1e (1.42 g) in dichloromethane (10 ml) was added dropwise followed by addition of N-methylmorpholine (2.7 ml). The mixture was gradually warmed to room temperature and stirred overnight. All volatiles were removed under reduced pressure (high vacuum) and the residue was dissolved in 350 ml of ethyl ether. The organic layer was washed with aqueous 1N HCL (30 ml), saturated aqueous NaHCO3 (30 ml), water (30 ml), and brine (30 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: ether / hexanes: 1: 9 to 5: 5) to give the diastereomeric products 1f and 1g in 72% yield.

Stage F Lithium hydroxide monohydrate (79 mg) was added to a solution of 300 mg of ester 1f in 15 ml of a solution of tetrahydrofuran / water / methanol (1: 1: 1). The reaction was stirred at room temperature for about 3 hours until no more starting material was detected by TLC analysis (ether / hexanes: 4: 6). The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and 1 N aqueous HCl (20 ml). The aqueous layer was extracted again with dichloromethane (2 x 20 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. No purification was carried out for product 1 which was obtained as a white solid with a yield of 91%.

Synthesis of intermediary 2: 2a 2b A stirred solution of ketimine 2a (50 g, 187.1 mmol) under N 2 in dry THF (400 ml) was cooled to -78 ° C and treated with a 1 M solution of K-'BuO (220 ml, 1.15 equiv. .) in THF. The reaction mixture was warmed to 0 ° C and stirred for 1 hour and treated with bromomethylcyclobutane (28 ml, 249 mmol). The reaction mixture was stirred at room temperature for 48 hours and concentrated in vacuo. The residue was dissolved in Et2O (300 ml) and treated with aqueous HCl (2 M, 300 ml). The resulting solution was stirred at room temperature for 5 hours and extracted with Et2O (1 L). The aqueous layer was basified to pH -12-14 with NaOH (50% aq.) And extracted with CH2Cl2 (3x300 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give the pure amine (2b, 18 g) as a colorless oil.

Stage B 2b 2c A solution of the amine 2b (18 g, 105.2 mmol) at 0 ° C in CH 2 Cl 2 (350 mL) was treated with di-fer-butyldicarbonate (23 g, 105.4 mmol) and stirred at room temperature for 12 hours. After completion of the reaction (TLC), the reaction mixture was concentrated in vacuo and the residue was dissolved in THF / H 2 O (200 ml, 1: 1) and treated with L 2 OH »H 2 O (6.5 g, 158.5 mmol) and was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the basic aqueous layer was extracted with Et2O. The aqueous layer was acidified with conc. HCl. at pH ~ 1-2 and extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to provide 2c as a colorless viscous oil which was used for the next step without any further purification.

Stage C BocHN A solution of 2c acid (15.0 g, 62 mmol) in CH2Cl2 (250 ml) was treated with BOP reagent (41.1 g, 93 mmol), N-methyl morpholine (27 ml), N, O-dimethyl hydroxylamine hydrochloride (9.07). g, 93 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with 1 N aqueous HCl (250 ml), and the layers were separated and the aqueous layer was extracted with CH2Cl2 (3x300 ml). The combined organic layers were dried (MgSO), they were filtered and concentrated in vacuo and purified by chromatography (SiO2, EtOAc / Hex 2: 3) to give the amide 2d (15.0 g) as a colorless solid.

Stage D 2 2e A solution of 2d amide (15 g, 52.1 mmol) in dry THF (200 ml) was treated dropwise with a solution of L1AIH4 (1 M, 93 ml, 93 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for one hour and carefully quenched at 0 ° C with a solution of KHS04 (10% aq.) And stirred for 0.5 hour. The reaction mixture was diluted with aqueous HCl (1 M, 150 mL) and extracted with CH2Cl2 (3x200 mL). The combined organic layers were washed with aqueous HCl (1 M), saturated NaHCO3, brine, and dried (MgSO4). The mixture was filtered and concentrated in vacuo to provide 2e as a viscous colorless oil (14 g).

Stage E 2e 2f A solution of aldehyde 2e (14 g, 61.6 mmol) in CH 2 Cl 2 (50 mL) was 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 h. hours. The reaction mixture was concentrated in vacuo and diluted with aqueous HCl (1 M, 200 mL) and extracted into CH2Cl2 (3x200 mL). The combined organic layer was washed with H20, brine, and dried (MgSO4), filtered, and concentrated in vacuo and purified by chromatography (SiO, EtOAc / Hex 1: 4) to give 2f (10.3 g) as of a colorless liquid.

Stage F BocHN 2f 2a Methanol saturated with HCl *, prepared by bubbling HCl gas through CH3OH (700 ml) at 0 ° C, with cyanohydrin 2f was treated and heated to reflux for 24 hours. The reaction was concentrated in vacuo to provide 2 g, which was used in the next step without purification. * Alternatively, 6M HCl prepared by addition of AcCl to dry methanol may also be used.

Stage G ? a 2 A solution of 2g amine hydrochloride in CH2Cl2 (200 ml) was treated with Et3N (45.0 ml, 315 mmol) and Boc2O (45.7 g, 209 mmol) at -78 ° C. The reaction mixture was then stirred at room temperature overnight and diluted with HCl (2M, 200 ml) and extracted into CH2Cl2. The combined organic layer was dried (MgSO4) filtered, concentrated in vacuo and purified by chromatography (EtOAc / Hex 1: 4) to give the hydroxy ester 2h.

Stage H 2h 2i A solution of 2h methyl ester (3g, 10.5 mmol) in THF / H20 (1: 1) was treated with LiOH "H2O (645 mg, 15.75 mmol) and stirred at room temperature for 2 hours. The reaction mixture was acidified with Aqueous HCl (1 M, 15 ml) and concentrated in vacuo. The residue was dried under vacuum to provide 2i with a quantitative yield.

Stage I * 21 A solution of 2i acid (above) in CH2Cl2 (50 ml) and DMF (25 ml) was treated with NH4CI (2.94 g, 55.5 mmol), EDCI (3.15 g, 16.5 mmol), HOOBt (2.69 g, 16.5 mmol) ), and NMM (4.4 g, 44 mmol). The reaction mixture was stirred at room temperature for 3 days. The solvents were removed in vacuo and the residue was diluted with aqueous HCl (250 ml) and extracted with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3, dried (MgSO4), filtered, concentrated in vacuo to obtain 2j, which was used as such in the following steps. (Alternatively, 2j can also be obtained directly by the reaction of 2f (4.5 g, 17.7 mmol) with aqueous H 2 O 2 (10 ml), L 2 OH 2 (820 mg, 20.8 mmol) at 0 ° C in 50 ml of CH 3 OH during 0.5 hours).

Stage J 2J A solution of 2j obtained in the previous step was dissolved in 4N HCl in dioxane and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to provide intermediate 2 in the form of a solid, which was used without further purification.

Synthesis of intermediary 3: Stage A 3a 3b l-tert-Leucine (1 eq, 10 g) was slowly added to a suspension of lithium aluminum hydride (150 mmol, 1 M solution in THF). The reaction mixture was refluxed for 6 hours. The mixture was cooled to 0 ° C and quenched by the addition of 10 ml of 10% aqueous NaOH and 10 ml of water. The mixture was stirred at room temperature for 10 minutes and then treated with di-tert-butyl carbonate (1.1 eq, 18.22 g) and the mixture was stirred at 60 ° C overnight. The reaction mixture was dried through sulphate of magnesium. The filtrate was concentrated and the residue was chromatographed on silica gel to give the product 3b in 62% yield.

Stage B To a solution of phthalimide (1.01 g) in 50 ml of dry THF was added triphenylphosphine (3 eq) and alcohol 3b (1 eq). The mixture was cooled in an ice water bath and diisopropyl azodicarboxylate (2.5 eq) was added dropwise. The resulting mixture was stirred at 0 ° C for 10 minutes and warmed to room temperature and stirred for about 2.5 hours until no more starting material was detected by TLC (ethyl acetate / hexanes: 3: 7). The mixture was concentrated under reduced pressure. The residue was resuspended in 80 ml of dichloromethane. The solids were removed by filtration. The filtrate was concentrated to half its volume and hexanes (30 ml) were added. The solids were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel (gradient: ethyl acetate / hexanes: 1: 9 to 4: 6) to give product 3c.

Stage C The amine 3c protected with N-Boc (1.4 g) was dissolved in 20 ml of a 4M HCl solution in dioxane. The mixture was stirred for about 2 hours. All volatiles were removed in vacuo. No further purification was carried out for the 3d product.

Stage D A mixture of 3d amine hydrochloride (1.14 g) in 20 ml of dichloromethane and 20 ml of a saturated aqueous NaHCO 3 solution at 0 ° C was treated with phosgene (10 ml, 15% solution in toluene) and stirred for two hours. The reaction mixture was diluted with 100 ml of dichloromethane and washed with 30 ml of a cold saturated aqueous NaHCO3 solution. The organic layer was dried over magnesium sulfate, filtered, and further diluted with 10 ml of toluene. The mixture was concentrated and product 3 was kept in the form of a 0.2 M solution in toluene.

Summary of Intermediary 4: Stage A 4a + b To the amide 4a (0.5 g, 1 eq) in THF was added cyclopropylmagnesium bromide (4 eq, 7.68 mmol) at 0 ° C. The reaction was warmed to room temperature after 15 minutes and the reaction was stirred at room temperature for 5 hours and then quenched by the addition of 1 N HCl. The reaction was diluted with EtOAc and washed with brine. The organic layer was dried over MgSO 4, purified by column chromatography with 10% EtOAc in hexane to obtain 0.2 g of product 4b. Performance 43.1%.

Stage B 4 a - To the amine 4b protected with N-Boc (0.2 g) was added 4M HCl (in dioxane). The reaction was stirred at room temperature for 5 minutes, when TLC indicated that the reaction was complete. The mixture was concentrated to dryness to obtain 0.162 g of product 4c.

Stage C 4c To phosgene in CH2Cl2 (2 eq, 1.65 mmol), NaHCO3 (5 mL of a saturated aqueous solution) was added 4c at 0 ° C. The mixture was stirred at room temperature for 2.5 hours. It was separated by a funnel. The organic layer was dried over Na2SO (anhydrous). It was concentrated to half the volume with a cooling bath. It was diluted to 10 ml to obtain the desired isocyanate 4 in the form of a 0.083 M solution in dichloromethane.

Synthesis of Intermediary 5: Stage A 5b 5a - KHMDS (200 ml of a 0.5 M solution in toluene) was added dropwise to a stirred solution of methyl cyclohexanecarboxylate 5a (11.1 g, 78 mmole) in anhydrous THF (200 ml) at -78 C under nitrogen atmosphere. After the addition was complete, the reaction was maintained at room temperature for an additional 0.5 hours before the addition of benzyl chloromethyl ether (18.6 ml, 134 mmol). The reaction was allowed to warm to room temperature overnight and water (100 ml) was added. Aqueous work-up provided a residue which was purified by silica gel column chromatography using EtOAc; hexanes (1:10) as eluent to provide the desired, impure intermediate ether (14.98 g) as a colorless oil.

A black suspension of 10% Pd / C (0.5 g) and the aforementioned crude ether (4.1 g) in MeOH (80 ml) were exposed to a nitrogen atmosphere (balloon) at room temperature overnight. The reaction was filtered through a pad of celite and the solid was carefully heated with methanol. The 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 provide the primary alcohol (5b, 0.62 g), as a colorless oil.

Stage B 5b 5 c Methanesulfonyl chloride (0.31 ml) followed by triethylamine (0.75 ml) was added to a stirred solution of the primary alcohol (5b, 0.62 g) at 0 ° C, under nitrogen atmosphere. The resulting mixture was stirred at this temperature for 0.5 hours. The reaction mixture was extracted with EtOAc and washed with 1 M HCl, saturated aqueous NaHCO3, water, dried (MgSO4) and concentrated. The residue (mesylate 5c, 0.74 g) was obtained in the form of a yellow oil which was used in the following steps without purification.

Stage C 5d 5e Dimethylformamide (20 ml, anhydrous, Aldrich) was added to sodium hydride (0.56 g, Aldrich) and tert-butyl mercaptan was added to the suspension, while cooling in an ice bath under nitrogen atmosphere. After the addition was complete, mesylate (5c, prepared as above from 2.00 g of alcohol; 5b) was added and the resulting mixture was stirred overnight at room temperature. The reaction was partitioned between EtOAc and water and the organic phase was separated, dried (MgSO). Column chromatography on silica gel using EtOAc-Hexanes (2:98) provided the methyl ester-sulfide (5d, 1.75 g). EtOAc was added to the aqueous phase and 10% aqueous HCl was added until the water layer was pH = 1. The organic layer was separated, washed with water and dried and concentrated under reduced pressure to give the sulfide carboxylic acid (5e, 0.747 g) as a white solid.

Stage D 5e 5f To the sulfide (5e, 2287 g) in methanol (75 ml) was added an oxone solution (18.00 g, Aldrich) and the resulting white suspension was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the white solid was partitioned between EtOAc and water. The phase The organic was separated, dried, and concentrated to provide the sulfone (5f, 2.52 g, contains a little solvent).

Stage E Sf 5 A solution of 5f acid (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 reaction mixture was heated at 100 ° C for 2 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with dichloromethane (2 x 100 ml). The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO, filtered and concentrated under reduced pressure until approximately 20 ml of solvent remained. The solution of product 5 was adjusted to a concentration of 0.2 M isocyanate using toluene.

Synthesis of Intermediary 6: To a solution of phthalimide 3c (7 g) in 100 ml of MeOH was added hydrazine (0.9 ml, 28.68 mmol, 1.4 eq) and the mixture was brought to reflux (under N2) for 6 hours. TLC showed that a little of the starting material was present and more hydrazine (0.45 ml) was added and stirring was continued at room temperature overnight. A white precipitate formed. The solids were removed by filtration and the filtrate was concentrated to give product 6a (4.48 g) as a white solid.

Stage B A solution of the amine 6a (2.16 g, 10 mmol) in 100 ml of dichloromethane was cooled to 0 ° C and treated with triethylamine (2 eq, 2.8 ml). Methanesulfonyl chloride (1.2 eq, 0.93 ml) was added dropwise. The heterogeneous mixture was stirred overnight (temp 0 at 25 ° C). The solids were removed by filtration and the filtrate was washed with a saturated aqueous solution of ammonium chloride (100 ml), and brine (100 ml). The organic layer was dried on sodium sulfate, dried and concentrated. The residue was taken up in a minimum amount of dichloromethane / ethyl acetate (approximately 10 ml) and the insoluble white solid was removed by filtration. The filtrate was purified by column chromatography on silica gel to give the product 6b (2.7 g) as a thick semi-solid.

Stage C A solution of sulfonamide 6b (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 minutes. The cooling bath was removed and the mixture was stirred for a further 4 hours. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with water (200 ml), brine (200 ml) and dried over sodium sulfate. The organic layer was filtered and concentrated. The residue was chromatographed on silica gel to give the product 6c (2.16 g).

Stage D The protected amine was dissolved with N-Boc 6c (2.1 g, 6.82 mmol) in 20 ml of 4M HCl in dioxane at room temperature. The reaction mixture was stirred for one hour and then all the volatiles were removed under reduced pressure to give the product 6d in a quantitative yield.

Stage E A mixture of 6d amine hydrochloride in dichloromethane and a saturated aqueous solution of NaHCO 3 at 0 ° C was treated with phosgene (15% solution in toluene) and stirred for 2 hours. The reaction mixture was diluted with dichloromethane and washed with a cold, cold, saturated aqueous solution of NaHCO3. The organic layer was dried over magnesium sulfate, filtered and further diluted with toluene. The mixture was concentrated and product 6 was adjusted and maintained as a 0.2 M solution in toluene.

Summary of Intermediary 7: Isocyanate 7 was prepared according to the procedure described for isocyanate 6. 2-Thiophenesulfonyl chloride was used in place of methanesulfonyl chloride in the sulfonamide synthesis step.

Synthesis of broker 8: Stage A To a solution of 4-pentyl-1-ol, 8a (4.15g, Aldrich) Dess-Martin periodinana (30.25g, Aldrich) was added and the resulting mixture was stirred for 45 minutes before the addition of (ter- Butoxycarbonylmethylene) triphenylphosphorane (26.75 g, Aldrich). The resulting dark reaction was stirred overnight, diluted with ethyl acetate, washed with aqueous sodium sulfite, saturated aqueous sodium bicarbonate, water, brine and dried. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography using 1% ethyl acetate in hexane as eluent to provide the desired compound 8b (3.92g). Some impure fractions were also obtained, but at that time they were left aside.

Stage B Using alkene 8b (1.9 g) in / 7-propanol (20mL; 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) 2PHAL (0.423 g, Aldrich)) in n-propanol (37.5 ml), and potassium osmate: dehydrate (0.1544 g, Aldrich) and the procedure indicated in Angew . Chem. Int. Ed. Engl (1998), 35, (23/24), pp. 2813-7 a crude product was obtained which was purified by silica gel column chromatography using EtOAc: Hexanes (1: 5) to provide the desired amino alcohol 8c (1.37 g, 37%) as a white solid.

Stage C To ester 8c (0.700 g) was added 4M HCl in dioxane (20 mL; Aldrich) and the resulting mixture was allowed to stand at room temperature overnight. The volatiles were removed under reduced pressure to provide the acid 8d (0.621 g) as a white solid.

Stage D The reagent BOP (3.65 g, Sigma) followed by triethylamine (3.45 ml) was added to a solution of dichloromethane (20 ml) of the carboxylic acid 8d (2.00 g) and allyl amine (0.616 ml) at room temperature and the resulting mixture was it stirred during the night. The reaction mixture was partitioned between EtOAc and 10% aqueous HCl. The organic phase was separated, washed with saturated aqueous sodium bicarbonate, water, dried (magnesium sulfate). The crude reaction product was purified by silica gel column chromatography using (EtOAc: Hexanes; 70:30) as eluent to provide the desired amide 8e (1.73 g) as a viscous yellow oil.

Stage E A solution of N-Cbz amine 8e (85.8 mg) in 5 ml of a 4: 1 mixture of trifluoroacetic acid / methyl sulfide was stirred at room temperature for about 3 hours. All volatiles were removed under reduced pressure. The product 8 was placed under high vacuum for about 3 hours and used without further purification.

Synthesis of broker 9: Stage 1 or; 1a 9a To a solution of 1a (13.24 g, 40 mmol, prepared as described by Monn and Valli, J. Org. Chem., 1994, 59, 2773-2778) in THF (200 ml) was added zinc powder (21 g, 320 mmol), zirconiocene dichloride (14.04 g, 48 mmol) and finally dibromomethane (6.18 ml, 44 mmol) per drop. The reaction mixture was heated to reflux for 5 hours. Then it was cooled to room temperature and then to 0 ° C using a ice bath. Water was added by dripping (caution: exotherm) until the evolution of gas ceased. Diethyl ether (400 ml) was added and the mixture was cooled through a pad of celite. The filter cake was rinsed with ether (200 ml) and the combined filtrate was washed with water (2 x 500 ml), 1 N aqueous HCl (500 ml), water (500 ml), brine (500 ml), dried ( Na2SO4), filtered and concentrated. The crude material was purified by evaporative chromatography using 10/90 to 20/80 EtOAc / hexanes which afforded 6.82 g of 9a as a pale yellow oil.

Stage 2 9a 9 b Diethyl zinc (1 M in heptanes, 73 ml, 73 mmol) was added to dichloromethane (100 ml) at 0 ° C under nitrogen atmosphere. Trifluoroacetic acid (5.6 ml, 73 mmol) was added dropwise over 30 minutes. The temperature was maintained for an additional 15-20 minutes. Diyodomethane (5.9 ml, 73 mmol) was then added dropwise over 20 minutes and the temperature was maintained for an additional 15-20 minutes. Finally, a solution of 9a (4.8 g, 14.6 mmol) in dichloromethane (20 ml) was added dropwise. The reaction mixture was heated at room temperature for 16 hours. The reaction mixture was cooled to 0 ° C and quenched by addition of a saturated solution of ammonium chloride (200 ml). The aqueous layer was separated and extracted with dichloromethane (125 ml). The combined organic layer was washed with saturated sodium bicarbonate, brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by evaporative chromatography using 15/85 EtOAc / hexanes which yielded 2.89 g of 9b.

Stage 3 9b 9 To a well stirred solution of 9b (2.41 g, 7.03 mmol) in ethanol (100 ml) was added 4M HCl in dioxane (2 ml) and a catalytic amount of 10% palladium on carbon. The mixture was hydrogenated using a balloon filled with hydrogen gas at room temperature for 5 hours. At this time another portion of the catalyst was added and the mixture was hydrogenated for 16 hours. The reaction was stopped, filtered through a pad of celite, rinsed with ethanol, and the filtrate was concentrated to give 1.74 g of 9, which was used without further purification.

Synthesis of the intermediary 10 9b 10 Compound 9b will be converted to the required material 10 using the above hydrogenation procedure (Step 3) using platinum (IV) oxide instead of 10% palladium on carbon.

Synthesis of : eleven Stage A A solution of 4.4-dimethylglutarimide 11a (1.5 eq, 4.86 g, Aldrich) in 200 ml of dry THF, cooled to 0 ° C and treated with triphenylphosphine (3 eq, 18.07 g) and S-Boc-tert-butylglycinol 11b (5 g, Aldrich). Diisopropyl azodicarboxylate (2.5 eq, 11.3 ml, d 1.027) was added dropwise and the solution The resulting mixture was stirred at 0 ° C. After 10 minutes, the mixture became a suspension and stirring was continued overnight (0 to 25 ° C). The mixture was concentrated under reduced pressure and the residue was dissolved in 80 ml of ether. Hexanes (100 ml) were added and the precipitated solids were removed by filtration. The filtrate was concentrated to half its volume and hexanes (100 ml) were added again. The solids were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel (ethyl acetate / hexanes: 2: 8) to give the product 11c (4.0 g, 51%) as a white solid.

The protected N-Boc 11c amine (3 g) was dissolved in 50 ml of a 4M HCl solution in dioxanes. The reaction mixture was stirred for about 1 hour until all of the starting material was consumed as determined by TLC analysis (ethyl acetate / hexanes, 2: 8). All volatiles were removed under reduced pressure to provide product 11d (2.4 g, 98%) as a white solid.

A solution of amine hydrochloride 11d (1.0 g) in 40 ml of dichloromethane was treated with 40 ml of a saturated aqueous solution of sodium bicarbonate and stirred vigorously for 10 minutes at 0 ° C. Stirring was interrupted and the layers were allowed to separate. Phosgene (10 ml) of a 20% solution in toluene) was added through a needle to the organic layer (lower layer) in one portion. The mixture was stirred vigorously immediately after the addition, for 10 minutes at 0 ° C and further stirred at room temperature for 2.5 hours. The mixture was diluted with 100 ml of dilichloromethane and the layers were separated. The organic layer was washed with 30 ml of a cold saturated aqueous solution of sodium bicarbonate and dried over magnesium sulfate. The organic layer was filtered and the filtrate was diluted with 50 ml of toluene. The resulting solution was concentrated and the product 11e remained in the form of a 0.241M solution.

Stage D A solution of acid 1 (2.19 g) in 40 ml of dry DMF was cooled to 0 ° C and treated with cesium carbonate (1.2 eq, 1.22 g) followed by addition of benzyl bromide (1.2 eq, 0.85 ml, d). 1.438). The reaction mixture was stirred for 24 hours (temperature: 0 to 25 ° C). The mixture was diluted with ethyl acetate (350 ml) and washed with water (3 x 50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: hexane to ethyl acetate / hexane 25:75) to provide the product 11f (2.1 g, 77%) as a clear oil.

Stage E The 11-protected amine with N-Boc (2.1 g) was dissolved in 50 ml of a 4M HCl solution in dioxane. The resulting solution was stirred at room temperature until all the starting material was consumed as determined by TLC analysis (ethyl acetate / hexane: 25:75). After 1 hour, all volatiles were removed under reduced pressure to provide the product 11g (1.8 g, 98%) as a white solid.

Stage F A solution of 11g amine hydrochloride in 10 ml of dry dichloromethane was treated with N-methylmorpholine (2.5 eq, 0.7 ml, d 0.920) at 0 ° C. The resulting solution was stirred for 5 minutes followed by addition of isocyanate 11e (1.3 eq, 13.6 ml of a 0.241 M solution in toluene). The reaction mixture was stirred for 5 minutes and the cooling bath was removed. The mixture was further stirred for 2 hours. The mixture was partitioned between dichloromethane (200 ml) and 1 M aqueous HCl (50 ml). The layers were separated and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate (50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 5:95 to 35:65) to give the product 11h (1.33 g, 84%) as a white solid.

Stage G The benzyl ester 11h (1.3 g) was dissolved in 30 ml of ethyl acetate and treated with 20% palladium hydroxide on carbon (0.1% moles, 145 mg). The heterogeneous mixture was hydrogenated at 345 kPa (3.515 kgf / cm2) for 2 hours. The mixture was diluted with 200 ml of dichloromethane and filtered through a short passage of celite. The filtrate was concentrated under reduced pressure to provide the product.11 (1.1 g, 98%) as a white solid.

Synthesis of: Stage A A solution of the acid 12a (2 g) in 100 ml of dry dichloromethane and 5 ml of DMF was treated with N, O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP reagent (1.1 eq, 4.47 g), and N -methylmorpholine (3.3 eq, 3.3 ml, d 0.920) in that order. The mixture was heated at 50 ° C overnight. The reaction mixture was heated to half its volume and diluted with 400 ml of ethyl acetate the organic layer was washed with water (80 ml), HCl aqueous 1 M (80 ml), saturated aqueous sodium bicarbonate solution (80 ml), and brine (80 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 5:95 to 3: 7) to give the product 12b as a clear oil.

Stage B A solution of the amide 12b (2.2 g) in 100 ml of dry THF was cooled to 0 ° C. A solution of lithium aluminum hydride (1.3 eq) was added dropwise. The cooling bath was removed after 5 minutes and the mixture was allowed to come to room temperature. Analysis of TLC (ethyl acetate / hexane: 2: 8) showed that all the starting material had been consumed. The excess LAH was carefully quenched by the addition of a few drops of saturated aqueous sodium hydrogen sulfate. The mixture was diluted with 200 ml of ether and saturated aqueous sodium sulfate was added in small portions until a white solid precipitated. The mixture was filtered through ceiite and the filtrate was washed with 50 ml of brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient: ethyl acetate / hexanes: 5:95 to 4: 6) to give the product 12c which is an aldehyde as a colorless oil.

Stage C A solution of the aldheido 12c (1.8 g) in 100 ml of dry dichloromethane was treated with isonitrile (1.1 eq, 680 mg) and acetic acid (2 eq, 1.02 ml, d 1.0149). The mixture was stirred overnight. All volatiles were removed in vacuo, and the residue was chromatographed on silica gel (gradient: ethyl acetate / hexane; 2: 8 to 6: 4) to give the product 12d as a white solid.

Stage D A solution of 12d acetate (1.6 g) in 60 ml of a 1: 1: 1 mixture of THF / MeOH / water was treated with lithium hydroxide monohydrate and stirred for about 1 hour until all the starting as determined by the TLC analysis (ethyl acetate / hexanes: 1: 1). The volatiles were extracted on the rotaevaporator and the residue was diluted with dichloromethane (150 ml). The layers separated and the The aqueous layer was diluted with 30 ml of a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane (3 x 80 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the product 12e as a white solid.

Stage E The N-Boc-protected amine 12e (1.5 g) was dissolved in 20 ml of 4M HCl in dioxane. The reaction mixture was stirred for about 1 hour until all the starting material was consumed.

All volatiles were removed in vacuo to provide the product 12 as a white solid.

Synthesis of: Amine hydrochloride 13 will be prepared following the synthesis route described for the preparation of amine hydrochloride 12. Commercially available N-Boc-D, L-norvaline will be used as the starting material and allyl isocyanide will be used in place of isopropyl isocyanide to form the corresponding allylamide.

Synthesis of: Amine hydrochloride 14 will be prepared following the synthesis route described for the preparation of amine hydrochloride 12. Commercially available N-Boc-D, L-norleucine will be used as the starting material and allyl isocyanide will be used instead of isocyanide of cyclopropyl to form the corresponding allylamide.

Synthesis of: The amine hydrochloride 15 will be prepared following the synthesis route described for the preparation of amine hydrochloride 12. Commercially available N-Boc-beta-cyclopropyl-D, L-alanine will be used as the starting material and allyl isocyanide will be used instead of cyclopropyl isocyanide to form the corresponding allylamide.

Synthesis of inhibitors PREPARED EXAMPLE A Stage 1 A solution of acid 1 (255 mg) in 5 ml of dry dichloromethane and 5 ml of dry DMF was stirred at 0 ° C and treated with HATU (368 mg). Amine hydrochloride 2 (201 mg) was added followed by addition of N-methylmorpholine (0.42 ml). The reaction mixture was gradually warmed to room temperature and stirred overnight. All volatiles were removed in vacuo and the residue was taken up in 100 ml of ethyl acetate, the organic layer was washed with aqueous 1 N HCl (15 ml), saturated aqueous NaHCO3 (15 ml), water (15 ml), brine (15 ml), dried over MgSO, filtered, and concentrated under reduced pressure to provide the desired product A1. No further purification was carried out for the product.

A solution of A1 (360 mg) in 20 ml of a 1: 1 mixture of toluene / DMSO was treated with EDCI (1.3 g) and dichloroacetic acid (0.42 ml, d 1.563). The reaction mixture was stirred at room temperature for about 3 hours. The reaction mixture was stirred at room temperature for about 3 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with saturated aqueous NaHCO3 (15 ml), aqueous 1N HCl (15 ml), and brine (15 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 2: 8 to 5: 5) to give the product A2 in a yield of 84%.

Stage 3 The A2 amine Protected with N-Boc was treated with 10 ml of formic acid. The resulting solution was stirred for 2 hours. All volatiles were removed under reduced pressure. No further purification was carried out for the A3 product.

Stage 4 To a solution of the amine salt A3 in 1 ml of dry methylene chloride was added N-methylmorpholine (0.037 ml, d 0.920). The resulting solution was cooled in an ice water bath and a solution of isocyanate in toluene (2.5 ml of a 0.135 M solution) was slowly added. The mixture was stirred for two hours (temperature 0 to 25 ° C). The reaction mixture was diluted with 60 ml of dichloromethane and washed with 15 ml of 1 N aqueous HCl. The aqueous layer was extracted again with dichloromethane (2 x 20 ml). They dried up the combined organic layers over magnesium sulfate were filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexanes; 1: 9 to 6: 4) to give product A (15 mg) as a white solid in 20% yield. HRMS (FAB) calculated for C 37 H 53 N 6 O 7 [M + H] 693.3976; found 693.3987.

PREPARED EXAMPLE B B Stage 1 To a solution of the amine salt A3 in 1 ml of dry methylene chloride was added N-methylmorpholine (0.037 ml, d 0.920). The resulting solution was cooled in an ice water bath and a solution of isocyanate 4 in toluene (0.64 ml of a 0.538 M solution) was slowly added. The mixture was stirred for two hours (temperature 0 to 25 ° C). The reaction mixture was diluted with 60 ml of dichloromethane and washed with 15 ml of 1 N aqueous HCl. The aqueous layer was extracted again with dichloromethane (2 x 20 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 1: 9 to 6: 4) to give product B (14.6 mg) as a white solid in 22% yield. HRMS (FAB) calculated for C3? H5oN5O6 [M + H] 588.3761; found 588.3757.

PREPARED EXAMPLE C Stage 1 To a solution of the amine salt A3 in 1 ml of dry methylene chloride was added N-methylmorpholine (0.037 ml, d 0.920). The resulting solution was cooled in an ice water bath and a solution of isocyanate 5 in toluene (1.4 ml of a 0.250 M solution) was slowly added. The mixture was stirred for two hours (temperature 0 to 25 ° C). The reaction mixture was diluted with 60 ml of dichloromethane and washed with 15 ml of 1 N aqueous HCl. The aqueous layer was extracted again with dichloromethane (2 x 20 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 1: 9 to 6: 4) to give product C (9.7 mg) as a white solid in 13% yield. HRMS (FAB) calculated for C34H58N5O7S [M + H] 680.4057; found 680.4066.

PREPARED EXAMPLE D Stage 1 To a solution of the A3 amine in 1 ml of dry methylene chloride was added N-methylmorpholine (0.037 ml., d 0.920). The resulting solution was cooled in an ice water bath and a solution of isocyanate 6 in toluene (1.0 ml of a 0.340 M solution) was slowly added. The mixture was stirred for two hours (temperature 0 to 25 ° C). The reaction mixture was diluted with 60 ml of dichloromethane and washed with 15 ml of 1 N aqueous HCl. The aqueous layer was extracted again with dichloromethane (2 x 20 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 1: 9 to 6: 4) to give product D (23 mg) as a white solid in 32% yield. HRMS (FAB) calculated for C 31 H 55 N 6 O 7 S [M + H] 655.3853; found 655.3870.

PREPARED EXAMPLE E Stage 1 To a solution of the amine A3 in 1 ml of dry methylene chloride was added N-methylmorpholine (0.037 ml, d 0.920). The resulting solution it was cooled in a bath of ice water and a solution of isocyanate 7 in toluene (1.4 ml of a 0.250 M solution) was slowly added. The mixture was stirred for two hours (temperature 0 to 25 ° C). The reaction mixture was diluted with 60 ml of dichloromethane and washed with 15 ml of 1N aqueous HCl. The aqueous layer was extracted again with dichloromethane (2 x 20 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 1: 9 to 6: 4) to give product D (11.5 mg) as a white solid in 14% yield. HRMS (FAB) calculated for C34H55N6O7S2 [M + H] 723.3574; found 723.3568.

PREPARED EXAMPLE F Stage 1 A solution of acid 1 (280 mg) in 10 ml of dry dichloromethane and 10 ml of dry DMF was stirred at 0 ° C and treated with HATU (1.4 eq, 405 mg). Amine salt 8 (1.3 eq, 569 mg) in dichloromethane was added. Then N-methylmorpholine (4 eq, 0.33 ml, d 0.920) was added. The reaction mixture was stirred at -20 ° C for 48 hours. All volatiles were removed in vacuo and the residue was dissolved in 200 ml of ethyl acetate. The organic layer was washed with water (30 ml), 1 N aqueous HCl (30 ml), saturated aqueous sodium bicarbonate (30 ml), and brine (30 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum pressure. The product F1 was used without further purification.

Stage 2 A solution of hydroxyamide F1 (415 mg) in 20 ml of dry dichloromethane was treated with Dess-Martin periodinnan (3 eq, 966 mg). The reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was treated with an aqueous solution of 1 M sodium thiosulfate (15 ml) and saturated aqueous sodium bicarbonate (15 ml) and stirred for 15 minutes. The mixture was extracted with dichloromethane (3 x 50 ml). The combined organic layers were dried over magnesium sulfate, filtered and they concentrated. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 1: 9 to 4: 6) to give product F2 as a colorless oil.

Stage 3 The protected amine was dissolved with N-Boc F2 (155 mg) in 5 ml of 4M HCl in dioxane at room temperature. The mixture was stirred until all the starting material was consumed as determined by TLC analysis (acetone / hexanes: 3: 7). After 45 minutes, all volatiles were removed in vacuo to obtain product F3 as a white solid which was used without further purification.

Stage 4 Solution of amine hydrochloride F3 (67 mg) in 2 ml of dry dichloromethane was treated with N-methylmorpholine (3.7 eq, 0.06 ml, d 0.920) and cooled to 0 ° C. The isocyanate was added dropwise (0.75 ml of a 0.2 solution) M in toluene) and the mixture was stirred overnight (temperature 0 to 25 ° C). The reaction mixture was diluted with 50 ml of dichloromethane and washed with 15 ml of 1 N aqueous HCl and 15 ml of a saturated solution of sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 1: 9 to 4: 6) to give the product F as a white solid. HRMS (FAB) calculated for C 36 H 58 N 5 O 7 S [M + H] 704.4057; found 704.4071.

PREPARED EXAMPLE G Stage 1 A solution of acid 11 (60 mg) in 2 ml of dry dichloromethane and 1 ml of dry DMF was stirred at 0 ° C and treated with HATU (1.4 eq, 60 mg).

Amine salt 12 (1.2 eq, 30 mg) was added followed by N-methylmorpholine (4 eq, 0.55 ml, d 0.920). The reaction mixture was stirred overnight (temp 0 to 25 ° C). All volatiles were removed in vacuo and the residue was dissolved in 50 ml of ethyl acetate. The organic layer was washed with water (20 ml), 1 M aqueous HCl (10 ml), saturated aqueous sodium bicarbonate solution (10 ml), and brine (30 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product G1 was used without further purification.

Stage 2 A solution of hydroxyamide G1 (0.112 mg) in 10 ml of dry dichloromethane was treated with Dess-Martin periodinnan (2.0 eq, 95 mg). The reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was treated with an aqueous solution of 1 M sodium thiosulfate (10 ml) and stirred for 5 minutes. A saturated aqueous solution of sodium bicarbonate (20 ml) was also added and stirring was continued for a further 10 minutes. The mixture was extracted with dichloromethane (3 x 30 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient: acetone / hexanes; 1: 9 to 4: 6) to provide product G (63 mg, 80%) as a white solid. HRMS (FAB) calculated for C 37 H 61 N 6 O 7 [M + H] 701.4601; found 701.4614.

PREPARED EXAMPLE H Stage 1 A solution of acid 11 (60 mg) in 2 ml of dry dichloromethane and 1 ml of dry DMF was stirred at 0 ° C and treated with HATU (1.4 eq, 60 mg). Amine salt 13 (1.2 eq, 30 mg) was added followed by N-methylmorpholine (4 eq, 0.05 ml, d 0.920). The reaction mixture was stirred overnight (temp 0 to 25 ° C). All volatiles were removed in vacuo and the residue was dissolved in 50 ml of ethyl acetate. The organic layer was washed with water (20 ml), HCl aqueous 1 M (10 ml), saturated aqueous sodium bicarbonate solution (10 ml), and brine (30 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product H1 was used without further purification.

Stage 2 A solution of hydroxyamide H1 (0.112 mg) in 10 ml of dry dichloromethane was treated with Dess-Martin periodinnan (2.0 eq, 95 mg). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was treated with an aqueous solution of 1 M sodium thiosulfate (10 ml) and stirred for 5 minutes. A saturated aqueous solution of sodium bicarbonate (20 ml) was also added and stirring was continued for a further 10 minutes. The mixture was extracted with dichloromethane (3 x 30 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 1: 9 to 45:55) to give the product H (64 mg, 82%) as a white solid. HRMS (FAB) calculated for C 37 H 6 N N 6 O 7 [M + H] 701.4601; found 701.4607.

PREPARED EXAMPLE I Stage 1 Ax A solution of acid 11 (60 mg) in 2 ml of dry dichloromethane and 1 ml of dry DMF was stirred at 0 ° C and treated with HATU (1.4 eq, 60 mg). Amine salt 14 (1.2 eq, 32 mg) was added followed by N-methylmorpholine (4 eq, 0.05 ml, d 0.920). The reaction mixture was stirred overnight (temp 0 to 25 ° C). All volatiles were removed in vacuo and the residue was dissolved in 50 ml of ethyl acetate. The organic layer was washed with water (20 ml), 1 M aqueous HCl (10 ml), saturated aqueous sodium bicarbonate solution (10 ml), and brine (10 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product 11 was used without further purification.

Stage 2 A solution of hydroxyamide 11 (0.112 mg) in 10 ml of dry dichloromethane was treated with Dess-Martin periodinnan (2.0 eq, 95 mg). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was treated with an aqueous solution of 1 M sodium thiosulfate (10 ml) and stirred for 5 minutes. A saturated aqueous solution of sodium bicarbonate (20 ml) was also added and stirring was continued for a further 10 minutes. The mixture was extracted with dichloromethane (3 x 30 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient: acetone / hexanes; 1: 9 to 45:55) to provide product I (64 mg, 80%) as a white solid.

PREPARED EXAMPLE J Stage 1 A solution of acid 11 (60 mg) in 2 ml of dry dichloromethane and 1 ml of dry DMF was stirred at 0 ° C and treated with HATU (1.4 eq, 60 mg). Amine salt 15 (1.2 eq, 31 mg) was added followed by N-methylmorpholine (4 eq, 0.05 ml, d 0.920). The reaction mixture was stirred overnight (temp 0 to 25 ° C). All volatiles were removed in vacuo and the residue was dissolved in 50 ml of ethyl acetate. The organic layer was washed with water (20 ml), with 1 M aqueous HCi (10 ml), with a saturated aqueous solution of sodium bicarbonate (10 ml), and brine (10 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product J1 was used without further purification.

Stage 2 A solution of hydroxyamide J1 (0.112 mg) in 10 ml of dry dichloromethane was treated with Dess-Martin periodinnan (2.0 eq, 95 mg). The The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was treated with an aqueous solution of 1 M sodium thiosulfate (10 ml) and stirred for 5 minutes. A saturated aqueous solution of sodium bicarbonate (20 ml) was also added and stirring was continued for a further 10 minutes. The mixture was extracted with dichloromethane (3 x 30 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient: acetone / hexanes: 1: 9 to 45:55) to give product J (57 mg, 71%) as a white solid. HRMS (FAB) calculated for C 38 H 6 N N 6 O 7 [M + H] 713.4601; found 713.4607. The present invention relates to novel HCV protease inhibitors. This utility may be manifested by its ability to inhibit HCV NS3 / NS4a serine protease. A general procedure for such demonstration is illustrated by the following in vitro assay.

Assay for the HCV Protease Inhibitory Activity: Spectrophotometric Assay: The spectrophotometric assay for serine protease HCV can be carried out in the compounds of the invention by the following procedure described by R. Zhang et al, Analytical Biochemistry, 270 (1999) 268 -275, whose description is hereby incorporated by reference. The assay based on the proteolysis of chromogenic ester substrates is appropriate for continuous monitoring of the HCV NS3 protease activity. The substrates are derived from the P side of the binding sequence NS5A-NS5B (Ac-DTEDVVX (Nva), where X = A or P) whose C-terminal carboxyl groups are esterified with from 1 to 4 different chromophoric alcohols (3- or 4) -nitrophenol, 7-hydroxy-4-methyl-coumarin, or 4-phenylazophenol). The synthesis, characterization and application of these new spectrophotometric ester substrates in a yield screening, and a detailed kinetic evaluation of HCV NS3 protease inhibitors are illustrated below.

Materials and Methods: Materials: Chemical reagents for the related pH regulator test were obtained from Sigma Chemical Company (St. Louis, Missouri). Reagents for peptide synthesis were from Aldrich Chemicals, Novabiochem (San Diego, California), Applied Biosystems (Foster City, California) and Perceptive Biosystems (Framingham, Massachusetts). The peptides were synthesized manually or with an automatic ABI model 431 A synthesizer (Applied Biosystems). The UV / VIS spectrometer model LAMBDA 12 was from Perkin Elmer (Norwalk, Connecticut) and the 96-well plates were obtained from Corning (Corning, New York). The pre-heating block can be from USA Scientific (Ocala, Florida) and the vortex device of the 96-well plate is from Labline Instruments (Melrose Park, Illinois). A microtiter plate reader with Spectramax Plus monocrometer is obtained from Molecular Devices (Sunnyvale, California). Enzyme preparation: HCV NS3 / NS4A recombinant heterodimeric protease (strain 1a) was prepared by using previously published procedures (D. L. Sali ef al, Biochemistry, 37 (1998) 3392-3401). Protein concentrations were determined by the Biorad staining method using the recombinant HCV protease standards previously quantified by amino acid analysis. Before starting the assay, the enzyme storage pH regulator (50 mM sodium phosphate at pH 8.0, 300 mM NaCl, 10% glyceroi, 0.05% lauryl maltoside and 10 mM DTT) were exchanged by the regulator of assay pH (25 mM MOPS at pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside, 5 μM EDTA and 5 μM DTT) using a pre-filled Biorad Bio-Spin P-6 column . Synthesis and Substrate Purification: the synthesis of the substrates was carried out as indicated by Zhang et al, (ibid.) And started by fixing Fmoc-Nva-OH to 2-chlorotryril chloride resin using a conventional protocol (K Barios et al, Int. J. Pept. Protein Res., 37 (1991), 513-520). Subsequently the peptides were assembled, using Fmoc chemistry, either manually or with an automatic ABI peptide synthesizer model 431. The completely protected and N-acetylated peptide fragments were dissociated from the resin with 10% acetic acid (HOAc) and 10% trifluoroethanol (TFE) in dichloromethane (DCM) for 30 minutes, or with 2% trifluoroacetic acid (TFA) in DCM for 10 min. The combined filtrate and washing of DCM were either azeotropically evaporated or repeatedly extracted by an aqueous solution of Na 2 C 3) to remove the acid used in the dissociation. The DCM phase was dried over Na 2 SO 4 and evaporated. The ester substrates were pooled using conventional acid-alcohol coupling procedures (K. Holmber et al, Acta Chem. Scand., B33 (1979) 410-412). The peptide fragments were dissolved in anhydrous pyridine (30-60 mg / ml) to which 10 molar equivalents of chromophore and a catalytic amount of (0.1 eq.) Of para-toluenesulfonic acid (pTSA) were added. Dicyclohexylcarbodiimide (DCC, 3 eq.) Was added to initiate the coupling reactions. The formation of the product was monitored by HPLC and found to be complete after 12-72 hours of reaction at room temperature. The pyridine solvent was evaporated in vacuo and further extracted by azeotropic evaporation with toluene. The peptide was deprotected with 95% TFA in DCM for two hours and extracted three times with anhydrous ethyl ether to remove excess chromophore. The deprotected substrate was purified by reverse phase HPLC on a C3 or C8 column with a gradient of 30% to 60% acetonitrile (using six column volumes). The overall yield after purification by HPLC can be about 20-30%. The molecular mass can be confirmed by mass spectroscopy by ionization of electrospray The substrates were stored in the form of dry powders by drying. Spectra of substrates and products: Substrate spectra and corresponding chromophore products are obtained in the pH 6.5 assay regulator. The extinction coefficients were determined at the optimum off-peak wavelength 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 optimum off-peak wavelength is defined as the wavelength that provides the maximum fractional difference of absorbance between the substrate and the product (Product OD - OD substrate) / OD substrate). Protease Assay: HCV protease assays were carried out at 30 ° C using a 200 μl reaction mixture in a 96-well microtiter plate. The test pH regulator conditions (25 mM MOPS pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside, 5 μM EDTA and 5 μM DTT) were optimized for the NS3 / NS4A heterodimer (DL Sali et al, ibid.)). Typically, blends of 150 μl of pH, substrate and inhibitor buffer (final DMSO concentration <4% v / v) were placed in the wells and allowed to pre-incubate at 30 ° C for about 3 minutes. Then 50 μl of preheated protease (12 nM, 30 ° C) was used in the assay pH regulator, to start the reaction (final volume 200 μl). Plates were monitored throughout the entire assay period (60 minutes) to determine the change in absorbance at the appropriate wavelength (340 nm for 3-Np and HMC, 370 nm for PAP, and 400 nm for 4-Np) using a Spectromax Plus microtitre plate reader equipped with a monochrometer (acceptable results can be obtained with plate readers using cut-off filters). The proteolytic cleavage of the ester bond in Nva and the chromophore were monitored at the appropriate wavelength against a non-enzymatic target as a control for non-enzymatic hydrolysis. The evaluation of the kinetic parameters of the substrate was carried out in a substrate concentration range of 30 times (-6-200 μM). The initial velocities were determined using linear regression, and the kinetic constants were obtained by fitting the data to the Michaelis-Menten equation using non-linear regression analysis (Mac Curve Fit 1.1, K. Raner). The change numbers (/ (cat) were calculated assuming that the enzyme is fully active.

Evaluation of inhibitors and inactivators: The inhibition constants (K) for the competitive inhibitors Ac-D- (D-Gla) -Ll- (Cha) -C-OH (27), Ac-DTEDWA (Nva) -OH and Ac-DTEDWP (Nva) -OH were determined experimentally in fixed concentrations of enzyme and substrate, plotting v <; v. vs. inhibitor concentration ([I] o) according to the Michaelis-Menten rearrangement equation for the competitive inhibition kinetics: v0 / v¡ = 1 + [I] o / (Kj (1 + [S] 0 / Km )), where v0 is the initial non-inhibited velocity, v i is the initial velocity in the presence of an inhibitor at any given inhibitor concentration, ([l] o) and [S] o is the substrate concentration used. The resulting data was adjusted using linear regression and the resulting slope, 1 / (Kj (1+ [S] o / m), was used to calculate the value of K. The Ki * values obtained (in nanoMolar) for some of the compounds of the invention are shown below in Table 2.

TABLE 2 Table 2A lists additional compounds of the invention and their activities. TABLE 2A Ki scale * indicated A < 75 nM; 75 < B < 250 nM; C > 250 nM.

While the present invention has been described in conjunction with the specific embodiments set forth above, such alternatives, modifications and other variations thereof will be apparent to those skilled in the art. All said alternatives, modifications and variations fall within the spirit and scope of the invention.

Claims (34)

NOVELTY OF THE INVENTION CLAIMS

1. A compound, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates of said compound, or a pharmaceutically acceptable salt, solvate or ester of said compound, wherein said compound has the general structure shown in Structural Formula 1: Formula 1 wherein: R1 is H, OR8, NR9R10, or CHR9R10, where R8, R9 and R10 may be the same or different, and each is independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-, aryl -, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, and heteroarylalkyl, or alternatively R9 and R10 in NR9R10 are connected together so that NR9R10 forms a heterocyclyl of four to eight members, and likewise, independently, alternatively R9 and R10 in CHR9R10 are connected together so that CHR9R10 forms a cycloalkyl of four to eight members; R2 and R3 may be the same or different, and each is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl or arylalkyl, heteroaryl, and heteroarylalkyl; And it is selected from the following portions: wherein G is NH or O; and R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 may be the same or different, and each is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl , heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; or alternatively, (i) R17 and R18 they are independently connected to each other to form a cycloalkyl or heterocyclyl of three to eight members; (ii) likewise, independently R15 and R19 are connected together to form a heterocyclyl of four to eight members; (iii) likewise independently R15 and R16 are connected to each other to form a heterocyclyl of four to eight members; (iv) likewise independently R15 and R20 are connected to each other to form a heterocyclyl of four to eight members; (v) likewise independently R22 and R23 are connected together to form a cycloalkyl of three to eight members or a heterocyclyl of four to eight members; and (vi) likewise independently R24 and R25 are connected together to form a cycloalkyl of three to eight members or a heterocyclyl of four to eight members; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl can be unsubstituted or can be independently optionally substituted with one or more portions 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.

2. The compound according to claim 1, further characterized in that R1 is NR9R10, and R9 is H, R10 is H, or R14 where R14 is H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl or heteroaryl-alkyl.

3. The compound according to claim 2, further characterized in that R14 is selected from the group consisting of:

4. The compound according to claim 1, further characterized in that R2 is selected from the group consisting of the following portions:

5. The compound according to claim 1, further characterized in that R3 is selected from the group consisting of: wherein R 31 is OH or O-alkyl; and R32 is H, C (O) CH3, C (0) OtBu or C (O) N (H) tBu.

6. The compound according to claim 5, further characterized in that R3 is selected from the group consisting of the following portions:

7. The compound according to claim 1, further characterized in that G is NH.

8. The compound according to claim 7, further characterized in that Y is selected from the following portions: R16 or R15 R16? 15 R 6 M R1A OR Rlß R 'A R17 18- - Y or R Y Y8 - «Y ° R17 R - O R17 R R YY R? X8' r wherein R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each independently selected from the group consisting of: H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl , heterocyclyl, aryl or arylalkyl, heteroaryl, and heteroarylalkyl; or alternatively, (i) R17 and R18 are independently connected to each other to form a cycloalkyl or heterocyclyl of three to eight members; (ii) likewise, independently R15 and R19 are connected together to form a heterocyclyl of four to eight members; (iii) likewise independently R15 and R16 are connected to each other to form a heterocyclyl of four to eight members; and (iv) likewise independently R15 and R20 are connected to each other to form a four to eight member heterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl can be unsubstituted or can be independently optionally substituted with one or more portions 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.

9. - The compound according to claim 8, further characterized in that the portion: It is selected from the following: in which Y32 is selected from the group consisting of ::

10. The compound according to claim 8, further characterized in that Y is selected from:

11. The compound according to claim 1, further characterized in that the portion: It is selected from the following structures:

12. The compound according to claim 1, further characterized in that R 'is NHR14, wherein R14 is selected from the group consisting of: ! -0H, • OMe, OMe OH 1-3 1-3 R2 is selected from the group consisting of the following portions: R is selected from the group consisting of the following portions: . Serving: is selected from and Y is selected from:

13. A pharmaceutical composition comprising as an active ingredient at least one compound according to claim 1.

14. The pharmaceutical composition according to claim 13, for use in the treatment of disorders associated with HCV.

15. The pharmaceutical composition according to claim 14, further characterized in that it additionally comprises at least one pharmaceutically acceptable carrier.

16. The pharmaceutical composition according to claim 15, further characterized in that it additionally comprises at least one antiviral agent.

17. The pharmaceutical composition according to claim 16, further characterized in that it additionally contains at least one interferon.

18. The pharmaceutical composition according to claim 17, further characterized in that said at least one antiviral agent is ribavirin and said at least one interferon is a-interferon or pegylated interferon.

19. The use of at least one compound according to claim 1 for the manufacture of a medicament for the treatment of disorders associated with HCV in a patient.

20. The use claimed in claim 19, wherein said administration is oral or subcutaneous.

21. A method for preparing a pharmaceutical composition for the treatment of disorders associated with HCV, wherein said method comprises bringing into intimate physical contact at least one compound according to claim 1 and at least one pharmaceutically acceptable carrier.

22. A compound exhibiting HCV protease activity, or enantiomers, stereoisomers, rotamers, tautomers, diastereomers or racemates of said compound, or a pharmaceutically acceptable salt, solvate or ester of said compound, wherein said compound is selected from compounds having the structures that are listed below:

23. A pharmaceutical composition for the treatment of disorders associated with HCV, wherein said composition comprises a therapeutically effective amount of one or more compounds according to claim 22 and a pharmaceutically acceptable carrier.

24. The pharmaceutical composition according to claim 23, further characterized in that it additionally contains at least one antiviral agent.

25. The pharmaceutical composition according to claim 24, further characterized in that it additionally contains at least one interferon or a conjugate of PEG-interferon alpha.

26. The pharmaceutical composition according to claim 25, further characterized in that said at least one antiviral agent is ribavirin and said at least one interferon is a-interferon or pegylated interferon.

27. The use of one or more compounds according to claim 22 in the manufacture of a medicament for the treatment of a disorder associated with the hepatitis C virus in a patient.

28. A method for modulating the activity of the hepatitis C virus protease (HCV), which comprises contacting the HCV protease with one or more compounds according to claim 22.

29. The use of one or more compounds according to claim 22 in the preparation of a medicament for the treatment, prevention or amelioration of one or more symptoms of hepatitis C in a patient.

30. The use claimed in claim 29, wherein the HCV protease is the NS3 / NS4a protease.

31. The use claimed in claim 30, wherein the compound or compounds inhibit the HCV NS3 / NS4a protease.

32. A method for modulating the process of the hepatitis C virus polypeptide (HCV), which comprises contacting a composition containing the HCV polypeptide, under conditions in which said polypeptide is processed with one or more compounds in accordance with claim 22.

33. The use of at least one compound, enantiomers, stereoisomers, rotamers, tautomers, diastereomers or racemates of said compound, or a pharmaceutically acceptable salt, solvate or ester of said compound in the manufacture of a medicament for treating disorders associated with HCV in a patient, wherein said compound is selected from:

34. The compound according to claim 1, further characterized in that it is in purified form.